From 26fec86603b5e667ec1f5485afa20bab67de2c45 Mon Sep 17 00:00:00 2001 From: Erik Westlund Date: Mon, 12 Aug 2024 15:21:23 -0400 Subject: [PATCH 1/2] docs: Add protocol.Rmd, supporting files, and compiled Protocol.html --- .gitignore | 1 + SemaglutideNaion.Rproj | 4 + docs/Abbreviations.Rmd | 30 + docs/Abstract.Rmd | 12 + docs/Appendix.Rmd | 166 + docs/Disclosures.Rmd | 2 + docs/MainText.Rmd | 189 + docs/OHDSI_page_header.pdf | Bin 0 -> 71316 bytes docs/OHDSI_toc_header.png | Bin 0 -> 53335 bytes docs/Protocol.Rmd | 180 + docs/Protocol.bib | 301 + docs/bmj.csl | 181 + docs/header.tex | 22 + docs/protocol.html | 43211 ++++++++++++++++++++++++++ docs/semaglutide-ndp-protocol.Rproj | 16 + docs/style.css | 13 + docs/title.tex | 1 + docs/utils.R | 145 + 18 files changed, 44474 insertions(+) create mode 100644 docs/Abbreviations.Rmd create mode 100644 docs/Abstract.Rmd create mode 100644 docs/Appendix.Rmd create mode 100644 docs/Disclosures.Rmd create mode 100644 docs/MainText.Rmd create mode 100644 docs/OHDSI_page_header.pdf create mode 100644 docs/OHDSI_toc_header.png create mode 100644 docs/Protocol.Rmd create mode 100644 docs/Protocol.bib create mode 100644 docs/bmj.csl create mode 100644 docs/header.tex create mode 100644 docs/protocol.html create mode 100644 docs/semaglutide-ndp-protocol.Rproj create mode 100644 docs/style.css create mode 100644 docs/title.tex create mode 100644 docs/utils.R diff --git a/.gitignore b/.gitignore index 5b6a0652..0f5219c1 100644 --- a/.gitignore +++ b/.gitignore @@ -2,3 +2,4 @@ .Rhistory .RData .Ruserdata +.idea/* \ No newline at end of file diff --git a/SemaglutideNaion.Rproj b/SemaglutideNaion.Rproj index 8e3c2ebc..21a4da08 100644 --- a/SemaglutideNaion.Rproj +++ b/SemaglutideNaion.Rproj @@ -11,3 +11,7 @@ Encoding: UTF-8 RnwWeave: Sweave LaTeX: pdfLaTeX + +BuildType: Package +PackageUseDevtools: Yes +PackageInstallArgs: --no-multiarch --with-keep.source diff --git a/docs/Abbreviations.Rmd b/docs/Abbreviations.Rmd new file mode 100644 index 00000000..3a70d336 --- /dev/null +++ b/docs/Abbreviations.Rmd @@ -0,0 +1,30 @@ +```{r abbreviations, echo=FALSE, message=FALSE} +abbreviations <- readr::read_delim(col_names = FALSE, delim = ";", trim_ws = TRUE, file = " + NAION; Non-arteritic ischemic optic neuropathy + DR; Diabetic retinopathy + PDR; Proliferative diabetic retinopathy + DME; Diabetic macular edema + VR; Vitreoretinal + GLP-1 RA; Glucagon-like peptide 1 receptor agonist + SGLT2; Sodium-glucose cotransporter -2 + DPP4; Dipeptidyl peptidase-4 + T2DM; Type 2 diabetes mellitus + VO; Vein occlusion + AO; Artery occlusion + AMD; Age-related macular degeneration + GCA; Giant cell arteritis + EASE; Expected Absolute Systematic Error + MDRR; Minimum Detectable Relative Risk + OHDSI; Observational Health Data Sciences and Informatics + ARVO; The Association for Research in Vision and Ophthalmology +") + +tab <- kable(abbreviations, col.names = NULL, linesep = "", booktabs = TRUE) + +if (knitr::is_latex_output()) { + tab %>% kable_styling(latex_options = c("striped", "hold_position"), + font_size = latex_table_font_size) +} else { + tab %>% kable_styling(bootstrap_options = "striped") +} +``` diff --git a/docs/Abstract.Rmd b/docs/Abstract.Rmd new file mode 100644 index 00000000..5accd4bf --- /dev/null +++ b/docs/Abstract.Rmd @@ -0,0 +1,12 @@ +**Background**: Despite its cardiovascular and kidney benefits, semaglutide has been recently linked to severe ophthalmic complications including non-arteritic ischemic optic neuropathy (NAION) as well as worsening of diabetic retinopathy (DR). + +**Purpose**: To estimate the risk of these ophthalmic complications, NAION and DR worsening, with semaglutide use compared with other non-GLP-1 RA medications (including empagliflozin, sitagliptin, and glipizide) among adults with type 2 diabetes mellitus. + +**Design**: Retrospective study employing an active comparator, new-user cohort design + +**Subjects**: Adults (≥ 18 years) with type 2 diabetes mellitus who are new users of semaglutide (a GLP-1 RA), dulaglutide (a GLP-1 RA), exenatide (a GLP-1 RA), empagliflozin (an SGLT2 inhibitor), sitagliptin (a DPP4 inhibitor), or glipizide (a sulfonylurea) + +**Methods**: Patients receiving semaglutide will be compared to propensity score matched patients with each of the other GLP-1 RA and non-GLP-1 RA medications. We will deploy the large-scale propensity score method that adjusts for a comprehensive range of baseline characteristics. Cox models will be used to compare the time to NAION or DR worsening between patients who receive semaglutide with patients who receive empagliflozin, sitagliptin, and glipizide. Similar comparisons will be made between the other GLP-1 RA (namely dulaglutide and exenatide) with each of the comparators. + +**Conclusions**: Clarifying the risk of severe ophthalmic complications associated with semaglutide (and other GLP-1 RA) by 1) characterizing the incidence in the exposed population, and 2) estimating the risk of exposure will help guide the appropriate use of this medication. + diff --git a/docs/Appendix.Rmd b/docs/Appendix.Rmd new file mode 100644 index 00000000..ff5c35c6 --- /dev/null +++ b/docs/Appendix.Rmd @@ -0,0 +1,166 @@ +# Study Population Cohort Definitions + +```{r study-population-cohorts, echo=FALSE, results="asis", warning=FALSE, message=FALSE} + +printCohortDefinitionFromNameAndJson(name = "Persons with Type 2 diabetes mellitus and no prior T1DM or secondary diabetes", + json = SqlRender::readSql("../inst/cohorts/17795_Persons with Type 2 diabetes mellitus and no prior T1DM or secondary diabetes.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "New user of semaglutide as 2nd-line treatment with prior T2DM and prior metformin", + json = SqlRender::readSql("../inst/cohorts/17793_New user of semaglutide as 2nd-line treatment with prior T2DM and prior metformin.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "New user of semaglutide as 2nd-line treatment with prior T2DM Dec2017-Jan2020", + json = SqlRender::readSql("../inst/cohorts/17809_New user of semaglutide as 2nd-line treatment with prior T2DM Dec2017-Jan2020.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "New user of semaglutide as 2nd-line treatment with prior T2DM Feb2020-Jun2021", + json = SqlRender::readSql("../inst/cohorts/17810_New user of semaglutide as 2nd-line treatment with prior T2DM Feb2020-Jun2021.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "New user of semaglutide as 2nd-line treatment with prior T2DM Jul2021-Dec2023", + json = SqlRender::readSql("../inst/cohorts/17811_New user of semaglutide as 2nd-line treatment with prior T2DM Jul2021-Dec2023.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "New user of semaglutide with prior T2DM and prior metformin and no insulin", + json = SqlRender::readSql("../inst/cohorts/17803_New user of semaglutide with prior T2DM and prior metformin and no insulin.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "New user of dulaglutide as 2nd-line treatment with prior T2DM and prior metformin", + json = SqlRender::readSql("../inst/cohorts/17796_New user of dulaglutide as 2nd-line treatment with prior T2DM and prior metformin.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "New user of dulaglutide with prior T2DM and prior metformin and no insulin", + json = SqlRender::readSql("../inst/cohorts/17807_New user of dulaglutide with prior T2DM and prior metformin and no insulin.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "New user of exenatide as 2nd-line treatment with prior T2DM and prior metformin", + json = SqlRender::readSql("../inst/cohorts/17797_New user of exenatide as 2nd-line treatment with prior T2DM and prior metformin.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "New user of exenatide with prior T2DM and prior metformin and no insulin", + json = SqlRender::readSql("../inst/cohorts/17808_New user of exenatide with prior T2DM and prior metformin and no insulin.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "New user of empagliflozin as 2nd-line treatment with prior T2DM and prior metformin", + json = SqlRender::readSql("../inst/cohorts/17798_New user of empagliflozin as 2nd-line treatment with prior T2DM and prior metformin.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "New user of empagliflozin as 2nd-line treatment with prior T2DM Dec2017-Jan2020", + json = SqlRender::readSql("../inst/cohorts/17812_New user of empagliflozin as 2nd-line treatment with prior T2DM Dec2017-Jan2020.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "New user of empagliflozin as 2nd-line treatment with prior T2DM Feb2020-Jun2021", + json = SqlRender::readSql("../inst/cohorts/17813_New user of empagliflozin as 2nd-line treatment with prior T2DM Feb2020-Jun2021.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "New user of empagliflozin as 2nd-line treatment with prior T2DM Jul2021-Dec2023", + json = SqlRender::readSql("../inst/cohorts/17814_New user of empagliflozin as 2nd-line treatment with prior T2DM Jul2021-Dec2023.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "New user of empagliflozin with prior T2DM and prior metformin and no insulin", + json = SqlRender::readSql("../inst/cohorts/17804_New user of empagliflozin with prior T2DM and prior metformin and no insulin.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "New user of sitagliptin as 2nd-line treatment with prior T2DM and prior metformin", + json = SqlRender::readSql("../inst/cohorts/17799_New user of sitagliptin as 2nd-line treatment with prior T2DM and prior metformin.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "New user of sitagliptin with prior T2DM and prior metformin and no insulin", + json = SqlRender::readSql("../inst/cohorts/17805_New user of sitagliptin with prior T2DM and prior metformin and no insulin.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "New user of glipizide as 2nd-line treatment with prior T2DM and prior metformin", + json = SqlRender::readSql("../inst/cohorts/17801_New user of glipizide as 2nd-line treatment with prior T2DM and prior metformin.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "New user of glipizide with prior T2DM and prior metformin and no insulin", + json = SqlRender::readSql("../inst/cohorts/17806_New user of glipizide with prior T2DM and prior metformin and no insulin.json"), + withConcepts = TRUE) + +``` + +# Exposure Cohort Definitions + + +```{r exposure-cohorts, echo=FALSE, results="asis", warning=FALSE, message=FALSE} +printCohortDefinitionFromNameAndJson(name = "Semaglutide (GLP-1RA) exposure", + json = SqlRender::readSql("../inst/cohorts/17816_semaglutide exposures.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "Dulaglutide (GLP-1RA) exposure", + json = SqlRender::readSql("../inst/cohorts/17817_dulaglutide exposures.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "Exenatide (GLP-1RA) exposure", + json = SqlRender::readSql("../inst/cohorts/17818_exenatide exposures.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "Empagliflozin (SGLT2 inhibitor) exposure", + json = SqlRender::readSql("../inst/cohorts/17819_empagliflozin exposures.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "Sitagliptin (DPP4 inhibitor) exposure", + json = SqlRender::readSql("../inst/cohorts/17820_sitagliptin exposures.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "Glipizide (Sulfonylurea) exposure", + json = SqlRender::readSql("../inst/cohorts/17821_glipizide exposures.json"), + withConcepts = TRUE) + +``` + +# Outcome Cohort Definitions + +```{r outcome-cohorts, echo=FALSE, results="asis", warning=FALSE, message=FALSE} + +printCohortDefinitionFromNameAndJson(name = "Nonarteric anterior ischemic neuropathy with index date correction and 2dxGCA", + json = SqlRender::readSql("../inst/cohorts/17760_Nonarteric anterior ischemic neuropathy with index date correction and 2dxGCA.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "Nonarteric anterior ischemic neuropathy with index date correction and 2nd dx and 2dxGCA", + json = SqlRender::readSql("../inst/cohorts/17761_Nonarteric anterior ischemic neuropathy with index date correction and 2nd dx and 2dxGCA.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "Proliferative diabetic retinopathy", + json = SqlRender::readSql("../inst/cohorts/17706_Proliferative diabetic retinopathy.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "Treatment-requiring Diabetic Retinopathy or Macular Edema", + json = SqlRender::readSql("../inst/cohorts/17815_Treatment-requiring Diabetic Retinopathy or Macular Edema.json"), + withConcepts = TRUE) + +printCohortDefinitionFromNameAndJson(name = "Treatment-requiring Diabetic Retinopathy or Macular Edema including vitrectomy", + json = SqlRender::readSql("../inst/cohorts/17788_Treatment-requiring Diabetic Retinopathy or Macular Edema including vitrectomy.json"), + withConcepts = TRUE) + +``` + +# Negative Control Concepts + +\captionsetup{labelformat=empty} + +```{r, echo=FALSE, warning=FALSE, message=FALSE} +negative_controls <- readr::read_csv("../inst/negativeControlOutcomes.csv") %>% + select(conceptid, conceptname) %>% + rename("Concept ID" = conceptid, "name" = conceptname) %>% + arrange(name) + +colnames(negative_controls) <- c("", "Concept ID") + +tab <- kable(negative_controls, booktabs = TRUE, linesep = "", longtable = TRUE, + caption = "Negative outcome controls specified through condition occurrences that map to (a descendent of) the indicated concept ID") %>% + kable_styling(bootstrap_options = "striped", latex_options = "striped") + +if (knitr::is_latex_output()) { + tab %>% + column_spec(1, width = "40em") %>% + column_spec(2, width = "15em") %>% + kable_styling(font_size = latex_table_font_size, + latex_options = c("repeat_header"), + repeat_header_continued = "\\textit{(Continued on Next Page...)}") + +} else { + tab +} +``` diff --git a/docs/Disclosures.Rmd b/docs/Disclosures.Rmd new file mode 100644 index 00000000..968edb35 --- /dev/null +++ b/docs/Disclosures.Rmd @@ -0,0 +1,2 @@ +This study is undertaken within Observational Health Data Sciences and Informatics (OHDSI), an open collaboration. + diff --git a/docs/MainText.Rmd b/docs/MainText.Rmd new file mode 100644 index 00000000..82e81800 --- /dev/null +++ b/docs/MainText.Rmd @@ -0,0 +1,189 @@ +# Rationale and Background + +Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), is approved by the US Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus. It has been shown to reduce the rate of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke in patients with type 2 diabetes at high cardiovascular risk.[@marso_semaglutide_2016] Furthermore, results from the recent FLOW trial suggest that semaglutide can reduce clinically important kidney outcomes and death from cardiovascular causes in patients with type 2 diabetes mellitus and chronic kidney disease.[@perkovic_effects_2024] Given their benefit, the American Diabetes Association’s Standards of Medical Care in Diabetes recommends GLP-1 RA as one of the two preferred options for add-on therapy in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease after lifestyle intervention and metformin.[@american_diabetes_association_professional_practice_committee_9_2021] + +Despite the benefits of semaglutide for treatment of type 2 diabetes mellitus, recent studies raise the concern of adverse ophthalmic consequences—non-arteritic ischemic optic neuropathy (NAION) and progression of diabetic retinopathy (DR). + +NAION is a rare acute ischemic injury to the optic nerve with an incidence of 2-10/100,000 people per year and resulting in blindness in nearly a quarter of affected patients.[@mollan_semaglutide_2024;@hayreh_nonarteritic_2008] In addition to anatomic characteristics that predispose certain optic nerves to this ischemic event, there are also known systemic risk factors including diabetes mellitus, hypertension, dyslipidemia, and obstructive sleep apnea.[@mollan_semaglutide_2024] A recent study published in JAMA Ophthalmology linked the use of semaglutide with an increased risk for NAION as compared with non-GLP-1 RA.[@hathaway_risk_2024] + +In 2016, the SUSTAIN-6 trial evaluating semaglutide identified a risk of DR complications which included vitreous hemorrhage, DR-related blindness, and intravitreal pharmacotherapy and laser photocoagulation compared with placebo.1 The increased risk for retinopathy appeared to be confirmed on meta-analysis.[@albert_glucagon-like_2023] Since then, multiple retrospective studies have not shown a difference in the risk of DR worsening, the largest of which included ~400,000 adults with diabetes.[@barkmeier_comparative_2024;@stevens_long-term_2024; @sharma_semaglutide_2022;@joo_effect_2024] + + +# Study Objectives + +The purpose of this study is to investigate three concerning ophthalmic complications (NAION and worsening of DR) from use of semaglutide for the treatment of type 2 diabetes mellitus. + +1. Among patients with type 2 diabetes mellitus, is the risk for NAION higher among patients who use semaglutide as compared with a non-GLP-1 RA anti-diabetic medication? +2. Among patients with types 2 diabetes mellitus, is the risk for DR progression higher among patients who use semaglutide as compared with a non-GLP-1 RA anti-diabetic medication? +3. Among patients with type 2 diabetes mellitus, is the risk for NAION higher among patients who use semaglutide as compared with other GLP-1 RA anti-diabetic medications? + + +# Research Methods + +## Study Design/Data Source(s) + +This will be a retrospective cohort study employing an active comparator, new-user cohort design, comparing the risk of NAION and DR worsening among adults with types 2 diabetes mellitus exposed to semaglutide compared with other GLP-1 RA medications and non-GLP-1 RA anti-diabetic medications. Other GLP-1 RA medications will include dulaglutide and exenatide. Non-GLP-1 RA comparators will include other second-line treatments for diabetes including empagliflozin (a SGLT2 inhibitor), sitagliptin (a DPP4 inhibitor), and glipizide (a sulfonylurea). These comparators were chosen based on the most commonly occurring medication within those classes from the LEGEND-T2DM study. (https://ohdsi-studies.github.io/LegendT2dm/Protocol) + +## Study Population + +We will include all adults (≥ 18 years) with type 2 diabetes mellitus in each data source who meet the cohort entry criteria for each exposure cohort (detailed below). + +## Exposures {#exposures} +The exposure is receipt of semaglutide (GLP-1 RA), dulaglutide (GLP-1RA), exenatide (GLP-1 RA), empagliflozin (a SGLT2 inhibitor), sitagliptin (a DPP4 inhibitor), or glipizide (a sulfonylurea) based on the definitions of LEGEND-T2DM. (https://ohdsi-studies.github.io/LegendT2dm/Protocol) In brief, these will include patients with T2DM with prior metformin monotherapy who initiate treatment with one of the four medications. Patients have to have one year of observation prior to the index date, no prior drug exposure to a comparator second-line or anti-diabetic agents, and at most 30 days of insulin exposure before the index date. + +As a sensitivity analysis, we will examine patients with each of these anti-diabetic medication exposures but without the second-line therapy requirement, meaning that they can be on another anti-diabetic medication at the time of cohort entry. + +## Outcomes {#outcomes} + +The outcomes are NAION and DR worsening. + +NAION will have two definitions, one designed to be more specific and one designed to be more sensitive: + +- NAION-specific: + + 1. 2 instances of ION diagnosis codes on separate days (within 90 days of each other) + 2. If the 2 diagnoses of ION are preceded by the following diagnoses within the prior 60 days, then use the occurrence of these prior diagnosis to mark the start date of the outcome + + Visual field defect + + Optic disc disorder + + Includes concepts of optic papillitis (concept ID 435269), and “other disorders of optic disc” + + Optic neuritis + + Includes “Unspecified” and “Other” optic neuritis + + Optic disc edema + + Includes papilledema + 3. Exclude patients who have 2 diagnoses of giant cell arteritis (GCA) any time before or after outcome start date + 4. Exclude patients with a diagnosis of traumatic optic neuropathy before outcome start date) + +- NAION-sensitive: + + 1. 1 instance of ION diagnosis code + 2. Adjustment to the start of the outcome (same ones as above) + 3. Exclude patients with 2 instances of GCA (any time before or after index date) + 4. Exclude patients with a diagnosis of traumatic optic neuropathy (before outcome start date) + +DR worsening is defined as: +- New-onset PDR +- Treatment-requiring DR/DME + 1. New exposure to anti-VEGF medication, procedure for focal laser photocoagulation, or panretinal photocoagulation + 2. Has to have a diagnosis of DR/DME within 90 days of the outcome start date + 3. Exclude patients with diagnosis of VO/AO if ever in the days prior to outcome start date + 4. Exclude patients withAMD in the 365 days prior to outcome start date +- Treatment-requiring DR/DME (including VR surgery) + 1. In addition to above, also add exposure to vitreoretinal surgery (mechanical vitrectomy by pars plana approach Concept ID 4314406) + + CPT Codes to include: 67036, 67039, 67040, 67041, 67042, 67113 + + CPT Codes to exclude: 67108, 67107 + + +## Covariates + +We will deploy the large-scale propensity score method that adjusts for a comprehensive range of baseline characteristic.[@tian_evaluating_2018] + +## Negative Controls + +Negative controls will be picked to represent exposure-outcome pairs where no causal effect is expected to exist. We will adapt the set of negative controls that was used in LEGEND-T2DM (https://ohdsi-studies.github.io/LegendT2dm/Protocol). (See full list located below) + +# Data Analysis Plan + +## General + +Although the primary aim of this study is a comparative safety study, various standardized analytics available in the OHDSI community will be applied. The Strategus pipeline will be used to call various packages in the HADES library for A) data characterization (A1‑cohort diagnostics, A2‑cohort features, A3‑incidence rates, A4-time-to-event), B) population-level effect estimation (C1--comparative cohort study, C2‑‑self-controlled case-series).[@noauthor_ohdsistrategus_2024;@schuemie_health-analytics_2024] + +## Data Characterization + +### Cohort Diagnostics + +The R package CohortDiagnostics will be executed for all target, comparator, indication, and outcome cohorts to evaluate measurement error in the phenotype development and evaluation process.[@rao_cohortdiagnostics_2023] + +### Cohort Features + +The Characterization and FeatureExtraction packages in HADES will be used to identify features of patients in each exposure group who had the outcome and those who did not have the outcome.14 Features will be extracted from the 365 day observation prior to cohort entry and will include variables such as demographic data (sex, age group, race, ethnicity), prior conditions/drug exposures/procedures/measurements/devices/observations, and risk scores (e.g., Charlson comorbidity index, DCSI, CHADS2VASC score). + +### Incidence Rates + +The Characterization package in HADES will be used to calculate the incidence rates of the outcome for each exposure cohort and indication cohort. The rate is calculated as the number of outcomes during the time-at-risk divided by the number of total person days. + +#### Calculation of time-at-risk + +The primary method of calculating time-at-risk will be while the patient is “on-treatment”. This is defined as from the start of cohort entry (or diabetes drug initiation) until the end of the continuous drug exposure, defined as a gap in exposure of >30 days, end of continuous observation period, or study period. The second method of calculating time-at-risk is based on “intent-to-treat”, which will be used as a sensitivity analysis. In this analysis, patients are analyzed according to the first diabetes medication drug cohort they enter, regardless of switching from one cohort to another. + +### Time-to-Event + +Time to the outcomes of NAION or DR worsening (as defined above) will be calculated for each exposure cohort. + +## Population-Level Effect Estimation + +### Comparative Cohort Study + +The CohortMethod and Cyclops packages in Hades will be used.14 Large-scale propensity score methods will be used to match the targe exposure cohort with the comparator export cohort (e.g., semaglutide vs empagliflozin) using 1:1 propensity score matching. Given the concern for increasing usage of semaglutide in recent years, we will also perform a sensitivity analysis with calendar year restriction: Dec2017-Jan2020, Feb2020-June2021, July2021-Dec2023. Cox proportional hazards models will be used to estimate the risk of NAION and separately DR progression while on treatment using the intent-to-treat design.[@cox_regression_1972] Negative controls will be used to assess residual bias. + +### Self-Controlled Case Series + +The SelfControlledCaseSeries and Cyclops packages in Hades will be used to estimate the relative incidence of NAION or DR progression using a self-controlled case-series design.[@schuemie_health-analytics_2024] Diagnostics will be run to evaluate whether this was an appropriate analysis. + +# Study Diagnostics + +1. Preference score distributions to evaluate empirical equipoise and population generalizability +2. Extensive patient characteristics to evaluate cohort balance before and after propensity score adjustment +3. Negative control calibration plots to assess residual bias +4. Kaplan-Meier plots to examine hazard ratio proportionality assumptions + +## Diagnostic Thresholds for Cohort Method + +```{r diagnostic-thresholds-cohort, echo=FALSE, message=FALSE} +abbreviations <- readr::read_delim(col_names = FALSE, delim = ";", trim_ws = TRUE, file = " +**Study Diagnostics**; **Threshold** + +Covariate balance (Standardized Mean Difference); <0.1 +Empirical Equipoise (Preference Score); >0.1 +Residual Bias (Expected Absolute Systematic Error (EASE)); <0.25 +Meta-analysis Heterogeneity; <0.4 +Meta-analysis Minimum Detectable Relative Risk (MDRR); <10 +") + +tab <- kable(abbreviations, col.names = NULL, linesep = "", booktabs = TRUE) + +if (knitr::is_latex_output()) { + tab %>% kable_styling(latex_options = c("striped", "hold_position"), + font_size = latex_table_font_size) +} else { + tab %>% kable_styling(bootstrap_options = "striped") +} +``` + +## Diagnostic Thresholds for Self-Controlled Case-Series + +```{r diagnostic-thresholds-sccs, echo=FALSE, message=FALSE} +abbreviations <- readr::read_delim(col_names = FALSE, delim = ";", trim_ws = TRUE, file = " +**Study Diagnostics**; **Threshold** + +Covariate balance (Standardized Mean Difference); <0.1 +Pre-exposure; >0.05 +Time Trend; >0.05 +EASE; <0.25 +Meta-analysis Heterogeneity; <0.4 +Meta-analysis MDRR; <10 +") + +tab <- kable(abbreviations, col.names = NULL, linesep = "", booktabs = TRUE) + +if (knitr::is_latex_output()) { + tab %>% kable_styling(latex_options = c("striped", "hold_position"), + font_size = latex_table_font_size) +} else { + tab %>% kable_styling(bootstrap_options = "striped") +} +``` + +# Strengths and Limitations {#strengths-limitations} + +When executed, this will be the largest study examining the association between semaglutide and the risk of NAION and DR progression. Other strengths of this study include the diversity of the sample (from multiple institutions, multiple countries), and rigorous study design. + +Limitations are mainly due to the retrospective nature of the study which might have confounding despite propensity score matching and stratified analyses. Additionally, unlike single-site studies, the diagnosis of NAION cannot be confirmed from manual review of patient records. + + +# Protection of Human Subjects + +Each participating institution will seek IRB approval for this study as dictated by local governance. + +# Plans for Disseminating and Communicating Study Results + +The results will be shared and discussed among the study participants and broader OHDSI community during the weekly Tuesday community calls. 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mellitus\n" +fontsize: 12pt +geometry: margin=1in +output: + bookdown::html_document2: + df_print: paged + toc: yes + toc_depth: 2 + toc_float: yes + number_sections: yes + number_tables: yes + css: style.css + bookdown::pdf_document2: + keep_tex: yes + latex_engine: xelatex + md_extensions: +raw_attribute + number_sections: yes + includes: + before_body: title.tex + word_document: + reference_docx: ohdsi-protocol-style.docx +header-includes: +- \usepackage[numbers,sort&compress]{natbib} +- \usepackage{booktabs} +- \usepackage{longtable} +- \usepackage{array} +- \usepackage{multirow} +- \usepackage{wrapfig} +- \usepackage{float} +- \usepackage{colortbl} +- \usepackage{pdflscape} +- \usepackage{tabu} +- \usepackage{threeparttable} +- \usepackage{threeparttablex} +- \usepackage[normalem]{ulem} +- \usepackage{makecell} +- \usepackage{caption} +- \usepackage{rotating} +- \usepackage{multirow} +- \usepackage{mwe,tikz} +- \usepackage[percent]{overpic} +- \usepackage{enumitem} +- \usepackage{hyperref} +- \newcolumntype{P}[1]{>{\raggedright\arraybackslash}p{#1}} +- \newcommand{\footerDate}{`r params$date`} +- \input{header.tex} +longtable: yes +mainfont: Arial +bibliography: Protocol.bib +params: + date: '8-Aug-2024' + version: 1.0 +subtitle: 'Version: `r params$version`' +link-citations: yes +csl: bmj.csl +--- + +```{r setup, include=FALSE} +source("utils.R") +knitr::opts_chunk$set(echo = TRUE, warning=FALSE) +options(kableExtra.latex.load_packages = FALSE) +library(kableExtra) +#knitr::knit_hooks$set(document = function(x) {sub('\\usepackage[]{color}', '\\usepackage[table]{xcolor}', x, fixed = TRUE)}) +library(dplyr) +options(knitr.kable.NA = "") +options(knitr.table.format = function() { + if (knitr::is_latex_output()) { + "latex" + } else if (knitr::is_html_output()) { + "html" + } else { + "pipe" + } +}) + +latex_table_font_size <- 8 +``` + +# List of Abbreviations + +```{r child = "Abbreviations.Rmd"} +``` + +\clearpage + +# Responsible Parties + +## Investigators + +```{r parties, echo=FALSE, message=FALSE, warning=FALSE} +parties <- readr::read_delim(col_names = TRUE, delim = ";", trim_ws = TRUE, file = " + Investigator; Institution/Affiliation + + Cindy Cai, MD, MS *; Wilmer Eye Institute, Johns Hopkins Hospital, ccai6@jhmi.edu + Michelle Hribar, PhD; Oregon Health & Science University, hribarm@ohsu.edu + ; Eye Care and Vision Research Workgroup + +") + +tab <- kable(parties, booktabs = TRUE, linesep = "") %>% + column_spec(1, width = "10em") %>% + column_spec(2, width = "35em") %>% + footnote(general = "* Principal Investigator", general_title = "") + +if (knitr::is_latex_output()) { + tab %>% kable_styling(latex_options = c("striped", "hold_position"), + font_size = latex_table_font_size) +} else { + tab %>% kable_styling(bootstrap_options = "striped") +} +``` + +## Disclosures + +```{r child = "Disclosures.Rmd"} +``` + + +\clearpage + +# Abstract + +```{r child = "Abstract.Rmd"} +``` + + +# Amendments and Updates + +```{r amendments, echo=FALSE, message=FALSE} +# amendments <- readr::read_delim(col_names = TRUE, delim = ";", trim_ws = TRUE, file = " +# Number; Date; Section of study protocol; Amendment or update; Reason +# ") +# +# tab <- kable(amendments, booktabs = TRUE, linesep = "") +# +# if (knitr::is_latex_output()) { +# tab %>% kable_styling(latex_options = c("striped", "hold_position"), font_size = latex_table_font_size) +# } else { +# tab %>% kable_styling(bootstrap_options = "striped") +# } +``` + + + +# Milestones + +```{r dates, echo=FALSE, message=FALSE} +dates <- readr::read_delim(col_names = TRUE, delim = ";", trim_ws = TRUE, file = " + +") + +tab <- kable(dates, booktabs = TRUE, linesep = "") + +if (knitr::is_latex_output()) { + tab %>% kable_styling(latex_options = c("striped", "hold_position"), font_size = latex_table_font_size) +} else { + tab %>% kable_styling(bootstrap_options = "striped") +} +``` + + +```{r child = "MainText.Rmd"} +``` + + +\clearpage + +# References {-} + +
+ +\clearpage + +\centerline{\Huge Appendix} + +# (APPENDIX) Appendix {-} + +```{r child = "Appendix.Rmd"} +``` diff --git a/docs/Protocol.bib b/docs/Protocol.bib new file mode 100644 index 00000000..4902b80b --- /dev/null +++ b/docs/Protocol.bib @@ -0,0 +1,301 @@ + +@article{marso_semaglutide_2016, + title = {Semaglutide and {Cardiovascular} {Outcomes} in {Patients} with {Type} 2 {Diabetes}}, + volume = {375}, + issn = {0028-4793, 1533-4406}, + url = {http://www.nejm.org/doi/10.1056/NEJMoa1607141}, + doi = {10.1056/NEJMoa1607141}, + language = {en}, + number = {19}, + urldate = {2024-08-08}, + journal = {New England Journal of Medicine}, + author = {Marso, Steven P. and Bain, Stephen C. and Consoli, Agostino and Eliaschewitz, Freddy G. and Jódar, Esteban and Leiter, Lawrence A. and Lingvay, Ildiko and Rosenstock, Julio and Seufert, Jochen and Warren, Mark L. and Woo, Vincent and Hansen, Oluf and Holst, Anders G. and Pettersson, Jonas and Vilsbøll, Tina}, + month = nov, + year = {2016}, + pages = {1834--1844}, + file = {Available Version (via Google Scholar):/Users/erikwestlund/Zotero/storage/9Q7AH5MD/Marso et al. - 2016 - Semaglutide and Cardiovascular Outcomes in Patient.pdf:application/pdf}, +} + +@article{perkovic_effects_2024, + title = {Effects of {Semaglutide} on {Chronic} {Kidney} {Disease} in {Patients} with {Type} 2 {Diabetes}}, + volume = {391}, + copyright = {http://www.nejmgroup.org/legal/terms-of-use.htm}, + issn = {0028-4793, 1533-4406}, + url = {http://www.nejm.org/doi/10.1056/NEJMoa2403347}, + doi = {10.1056/NEJMoa2403347}, + language = {en}, + number = {2}, + urldate = {2024-08-08}, + journal = {New England Journal of Medicine}, + author = {Perkovic, Vlado and Tuttle, Katherine R. and Rossing, Peter and Mahaffey, Kenneth W. and Mann, Johannes F.E. and Bakris, George and Baeres, Florian M.M. and Idorn, Thomas and Bosch-Traberg, Heidrun and Lausvig, Nanna Leonora and Pratley, Richard}, + month = jul, + year = {2024}, + pages = {109--121}, +} + +@article{american_diabetes_association_professional_practice_committee_9_2021, + title = {9. {Pharmacologic} {Approaches} to {Glycemic} {Treatment}: {Standards} of {Medical} {Care} in {Diabetes}—2022}, + volume = {45}, + issn = {0149-5992}, + shorttitle = {9. {Pharmacologic} {Approaches} to {Glycemic} {Treatment}}, + url = {https://doi.org/10.2337/dc22-S009}, + doi = {10.2337/dc22-S009}, + abstract = {The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.}, + number = {Supplement\_1}, + urldate = {2024-08-08}, + journal = {Diabetes Care}, + author = {{American Diabetes Association Professional Practice Committee}}, + month = dec, + year = {2021}, + pages = {S125--S143}, + file = {Full Text PDF:/Users/erikwestlund/Zotero/storage/MDWM5359/American Diabetes Association Professional Practice Committee - 2021 - 9. Pharmacologic Approaches to Glycemic Treatment.pdf:application/pdf;Snapshot:/Users/erikwestlund/Zotero/storage/X5UQNKHH/9-Pharmacologic-Approaches-to-Glycemic-Treatment.html:text/html}, +} + +@article{hathaway_risk_2024, + title = {Risk of nonarteritic anterior ischemic optic neuropathy in patients prescribed semaglutide}, + url = {https://jamanetwork.com/journals/jamaophthalmology/article-abstract/2820255}, + doi = {10.1001/jamaophthalmol.2024.2296}, + urldate = {2024-08-08}, + journal = {JAMA ophthalmology}, + author = {Hathaway, Jimena Tatiana and Shah, Madhura P. and Hathaway, David B. and Zekavat, Seyedeh Maryam and Krasniqi, Drenushe and Gittinger, John W. and Cestari, Dean and Mallery, Robert and Abbasi, Bardia and Bouffard, Marc}, + year = {2024}, + file = {Available Version (via Google Scholar):/Users/erikwestlund/Zotero/storage/8I7A4I5P/2820255.html:text/html}, +} + +@article{albert_glucagon-like_2023, + title = {Glucagon-like peptide 1-receptor agonists and {A1c}: good for the heart but less so for the eyes?}, + volume = {17}, + shorttitle = {Glucagon-like peptide 1-receptor agonists and {A1c}}, + url = {https://www.sciencedirect.com/science/article/pii/S1871402122003137?casa_token=R8Qw9BLOA98AAAAA:l8BNLl5HuAtHzXL3N1LUjEy1j83aoCfwqbHeq3yHevOqT7FwwlyOm9Iynp5D4VSKgWQxgHdy}, + doi = {10.1016/j.dsx.2022.102696}, + number = {1}, + urldate = {2024-08-08}, + journal = {Diabetes \& Metabolic Syndrome: Clinical Research \& Reviews}, + author = {Albert, Stewart G. and Wood, Emily M. and Ahir, Vaishaliben}, + year = {2023}, + note = {Publisher: Elsevier}, + pages = {102696}, + file = {Available Version (via Google Scholar):/Users/erikwestlund/Zotero/storage/98NU6PT7/S1871402122003137.html:text/html}, +} + +@article{barkmeier_comparative_2024, + title = {Comparative {Effectiveness} of {Glucagon}-{Like} {Peptide}-1 {Receptor} {Agonists}, {Sodium}-{Glucose} {Cotransporter} 2 {Inhibitors}, {Dipeptidyl} {Peptidase}-4 {Inhibitors}, and {Sulfonylureas} for {Sight}-{Threatening} {Diabetic} {Retinopathy}}, + url = {https://www.sciencedirect.com/science/article/pii/S246865302400229X?casa_token=g0OKdr9FZSEAAAAA:N_XVHHruQwdscyp77Qd0B1d_r-u_UYB37qV_68jZpYGRigfUiQSgMLDxRT5LcVBoZbZFN-ss}, + doi = {10.1016/j.oret.2024.05.003}, + urldate = {2024-08-08}, + journal = {Ophthalmology Retina}, + author = {Barkmeier, Andrew J. and Herrin, Jeph and Swarna, Kavya Sindhu and Deng, Yihong and Polley, Eric C. and Umpierrez, Guillermo E. and Galindo, Rodolfo J. and Ross, Joseph S. and Mickelson, Mindy M. and McCoy, Rozalina G.}, + year = {2024}, + note = {Publisher: Elsevier}, + file = {Available Version (via Google Scholar):/Users/erikwestlund/Zotero/storage/GEGP8ECB/S246865302400229X.html:text/html}, +} + +@article{stevens_long-term_2024, + title = {Long-term use of semaglutide and risk of diabetic retinopathy progression}, + volume = {15}, + issn = {2666-3961}, + url = {https://www.sciencedirect.com/science/article/pii/S2666396124000128}, + doi = {10.1016/j.endmts.2024.100168}, + abstract = {Objective +Concerns exist about semaglutide, potentially worsening sight-threatening diabetic retinopathy (DR) in individuals with diabetes. This study aimed to explore the association between semaglutide and the risk of DR progression over three years in patients with type 2 diabetes (T2D). It is hypothesized that any observed deterioration in DR among T2D patients following semaglutide use would be temporary and unrelated to long-term progression. +Methods +Retrospective data analysis identified 4086 patients with T2D and DR by ICD-10 codes in a Retina only practice from January to June 2020. Use of semaglutide was found in 116 patients. Inclusion criteria included at least 1 year of semaglutide use and documentation of level of non-proliferative (NPDR) and proliferative (PDR) retinopathy, visual acuity (VA) and Central Subfield Thickness (CST). +Results +87 patients meeting the eligibility criteria, ranging in age from 38 to 84 years (mean age of 62.4 years), and having an average duration of semaglutide usage of approximately 2.9 years. Gender distribution included 58.6 \% male and 41.4 \% female patients, with 83.9 \% Caucasian, 11.5 \% Black, and 10.3 \% Hispanic backgrounds. The baseline HbA1c level averaged 7.6 \%, ranging from 5.9 \% to 10.9 \%, with a standard deviation of 1.1. The last self-reported HbA1c level averaged 7.4 \%, ranging from 5.2 \% to 14 \%, with a standard deviation of 1.5. Baseline DR severity correlated with progression risk: 2.7 \% for DRSS level ≤ 43, 28 \% for levels 47/53, and 45 \% for baseline PDR. Patients required an average of 12.6 intravitreal injections. Visual acuity remained stable for 72.4 \% of patients, with 16.1 \% experiencing a loss and 11.5 \% achieving improvement. +Conclusion +Semaglutide use was not associated with increased risk of progression of DR, visual loss, or an increased number of intravitreal injections over a 3-year period of time.}, + urldate = {2024-08-08}, + journal = {Endocrine and Metabolic Science}, + author = {Stevens, Henry and de la Paz, Max and Cooper, Blake and Bhattacharya, Rajib}, + month = jun, + year = {2024}, + keywords = {Diabetic retinopathy progression, Ocular complications, Retrospective study, Semaglutide, Type 2 diabetes}, + pages = {100168}, + file = {ScienceDirect Snapshot:/Users/erikwestlund/Zotero/storage/CDIMDGYJ/S2666396124000128.html:text/html}, +} + +@article{sharma_semaglutide_2022, + title = {Semaglutide and the risk of diabetic retinopathy-current perspective}, + volume = {36}, + issn = {1476-5454}, + doi = {10.1038/s41433-021-01741-5}, + language = {eng}, + number = {1}, + journal = {Eye (London, England)}, + author = {Sharma, Ashish and Parachuri, Nikulaa and Kumar, Nilesh and Saboo, Bharat and Tripathi, Hridaya Nath and Kuppermann, Baruch D. and Bandello, Francesco}, + month = jan, + year = {2022}, + pmid = {34373613}, + pmcid = {PMC8727607}, + keywords = {Diabetes Mellitus, Type 2, Diabetic Retinopathy, Glucagon-Like Peptides, Humans, Hypoglycemic Agents}, + pages = {10--11}, + file = {Full Text:/Users/erikwestlund/Zotero/storage/7FIDJNMC/Sharma et al. - 2022 - Semaglutide and the risk of diabetic retinopathy-c.pdf:application/pdf}, +} + +@article{tian_evaluating_2018, + title = {Evaluating large-scale propensity score performance through real-world and synthetic data experiments}, + volume = {47}, + issn = {1464-3685}, + doi = {10.1093/ije/dyy120}, + abstract = {BACKGROUND: Propensity score adjustment is a popular approach for confounding control in observational studies. Reliable frameworks are needed to determine relative propensity score performance in large-scale studies, and to establish optimal propensity score model selection methods. +METHODS: We detail a propensity score evaluation framework that includes synthetic and real-world data experiments. Our synthetic experimental design extends the 'plasmode' framework and simulates survival data under known effect sizes, and our real-world experiments use a set of negative control outcomes with presumed null effect sizes. In reproductions of two published cohort studies, we compare two propensity score estimation methods that contrast in their model selection approach: L1-regularized regression that conducts a penalized likelihood regression, and the 'high-dimensional propensity score' (hdPS) that employs a univariate covariate screen. We evaluate methods on a range of outcome-dependent and outcome-independent metrics. +RESULTS: L1-regularization propensity score methods achieve superior model fit, covariate balance and negative control bias reduction compared with the hdPS. Simulation results are mixed and fluctuate with simulation parameters, revealing a limitation of simulation under the proportional hazards framework. Including regularization with the hdPS reduces commonly reported non-convergence issues but has little effect on propensity score performance. +CONCLUSIONS: L1-regularization incorporates all covariates simultaneously into the propensity score model and offers propensity score performance superior to the hdPS marginal screen.}, + language = {eng}, + number = {6}, + journal = {International Journal of Epidemiology}, + author = {Tian, Yuxi and Schuemie, Martijn J. and Suchard, Marc A.}, + month = dec, + year = {2018}, + pmid = {29939268}, + pmcid = {PMC6280944}, + keywords = {Humans, Algorithms, Bias, Confounding Factors, Epidemiologic, Logistic Models, Observational Studies as Topic, Propensity Score, Research Design, Sample Size}, + pages = {2005--2014}, + file = {Full Text:/Users/erikwestlund/Zotero/storage/P5363RL8/Tian et al. - 2018 - Evaluating large-scale propensity score performanc.pdf:application/pdf}, +} + +@misc{noauthor_ohdsistrategus_2024, + title = {{OHDSI}/{Strategus}}, + url = {https://github.com/OHDSI/Strategus}, + abstract = {[Under development] An R packages for coordinating and executing analytics using HADES modules}, + urldate = {2023-04-29}, + publisher = {Observational Health Data Sciences and Informatics}, + month = jun, + year = {2024}, + note = {original-date: 2022-03-24T15:08:20Z}, +} + +@misc{noauthor_reps_nodate, + title = {Reps {JM}, {Schuemie} {MJ}, {Suchard} {MA}, {Ryan} {PB}, {Rijnbeek} {PR}. {Design} and implementation of a standardized framework to generate and evaluate patient-level prediction models using observational healthcare data. {J} {Am} {Med} {Inform} {Assn}. 2018;25(8):969-975. doi:10.1093/jamia/ocy032 - {Google} {Search}}, + url = {https://www.google.com/search?q=Reps+JM%2C+Schuemie+MJ%2C+Suchard+MA%2C+Ryan+PB%2C+Rijnbeek+PR.+Design+and+implementation+of+a+standardized+framework+to+generate+and+evaluate+patient-level+prediction+models+using+observational+healthcare+data.+J+Am+Med+Inform+Assn.+2018%3B25(8)%3A969-975.+doi%3A10.1093%2Fjamia%2Focy032&rlz=1C5GCCM_en&oq=Reps+JM%2C+Schuemie+MJ%2C+Suchard+MA%2C+Ryan+PB%2C+Rijnbeek+PR.+Design+and+implementation+of+a+standardized+framework+to+generate+and+evaluate+patient-level+prediction+models+using+observational+healthcare+data.+J+Am+Med+Inform+Assn.+2018%3B25(8)%3A969-975.+doi%3A10.1093%2Fjamia%2Focy032&gs_lcrp=EgZjaHJvbWUyBggAEEUYOdIBBzE0M2owajSoAgCwAgE&sourceid=chrome&ie=UTF-8}, + urldate = {2024-08-08}, + file = {Reps JM, Schuemie MJ, Suchard MA, Ryan PB, Rijnbeek PR. Design and implementation of a standardized framework to generate and evaluate patient-level prediction models using observational healthcare data. J Am Med Inform Assn. 2018\;25(8)\:969-975. doi\:10.1093/jamia/ocy032 - Google Search:/Users/erikwestlund/Zotero/storage/YYYCJD68/search.html:text/html}, +} + +@article{cox_regression_1972, + title = {Regression {Models} and {Life}-{Tables}}, + volume = {34}, + copyright = {© 1972 The Authors}, + issn = {2517-6161}, + url = {https://onlinelibrary.wiley.com/doi/abs/10.1111/j.2517-6161.1972.tb00899.x}, + doi = {10.1111/j.2517-6161.1972.tb00899.x}, + abstract = {The analysis of censored failure times is considered. It is assumed that on each individual are available values of one or more explanatory variables. The hazard function (age-specific failure rate) is taken to be a function of the explanatory variables and unknown regression coefficients multiplied by an arbitrary and unknown function of time. A conditional likelihood is obtained, leading to inferences about the unknown regression coefficients. Some generalizations are outlined.}, + language = {en}, + number = {2}, + urldate = {2024-08-08}, + journal = {Journal of the Royal Statistical Society: Series B (Methodological)}, + author = {Cox, D. R.}, + year = {1972}, + note = {\_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.2517-6161.1972.tb00899.x}, + keywords = {accelerated life tests, age-specific failure rate, asymptotic theory, censored data, conditional inference, hazard function, life table, medical applications, product limit estimate, regression, reliability theory, two-sample rank tests}, + pages = {187--202}, + file = {Snapshot:/Users/erikwestlund/Zotero/storage/2RNVJQAX/j.2517-6161.1972.tb00899.html:text/html}, +} + +@article{mollan_semaglutide_2024, + title = {Semaglutide and {Nonarteritic} {Anterior} {Ischemic} {Optic} {Neuropathy}}, + issn = {2168-6173}, + doi = {10.1001/jamaophthalmol.2024.2514}, + language = {eng}, + journal = {JAMA ophthalmology}, + author = {Mollan, Susan P.}, + month = jul, + year = {2024}, + pmid = {38958953}, +} + +@article{hui_glucagon-like_2024, + title = {Glucagon-like {Peptide} 1 {Receptor} {Agonist} use and the effect on diabetic retinopathy: {An} uncertain relationship}, + volume = {178}, + issn = {1873-5169}, + shorttitle = {Glucagon-like {Peptide} 1 {Receptor} {Agonist} use and the effect on diabetic retinopathy}, + doi = {10.1016/j.peptides.2024.171240}, + abstract = {Glucagon-like Peptide 1 Receptor Agonists (GLP-1 RAs) are a group of relatively novel medications for the treatment of diabetes mellitus. These medications can mimic the naturally occurring incretins of the body, which promote the release of insulin in response to hyperglycaemia. The anti-glycaemic effects of these medications can be profound and carry other metabolic benefits such as promoting weight loss. Clinical trials have shown GLP-1 RAs are safe to use from a cardiovascular perspective. However, some trials have suggested a link between GLP-1 RA use and worsening diabetic retinopathy. The conclusions surrounding this link are poorly established as data is drawn primarily from cardiovascular outcome trials. If an association does exist, a possible explanation might be the observed phenomenon of early worsening diabetic retinopathy with rapid correction of hyperglycaemic states. Trials which look at diabetic retinopathy as a primary outcome in relation to use of GLP-1 RAs are sparse and warrant investigation given the growing use of this group of medications. Therefore currently, it is uncertain what effect, beneficial or adverse, GLP-1 RA use has on diabetic retinopathy. This article provides an overview of GLP-1 RA use as a treatment for diabetes mellitus and the current understanding of their relationship with diabetic retinopathy.}, + language = {eng}, + journal = {Peptides}, + author = {Hui, Benjamin T. K. and Yeong, Jian Lee and Peto, Tunde and Willoughby, Colin E.}, + month = aug, + year = {2024}, + pmid = {38705472}, + keywords = {Diabetes Mellitus, Type 2, Diabetic Retinopathy, Humans, Hypoglycemic Agents, Diabetes mellitus, Diabetic retinopathy, Glucagon-like Peptide 1 Receptor Agonists, Glucagon-Like Peptide-1 Receptor}, + pages = {171240}, +} + +@article{hayreh_nonarteritic_2008, + title = {Nonarteritic anterior ischemic optic neuropathy: natural history of visual outcome}, + volume = {115}, + issn = {1549-4713}, + shorttitle = {Nonarteritic anterior ischemic optic neuropathy}, + doi = {10.1016/j.ophtha.2007.05.027}, + abstract = {OBJECTIVE: To investigate systematically the natural history of visual outcome in nonarteritic anterior ischemic optic neuropathy (NAION). +DESIGN: Cohort study. +PARTICIPANTS: Three hundred forty consecutive untreated patients (386 eyes) with NAION, first seen in our clinic from 1973 to 2000. +METHODS: At first visit, all patients gave a detailed ophthalmic and medical history and underwent a comprehensive ophthalmic evaluation. Visual evaluation was done by recording visual acuity, using the Snellen visual acuity chart, and visual fields with a Goldmann perimeter. The same ophthalmic evaluation was performed at each follow-up visit. +MAIN OUTCOME MEASURES: Natural history of visual acuity and visual field outcome in NAION. +RESULTS: Of the 386 eyes, 332 had 8 weeks or more of follow-up from the initial visit. At the initial visit, in eyes seen {\textless} or =2 weeks from onset of symptoms, 49\% had visual acuity of {\textgreater} or =20/30 and 23\% had {\textless} or =20/200; in these eyes, 38\% had minimal to mild visual field defect and 43\% marked to severe defect. In those who were first seen {\textless} or =2 weeks after onset with visual acuity {\textless} or =20/70, there was improvement in 41\% at 6 months and in 42\% at 1 year after the initial visit. Two years after the initial visit, there was deterioration in 9\% of eyes with initial visual acuity of {\textgreater} or =20/60, and in 18\% of those with initial visual acuity of {\textless} or =20/70. In those who were first seen {\textless} or =2 weeks of onset with moderate to severe visual field defect, there was improvement in 26\% at 6 months and 27\% at 1 year after the initial visit. Two years after the initial visit, 27\% of eyes with initial minimal to mild field defects showed worsening, as did 19\% of those with moderate to severe defects. +CONCLUSIONS: About half of the eyes with NAION presented with almost normal visual acuity (20/15 to 20/30) at the initial visit. Thus, the presence of normal visual acuity does not rule out NAION. Visual acuity and visual fields showed improvement or further deterioration mainly up to 6 months, with no significant change after that.}, + language = {eng}, + number = {2}, + journal = {Ophthalmology}, + author = {Hayreh, Sohan Singh and Zimmerman, M. Bridget}, + month = feb, + year = {2008}, + pmid = {17698200}, + pmcid = {PMC2782939}, + keywords = {Humans, Arteritis, Cohort Studies, Female, Follow-Up Studies, Male, Middle Aged, Optic Neuropathy, Ischemic, Papilledema, Vision Disorders, Visual Acuity, Visual Field Tests, Visual Fields}, + pages = {298--305.e2}, + file = {Accepted Version:/Users/erikwestlund/Zotero/storage/8G9QW32S/Hayreh and Zimmerman - 2008 - Nonarteritic anterior ischemic optic neuropathy n.pdf:application/pdf}, +} + +@incollection{schuemie_health-analytics_2024, + title = {Health-{Analytics} {Data} to {Evidence} {Suite} ({HADES}): {Open}-{Source} {Software} for {Observational} {Research}}, + shorttitle = {Health-{Analytics} {Data} to {Evidence} {Suite} ({HADES})}, + url = {https://ebooks.iospress.nl/doi/10.3233/SHTI231108}, + urldate = {2024-08-08}, + publisher = {IOS Press}, + author = {Schuemie, Martijn and Reps, Jenna and Black, Adam and Defalco, Frank and Evans, Lee and Fridgeirsson, Egill and Gilbert, James P. and Knoll, Chris and Lavallee, Martin and Rao, Gowtham A. and Rijnbeek, Peter and Sadowski, Katy and Sena, Anthony and Swerdel, Joel and Williams, Ross D. and Suchard, Marc}, + year = {2024}, + doi = {10.3233/SHTI231108}, + pages = {966--970}, + file = {Full Text PDF:/Users/erikwestlund/Zotero/storage/JKRHDT6E/Schuemie et al. - 2024 - Health-Analytics Data to Evidence Suite (HADES) O.pdf:application/pdf}, +} + +@article{joo_effect_2024, + title = {The {Effect} of {Glucagon}-{Like} {Peptide}-1 {Receptor} {Agonists} on {Diabetic} {Retinopathy} at a {Tertiary} {Care} {Center}}, + volume = {4}, + issn = {2666-9145}, + url = {https://www.ophthalmologyscience.org/article/S2666-9145(24)00083-6/fulltext}, + doi = {10.1016/j.xops.2024.100547}, + language = {English}, + number = {6}, + urldate = {2024-08-08}, + journal = {Ophthalmology Science}, + author = {Joo, Julia H. and Sharma, Neha and Shaia, Jacqueline and Wu, Anna K. and Skugor, Mario and Singh, Rishi P. and Rachitskaya, Aleksandra V.}, + month = nov, + year = {2024}, + note = {Publisher: Elsevier}, + keywords = {Diabetes mellitus, Diabetic retinopathy, BMI, body mass index, cardiovascular outcome trial, CI, confidence interval, CVOT, diabetic retinopathy, DR, Early worsening, GLP-1 receptor agonists, GLP-1RA, glucagon-like peptide-1 agonists, HbA1C, hemoglobin A1c, ICD, International Classification of Diseases, odds ratio, OR, panretinal photocoagulation, pars plana vitrectomy, PDR, PPV, proliferative diabetic retinopathy, PRP, SD, SGLT-2 inhibitors, SGLT-2I, standard deviation}, + file = {Full Text PDF:/Users/erikwestlund/Zotero/storage/EYXM33KB/Joo et al. - 2024 - The Effect of Glucagon-Like Peptide-1 Receptor Ago.pdf:application/pdf}, +} + +@misc{rao_cohortdiagnostics_2023, + title = {{CohortDiagnostics}: phenotype evaluation across a network of observational data sources using population-level characterization}, + copyright = {© 2023, Posted by Cold Spring Harbor Laboratory. This pre-print is available under a Creative Commons License (Attribution-NoDerivs 4.0 International), CC BY-ND 4.0, as described at http://creativecommons.org/licenses/by-nd/4.0/}, + shorttitle = {{CohortDiagnostics}}, + url = {https://www.medrxiv.org/content/10.1101/2023.06.28.23291982v1}, + doi = {10.1101/2023.06.28.23291982}, + abstract = {Objective This paper introduces a novel framework for evaluating phenotype algorithms (PAs) using the open-source tool, Cohort Diagnostics. +Materials and Methods The method is based on several diagnostic criteria to evaluate a patient cohort returned by a PA. Diagnostics include estimates of incidence rate, index date entry code breakdown, and prevalence of all observed clinical events prior to, on, and after index date. We test our framework by evaluating one PA for systemic lupus erythematosus (SLE) and two PAs for Alzheimer’s disease (AD) across 10 different observational data sources. +Results By utilizing CohortDiagnostics, we found that the population-level characteristics of individuals in the cohort of SLE closely matched the disease’s anticipated clinical profile. Specifically, the incidence rate of SLE was consistently higher in occurrence among females. Moreover, expected clinical events like laboratory tests, treatments, and repeated diagnoses were also observed. For AD, although one PA identified considerably fewer patients, absence of notable differences in clinical characteristics between the two cohorts suggested similar specificity. +Discussion We provide a practical and data-driven approach to evaluate PAs, using two clinical diseases as examples, across a network of OMOP data sources. Cohort Diagnostics can ensure the subjects identified by a specific PA align with those intended for inclusion in a research study. +Conclusion Diagnostics based on large-scale population-level characterization can offer insights into the misclassification errors of PAs.}, + language = {en}, + urldate = {2024-08-09}, + publisher = {medRxiv}, + author = {Rao, Gowtham A. and Shoaibi, Azza and Makadia, Rupa and Hardin, Jill and Swerdel, Joel and Weaver, James and Voss, Erica A. and Conover, Mitchell M. and Fortin, Stephen and Sena, Anthony G. and Knoll, Chris and Hughes, Nigel and Gilbert, James P. and Blacketer, Clair and Andryc, Alan and DeFalco, Frank and Molinaro, Anthony and Reps, Jenna and Schuemie, Martijn J. and Ryan, Patrick B.}, + month = jun, + year = {2023}, + note = {ISSN: 2329-1982 +Pages: 2023.06.28.23291982}, + file = {Full Text PDF:/Users/erikwestlund/Zotero/storage/4BSQTQM2/Rao et al. - 2023 - CohortDiagnostics phenotype evaluation across a n.pdf:application/pdf}, +} diff --git a/docs/bmj.csl b/docs/bmj.csl new file mode 100644 index 00000000..68a4a822 --- /dev/null +++ b/docs/bmj.csl @@ -0,0 +1,181 @@ + + diff --git a/docs/header.tex b/docs/header.tex new file mode 100644 index 00000000..c3edbb7d --- /dev/null +++ b/docs/header.tex @@ -0,0 +1,22 @@ +\usepackage{fancyhdr} +\pagestyle{fancy} +\renewcommand{\headrulewidth}{0pt} +\renewcommand{\footrulewidth}{0pt} +\setlength\headheight{30.0pt} +\addtolength{\textheight}{-30.0pt} +\chead{\includegraphics[width=\textwidth]{OHDSI_page_header}} +\lhead{} +\rhead{} +\lfoot{\footerDate} +\cfoot{} +\rfoot{\thepage} + +%\AtBeginDocument{\thispagestyle{fancy}} + +%\let\oldmaketitle\maketitle +%\AtBeginDocument{\let\maketitle\relax} + +\patchcmd{\maketitle} + {\end{titlepage}} + {\thispagestyle{fancy}\end{titlepage}} + {}{} diff --git a/docs/protocol.html b/docs/protocol.html new file mode 100644 index 00000000..5890ca67 --- /dev/null +++ b/docs/protocol.html @@ -0,0 +1,43211 @@ + + + + + + + + + + + + + +Protocol.knit + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+ + + +
+
+
+
+
+ +
+ + + + + + + +
+

1 List of Abbreviations

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+NAION + +Non-arteritic ischemic optic neuropathy +
+DR + +Diabetic retinopathy +
+PDR + +Proliferative diabetic retinopathy +
+DME + +Diabetic macular edema +
+VR + +Vitreoretinal +
+GLP-1 RA + +Glucagon-like peptide 1 receptor agonist +
+SGLT2 + +Sodium-glucose cotransporter -2 +
+DPP4 + +Dipeptidyl peptidase-4 +
+T2DM + +Type 2 diabetes mellitus +
+VO + +Vein occlusion +
+AO + +Artery occlusion +
+AMD + +Age-related macular degeneration +
+GCA + +Giant cell arteritis +
+EASE + +Expected Absolute Systematic Error +
+MDRR + +Minimum Detectable Relative Risk +
+OHDSI + +Observational Health Data Sciences and Informatics +
+ARVO + +The Association for Research in Vision and Ophthalmology +
+
+
+

2 Responsible Parties

+
+

2.1 Investigators

+ + + + + + + + + + + + + + + + + + + + + + + + + + +
+Investigator + +Institution/Affiliation +
+Cindy Cai, MD, MS * + +Wilmer Eye Institute, Johns Hopkins Hospital, +
+Michelle Hribar, PhD + +Oregon Health & Science University, +
+ +Eye Care and Vision Research Workgroup +
+ * Principal Investigator +
+
+
+

2.2 Disclosures

+

This study is undertaken within Observational Health Data Sciences and Informatics (OHDSI), an open collaboration.

+
+
+
+

3 Abstract

+

Background: Despite its cardiovascular and kidney benefits, semaglutide has been recently linked to severe ophthalmic complications including non-arteritic ischemic optic neuropathy (NAION) as well as worsening of diabetic retinopathy (DR).

+

Purpose: To estimate the risk of these ophthalmic complications, NAION and DR worsening, with semaglutide use compared with other non-GLP-1 RA medications (including empagliflozin, sitagliptin, and glipizide) among adults with type 2 diabetes mellitus.

+

Design: Retrospective study employing an active comparator, new-user cohort design

+

Subjects: Adults (≥ 18 years) with type 2 diabetes mellitus who are new users of semaglutide (a GLP-1 RA), dulaglutide (a GLP-1 RA), exenatide (a GLP-1 RA), empagliflozin (an SGLT2 inhibitor), sitagliptin (a DPP4 inhibitor), or glipizide (a sulfonylurea)

+

Methods: Patients receiving semaglutide will be compared to propensity score matched patients with each of the other GLP-1 RA and non-GLP-1 RA medications. We will deploy the large-scale propensity score method that adjusts for a comprehensive range of baseline characteristics. Cox models will be used to compare the time to NAION or DR worsening between patients who receive semaglutide with patients who receive empagliflozin, sitagliptin, and glipizide. Similar comparisons will be made between the other GLP-1 RA (namely dulaglutide and exenatide) with each of the comparators.

+

Conclusions: Clarifying the risk of severe ophthalmic complications associated with semaglutide (and other GLP-1 RA) by 1) characterizing the incidence in the exposed population, and 2) estimating the risk of exposure will help guide the appropriate use of this medication.

+
+
+

4 Amendments and Updates

+
+
+

5 Milestones

+ + + + + +
+
+
+

6 Rationale and Background

+

Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), is approved by the US Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus. It has been shown to reduce the rate of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke in patients with type 2 diabetes at high cardiovascular risk.[1] Furthermore, results from the recent FLOW trial suggest that semaglutide can reduce clinically important kidney outcomes and death from cardiovascular causes in patients with type 2 diabetes mellitus and chronic kidney disease.[2] Given their benefit, the American Diabetes Association’s Standards of Medical Care in Diabetes recommends GLP-1 RA as one of the two preferred options for add-on therapy in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease after lifestyle intervention and metformin.[3]

+

Despite the benefits of semaglutide for treatment of type 2 diabetes mellitus, recent studies raise the concern of adverse ophthalmic consequences—non-arteritic ischemic optic neuropathy (NAION) and progression of diabetic retinopathy (DR).

+

NAION is a rare acute ischemic injury to the optic nerve with an incidence of 2-10/100,000 people per year and resulting in blindness in nearly a quarter of affected patients.[4,5] In addition to anatomic characteristics that predispose certain optic nerves to this ischemic event, there are also known systemic risk factors including diabetes mellitus, hypertension, dyslipidemia, and obstructive sleep apnea.[4] A recent study published in JAMA Ophthalmology linked the use of semaglutide with an increased risk for NAION as compared with non-GLP-1 RA.[6]

+

In 2016, the SUSTAIN-6 trial evaluating semaglutide identified a risk of DR complications which included vitreous hemorrhage, DR-related blindness, and intravitreal pharmacotherapy and laser photocoagulation compared with placebo.1 The increased risk for retinopathy appeared to be confirmed on meta-analysis.[7] Since then, multiple retrospective studies have not shown a difference in the risk of DR worsening, the largest of which included ~400,000 adults with diabetes.[8–11]

+
+
+

7 Study Objectives

+

The purpose of this study is to investigate three concerning ophthalmic complications (NAION and worsening of DR) from use of semaglutide for the treatment of type 2 diabetes mellitus.

+
    +
  1. Among patients with type 2 diabetes mellitus, is the risk for NAION higher among patients who use semaglutide as compared with a non-GLP-1 RA anti-diabetic medication?
    2. +
  2. Among patients with types 2 diabetes mellitus, is the risk for DR progression higher among patients who use semaglutide as compared with a non-GLP-1 RA anti-diabetic medication?
    3. +
  3. Among patients with type 2 diabetes mellitus, is the risk for NAION higher among patients who use semaglutide as compared with other GLP-1 RA anti-diabetic medications?
    4. +
+
+
+

8 Research Methods

+
+

8.1 Study Design/Data Source(s)

+

This will be a retrospective cohort study employing an active comparator, new-user cohort design, comparing the risk of NAION and DR worsening among adults with types 2 diabetes mellitus exposed to semaglutide compared with other GLP-1 RA medications and non-GLP-1 RA anti-diabetic medications. Other GLP-1 RA medications will include dulaglutide and exenatide. Non-GLP-1 RA comparators will include other second-line treatments for diabetes including empagliflozin (a SGLT2 inhibitor), sitagliptin (a DPP4 inhibitor), and glipizide (a sulfonylurea). These comparators were chosen based on the most commonly occurring medication within those classes from the LEGEND-T2DM study. (https://ohdsi-studies.github.io/LegendT2dm/Protocol)

+
+
+

8.2 Study Population

+

We will include all adults (≥ 18 years) with type 2 diabetes mellitus in each data source who meet the cohort entry criteria for each exposure cohort (detailed below).

+
+
+

8.3 Exposures

+

The exposure is receipt of semaglutide (GLP-1 RA), dulaglutide (GLP-1RA), exenatide (GLP-1 RA), empagliflozin (a SGLT2 inhibitor), sitagliptin (a DPP4 inhibitor), or glipizide (a sulfonylurea) based on the definitions of LEGEND-T2DM. (https://ohdsi-studies.github.io/LegendT2dm/Protocol) In brief, these will include patients with T2DM with prior metformin monotherapy who initiate treatment with one of the four medications. Patients have to have one year of observation prior to the index date, no prior drug exposure to a comparator second-line or anti-diabetic agents, and at most 30 days of insulin exposure before the index date.

+

As a sensitivity analysis, we will examine patients with each of these anti-diabetic medication exposures but without the second-line therapy requirement, meaning that they can be on another anti-diabetic medication at the time of cohort entry.

+
+
+

8.4 Outcomes

+

The outcomes are NAION and DR worsening.

+

NAION will have two definitions, one designed to be more specific and one designed to be more sensitive:

+
    +

  • NAION-specific:

    +
      +
    1. 2 instances of ION diagnosis codes on separate days (within 90 days of each other)
      2. +
    2. If the 2 diagnoses of ION are preceded by the following diagnoses within the prior 60 days, then use the occurrence of these prior diagnosis to mark the start date of the outcome +
        +
      • Visual field defect
        • +
      • Optic disc disorder +
          +
        • Includes concepts of optic papillitis (concept ID 435269), and “other disorders of optic disc”
          • +
        • +
      • Optic neuritis +
          +
        • Includes “Unspecified” and “Other” optic neuritis
          • +
        • +
      • Optic disc edema +
          +
        • Includes papilledema
          • +
        • +
      3. +
    3. Exclude patients who have 2 diagnoses of giant cell arteritis (GCA) any time before or after outcome start date
      4. +
    4. Exclude patients with a diagnosis of traumatic optic neuropathy before outcome start date)
      5. +
    • +

  • NAION-sensitive:

    +
      +
    1. 1 instance of ION diagnosis code
      2. +
    2. Adjustment to the start of the outcome (same ones as above)
      3. +
    3. Exclude patients with 2 instances of GCA (any time before or after index date)
      4. +
    4. Exclude patients with a diagnosis of traumatic optic neuropathy (before outcome start date)
      5. +
    • +
+

DR worsening is defined as: +- New-onset PDR +- Treatment-requiring DR/DME +1. New exposure to anti-VEGF medication, procedure for focal laser photocoagulation, or panretinal photocoagulation +2. Has to have a diagnosis of DR/DME within 90 days of the outcome start date +3. Exclude patients with diagnosis of VO/AO if ever in the days prior to outcome start date +4. Exclude patients withAMD in the 365 days prior to outcome start date +- Treatment-requiring DR/DME (including VR surgery) +1. In addition to above, also add exposure to vitreoretinal surgery (mechanical vitrectomy by pars plana approach Concept ID 4314406) ++ CPT Codes to include: 67036, 67039, 67040, 67041, 67042, 67113 ++ CPT Codes to exclude: 67108, 67107

+
+
+

8.5 Covariates

+

We will deploy the large-scale propensity score method that adjusts for a comprehensive range of baseline characteristic.[12]

+
+
+

8.6 Negative Controls

+

Negative controls will be picked to represent exposure-outcome pairs where no causal effect is expected to exist. We will adapt the set of negative controls that was used in LEGEND-T2DM (https://ohdsi-studies.github.io/LegendT2dm/Protocol). (See full list located below)

+
+
+
+

9 Data Analysis Plan

+
+

9.1 General

+

Although the primary aim of this study is a comparative safety study, various standardized analytics available in the OHDSI community will be applied. The Strategus pipeline will be used to call various packages in the HADES library for A) data characterization (A1‑cohort diagnostics, A2‑cohort features, A3‑incidence rates, A4-time-to-event), B) population-level effect estimation (C1–comparative cohort study, C2‑‑self-controlled case-series).[13,14]

+
+
+

9.2 Data Characterization

+
+

9.2.1 Cohort Diagnostics

+

The R package CohortDiagnostics will be executed for all target, comparator, indication, and outcome cohorts to evaluate measurement error in the phenotype development and evaluation process.[15]

+
+
+

9.2.2 Cohort Features

+

The Characterization and FeatureExtraction packages in HADES will be used to identify features of patients in each exposure group who had the outcome and those who did not have the outcome.14 Features will be extracted from the 365 day observation prior to cohort entry and will include variables such as demographic data (sex, age group, race, ethnicity), prior conditions/drug exposures/procedures/measurements/devices/observations, and risk scores (e.g., Charlson comorbidity index, DCSI, CHADS2VASC score).

+
+
+

9.2.3 Incidence Rates

+

The Characterization package in HADES will be used to calculate the incidence rates of the outcome for each exposure cohort and indication cohort. The rate is calculated as the number of outcomes during the time-at-risk divided by the number of total person days.

+
+

9.2.3.1 Calculation of time-at-risk

+

The primary method of calculating time-at-risk will be while the patient is “on-treatment”. This is defined as from the start of cohort entry (or diabetes drug initiation) until the end of the continuous drug exposure, defined as a gap in exposure of >30 days, end of continuous observation period, or study period. The second method of calculating time-at-risk is based on “intent-to-treat”, which will be used as a sensitivity analysis. In this analysis, patients are analyzed according to the first diabetes medication drug cohort they enter, regardless of switching from one cohort to another.

+
+
+
+

9.2.4 Time-to-Event

+

Time to the outcomes of NAION or DR worsening (as defined above) will be calculated for each exposure cohort.

+
+
+
+

9.3 Population-Level Effect Estimation

+
+

9.3.1 Comparative Cohort Study

+

The CohortMethod and Cyclops packages in Hades will be used.14 Large-scale propensity score methods will be used to match the targe exposure cohort with the comparator export cohort (e.g., semaglutide vs empagliflozin) using 1:1 propensity score matching. Given the concern for increasing usage of semaglutide in recent years, we will also perform a sensitivity analysis with calendar year restriction: Dec2017-Jan2020, Feb2020-June2021, July2021-Dec2023. Cox proportional hazards models will be used to estimate the risk of NAION and separately DR progression while on treatment using the intent-to-treat design.[16] Negative controls will be used to assess residual bias.

+
+
+

9.3.2 Self-Controlled Case Series

+

The SelfControlledCaseSeries and Cyclops packages in Hades will be used to estimate the relative incidence of NAION or DR progression using a self-controlled case-series design.[14] Diagnostics will be run to evaluate whether this was an appropriate analysis.

+
+
+
+
+

10 Study Diagnostics

+
    +
  1. Preference score distributions to evaluate empirical equipoise and population generalizability
    2. +
  2. Extensive patient characteristics to evaluate cohort balance before and after propensity score adjustment
    3. +
  3. Negative control calibration plots to assess residual bias
    4. +
  4. Kaplan-Meier plots to examine hazard ratio proportionality assumptions
    5. +
+
+

10.1 Diagnostic Thresholds for Cohort Method

+ + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Study Diagnostics + +Threshold +
+Covariate balance (Standardized Mean Difference) + +<0.1 +
+Empirical Equipoise (Preference Score) + +>0.1 +
+Residual Bias (Expected Absolute Systematic Error (EASE)) + +<0.25 +
+Meta-analysis Heterogeneity + +<0.4 +
+Meta-analysis Minimum Detectable Relative Risk (MDRR) + +<10 +
+
+
+

10.2 Diagnostic Thresholds for Self-Controlled Case-Series

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Study Diagnostics + +Threshold +
+Covariate balance (Standardized Mean Difference) + +<0.1 +
+Pre-exposure + +>0.05 +
+Time Trend + +>0.05 +
+EASE + +<0.25 +
+Meta-analysis Heterogeneity + +<0.4 +
+Meta-analysis MDRR + +<10 +
+
+
+
+

11 Strengths and Limitations

+

When executed, this will be the largest study examining the association between semaglutide and the risk of NAION and DR progression. Other strengths of this study include the diversity of the sample (from multiple institutions, multiple countries), and rigorous study design.

+

Limitations are mainly due to the retrospective nature of the study which might have confounding despite propensity score matching and stratified analyses. Additionally, unlike single-site studies, the diagnosis of NAION cannot be confirmed from manual review of patient records.

+
+
+

12 Protection of Human Subjects

+

Each participating institution will seek IRB approval for this study as dictated by local governance.

+
+
+

13 Plans for Disseminating and Communicating Study Results

+

The results will be shared and discussed among the study participants and broader OHDSI community during the weekly Tuesday community calls. This work will be presented at conferences (OHDSI Global Symposium and/or ARVO) and published as a manuscript.

+
+
+

References

+
+
+
1
Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine 2016;375:1834–44. doi:10.1056/NEJMoa1607141
+
+
+
2
Perkovic V, Tuttle KR, Rossing P, et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. New England Journal of Medicine 2024;391:109–21. doi:10.1056/NEJMoa2403347
+
+
+
3
American Diabetes Association Professional Practice Committee. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2022. Diabetes Care 2021;45:S125–43. doi:10.2337/dc22-S009
+
+
+
4
Mollan SP. Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy. JAMA Ophthalmology Published Online First: July 2024. doi:10.1001/jamaophthalmol.2024.2514
+
+
+
5
Hayreh SS, Zimmerman MB. Nonarteritic anterior ischemic optic neuropathy: Natural history of visual outcome. Ophthalmology 2008;115:298–305.e2. doi:10.1016/j.ophtha.2007.05.027
+
+
+
6
Hathaway JT, Shah MP, Hathaway DB, et al. Risk of nonarteritic anterior ischemic optic neuropathy in patients prescribed semaglutide. JAMA Ophthalmology Published Online First: 2024. doi:10.1001/jamaophthalmol.2024.2296
+
+
+
7
Albert SG, Wood EM, Ahir V. Glucagon-like peptide 1-receptor agonists and A1c: Good for the heart but less so for the eyes? Diabetes & Metabolic Syndrome: Clinical Research & Reviews 2023;17:102696. doi:10.1016/j.dsx.2022.102696
+
+
+
8
Barkmeier AJ, Herrin J, Swarna KS, et al. Comparative Effectiveness of Glucagon-Like Peptide-1 Receptor Agonists, Sodium-Glucose Cotransporter 2 Inhibitors, Dipeptidyl Peptidase-4 Inhibitors, and Sulfonylureas for Sight-Threatening Diabetic Retinopathy. Ophthalmology Retina Published Online First: 2024. doi:10.1016/j.oret.2024.05.003
+
+
+
9
Stevens H, Paz M de la, Cooper B, et al. Long-term use of semaglutide and risk of diabetic retinopathy progression. Endocrine and Metabolic Science 2024;15:100168. doi:10.1016/j.endmts.2024.100168
+
+
+
10
Sharma A, Parachuri N, Kumar N, et al. Semaglutide and the risk of diabetic retinopathy-current perspective. Eye (London, England) 2022;36:10–1. doi:10.1038/s41433-021-01741-5
+
+
+
11
Joo JH, Sharma N, Shaia J, et al. The Effect of Glucagon-Like Peptide-1 Receptor Agonists on Diabetic Retinopathy at a Tertiary Care Center. Ophthalmology Science 2024;4. doi:10.1016/j.xops.2024.100547
+
+
+
12
Tian Y, Schuemie MJ, Suchard MA. Evaluating large-scale propensity score performance through real-world and synthetic data experiments. International Journal of Epidemiology 2018;47:2005–14. doi:10.1093/ije/dyy120
+
+
+
13
OHDSI/Strategus. 2024.https://github.com/OHDSI/Strategus (accessed 29 Apr 2023).
+
+
+
14
Schuemie M, Reps J, Black A, et al. Health-Analytics Data to Evidence Suite (HADES): Open-Source Software for Observational Research. IOS Press 2024. 966–70. doi:10.3233/SHTI231108
+
+
+
15
Rao GA, Shoaibi A, Makadia R, et al. CohortDiagnostics: Phenotype evaluation across a network of observational data sources using population-level characterization. 2023. doi:10.1101/2023.06.28.23291982
+
+
+
16
Cox DR. Regression Models and Life-Tables. Journal of the Royal Statistical Society: Series B (Methodological) 1972;34:187–202. doi:10.1111/j.2517-6161.1972.tb00899.x
+
+
+
+
+

Appendix

+
+
+

A Study Population Cohort Definitions

+
+

A.1 Persons with Type 2 diabetes mellitus and no prior T1DM or secondary diabetes

+
+

A.1.1 Cohort Entry Events

+

People may enter the cohort when observing any of the following:

+
    +
  1. condition occurrences of ‘Type 2 diabetes mellitus’.
    2. +
+

Limit cohort entry events to the earliest event per person.

+

Restrict entry events to with all of the following criteria:

+
    +
  1. having no condition occurrences of ‘Type 1 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    2. +
  2. having no condition occurrences of ‘Secondary diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

A.1.2 Cohort Exit

+

The person also exists the cohort at the end of continuous observation.

+
+
+

A.1.3 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

A.1.4 Concept: Secondary diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +NO + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.1.5 Concept: Type 1 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +NO + +YES + +NO +
+42689695 + +Eating disorder co-occurrent with diabetes mellitus type 1 + +1067201000000106 + +SNOMED + +NO + +YES + +NO +
+765533 + +Glaucoma due to diabetes mellitus type 1 + +60981000119103 + +SNOMED + +NO + +YES + +NO +
+43531006 + +Maturity onset diabetes of the young, type 1 + +609562003 + +SNOMED + +NO + +YES + +NO +
+765650 + +Cranial nerve palsy due to diabetes mellitus type 1 + +82561000119101 + +SNOMED + +NO + +YES + +NO +
+45770986 + +Retinopathy due to unstable diabetes mellitus type 1 + +706894000 + +SNOMED + +NO + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +NO + +YES + +NO +
+45768456 + +Neuropathy due to unstable diabetes mellitus type 1 + +706891008 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +NO + +YES + +NO +
+4128019 + +Brittle type 1 diabetes mellitus + +290002008 + +SNOMED + +NO + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.1.6 Concept: Type 2 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+443238 + +Diabetic - poor control + +268519009 + +SNOMED + +NO + +YES + +NO +
+201820 + +Diabetes mellitus + +73211009 + +SNOMED + +NO + +YES + +NO +
+442793 + +Complication due to diabetes mellitus + +74627003 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +YES + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +YES + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +YES + +YES + +NO +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +YES + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +YES + +YES + +NO +
+4016045 + +Diabetic - good control + +170763003 + +SNOMED + +NO + +YES + +NO +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +YES + +YES + +NO +
+43531009 + +Pregnancy and type 1 diabetes mellitus + +609566000 + +SNOMED + +YES + +YES + +NO +
+4024659 + +Gestational diabetes mellitus + +11687002 + +SNOMED + +YES + +YES + +NO +
+
+ +
+
+
+

A.2 New user of semaglutide as 2nd-line treatment with prior T2DM and prior metformin

+
+

A.2.1 Cohort Entry Events

+

People with continuous observation of 365 days before event may enter the cohort when observing any of the following:

+
    +
  1. drug exposure of ‘semaglutide’ for the first time in the person’s history.
    2. +
+

Limit cohort entry events to the earliest event per person.

+

Restrict entry events to with all of the following criteria:

+
    +
  1. with the following event criteria: who are >= 18 years old.
    2. +
  2. having at least 1 condition occurrence of ‘Type 2 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
  3. having no condition occurrences of ‘Type 1 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    4. +
  4. having no condition occurrences of ‘Secondary diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    5. +
+
+
+

A.2.2 Additional Inclusion Criteria

+
+

I. Prior metformin use

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 drug era of ‘Metformin’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period; with era length >= 90 days.
    2. +
  2. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

II. No prior GLP-1 RA exposure

+

Entry events having no drug exposures of ‘GLP-1 receptor agonists excluding semaglutide’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

III. No prior DPP4 inhibitor exposure

+

Entry events having no drug exposures of ‘DPP4 inhibitors’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

IV. No prior SGLT-2 inhibitor exposure

+

Entry events having no drug exposures of ‘SGLT2 inhibitors’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

V. No prior SU exposure

+

Entry events having no drug exposures of ‘Sulfonylureas’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VI. No prior other anti-diabetic exposure

+

Entry events having no drug exposures of ‘Other anti-diabetics’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VII. No prior insulin use or combo initiation: Proxy for < 30 days drug era anytime before index and no combination use on index

+

Entry events with all of the following criteria:

+
    +
  1. having no drug eras of ‘Insulin’, starting anytime up to 30 days before cohort entry start date; allow events outside observation period; with era length > 30 days.
    2. +
  2. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.
    3. +
+
+
+
+

A.2.3 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘semaglutide’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

A.2.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

A.2.5 Concept: DPP4 inhibitors

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43013884 + +alogliptin + +1368001 + +RxNorm + +NO + +YES + +NO +
+40239216 + +linagliptin + +1100699 + +RxNorm + +NO + +YES + +NO +
+40166035 + +saxagliptin + +857974 + +RxNorm + +NO + +YES + +NO +
+1580747 + +sitagliptin + +593411 + +RxNorm + +NO + +YES + +NO +
+19122137 + +vildagliptin + +596554 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.2.6 Concept: semaglutide

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+793143 + +semaglutide + +1991302 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.2.7 Concept: SGLT2 inhibitors

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43526465 + +canagliflozin + +1373458 + +RxNorm + +NO + +YES + +NO +
+44785829 + +dapagliflozin + +1488564 + +RxNorm + +NO + +YES + +NO +
+45774751 + +empagliflozin + +1545653 + +RxNorm + +NO + +YES + +NO +
+793293 + +ertugliflozin + +1992672 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.2.8 Concept: Sulfonylureas

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1594973 + +chlorpropamide + +2404 + +RxNorm + +NO + +YES + +NO +
+1597756 + +glimepiride + +25789 + +RxNorm + +NO + +YES + +NO +
+1560171 + +glipizide + +4821 + +RxNorm + +NO + +YES + +NO +
+19097821 + +gliquidone + +25793 + +RxNorm + +NO + +YES + +NO +
+1559684 + +glyburide + +4815 + +RxNorm + +NO + +YES + +NO +
+1502809 + +tolazamide + +10633 + +RxNorm + +NO + +YES + +NO +
+1502855 + +tolbutamide + +10635 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.2.9 Concept: Other anti-diabetics

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1529331 + +acarbose + +16681 + +RxNorm + +NO + +YES + +NO +
+1530014 + +acetohexamide + +173 + +RxNorm + +NO + +YES + +NO +
+730548 + +bromocriptine + +1760 + +RxNorm + +NO + +YES + +NO +
+19033498 + +carbutamide + +2068 + +RxNorm + +NO + +YES + +NO +
+19001409 + +glibornuride + +102846 + +RxNorm + +NO + +YES + +NO +
+19059796 + +gliclazide + +4816 + +RxNorm + +NO + +YES + +NO +
+19001441 + +glymidine + +102848 + +RxNorm + +NO + +YES + +NO +
+1510202 + +miglitol + +30009 + +RxNorm + +NO + +YES + +NO +
+1502826 + +nateglinide + +274332 + +RxNorm + +NO + +YES + +NO +
+1525215 + +pioglitazone + +33738 + +RxNorm + +NO + +YES + +NO +
+1516766 + +repaglinide + +73044 + +RxNorm + +NO + +YES + +NO +
+1547504 + +rosiglitazone + +84108 + +RxNorm + +NO + +YES + +NO +
+1515249 + +troglitazone + +72610 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.2.10 Concept: Insulin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1596977 + +insulin, regular, human + +253182 + +RxNorm + +NO + +YES + +NO +
+1550023 + +insulin lispro + +86009 + +RxNorm + +NO + +YES + +NO +
+1567198 + +insulin aspart, human + +51428 + +RxNorm + +NO + +YES + +NO +
+1502905 + +insulin glargine + +274783 + +RxNorm + +NO + +YES + +NO +
+1513876 + +insulin lispro protamine, human + +314684 + +RxNorm + +NO + +YES + +NO +
+1531601 + +insulin aspart protamine, human + +352385 + +RxNorm + +NO + +YES + +NO +
+1586346 + +insulin, regular, pork + +221109 + +RxNorm + +NO + +YES + +NO +
+1544838 + +insulin glulisine, human + +400008 + +RxNorm + +NO + +YES + +NO +
+1516976 + +insulin detemir + +139825 + +RxNorm + +NO + +YES + +NO +
+1590165 + +insulin, regular, beef-pork + +235275 + +RxNorm + +NO + +YES + +NO +
+1513849 + +lente insulin, human + +314683 + +RxNorm + +NO + +YES + +NO +
+1562586 + +lente insulin, pork + +93108 + +RxNorm + +NO + +YES + +NO +
+1588986 + +insulin human, rDNA origin + +631657 + +RxNorm + +NO + +YES + +NO +
+1513843 + +lente insulin, beef-pork + +314682 + +RxNorm + +NO + +YES + +NO +
+1586369 + +ultralente insulin, human + +221110 + +RxNorm + +NO + +YES + +NO +
+35605670 + +insulin argine + +1740938 + +RxNorm + +NO + +YES + +NO +
+35602717 + +insulin degludec + +1670007 + +RxNorm + +NO + +YES + +NO +
+21600713 + +INSULINS AND ANALOGUES + +A10A + +ATC + +NO + +YES + +NO +
+19078608 + +insulin, protamine zinc, beef-pork 100 UNT/ML Injectable Suspension + +311053 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.2.11 Concept: Metformin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1503297 + +metformin + +6809 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.2.12 Concept: Secondary diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +NO + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.2.13 Concept: Type 1 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +NO + +YES + +NO +
+42689695 + +Eating disorder co-occurrent with diabetes mellitus type 1 + +1067201000000106 + +SNOMED + +NO + +YES + +NO +
+765533 + +Glaucoma due to diabetes mellitus type 1 + +60981000119103 + +SNOMED + +NO + +YES + +NO +
+43531006 + +Maturity onset diabetes of the young, type 1 + +609562003 + +SNOMED + +NO + +YES + +NO +
+765650 + +Cranial nerve palsy due to diabetes mellitus type 1 + +82561000119101 + +SNOMED + +NO + +YES + +NO +
+45770986 + +Retinopathy due to unstable diabetes mellitus type 1 + +706894000 + +SNOMED + +NO + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +NO + +YES + +NO +
+45768456 + +Neuropathy due to unstable diabetes mellitus type 1 + +706891008 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +NO + +YES + +NO +
+4128019 + +Brittle type 1 diabetes mellitus + +290002008 + +SNOMED + +NO + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.2.14 Concept: Type 2 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+443238 + +Diabetic - poor control + +268519009 + +SNOMED + +NO + +YES + +NO +
+201820 + +Diabetes mellitus + +73211009 + +SNOMED + +NO + +YES + +NO +
+442793 + +Complication due to diabetes mellitus + +74627003 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +YES + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +YES + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +YES + +YES + +NO +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +YES + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +YES + +YES + +NO +
+4016045 + +Diabetic - good control + +170763003 + +SNOMED + +NO + +YES + +NO +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +YES + +YES + +NO +
+43531009 + +Pregnancy and type 1 diabetes mellitus + +609566000 + +SNOMED + +YES + +YES + +NO +
+4024659 + +Gestational diabetes mellitus + +11687002 + +SNOMED + +YES + +YES + +NO +
+
+
+

A.2.15 Concept: GLP-1 receptor agonists excluding semaglutide

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774435 + +dulaglutide + +1551291 + +RxNorm + +NO + +YES + +NO +
+1583722 + +exenatide + +60548 + +RxNorm + +NO + +YES + +NO +
+40170911 + +liraglutide + +475968 + +RxNorm + +NO + +YES + +NO +
+44506754 + +lixisenatide + +1440051 + +RxNorm + +NO + +YES + +NO +
+793143 + +semaglutide + +1991302 + +RxNorm + +YES + +YES + +NO +
+44816332 + +albiglutide + +1534763 + +RxNorm + +NO + +YES + +NO +
+
+ +
+
+
+

A.3 New user of semaglutide as 2nd-line treatment with prior T2DM Dec2017-Jan2020

+
+

A.3.1 Cohort Entry Events

+

People with continuous observation of 365 days before event may enter the cohort when observing any of the following:

+
    +
  1. drug exposure of ‘semaglutide’ for the first time in the person’s history.
    2. +
+

Limit cohort entry events to the earliest event per person.

+

Restrict entry events to with all of the following criteria:

+
    +
  1. with the following event criteria: who are >= 18 years old.
    2. +
  2. having at least 1 condition occurrence of ‘Type 2 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
  3. having no condition occurrences of ‘Type 1 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    4. +
  4. having no condition occurrences of ‘Secondary diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    5. +
+
+
+

A.3.2 Additional Inclusion Criteria

+
+

I. Prior metformin use

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 drug era of ‘Metformin’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period; with era length >= 90 days.
    2. +
  2. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

II. No prior GLP-1 RA exposure

+

Entry events having no drug exposures of ‘GLP-1 receptor agonists excluding semaglutide’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

III. No prior DPP4 inhibitor exposure

+

Entry events having no drug exposures of ‘DPP4 inhibitors’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

IV. No prior SGLT-2 inhibitor exposure

+

Entry events having no drug exposures of ‘SGLT2 inhibitors’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

V. No prior SU exposure

+

Entry events having no drug exposures of ‘Sulfonylureas’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VI. No prior other anti-diabetic exposure

+

Entry events having no drug exposures of ‘Other anti-diabetics’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VII. No prior insulin use or combo initiation: Proxy for < 30 days drug era anytime before index and no combination use on index

+

Entry events with all of the following criteria:

+
    +
  1. having no drug eras of ‘Insulin’, starting anytime up to 30 days before cohort entry start date; allow events outside observation period; with era length > 30 days.
    2. +
  2. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.
    3. +
+
+
+

VIII. index date between 1Dec2017 and 31Jan2020

+

Entry events with the following event criteria: starting between December 1, 2017 and January 31, 2020.

+
+
+
+

A.3.3 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘semaglutide’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

A.3.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

A.3.5 Concept: DPP4 inhibitors

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43013884 + +alogliptin + +1368001 + +RxNorm + +NO + +YES + +NO +
+40239216 + +linagliptin + +1100699 + +RxNorm + +NO + +YES + +NO +
+40166035 + +saxagliptin + +857974 + +RxNorm + +NO + +YES + +NO +
+1580747 + +sitagliptin + +593411 + +RxNorm + +NO + +YES + +NO +
+19122137 + +vildagliptin + +596554 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.3.6 Concept: semaglutide

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+793143 + +semaglutide + +1991302 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.3.7 Concept: SGLT2 inhibitors

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43526465 + +canagliflozin + +1373458 + +RxNorm + +NO + +YES + +NO +
+44785829 + +dapagliflozin + +1488564 + +RxNorm + +NO + +YES + +NO +
+45774751 + +empagliflozin + +1545653 + +RxNorm + +NO + +YES + +NO +
+793293 + +ertugliflozin + +1992672 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.3.8 Concept: Sulfonylureas

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1594973 + +chlorpropamide + +2404 + +RxNorm + +NO + +YES + +NO +
+1597756 + +glimepiride + +25789 + +RxNorm + +NO + +YES + +NO +
+1560171 + +glipizide + +4821 + +RxNorm + +NO + +YES + +NO +
+19097821 + +gliquidone + +25793 + +RxNorm + +NO + +YES + +NO +
+1559684 + +glyburide + +4815 + +RxNorm + +NO + +YES + +NO +
+1502809 + +tolazamide + +10633 + +RxNorm + +NO + +YES + +NO +
+1502855 + +tolbutamide + +10635 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.3.9 Concept: Other anti-diabetics

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1529331 + +acarbose + +16681 + +RxNorm + +NO + +YES + +NO +
+1530014 + +acetohexamide + +173 + +RxNorm + +NO + +YES + +NO +
+730548 + +bromocriptine + +1760 + +RxNorm + +NO + +YES + +NO +
+19033498 + +carbutamide + +2068 + +RxNorm + +NO + +YES + +NO +
+19001409 + +glibornuride + +102846 + +RxNorm + +NO + +YES + +NO +
+19059796 + +gliclazide + +4816 + +RxNorm + +NO + +YES + +NO +
+19001441 + +glymidine + +102848 + +RxNorm + +NO + +YES + +NO +
+1510202 + +miglitol + +30009 + +RxNorm + +NO + +YES + +NO +
+1502826 + +nateglinide + +274332 + +RxNorm + +NO + +YES + +NO +
+1525215 + +pioglitazone + +33738 + +RxNorm + +NO + +YES + +NO +
+1516766 + +repaglinide + +73044 + +RxNorm + +NO + +YES + +NO +
+1547504 + +rosiglitazone + +84108 + +RxNorm + +NO + +YES + +NO +
+1515249 + +troglitazone + +72610 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.3.10 Concept: Insulin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1596977 + +insulin, regular, human + +253182 + +RxNorm + +NO + +YES + +NO +
+1550023 + +insulin lispro + +86009 + +RxNorm + +NO + +YES + +NO +
+1567198 + +insulin aspart, human + +51428 + +RxNorm + +NO + +YES + +NO +
+1502905 + +insulin glargine + +274783 + +RxNorm + +NO + +YES + +NO +
+1513876 + +insulin lispro protamine, human + +314684 + +RxNorm + +NO + +YES + +NO +
+1531601 + +insulin aspart protamine, human + +352385 + +RxNorm + +NO + +YES + +NO +
+1586346 + +insulin, regular, pork + +221109 + +RxNorm + +NO + +YES + +NO +
+1544838 + +insulin glulisine, human + +400008 + +RxNorm + +NO + +YES + +NO +
+1516976 + +insulin detemir + +139825 + +RxNorm + +NO + +YES + +NO +
+1590165 + +insulin, regular, beef-pork + +235275 + +RxNorm + +NO + +YES + +NO +
+1513849 + +lente insulin, human + +314683 + +RxNorm + +NO + +YES + +NO +
+1562586 + +lente insulin, pork + +93108 + +RxNorm + +NO + +YES + +NO +
+1588986 + +insulin human, rDNA origin + +631657 + +RxNorm + +NO + +YES + +NO +
+1513843 + +lente insulin, beef-pork + +314682 + +RxNorm + +NO + +YES + +NO +
+1586369 + +ultralente insulin, human + +221110 + +RxNorm + +NO + +YES + +NO +
+35605670 + +insulin argine + +1740938 + +RxNorm + +NO + +YES + +NO +
+35602717 + +insulin degludec + +1670007 + +RxNorm + +NO + +YES + +NO +
+21600713 + +INSULINS AND ANALOGUES + +A10A + +ATC + +NO + +YES + +NO +
+19078608 + +insulin, protamine zinc, beef-pork 100 UNT/ML Injectable Suspension + +311053 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.3.11 Concept: Metformin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1503297 + +metformin + +6809 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.3.12 Concept: Secondary diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +NO + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.3.13 Concept: Type 1 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +NO + +YES + +NO +
+42689695 + +Eating disorder co-occurrent with diabetes mellitus type 1 + +1067201000000106 + +SNOMED + +NO + +YES + +NO +
+765533 + +Glaucoma due to diabetes mellitus type 1 + +60981000119103 + +SNOMED + +NO + +YES + +NO +
+43531006 + +Maturity onset diabetes of the young, type 1 + +609562003 + +SNOMED + +NO + +YES + +NO +
+765650 + +Cranial nerve palsy due to diabetes mellitus type 1 + +82561000119101 + +SNOMED + +NO + +YES + +NO +
+45770986 + +Retinopathy due to unstable diabetes mellitus type 1 + +706894000 + +SNOMED + +NO + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +NO + +YES + +NO +
+45768456 + +Neuropathy due to unstable diabetes mellitus type 1 + +706891008 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +NO + +YES + +NO +
+4128019 + +Brittle type 1 diabetes mellitus + +290002008 + +SNOMED + +NO + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.3.14 Concept: Type 2 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+443238 + +Diabetic - poor control + +268519009 + +SNOMED + +NO + +YES + +NO +
+201820 + +Diabetes mellitus + +73211009 + +SNOMED + +NO + +YES + +NO +
+442793 + +Complication due to diabetes mellitus + +74627003 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +YES + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +YES + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +YES + +YES + +NO +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +YES + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +YES + +YES + +NO +
+4016045 + +Diabetic - good control + +170763003 + +SNOMED + +NO + +YES + +NO +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +YES + +YES + +NO +
+43531009 + +Pregnancy and type 1 diabetes mellitus + +609566000 + +SNOMED + +YES + +YES + +NO +
+4024659 + +Gestational diabetes mellitus + +11687002 + +SNOMED + +YES + +YES + +NO +
+
+
+

A.3.15 Concept: GLP-1 receptor agonists excluding semaglutide

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774435 + +dulaglutide + +1551291 + +RxNorm + +NO + +YES + +NO +
+1583722 + +exenatide + +60548 + +RxNorm + +NO + +YES + +NO +
+40170911 + +liraglutide + +475968 + +RxNorm + +NO + +YES + +NO +
+44506754 + +lixisenatide + +1440051 + +RxNorm + +NO + +YES + +NO +
+793143 + +semaglutide + +1991302 + +RxNorm + +YES + +YES + +NO +
+44816332 + +albiglutide + +1534763 + +RxNorm + +NO + +YES + +NO +
+
+ +
+
+
+

A.4 New user of semaglutide as 2nd-line treatment with prior T2DM Feb2020-Jun2021

+
+

A.4.1 Cohort Entry Events

+

People with continuous observation of 365 days before event may enter the cohort when observing any of the following:

+
    +
  1. drug exposure of ‘semaglutide’ for the first time in the person’s history.
    2. +
+

Limit cohort entry events to the earliest event per person.

+

Restrict entry events to with all of the following criteria:

+
    +
  1. with the following event criteria: who are >= 18 years old.
    2. +
  2. having at least 1 condition occurrence of ‘Type 2 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
  3. having no condition occurrences of ‘Type 1 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    4. +
  4. having no condition occurrences of ‘Secondary diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    5. +
+
+
+

A.4.2 Additional Inclusion Criteria

+
+

I. Prior metformin use

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 drug era of ‘Metformin’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period; with era length >= 90 days.
    2. +
  2. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

II. No prior GLP-1 RA exposure

+

Entry events having no drug exposures of ‘GLP-1 receptor agonists excluding semaglutide’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

III. No prior DPP4 inhibitor exposure

+

Entry events having no drug exposures of ‘DPP4 inhibitors’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

IV. No prior SGLT-2 inhibitor exposure

+

Entry events having no drug exposures of ‘SGLT2 inhibitors’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

V. No prior SU exposure

+

Entry events having no drug exposures of ‘Sulfonylureas’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VI. No prior other anti-diabetic exposure

+

Entry events having no drug exposures of ‘Other anti-diabetics’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VII. No prior insulin use or combo initiation: Proxy for < 30 days drug era anytime before index and no combination use on index

+

Entry events with all of the following criteria:

+
    +
  1. having no drug eras of ‘Insulin’, starting anytime up to 30 days before cohort entry start date; allow events outside observation period; with era length > 30 days.
    2. +
  2. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.
    3. +
+
+
+

VIII. index date between 1Feb2020 and 30Jun2021

+

Entry events with the following event criteria: starting between February 1, 2020 and June 30, 2021.

+
+
+
+

A.4.3 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘semaglutide’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

A.4.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

A.4.5 Concept: DPP4 inhibitors

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43013884 + +alogliptin + +1368001 + +RxNorm + +NO + +YES + +NO +
+40239216 + +linagliptin + +1100699 + +RxNorm + +NO + +YES + +NO +
+40166035 + +saxagliptin + +857974 + +RxNorm + +NO + +YES + +NO +
+1580747 + +sitagliptin + +593411 + +RxNorm + +NO + +YES + +NO +
+19122137 + +vildagliptin + +596554 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.4.6 Concept: semaglutide

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+793143 + +semaglutide + +1991302 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.4.7 Concept: SGLT2 inhibitors

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43526465 + +canagliflozin + +1373458 + +RxNorm + +NO + +YES + +NO +
+44785829 + +dapagliflozin + +1488564 + +RxNorm + +NO + +YES + +NO +
+45774751 + +empagliflozin + +1545653 + +RxNorm + +NO + +YES + +NO +
+793293 + +ertugliflozin + +1992672 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.4.8 Concept: Sulfonylureas

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1594973 + +chlorpropamide + +2404 + +RxNorm + +NO + +YES + +NO +
+1597756 + +glimepiride + +25789 + +RxNorm + +NO + +YES + +NO +
+1560171 + +glipizide + +4821 + +RxNorm + +NO + +YES + +NO +
+19097821 + +gliquidone + +25793 + +RxNorm + +NO + +YES + +NO +
+1559684 + +glyburide + +4815 + +RxNorm + +NO + +YES + +NO +
+1502809 + +tolazamide + +10633 + +RxNorm + +NO + +YES + +NO +
+1502855 + +tolbutamide + +10635 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.4.9 Concept: Other anti-diabetics

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1529331 + +acarbose + +16681 + +RxNorm + +NO + +YES + +NO +
+1530014 + +acetohexamide + +173 + +RxNorm + +NO + +YES + +NO +
+730548 + +bromocriptine + +1760 + +RxNorm + +NO + +YES + +NO +
+19033498 + +carbutamide + +2068 + +RxNorm + +NO + +YES + +NO +
+19001409 + +glibornuride + +102846 + +RxNorm + +NO + +YES + +NO +
+19059796 + +gliclazide + +4816 + +RxNorm + +NO + +YES + +NO +
+19001441 + +glymidine + +102848 + +RxNorm + +NO + +YES + +NO +
+1510202 + +miglitol + +30009 + +RxNorm + +NO + +YES + +NO +
+1502826 + +nateglinide + +274332 + +RxNorm + +NO + +YES + +NO +
+1525215 + +pioglitazone + +33738 + +RxNorm + +NO + +YES + +NO +
+1516766 + +repaglinide + +73044 + +RxNorm + +NO + +YES + +NO +
+1547504 + +rosiglitazone + +84108 + +RxNorm + +NO + +YES + +NO +
+1515249 + +troglitazone + +72610 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.4.10 Concept: Insulin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1596977 + +insulin, regular, human + +253182 + +RxNorm + +NO + +YES + +NO +
+1550023 + +insulin lispro + +86009 + +RxNorm + +NO + +YES + +NO +
+1567198 + +insulin aspart, human + +51428 + +RxNorm + +NO + +YES + +NO +
+1502905 + +insulin glargine + +274783 + +RxNorm + +NO + +YES + +NO +
+1513876 + +insulin lispro protamine, human + +314684 + +RxNorm + +NO + +YES + +NO +
+1531601 + +insulin aspart protamine, human + +352385 + +RxNorm + +NO + +YES + +NO +
+1586346 + +insulin, regular, pork + +221109 + +RxNorm + +NO + +YES + +NO +
+1544838 + +insulin glulisine, human + +400008 + +RxNorm + +NO + +YES + +NO +
+1516976 + +insulin detemir + +139825 + +RxNorm + +NO + +YES + +NO +
+1590165 + +insulin, regular, beef-pork + +235275 + +RxNorm + +NO + +YES + +NO +
+1513849 + +lente insulin, human + +314683 + +RxNorm + +NO + +YES + +NO +
+1562586 + +lente insulin, pork + +93108 + +RxNorm + +NO + +YES + +NO +
+1588986 + +insulin human, rDNA origin + +631657 + +RxNorm + +NO + +YES + +NO +
+1513843 + +lente insulin, beef-pork + +314682 + +RxNorm + +NO + +YES + +NO +
+1586369 + +ultralente insulin, human + +221110 + +RxNorm + +NO + +YES + +NO +
+35605670 + +insulin argine + +1740938 + +RxNorm + +NO + +YES + +NO +
+35602717 + +insulin degludec + +1670007 + +RxNorm + +NO + +YES + +NO +
+21600713 + +INSULINS AND ANALOGUES + +A10A + +ATC + +NO + +YES + +NO +
+19078608 + +insulin, protamine zinc, beef-pork 100 UNT/ML Injectable Suspension + +311053 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.4.11 Concept: Metformin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1503297 + +metformin + +6809 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.4.12 Concept: Secondary diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +NO + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.4.13 Concept: Type 1 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +NO + +YES + +NO +
+42689695 + +Eating disorder co-occurrent with diabetes mellitus type 1 + +1067201000000106 + +SNOMED + +NO + +YES + +NO +
+765533 + +Glaucoma due to diabetes mellitus type 1 + +60981000119103 + +SNOMED + +NO + +YES + +NO +
+43531006 + +Maturity onset diabetes of the young, type 1 + +609562003 + +SNOMED + +NO + +YES + +NO +
+765650 + +Cranial nerve palsy due to diabetes mellitus type 1 + +82561000119101 + +SNOMED + +NO + +YES + +NO +
+45770986 + +Retinopathy due to unstable diabetes mellitus type 1 + +706894000 + +SNOMED + +NO + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +NO + +YES + +NO +
+45768456 + +Neuropathy due to unstable diabetes mellitus type 1 + +706891008 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +NO + +YES + +NO +
+4128019 + +Brittle type 1 diabetes mellitus + +290002008 + +SNOMED + +NO + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.4.14 Concept: Type 2 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+443238 + +Diabetic - poor control + +268519009 + +SNOMED + +NO + +YES + +NO +
+201820 + +Diabetes mellitus + +73211009 + +SNOMED + +NO + +YES + +NO +
+442793 + +Complication due to diabetes mellitus + +74627003 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +YES + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +YES + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +YES + +YES + +NO +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +YES + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +YES + +YES + +NO +
+4016045 + +Diabetic - good control + +170763003 + +SNOMED + +NO + +YES + +NO +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +YES + +YES + +NO +
+43531009 + +Pregnancy and type 1 diabetes mellitus + +609566000 + +SNOMED + +YES + +YES + +NO +
+4024659 + +Gestational diabetes mellitus + +11687002 + +SNOMED + +YES + +YES + +NO +
+
+
+

A.4.15 Concept: GLP-1 receptor agonists excluding semaglutide

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774435 + +dulaglutide + +1551291 + +RxNorm + +NO + +YES + +NO +
+1583722 + +exenatide + +60548 + +RxNorm + +NO + +YES + +NO +
+40170911 + +liraglutide + +475968 + +RxNorm + +NO + +YES + +NO +
+44506754 + +lixisenatide + +1440051 + +RxNorm + +NO + +YES + +NO +
+793143 + +semaglutide + +1991302 + +RxNorm + +YES + +YES + +NO +
+44816332 + +albiglutide + +1534763 + +RxNorm + +NO + +YES + +NO +
+
+ +
+
+
+

A.5 New user of semaglutide as 2nd-line treatment with prior T2DM Jul2021-Dec2023

+
+

A.5.1 Cohort Entry Events

+

People with continuous observation of 365 days before event may enter the cohort when observing any of the following:

+
    +
  1. drug exposure of ‘semaglutide’ for the first time in the person’s history.
    2. +
+

Limit cohort entry events to the earliest event per person.

+

Restrict entry events to with all of the following criteria:

+
    +
  1. with the following event criteria: who are >= 18 years old.
    2. +
  2. having at least 1 condition occurrence of ‘Type 2 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
  3. having no condition occurrences of ‘Type 1 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    4. +
  4. having no condition occurrences of ‘Secondary diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    5. +
+
+
+

A.5.2 Additional Inclusion Criteria

+
+

I. Prior metformin use

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 drug era of ‘Metformin’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period; with era length >= 90 days.
    2. +
  2. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

II. No prior GLP-1 RA exposure

+

Entry events having no drug exposures of ‘GLP-1 receptor agonists excluding semaglutide’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

III. No prior DPP4 inhibitor exposure

+

Entry events having no drug exposures of ‘DPP4 inhibitors’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

IV. No prior SGLT-2 inhibitor exposure

+

Entry events having no drug exposures of ‘SGLT2 inhibitors’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

V. No prior SU exposure

+

Entry events having no drug exposures of ‘Sulfonylureas’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VI. No prior other anti-diabetic exposure

+

Entry events having no drug exposures of ‘Other anti-diabetics’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VII. No prior insulin use or combo initiation: Proxy for < 30 days drug era anytime before index and no combination use on index

+

Entry events with all of the following criteria:

+
    +
  1. having no drug eras of ‘Insulin’, starting anytime up to 30 days before cohort entry start date; allow events outside observation period; with era length > 30 days.
    2. +
  2. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.
    3. +
+
+
+

VIII. index date between 1Jul2021 and 31Dec2023

+

Entry events with the following event criteria: starting between July 1, 2021 and December 31, 2023.

+
+
+
+

A.5.3 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘semaglutide’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

A.5.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

A.5.5 Concept: DPP4 inhibitors

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43013884 + +alogliptin + +1368001 + +RxNorm + +NO + +YES + +NO +
+40239216 + +linagliptin + +1100699 + +RxNorm + +NO + +YES + +NO +
+40166035 + +saxagliptin + +857974 + +RxNorm + +NO + +YES + +NO +
+1580747 + +sitagliptin + +593411 + +RxNorm + +NO + +YES + +NO +
+19122137 + +vildagliptin + +596554 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.5.6 Concept: semaglutide

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+793143 + +semaglutide + +1991302 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.5.7 Concept: SGLT2 inhibitors

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43526465 + +canagliflozin + +1373458 + +RxNorm + +NO + +YES + +NO +
+44785829 + +dapagliflozin + +1488564 + +RxNorm + +NO + +YES + +NO +
+45774751 + +empagliflozin + +1545653 + +RxNorm + +NO + +YES + +NO +
+793293 + +ertugliflozin + +1992672 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.5.8 Concept: Sulfonylureas

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1594973 + +chlorpropamide + +2404 + +RxNorm + +NO + +YES + +NO +
+1597756 + +glimepiride + +25789 + +RxNorm + +NO + +YES + +NO +
+1560171 + +glipizide + +4821 + +RxNorm + +NO + +YES + +NO +
+19097821 + +gliquidone + +25793 + +RxNorm + +NO + +YES + +NO +
+1559684 + +glyburide + +4815 + +RxNorm + +NO + +YES + +NO +
+1502809 + +tolazamide + +10633 + +RxNorm + +NO + +YES + +NO +
+1502855 + +tolbutamide + +10635 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.5.9 Concept: Other anti-diabetics

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1529331 + +acarbose + +16681 + +RxNorm + +NO + +YES + +NO +
+1530014 + +acetohexamide + +173 + +RxNorm + +NO + +YES + +NO +
+730548 + +bromocriptine + +1760 + +RxNorm + +NO + +YES + +NO +
+19033498 + +carbutamide + +2068 + +RxNorm + +NO + +YES + +NO +
+19001409 + +glibornuride + +102846 + +RxNorm + +NO + +YES + +NO +
+19059796 + +gliclazide + +4816 + +RxNorm + +NO + +YES + +NO +
+19001441 + +glymidine + +102848 + +RxNorm + +NO + +YES + +NO +
+1510202 + +miglitol + +30009 + +RxNorm + +NO + +YES + +NO +
+1502826 + +nateglinide + +274332 + +RxNorm + +NO + +YES + +NO +
+1525215 + +pioglitazone + +33738 + +RxNorm + +NO + +YES + +NO +
+1516766 + +repaglinide + +73044 + +RxNorm + +NO + +YES + +NO +
+1547504 + +rosiglitazone + +84108 + +RxNorm + +NO + +YES + +NO +
+1515249 + +troglitazone + +72610 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.5.10 Concept: Insulin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1596977 + +insulin, regular, human + +253182 + +RxNorm + +NO + +YES + +NO +
+1550023 + +insulin lispro + +86009 + +RxNorm + +NO + +YES + +NO +
+1567198 + +insulin aspart, human + +51428 + +RxNorm + +NO + +YES + +NO +
+1502905 + +insulin glargine + +274783 + +RxNorm + +NO + +YES + +NO +
+1513876 + +insulin lispro protamine, human + +314684 + +RxNorm + +NO + +YES + +NO +
+1531601 + +insulin aspart protamine, human + +352385 + +RxNorm + +NO + +YES + +NO +
+1586346 + +insulin, regular, pork + +221109 + +RxNorm + +NO + +YES + +NO +
+1544838 + +insulin glulisine, human + +400008 + +RxNorm + +NO + +YES + +NO +
+1516976 + +insulin detemir + +139825 + +RxNorm + +NO + +YES + +NO +
+1590165 + +insulin, regular, beef-pork + +235275 + +RxNorm + +NO + +YES + +NO +
+1513849 + +lente insulin, human + +314683 + +RxNorm + +NO + +YES + +NO +
+1562586 + +lente insulin, pork + +93108 + +RxNorm + +NO + +YES + +NO +
+1588986 + +insulin human, rDNA origin + +631657 + +RxNorm + +NO + +YES + +NO +
+1513843 + +lente insulin, beef-pork + +314682 + +RxNorm + +NO + +YES + +NO +
+1586369 + +ultralente insulin, human + +221110 + +RxNorm + +NO + +YES + +NO +
+35605670 + +insulin argine + +1740938 + +RxNorm + +NO + +YES + +NO +
+35602717 + +insulin degludec + +1670007 + +RxNorm + +NO + +YES + +NO +
+21600713 + +INSULINS AND ANALOGUES + +A10A + +ATC + +NO + +YES + +NO +
+19078608 + +insulin, protamine zinc, beef-pork 100 UNT/ML Injectable Suspension + +311053 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.5.11 Concept: Metformin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1503297 + +metformin + +6809 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.5.12 Concept: Secondary diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +NO + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.5.13 Concept: Type 1 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +NO + +YES + +NO +
+42689695 + +Eating disorder co-occurrent with diabetes mellitus type 1 + +1067201000000106 + +SNOMED + +NO + +YES + +NO +
+765533 + +Glaucoma due to diabetes mellitus type 1 + +60981000119103 + +SNOMED + +NO + +YES + +NO +
+43531006 + +Maturity onset diabetes of the young, type 1 + +609562003 + +SNOMED + +NO + +YES + +NO +
+765650 + +Cranial nerve palsy due to diabetes mellitus type 1 + +82561000119101 + +SNOMED + +NO + +YES + +NO +
+45770986 + +Retinopathy due to unstable diabetes mellitus type 1 + +706894000 + +SNOMED + +NO + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +NO + +YES + +NO +
+45768456 + +Neuropathy due to unstable diabetes mellitus type 1 + +706891008 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +NO + +YES + +NO +
+4128019 + +Brittle type 1 diabetes mellitus + +290002008 + +SNOMED + +NO + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.5.14 Concept: Type 2 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+443238 + +Diabetic - poor control + +268519009 + +SNOMED + +NO + +YES + +NO +
+201820 + +Diabetes mellitus + +73211009 + +SNOMED + +NO + +YES + +NO +
+442793 + +Complication due to diabetes mellitus + +74627003 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +YES + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +YES + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +YES + +YES + +NO +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +YES + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +YES + +YES + +NO +
+4016045 + +Diabetic - good control + +170763003 + +SNOMED + +NO + +YES + +NO +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +YES + +YES + +NO +
+43531009 + +Pregnancy and type 1 diabetes mellitus + +609566000 + +SNOMED + +YES + +YES + +NO +
+4024659 + +Gestational diabetes mellitus + +11687002 + +SNOMED + +YES + +YES + +NO +
+
+
+

A.5.15 Concept: GLP-1 receptor agonists excluding semaglutide

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774435 + +dulaglutide + +1551291 + +RxNorm + +NO + +YES + +NO +
+1583722 + +exenatide + +60548 + +RxNorm + +NO + +YES + +NO +
+40170911 + +liraglutide + +475968 + +RxNorm + +NO + +YES + +NO +
+44506754 + +lixisenatide + +1440051 + +RxNorm + +NO + +YES + +NO +
+793143 + +semaglutide + +1991302 + +RxNorm + +YES + +YES + +NO +
+44816332 + +albiglutide + +1534763 + +RxNorm + +NO + +YES + +NO +
+
+ +
+
+
+

A.6 New user of semaglutide with prior T2DM and prior metformin and no insulin

+
+

A.6.1 Cohort Entry Events

+

People with continuous observation of 365 days before event may enter the cohort when observing any of the following:

+
    +
  1. drug exposure of ‘semaglutide’ for the first time in the person’s history.
    2. +
+

Limit cohort entry events to the earliest event per person.

+

Restrict entry events to with all of the following criteria:

+
    +
  1. with the following event criteria: who are >= 18 years old.
    2. +
  2. having at least 1 condition occurrence of ‘Type 2 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
  3. having no condition occurrences of ‘Type 1 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    4. +
  4. having no condition occurrences of ‘Secondary diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    5. +
+
+
+

A.6.2 Additional Inclusion Criteria

+
+

I. Prior metformin use

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 drug era of ‘Metformin’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period; with era length >= 90 days.
    2. +
  2. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

II. No prior insulin use or combo initiation: Proxy for < 30 days drug era anytime before index and no combination use on index

+

Entry events with all of the following criteria:

+
    +
  1. having no drug eras of ‘Insulin’, starting anytime up to 30 days before cohort entry start date; allow events outside observation period; with era length > 30 days.
    2. +
  2. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.
    3. +
+
+
+
+

A.6.3 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘semaglutide’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

A.6.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

A.6.5 Concept: semaglutide

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+793143 + +semaglutide + +1991302 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.6.6 Concept: Insulin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1596977 + +insulin, regular, human + +253182 + +RxNorm + +NO + +YES + +NO +
+1550023 + +insulin lispro + +86009 + +RxNorm + +NO + +YES + +NO +
+1567198 + +insulin aspart, human + +51428 + +RxNorm + +NO + +YES + +NO +
+1502905 + +insulin glargine + +274783 + +RxNorm + +NO + +YES + +NO +
+1513876 + +insulin lispro protamine, human + +314684 + +RxNorm + +NO + +YES + +NO +
+1531601 + +insulin aspart protamine, human + +352385 + +RxNorm + +NO + +YES + +NO +
+1586346 + +insulin, regular, pork + +221109 + +RxNorm + +NO + +YES + +NO +
+1544838 + +insulin glulisine, human + +400008 + +RxNorm + +NO + +YES + +NO +
+1516976 + +insulin detemir + +139825 + +RxNorm + +NO + +YES + +NO +
+1590165 + +insulin, regular, beef-pork + +235275 + +RxNorm + +NO + +YES + +NO +
+1513849 + +lente insulin, human + +314683 + +RxNorm + +NO + +YES + +NO +
+1562586 + +lente insulin, pork + +93108 + +RxNorm + +NO + +YES + +NO +
+1588986 + +insulin human, rDNA origin + +631657 + +RxNorm + +NO + +YES + +NO +
+1513843 + +lente insulin, beef-pork + +314682 + +RxNorm + +NO + +YES + +NO +
+1586369 + +ultralente insulin, human + +221110 + +RxNorm + +NO + +YES + +NO +
+35605670 + +insulin argine + +1740938 + +RxNorm + +NO + +YES + +NO +
+35602717 + +insulin degludec + +1670007 + +RxNorm + +NO + +YES + +NO +
+21600713 + +INSULINS AND ANALOGUES + +A10A + +ATC + +NO + +YES + +NO +
+19078608 + +insulin, protamine zinc, beef-pork 100 UNT/ML Injectable Suspension + +311053 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.6.7 Concept: Metformin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1503297 + +metformin + +6809 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.6.8 Concept: Secondary diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +NO + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.6.9 Concept: Type 1 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +NO + +YES + +NO +
+42689695 + +Eating disorder co-occurrent with diabetes mellitus type 1 + +1067201000000106 + +SNOMED + +NO + +YES + +NO +
+765533 + +Glaucoma due to diabetes mellitus type 1 + +60981000119103 + +SNOMED + +NO + +YES + +NO +
+43531006 + +Maturity onset diabetes of the young, type 1 + +609562003 + +SNOMED + +NO + +YES + +NO +
+765650 + +Cranial nerve palsy due to diabetes mellitus type 1 + +82561000119101 + +SNOMED + +NO + +YES + +NO +
+45770986 + +Retinopathy due to unstable diabetes mellitus type 1 + +706894000 + +SNOMED + +NO + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +NO + +YES + +NO +
+45768456 + +Neuropathy due to unstable diabetes mellitus type 1 + +706891008 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +NO + +YES + +NO +
+4128019 + +Brittle type 1 diabetes mellitus + +290002008 + +SNOMED + +NO + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.6.10 Concept: Type 2 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+443238 + +Diabetic - poor control + +268519009 + +SNOMED + +NO + +YES + +NO +
+201820 + +Diabetes mellitus + +73211009 + +SNOMED + +NO + +YES + +NO +
+442793 + +Complication due to diabetes mellitus + +74627003 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +YES + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +YES + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +YES + +YES + +NO +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +YES + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +YES + +YES + +NO +
+4016045 + +Diabetic - good control + +170763003 + +SNOMED + +NO + +YES + +NO +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +YES + +YES + +NO +
+43531009 + +Pregnancy and type 1 diabetes mellitus + +609566000 + +SNOMED + +YES + +YES + +NO +
+4024659 + +Gestational diabetes mellitus + +11687002 + +SNOMED + +YES + +YES + +NO +
+
+ +
+
+
+

A.7 New user of dulaglutide as 2nd-line treatment with prior T2DM and prior metformin

+
+

A.7.1 Cohort Entry Events

+

People with continuous observation of 365 days before event may enter the cohort when observing any of the following:

+
    +
  1. drug exposure of ‘dulaglutide’ for the first time in the person’s history.
    2. +
+

Limit cohort entry events to the earliest event per person.

+

Restrict entry events to with all of the following criteria:

+
    +
  1. with the following event criteria: who are >= 18 years old.
    2. +
  2. having at least 1 condition occurrence of ‘Type 2 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
  3. having no condition occurrences of ‘Type 1 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    4. +
  4. having no condition occurrences of ‘Secondary diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    5. +
+
+
+

A.7.2 Additional Inclusion Criteria

+
+

I. Prior metformin use

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 drug era of ‘Metformin’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period; with era length >= 90 days.
    2. +
  2. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

II. No prior GLP-1 RA exposure

+

Entry events having no drug exposures of ‘GLP-1 receptor agonists excluding dulaglutide’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

III. No prior DPP4 inhibitor exposure

+

Entry events having no drug exposures of ‘DPP4 inhibitors’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

IV. No prior SGLT-2 inhibitor exposure

+

Entry events having no drug exposures of ‘SGLT2 inhibitors’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

V. No prior SU exposure

+

Entry events having no drug exposures of ‘Sulfonylureas’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VI. No prior other anti-diabetic exposure

+

Entry events having no drug exposures of ‘Other anti-diabetics’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VII. No prior insulin use or combo initiation: Proxy for < 30 days drug era anytime before index and no combination use on index

+

Entry events with all of the following criteria:

+
    +
  1. having no drug eras of ‘Insulin’, starting anytime up to 30 days before cohort entry start date; allow events outside observation period; with era length > 30 days.
    2. +
  2. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.
    3. +
+
+
+
+

A.7.3 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘dulaglutide’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

A.7.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

A.7.5 Concept: DPP4 inhibitors

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43013884 + +alogliptin + +1368001 + +RxNorm + +NO + +YES + +NO +
+40239216 + +linagliptin + +1100699 + +RxNorm + +NO + +YES + +NO +
+40166035 + +saxagliptin + +857974 + +RxNorm + +NO + +YES + +NO +
+1580747 + +sitagliptin + +593411 + +RxNorm + +NO + +YES + +NO +
+19122137 + +vildagliptin + +596554 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.7.6 Concept: dulaglutide

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774435 + +dulaglutide + +1551291 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.7.7 Concept: SGLT2 inhibitors

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43526465 + +canagliflozin + +1373458 + +RxNorm + +NO + +YES + +NO +
+44785829 + +dapagliflozin + +1488564 + +RxNorm + +NO + +YES + +NO +
+45774751 + +empagliflozin + +1545653 + +RxNorm + +NO + +YES + +NO +
+793293 + +ertugliflozin + +1992672 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.7.8 Concept: Sulfonylureas

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1594973 + +chlorpropamide + +2404 + +RxNorm + +NO + +YES + +NO +
+1597756 + +glimepiride + +25789 + +RxNorm + +NO + +YES + +NO +
+1560171 + +glipizide + +4821 + +RxNorm + +NO + +YES + +NO +
+19097821 + +gliquidone + +25793 + +RxNorm + +NO + +YES + +NO +
+1559684 + +glyburide + +4815 + +RxNorm + +NO + +YES + +NO +
+1502809 + +tolazamide + +10633 + +RxNorm + +NO + +YES + +NO +
+1502855 + +tolbutamide + +10635 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.7.9 Concept: Other anti-diabetics

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1529331 + +acarbose + +16681 + +RxNorm + +NO + +YES + +NO +
+1530014 + +acetohexamide + +173 + +RxNorm + +NO + +YES + +NO +
+730548 + +bromocriptine + +1760 + +RxNorm + +NO + +YES + +NO +
+19033498 + +carbutamide + +2068 + +RxNorm + +NO + +YES + +NO +
+19001409 + +glibornuride + +102846 + +RxNorm + +NO + +YES + +NO +
+19059796 + +gliclazide + +4816 + +RxNorm + +NO + +YES + +NO +
+19001441 + +glymidine + +102848 + +RxNorm + +NO + +YES + +NO +
+1510202 + +miglitol + +30009 + +RxNorm + +NO + +YES + +NO +
+1502826 + +nateglinide + +274332 + +RxNorm + +NO + +YES + +NO +
+1525215 + +pioglitazone + +33738 + +RxNorm + +NO + +YES + +NO +
+1516766 + +repaglinide + +73044 + +RxNorm + +NO + +YES + +NO +
+1547504 + +rosiglitazone + +84108 + +RxNorm + +NO + +YES + +NO +
+1515249 + +troglitazone + +72610 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.7.10 Concept: Insulin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1596977 + +insulin, regular, human + +253182 + +RxNorm + +NO + +YES + +NO +
+1550023 + +insulin lispro + +86009 + +RxNorm + +NO + +YES + +NO +
+1567198 + +insulin aspart, human + +51428 + +RxNorm + +NO + +YES + +NO +
+1502905 + +insulin glargine + +274783 + +RxNorm + +NO + +YES + +NO +
+1513876 + +insulin lispro protamine, human + +314684 + +RxNorm + +NO + +YES + +NO +
+1531601 + +insulin aspart protamine, human + +352385 + +RxNorm + +NO + +YES + +NO +
+1586346 + +insulin, regular, pork + +221109 + +RxNorm + +NO + +YES + +NO +
+1544838 + +insulin glulisine, human + +400008 + +RxNorm + +NO + +YES + +NO +
+1516976 + +insulin detemir + +139825 + +RxNorm + +NO + +YES + +NO +
+1590165 + +insulin, regular, beef-pork + +235275 + +RxNorm + +NO + +YES + +NO +
+1513849 + +lente insulin, human + +314683 + +RxNorm + +NO + +YES + +NO +
+1562586 + +lente insulin, pork + +93108 + +RxNorm + +NO + +YES + +NO +
+1588986 + +insulin human, rDNA origin + +631657 + +RxNorm + +NO + +YES + +NO +
+1513843 + +lente insulin, beef-pork + +314682 + +RxNorm + +NO + +YES + +NO +
+1586369 + +ultralente insulin, human + +221110 + +RxNorm + +NO + +YES + +NO +
+35605670 + +insulin argine + +1740938 + +RxNorm + +NO + +YES + +NO +
+35602717 + +insulin degludec + +1670007 + +RxNorm + +NO + +YES + +NO +
+21600713 + +INSULINS AND ANALOGUES + +A10A + +ATC + +NO + +YES + +NO +
+19078608 + +insulin, protamine zinc, beef-pork 100 UNT/ML Injectable Suspension + +311053 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.7.11 Concept: Metformin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1503297 + +metformin + +6809 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.7.12 Concept: Secondary diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +NO + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.7.13 Concept: Type 1 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +NO + +YES + +NO +
+42689695 + +Eating disorder co-occurrent with diabetes mellitus type 1 + +1067201000000106 + +SNOMED + +NO + +YES + +NO +
+765533 + +Glaucoma due to diabetes mellitus type 1 + +60981000119103 + +SNOMED + +NO + +YES + +NO +
+43531006 + +Maturity onset diabetes of the young, type 1 + +609562003 + +SNOMED + +NO + +YES + +NO +
+765650 + +Cranial nerve palsy due to diabetes mellitus type 1 + +82561000119101 + +SNOMED + +NO + +YES + +NO +
+45770986 + +Retinopathy due to unstable diabetes mellitus type 1 + +706894000 + +SNOMED + +NO + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +NO + +YES + +NO +
+45768456 + +Neuropathy due to unstable diabetes mellitus type 1 + +706891008 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +NO + +YES + +NO +
+4128019 + +Brittle type 1 diabetes mellitus + +290002008 + +SNOMED + +NO + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.7.14 Concept: Type 2 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+443238 + +Diabetic - poor control + +268519009 + +SNOMED + +NO + +YES + +NO +
+201820 + +Diabetes mellitus + +73211009 + +SNOMED + +NO + +YES + +NO +
+442793 + +Complication due to diabetes mellitus + +74627003 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +YES + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +YES + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +YES + +YES + +NO +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +YES + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +YES + +YES + +NO +
+4016045 + +Diabetic - good control + +170763003 + +SNOMED + +NO + +YES + +NO +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +YES + +YES + +NO +
+43531009 + +Pregnancy and type 1 diabetes mellitus + +609566000 + +SNOMED + +YES + +YES + +NO +
+4024659 + +Gestational diabetes mellitus + +11687002 + +SNOMED + +YES + +YES + +NO +
+
+
+

A.7.15 Concept: GLP-1 receptor agonists excluding dulaglutide

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774435 + +dulaglutide + +1551291 + +RxNorm + +YES + +YES + +NO +
+1583722 + +exenatide + +60548 + +RxNorm + +NO + +YES + +NO +
+40170911 + +liraglutide + +475968 + +RxNorm + +NO + +YES + +NO +
+44506754 + +lixisenatide + +1440051 + +RxNorm + +NO + +YES + +NO +
+793143 + +semaglutide + +1991302 + +RxNorm + +NO + +YES + +NO +
+44816332 + +albiglutide + +1534763 + +RxNorm + +NO + +YES + +NO +
+
+ +
+
+
+

A.8 New user of dulaglutide with prior T2DM and prior metformin and no insulin

+
+

A.8.1 Cohort Entry Events

+

People with continuous observation of 365 days before event may enter the cohort when observing any of the following:

+
    +
  1. drug exposure of ‘dulaglutide’ for the first time in the person’s history.
    2. +
+

Limit cohort entry events to the earliest event per person.

+

Restrict entry events to with all of the following criteria:

+
    +
  1. with the following event criteria: who are >= 18 years old.
    2. +
  2. having at least 1 condition occurrence of ‘Type 2 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
  3. having no condition occurrences of ‘Type 1 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    4. +
  4. having no condition occurrences of ‘Secondary diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    5. +
+
+
+

A.8.2 Additional Inclusion Criteria

+
+

I. Prior metformin use

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 drug era of ‘Metformin’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period; with era length >= 90 days.
    2. +
  2. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

II. No prior insulin use or combo initiation: Proxy for < 30 days drug era anytime before index and no combination use on index

+

Entry events with all of the following criteria:

+
    +
  1. having no drug eras of ‘Insulin’, starting anytime up to 30 days before cohort entry start date; allow events outside observation period; with era length > 30 days.
    2. +
  2. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.
    3. +
+
+
+
+

A.8.3 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘dulaglutide’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

A.8.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

A.8.5 Concept: dulaglutide

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774435 + +dulaglutide + +1551291 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.8.6 Concept: Insulin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1596977 + +insulin, regular, human + +253182 + +RxNorm + +NO + +YES + +NO +
+1550023 + +insulin lispro + +86009 + +RxNorm + +NO + +YES + +NO +
+1567198 + +insulin aspart, human + +51428 + +RxNorm + +NO + +YES + +NO +
+1502905 + +insulin glargine + +274783 + +RxNorm + +NO + +YES + +NO +
+1513876 + +insulin lispro protamine, human + +314684 + +RxNorm + +NO + +YES + +NO +
+1531601 + +insulin aspart protamine, human + +352385 + +RxNorm + +NO + +YES + +NO +
+1586346 + +insulin, regular, pork + +221109 + +RxNorm + +NO + +YES + +NO +
+1544838 + +insulin glulisine, human + +400008 + +RxNorm + +NO + +YES + +NO +
+1516976 + +insulin detemir + +139825 + +RxNorm + +NO + +YES + +NO +
+1590165 + +insulin, regular, beef-pork + +235275 + +RxNorm + +NO + +YES + +NO +
+1513849 + +lente insulin, human + +314683 + +RxNorm + +NO + +YES + +NO +
+1562586 + +lente insulin, pork + +93108 + +RxNorm + +NO + +YES + +NO +
+1588986 + +insulin human, rDNA origin + +631657 + +RxNorm + +NO + +YES + +NO +
+1513843 + +lente insulin, beef-pork + +314682 + +RxNorm + +NO + +YES + +NO +
+1586369 + +ultralente insulin, human + +221110 + +RxNorm + +NO + +YES + +NO +
+35605670 + +insulin argine + +1740938 + +RxNorm + +NO + +YES + +NO +
+35602717 + +insulin degludec + +1670007 + +RxNorm + +NO + +YES + +NO +
+21600713 + +INSULINS AND ANALOGUES + +A10A + +ATC + +NO + +YES + +NO +
+19078608 + +insulin, protamine zinc, beef-pork 100 UNT/ML Injectable Suspension + +311053 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.8.7 Concept: Metformin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1503297 + +metformin + +6809 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.8.8 Concept: Secondary diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +NO + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.8.9 Concept: Type 1 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +NO + +YES + +NO +
+42689695 + +Eating disorder co-occurrent with diabetes mellitus type 1 + +1067201000000106 + +SNOMED + +NO + +YES + +NO +
+765533 + +Glaucoma due to diabetes mellitus type 1 + +60981000119103 + +SNOMED + +NO + +YES + +NO +
+43531006 + +Maturity onset diabetes of the young, type 1 + +609562003 + +SNOMED + +NO + +YES + +NO +
+765650 + +Cranial nerve palsy due to diabetes mellitus type 1 + +82561000119101 + +SNOMED + +NO + +YES + +NO +
+45770986 + +Retinopathy due to unstable diabetes mellitus type 1 + +706894000 + +SNOMED + +NO + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +NO + +YES + +NO +
+45768456 + +Neuropathy due to unstable diabetes mellitus type 1 + +706891008 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +NO + +YES + +NO +
+4128019 + +Brittle type 1 diabetes mellitus + +290002008 + +SNOMED + +NO + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.8.10 Concept: Type 2 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+443238 + +Diabetic - poor control + +268519009 + +SNOMED + +NO + +YES + +NO +
+201820 + +Diabetes mellitus + +73211009 + +SNOMED + +NO + +YES + +NO +
+442793 + +Complication due to diabetes mellitus + +74627003 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +YES + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +YES + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +YES + +YES + +NO +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +YES + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +YES + +YES + +NO +
+4016045 + +Diabetic - good control + +170763003 + +SNOMED + +NO + +YES + +NO +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +YES + +YES + +NO +
+43531009 + +Pregnancy and type 1 diabetes mellitus + +609566000 + +SNOMED + +YES + +YES + +NO +
+4024659 + +Gestational diabetes mellitus + +11687002 + +SNOMED + +YES + +YES + +NO +
+
+ +
+
+
+

A.9 New user of exenatide as 2nd-line treatment with prior T2DM and prior metformin

+
+

A.9.1 Cohort Entry Events

+

People with continuous observation of 365 days before event may enter the cohort when observing any of the following:

+
    +
  1. drug exposure of ‘exenatide’ for the first time in the person’s history.
    2. +
+

Limit cohort entry events to the earliest event per person.

+

Restrict entry events to with all of the following criteria:

+
    +
  1. with the following event criteria: who are >= 18 years old.
    2. +
  2. having at least 1 condition occurrence of ‘Type 2 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
  3. having no condition occurrences of ‘Type 1 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    4. +
  4. having no condition occurrences of ‘Secondary diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    5. +
+
+
+

A.9.2 Additional Inclusion Criteria

+
+

I. Prior metformin use

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 drug era of ‘Metformin’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period; with era length >= 90 days.
    2. +
  2. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

II. No prior GLP-1 RA exposure

+

Entry events having no drug exposures of ‘GLP-1 receptor agonists excluding exenatide’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

III. No prior DPP4 inhibitor exposure

+

Entry events having no drug exposures of ‘DPP4 inhibitors’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

IV. No prior SGLT-2 inhibitor exposure

+

Entry events having no drug exposures of ‘SGLT2 inhibitors’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

V. No prior SU exposure

+

Entry events having no drug exposures of ‘Sulfonylureas’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VI. No prior other anti-diabetic exposure

+

Entry events having no drug exposures of ‘Other anti-diabetics’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VII. No prior insulin use or combo initiation: Proxy for < 30 days drug era anytime before index and no combination use on index

+

Entry events with all of the following criteria:

+
    +
  1. having no drug eras of ‘Insulin’, starting anytime up to 30 days before cohort entry start date; allow events outside observation period; with era length > 30 days.
    2. +
  2. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.
    3. +
+
+
+
+

A.9.3 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘exenatide’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

A.9.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

A.9.5 Concept: DPP4 inhibitors

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43013884 + +alogliptin + +1368001 + +RxNorm + +NO + +YES + +NO +
+40239216 + +linagliptin + +1100699 + +RxNorm + +NO + +YES + +NO +
+40166035 + +saxagliptin + +857974 + +RxNorm + +NO + +YES + +NO +
+1580747 + +sitagliptin + +593411 + +RxNorm + +NO + +YES + +NO +
+19122137 + +vildagliptin + +596554 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.9.6 Concept: exenatide

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1583722 + +exenatide + +60548 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.9.7 Concept: SGLT2 inhibitors

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43526465 + +canagliflozin + +1373458 + +RxNorm + +NO + +YES + +NO +
+44785829 + +dapagliflozin + +1488564 + +RxNorm + +NO + +YES + +NO +
+45774751 + +empagliflozin + +1545653 + +RxNorm + +NO + +YES + +NO +
+793293 + +ertugliflozin + +1992672 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.9.8 Concept: Sulfonylureas

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1594973 + +chlorpropamide + +2404 + +RxNorm + +NO + +YES + +NO +
+1597756 + +glimepiride + +25789 + +RxNorm + +NO + +YES + +NO +
+1560171 + +glipizide + +4821 + +RxNorm + +NO + +YES + +NO +
+19097821 + +gliquidone + +25793 + +RxNorm + +NO + +YES + +NO +
+1559684 + +glyburide + +4815 + +RxNorm + +NO + +YES + +NO +
+1502809 + +tolazamide + +10633 + +RxNorm + +NO + +YES + +NO +
+1502855 + +tolbutamide + +10635 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.9.9 Concept: Other anti-diabetics

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1529331 + +acarbose + +16681 + +RxNorm + +NO + +YES + +NO +
+1530014 + +acetohexamide + +173 + +RxNorm + +NO + +YES + +NO +
+730548 + +bromocriptine + +1760 + +RxNorm + +NO + +YES + +NO +
+19033498 + +carbutamide + +2068 + +RxNorm + +NO + +YES + +NO +
+19001409 + +glibornuride + +102846 + +RxNorm + +NO + +YES + +NO +
+19059796 + +gliclazide + +4816 + +RxNorm + +NO + +YES + +NO +
+19001441 + +glymidine + +102848 + +RxNorm + +NO + +YES + +NO +
+1510202 + +miglitol + +30009 + +RxNorm + +NO + +YES + +NO +
+1502826 + +nateglinide + +274332 + +RxNorm + +NO + +YES + +NO +
+1525215 + +pioglitazone + +33738 + +RxNorm + +NO + +YES + +NO +
+1516766 + +repaglinide + +73044 + +RxNorm + +NO + +YES + +NO +
+1547504 + +rosiglitazone + +84108 + +RxNorm + +NO + +YES + +NO +
+1515249 + +troglitazone + +72610 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.9.10 Concept: Insulin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1596977 + +insulin, regular, human + +253182 + +RxNorm + +NO + +YES + +NO +
+1550023 + +insulin lispro + +86009 + +RxNorm + +NO + +YES + +NO +
+1567198 + +insulin aspart, human + +51428 + +RxNorm + +NO + +YES + +NO +
+1502905 + +insulin glargine + +274783 + +RxNorm + +NO + +YES + +NO +
+1513876 + +insulin lispro protamine, human + +314684 + +RxNorm + +NO + +YES + +NO +
+1531601 + +insulin aspart protamine, human + +352385 + +RxNorm + +NO + +YES + +NO +
+1586346 + +insulin, regular, pork + +221109 + +RxNorm + +NO + +YES + +NO +
+1544838 + +insulin glulisine, human + +400008 + +RxNorm + +NO + +YES + +NO +
+1516976 + +insulin detemir + +139825 + +RxNorm + +NO + +YES + +NO +
+1590165 + +insulin, regular, beef-pork + +235275 + +RxNorm + +NO + +YES + +NO +
+1513849 + +lente insulin, human + +314683 + +RxNorm + +NO + +YES + +NO +
+1562586 + +lente insulin, pork + +93108 + +RxNorm + +NO + +YES + +NO +
+1588986 + +insulin human, rDNA origin + +631657 + +RxNorm + +NO + +YES + +NO +
+1513843 + +lente insulin, beef-pork + +314682 + +RxNorm + +NO + +YES + +NO +
+1586369 + +ultralente insulin, human + +221110 + +RxNorm + +NO + +YES + +NO +
+35605670 + +insulin argine + +1740938 + +RxNorm + +NO + +YES + +NO +
+35602717 + +insulin degludec + +1670007 + +RxNorm + +NO + +YES + +NO +
+21600713 + +INSULINS AND ANALOGUES + +A10A + +ATC + +NO + +YES + +NO +
+19078608 + +insulin, protamine zinc, beef-pork 100 UNT/ML Injectable Suspension + +311053 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.9.11 Concept: Metformin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1503297 + +metformin + +6809 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.9.12 Concept: Secondary diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +NO + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.9.13 Concept: Type 1 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +NO + +YES + +NO +
+42689695 + +Eating disorder co-occurrent with diabetes mellitus type 1 + +1067201000000106 + +SNOMED + +NO + +YES + +NO +
+765533 + +Glaucoma due to diabetes mellitus type 1 + +60981000119103 + +SNOMED + +NO + +YES + +NO +
+43531006 + +Maturity onset diabetes of the young, type 1 + +609562003 + +SNOMED + +NO + +YES + +NO +
+765650 + +Cranial nerve palsy due to diabetes mellitus type 1 + +82561000119101 + +SNOMED + +NO + +YES + +NO +
+45770986 + +Retinopathy due to unstable diabetes mellitus type 1 + +706894000 + +SNOMED + +NO + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +NO + +YES + +NO +
+45768456 + +Neuropathy due to unstable diabetes mellitus type 1 + +706891008 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +NO + +YES + +NO +
+4128019 + +Brittle type 1 diabetes mellitus + +290002008 + +SNOMED + +NO + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.9.14 Concept: Type 2 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+443238 + +Diabetic - poor control + +268519009 + +SNOMED + +NO + +YES + +NO +
+201820 + +Diabetes mellitus + +73211009 + +SNOMED + +NO + +YES + +NO +
+442793 + +Complication due to diabetes mellitus + +74627003 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +YES + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +YES + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +YES + +YES + +NO +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +YES + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +YES + +YES + +NO +
+4016045 + +Diabetic - good control + +170763003 + +SNOMED + +NO + +YES + +NO +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +YES + +YES + +NO +
+43531009 + +Pregnancy and type 1 diabetes mellitus + +609566000 + +SNOMED + +YES + +YES + +NO +
+4024659 + +Gestational diabetes mellitus + +11687002 + +SNOMED + +YES + +YES + +NO +
+
+
+

A.9.15 Concept: GLP-1 receptor agonists excluding exenatide

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774435 + +dulaglutide + +1551291 + +RxNorm + +NO + +YES + +NO +
+1583722 + +exenatide + +60548 + +RxNorm + +YES + +YES + +NO +
+40170911 + +liraglutide + +475968 + +RxNorm + +NO + +YES + +NO +
+44506754 + +lixisenatide + +1440051 + +RxNorm + +NO + +YES + +NO +
+793143 + +semaglutide + +1991302 + +RxNorm + +NO + +YES + +NO +
+44816332 + +albiglutide + +1534763 + +RxNorm + +NO + +YES + +NO +
+
+ +
+
+
+

A.10 New user of exenatide with prior T2DM and prior metformin and no insulin

+
+

A.10.1 Cohort Entry Events

+

People with continuous observation of 365 days before event may enter the cohort when observing any of the following:

+
    +
  1. drug exposure of ‘exenatide’ for the first time in the person’s history.
    2. +
+

Limit cohort entry events to the earliest event per person.

+

Restrict entry events to with all of the following criteria:

+
    +
  1. with the following event criteria: who are >= 18 years old.
    2. +
  2. having at least 1 condition occurrence of ‘Type 2 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
  3. having no condition occurrences of ‘Type 1 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    4. +
  4. having no condition occurrences of ‘Secondary diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    5. +
+
+
+

A.10.2 Additional Inclusion Criteria

+
+

I. Prior metformin use

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 drug era of ‘Metformin’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period; with era length >= 90 days.
    2. +
  2. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

II. No prior insulin use or combo initiation: Proxy for < 30 days drug era anytime before index and no combination use on index

+

Entry events with all of the following criteria:

+
    +
  1. having no drug eras of ‘Insulin’, starting anytime up to 30 days before cohort entry start date; allow events outside observation period; with era length > 30 days.
    2. +
  2. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.
    3. +
+
+
+
+

A.10.3 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘exenatide’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

A.10.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

A.10.5 Concept: exenatide

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1583722 + +exenatide + +60548 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.10.6 Concept: Insulin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1596977 + +insulin, regular, human + +253182 + +RxNorm + +NO + +YES + +NO +
+1550023 + +insulin lispro + +86009 + +RxNorm + +NO + +YES + +NO +
+1567198 + +insulin aspart, human + +51428 + +RxNorm + +NO + +YES + +NO +
+1502905 + +insulin glargine + +274783 + +RxNorm + +NO + +YES + +NO +
+1513876 + +insulin lispro protamine, human + +314684 + +RxNorm + +NO + +YES + +NO +
+1531601 + +insulin aspart protamine, human + +352385 + +RxNorm + +NO + +YES + +NO +
+1586346 + +insulin, regular, pork + +221109 + +RxNorm + +NO + +YES + +NO +
+1544838 + +insulin glulisine, human + +400008 + +RxNorm + +NO + +YES + +NO +
+1516976 + +insulin detemir + +139825 + +RxNorm + +NO + +YES + +NO +
+1590165 + +insulin, regular, beef-pork + +235275 + +RxNorm + +NO + +YES + +NO +
+1513849 + +lente insulin, human + +314683 + +RxNorm + +NO + +YES + +NO +
+1562586 + +lente insulin, pork + +93108 + +RxNorm + +NO + +YES + +NO +
+1588986 + +insulin human, rDNA origin + +631657 + +RxNorm + +NO + +YES + +NO +
+1513843 + +lente insulin, beef-pork + +314682 + +RxNorm + +NO + +YES + +NO +
+1586369 + +ultralente insulin, human + +221110 + +RxNorm + +NO + +YES + +NO +
+35605670 + +insulin argine + +1740938 + +RxNorm + +NO + +YES + +NO +
+35602717 + +insulin degludec + +1670007 + +RxNorm + +NO + +YES + +NO +
+21600713 + +INSULINS AND ANALOGUES + +A10A + +ATC + +NO + +YES + +NO +
+19078608 + +insulin, protamine zinc, beef-pork 100 UNT/ML Injectable Suspension + +311053 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.10.7 Concept: Metformin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1503297 + +metformin + +6809 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.10.8 Concept: Secondary diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +NO + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.10.9 Concept: Type 1 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +NO + +YES + +NO +
+42689695 + +Eating disorder co-occurrent with diabetes mellitus type 1 + +1067201000000106 + +SNOMED + +NO + +YES + +NO +
+765533 + +Glaucoma due to diabetes mellitus type 1 + +60981000119103 + +SNOMED + +NO + +YES + +NO +
+43531006 + +Maturity onset diabetes of the young, type 1 + +609562003 + +SNOMED + +NO + +YES + +NO +
+765650 + +Cranial nerve palsy due to diabetes mellitus type 1 + +82561000119101 + +SNOMED + +NO + +YES + +NO +
+45770986 + +Retinopathy due to unstable diabetes mellitus type 1 + +706894000 + +SNOMED + +NO + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +NO + +YES + +NO +
+45768456 + +Neuropathy due to unstable diabetes mellitus type 1 + +706891008 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +NO + +YES + +NO +
+4128019 + +Brittle type 1 diabetes mellitus + +290002008 + +SNOMED + +NO + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.10.10 Concept: Type 2 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+443238 + +Diabetic - poor control + +268519009 + +SNOMED + +NO + +YES + +NO +
+201820 + +Diabetes mellitus + +73211009 + +SNOMED + +NO + +YES + +NO +
+442793 + +Complication due to diabetes mellitus + +74627003 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +YES + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +YES + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +YES + +YES + +NO +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +YES + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +YES + +YES + +NO +
+4016045 + +Diabetic - good control + +170763003 + +SNOMED + +NO + +YES + +NO +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +YES + +YES + +NO +
+43531009 + +Pregnancy and type 1 diabetes mellitus + +609566000 + +SNOMED + +YES + +YES + +NO +
+4024659 + +Gestational diabetes mellitus + +11687002 + +SNOMED + +YES + +YES + +NO +
+
+ +
+
+
+

A.11 New user of empagliflozin as 2nd-line treatment with prior T2DM and prior metformin

+
+

A.11.1 Cohort Entry Events

+

People with continuous observation of 365 days before event may enter the cohort when observing any of the following:

+
    +
  1. drug exposure of ‘empagliflozin’ for the first time in the person’s history.
    2. +
+

Limit cohort entry events to the earliest event per person.

+

Restrict entry events to with all of the following criteria:

+
    +
  1. with the following event criteria: who are >= 18 years old.
    2. +
  2. having at least 1 condition occurrence of ‘Type 2 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
  3. having no condition occurrences of ‘Type 1 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    4. +
  4. having no condition occurrences of ‘Secondary diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    5. +
+
+
+

A.11.2 Additional Inclusion Criteria

+
+

I. Prior metformin use

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 drug era of ‘Metformin’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period; with era length >= 90 days.
    2. +
  2. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

II. No prior GLP-1 RA exposure

+

Entry events having no drug exposures of ‘GLP-1 receptor agonists’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

III. No prior DPP4 inhibitor exposure

+

Entry events having no drug exposures of ‘DPP4 inhibitors’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

IV. No prior SGLT-2 inhibitor exposure

+

Entry events having no drug exposures of ‘SGLT2 inhibitors except empagliflozin’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

V. No prior SU exposure

+

Entry events having no drug exposures of ‘Sulfonylureas’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VI. No prior other anti-diabetic exposure

+

Entry events having no drug exposures of ‘Other anti-diabetics’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VII. No prior insulin use or combo initiation: Proxy for < 30 days drug era anytime before index and no combination use on index

+

Entry events with all of the following criteria:

+
    +
  1. having no drug eras of ‘Insulin’, starting anytime up to 30 days before cohort entry start date; allow events outside observation period; with era length > 30 days.
    2. +
  2. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.
    3. +
+
+
+
+

A.11.3 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘empagliflozin’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

A.11.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

A.11.5 Concept: DPP4 inhibitors

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43013884 + +alogliptin + +1368001 + +RxNorm + +NO + +YES + +NO +
+40239216 + +linagliptin + +1100699 + +RxNorm + +NO + +YES + +NO +
+40166035 + +saxagliptin + +857974 + +RxNorm + +NO + +YES + +NO +
+1580747 + +sitagliptin + +593411 + +RxNorm + +NO + +YES + +NO +
+19122137 + +vildagliptin + +596554 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.11.6 Concept: empagliflozin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774751 + +empagliflozin + +1545653 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.11.7 Concept: SGLT2 inhibitors except empagliflozin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43526465 + +canagliflozin + +1373458 + +RxNorm + +NO + +YES + +NO +
+44785829 + +dapagliflozin + +1488564 + +RxNorm + +NO + +YES + +NO +
+45774751 + +empagliflozin + +1545653 + +RxNorm + +YES + +YES + +NO +
+793293 + +ertugliflozin + +1992672 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.11.8 Concept: Sulfonylureas

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1594973 + +chlorpropamide + +2404 + +RxNorm + +NO + +YES + +NO +
+1597756 + +glimepiride + +25789 + +RxNorm + +NO + +YES + +NO +
+1560171 + +glipizide + +4821 + +RxNorm + +NO + +YES + +NO +
+19097821 + +gliquidone + +25793 + +RxNorm + +NO + +YES + +NO +
+1559684 + +glyburide + +4815 + +RxNorm + +NO + +YES + +NO +
+1502809 + +tolazamide + +10633 + +RxNorm + +NO + +YES + +NO +
+1502855 + +tolbutamide + +10635 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.11.9 Concept: Other anti-diabetics

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1529331 + +acarbose + +16681 + +RxNorm + +NO + +YES + +NO +
+1530014 + +acetohexamide + +173 + +RxNorm + +NO + +YES + +NO +
+730548 + +bromocriptine + +1760 + +RxNorm + +NO + +YES + +NO +
+19033498 + +carbutamide + +2068 + +RxNorm + +NO + +YES + +NO +
+19001409 + +glibornuride + +102846 + +RxNorm + +NO + +YES + +NO +
+19059796 + +gliclazide + +4816 + +RxNorm + +NO + +YES + +NO +
+19001441 + +glymidine + +102848 + +RxNorm + +NO + +YES + +NO +
+1510202 + +miglitol + +30009 + +RxNorm + +NO + +YES + +NO +
+1502826 + +nateglinide + +274332 + +RxNorm + +NO + +YES + +NO +
+1525215 + +pioglitazone + +33738 + +RxNorm + +NO + +YES + +NO +
+1516766 + +repaglinide + +73044 + +RxNorm + +NO + +YES + +NO +
+1547504 + +rosiglitazone + +84108 + +RxNorm + +NO + +YES + +NO +
+1515249 + +troglitazone + +72610 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.11.10 Concept: Insulin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1596977 + +insulin, regular, human + +253182 + +RxNorm + +NO + +YES + +NO +
+1550023 + +insulin lispro + +86009 + +RxNorm + +NO + +YES + +NO +
+1567198 + +insulin aspart, human + +51428 + +RxNorm + +NO + +YES + +NO +
+1502905 + +insulin glargine + +274783 + +RxNorm + +NO + +YES + +NO +
+1513876 + +insulin lispro protamine, human + +314684 + +RxNorm + +NO + +YES + +NO +
+1531601 + +insulin aspart protamine, human + +352385 + +RxNorm + +NO + +YES + +NO +
+1586346 + +insulin, regular, pork + +221109 + +RxNorm + +NO + +YES + +NO +
+1544838 + +insulin glulisine, human + +400008 + +RxNorm + +NO + +YES + +NO +
+1516976 + +insulin detemir + +139825 + +RxNorm + +NO + +YES + +NO +
+1590165 + +insulin, regular, beef-pork + +235275 + +RxNorm + +NO + +YES + +NO +
+1513849 + +lente insulin, human + +314683 + +RxNorm + +NO + +YES + +NO +
+1562586 + +lente insulin, pork + +93108 + +RxNorm + +NO + +YES + +NO +
+1588986 + +insulin human, rDNA origin + +631657 + +RxNorm + +NO + +YES + +NO +
+1513843 + +lente insulin, beef-pork + +314682 + +RxNorm + +NO + +YES + +NO +
+1586369 + +ultralente insulin, human + +221110 + +RxNorm + +NO + +YES + +NO +
+35605670 + +insulin argine + +1740938 + +RxNorm + +NO + +YES + +NO +
+35602717 + +insulin degludec + +1670007 + +RxNorm + +NO + +YES + +NO +
+21600713 + +INSULINS AND ANALOGUES + +A10A + +ATC + +NO + +YES + +NO +
+19078608 + +insulin, protamine zinc, beef-pork 100 UNT/ML Injectable Suspension + +311053 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.11.11 Concept: Metformin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1503297 + +metformin + +6809 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.11.12 Concept: Secondary diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +NO + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.11.13 Concept: Type 1 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +NO + +YES + +NO +
+42689695 + +Eating disorder co-occurrent with diabetes mellitus type 1 + +1067201000000106 + +SNOMED + +NO + +YES + +NO +
+765533 + +Glaucoma due to diabetes mellitus type 1 + +60981000119103 + +SNOMED + +NO + +YES + +NO +
+43531006 + +Maturity onset diabetes of the young, type 1 + +609562003 + +SNOMED + +NO + +YES + +NO +
+765650 + +Cranial nerve palsy due to diabetes mellitus type 1 + +82561000119101 + +SNOMED + +NO + +YES + +NO +
+45770986 + +Retinopathy due to unstable diabetes mellitus type 1 + +706894000 + +SNOMED + +NO + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +NO + +YES + +NO +
+45768456 + +Neuropathy due to unstable diabetes mellitus type 1 + +706891008 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +NO + +YES + +NO +
+4128019 + +Brittle type 1 diabetes mellitus + +290002008 + +SNOMED + +NO + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.11.14 Concept: Type 2 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+443238 + +Diabetic - poor control + +268519009 + +SNOMED + +NO + +YES + +NO +
+201820 + +Diabetes mellitus + +73211009 + +SNOMED + +NO + +YES + +NO +
+442793 + +Complication due to diabetes mellitus + +74627003 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +YES + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +YES + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +YES + +YES + +NO +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +YES + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +YES + +YES + +NO +
+4016045 + +Diabetic - good control + +170763003 + +SNOMED + +NO + +YES + +NO +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +YES + +YES + +NO +
+43531009 + +Pregnancy and type 1 diabetes mellitus + +609566000 + +SNOMED + +YES + +YES + +NO +
+4024659 + +Gestational diabetes mellitus + +11687002 + +SNOMED + +YES + +YES + +NO +
+
+
+

A.11.15 Concept: GLP-1 receptor agonists

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774435 + +dulaglutide + +1551291 + +RxNorm + +NO + +YES + +NO +
+1583722 + +exenatide + +60548 + +RxNorm + +NO + +YES + +NO +
+40170911 + +liraglutide + +475968 + +RxNorm + +NO + +YES + +NO +
+44506754 + +lixisenatide + +1440051 + +RxNorm + +NO + +YES + +NO +
+793143 + +semaglutide + +1991302 + +RxNorm + +NO + +YES + +NO +
+44816332 + +albiglutide + +1534763 + +RxNorm + +NO + +YES + +NO +
+
+ +
+
+
+

A.12 New user of empagliflozin as 2nd-line treatment with prior T2DM Dec2017-Jan2020

+
+

A.12.1 Cohort Entry Events

+

People with continuous observation of 365 days before event may enter the cohort when observing any of the following:

+
    +
  1. drug exposure of ‘empagliflozin’ for the first time in the person’s history.
    2. +
+

Limit cohort entry events to the earliest event per person.

+

Restrict entry events to with all of the following criteria:

+
    +
  1. with the following event criteria: who are >= 18 years old.
    2. +
  2. having at least 1 condition occurrence of ‘Type 2 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
  3. having no condition occurrences of ‘Type 1 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    4. +
  4. having no condition occurrences of ‘Secondary diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    5. +
+
+
+

A.12.2 Additional Inclusion Criteria

+
+

I. Prior metformin use

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 drug era of ‘Metformin’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period; with era length >= 90 days.
    2. +
  2. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

II. No prior GLP-1 RA exposure

+

Entry events having no drug exposures of ‘GLP-1 receptor agonists’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

III. No prior DPP4 inhibitor exposure

+

Entry events having no drug exposures of ‘DPP4 inhibitors’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

IV. No prior SGLT-2 inhibitor exposure

+

Entry events having no drug exposures of ‘SGLT2 inhibitors except empagliflozin’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

V. No prior SU exposure

+

Entry events having no drug exposures of ‘Sulfonylureas’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VI. No prior other anti-diabetic exposure

+

Entry events having no drug exposures of ‘Other anti-diabetics’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VII. No prior insulin use or combo initiation: Proxy for < 30 days drug era anytime before index and no combination use on index

+

Entry events with all of the following criteria:

+
    +
  1. having no drug eras of ‘Insulin’, starting anytime up to 30 days before cohort entry start date; allow events outside observation period; with era length > 30 days.
    2. +
  2. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.
    3. +
+
+
+

VIII. index date between 1Dec2017 and 31Jan2020

+

Entry events with the following event criteria: starting between December 1, 2017 and January 31, 2020.

+
+
+
+

A.12.3 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘empagliflozin’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

A.12.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

A.12.5 Concept: DPP4 inhibitors

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43013884 + +alogliptin + +1368001 + +RxNorm + +NO + +YES + +NO +
+40239216 + +linagliptin + +1100699 + +RxNorm + +NO + +YES + +NO +
+40166035 + +saxagliptin + +857974 + +RxNorm + +NO + +YES + +NO +
+1580747 + +sitagliptin + +593411 + +RxNorm + +NO + +YES + +NO +
+19122137 + +vildagliptin + +596554 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.12.6 Concept: empagliflozin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774751 + +empagliflozin + +1545653 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.12.7 Concept: SGLT2 inhibitors except empagliflozin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43526465 + +canagliflozin + +1373458 + +RxNorm + +NO + +YES + +NO +
+44785829 + +dapagliflozin + +1488564 + +RxNorm + +NO + +YES + +NO +
+45774751 + +empagliflozin + +1545653 + +RxNorm + +YES + +YES + +NO +
+793293 + +ertugliflozin + +1992672 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.12.8 Concept: Sulfonylureas

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1594973 + +chlorpropamide + +2404 + +RxNorm + +NO + +YES + +NO +
+1597756 + +glimepiride + +25789 + +RxNorm + +NO + +YES + +NO +
+1560171 + +glipizide + +4821 + +RxNorm + +NO + +YES + +NO +
+19097821 + +gliquidone + +25793 + +RxNorm + +NO + +YES + +NO +
+1559684 + +glyburide + +4815 + +RxNorm + +NO + +YES + +NO +
+1502809 + +tolazamide + +10633 + +RxNorm + +NO + +YES + +NO +
+1502855 + +tolbutamide + +10635 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.12.9 Concept: Other anti-diabetics

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1529331 + +acarbose + +16681 + +RxNorm + +NO + +YES + +NO +
+1530014 + +acetohexamide + +173 + +RxNorm + +NO + +YES + +NO +
+730548 + +bromocriptine + +1760 + +RxNorm + +NO + +YES + +NO +
+19033498 + +carbutamide + +2068 + +RxNorm + +NO + +YES + +NO +
+19001409 + +glibornuride + +102846 + +RxNorm + +NO + +YES + +NO +
+19059796 + +gliclazide + +4816 + +RxNorm + +NO + +YES + +NO +
+19001441 + +glymidine + +102848 + +RxNorm + +NO + +YES + +NO +
+1510202 + +miglitol + +30009 + +RxNorm + +NO + +YES + +NO +
+1502826 + +nateglinide + +274332 + +RxNorm + +NO + +YES + +NO +
+1525215 + +pioglitazone + +33738 + +RxNorm + +NO + +YES + +NO +
+1516766 + +repaglinide + +73044 + +RxNorm + +NO + +YES + +NO +
+1547504 + +rosiglitazone + +84108 + +RxNorm + +NO + +YES + +NO +
+1515249 + +troglitazone + +72610 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.12.10 Concept: Insulin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1596977 + +insulin, regular, human + +253182 + +RxNorm + +NO + +YES + +NO +
+1550023 + +insulin lispro + +86009 + +RxNorm + +NO + +YES + +NO +
+1567198 + +insulin aspart, human + +51428 + +RxNorm + +NO + +YES + +NO +
+1502905 + +insulin glargine + +274783 + +RxNorm + +NO + +YES + +NO +
+1513876 + +insulin lispro protamine, human + +314684 + +RxNorm + +NO + +YES + +NO +
+1531601 + +insulin aspart protamine, human + +352385 + +RxNorm + +NO + +YES + +NO +
+1586346 + +insulin, regular, pork + +221109 + +RxNorm + +NO + +YES + +NO +
+1544838 + +insulin glulisine, human + +400008 + +RxNorm + +NO + +YES + +NO +
+1516976 + +insulin detemir + +139825 + +RxNorm + +NO + +YES + +NO +
+1590165 + +insulin, regular, beef-pork + +235275 + +RxNorm + +NO + +YES + +NO +
+1513849 + +lente insulin, human + +314683 + +RxNorm + +NO + +YES + +NO +
+1562586 + +lente insulin, pork + +93108 + +RxNorm + +NO + +YES + +NO +
+1588986 + +insulin human, rDNA origin + +631657 + +RxNorm + +NO + +YES + +NO +
+1513843 + +lente insulin, beef-pork + +314682 + +RxNorm + +NO + +YES + +NO +
+1586369 + +ultralente insulin, human + +221110 + +RxNorm + +NO + +YES + +NO +
+35605670 + +insulin argine + +1740938 + +RxNorm + +NO + +YES + +NO +
+35602717 + +insulin degludec + +1670007 + +RxNorm + +NO + +YES + +NO +
+21600713 + +INSULINS AND ANALOGUES + +A10A + +ATC + +NO + +YES + +NO +
+19078608 + +insulin, protamine zinc, beef-pork 100 UNT/ML Injectable Suspension + +311053 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.12.11 Concept: Metformin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1503297 + +metformin + +6809 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.12.12 Concept: Secondary diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +NO + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.12.13 Concept: Type 1 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +NO + +YES + +NO +
+42689695 + +Eating disorder co-occurrent with diabetes mellitus type 1 + +1067201000000106 + +SNOMED + +NO + +YES + +NO +
+765533 + +Glaucoma due to diabetes mellitus type 1 + +60981000119103 + +SNOMED + +NO + +YES + +NO +
+43531006 + +Maturity onset diabetes of the young, type 1 + +609562003 + +SNOMED + +NO + +YES + +NO +
+765650 + +Cranial nerve palsy due to diabetes mellitus type 1 + +82561000119101 + +SNOMED + +NO + +YES + +NO +
+45770986 + +Retinopathy due to unstable diabetes mellitus type 1 + +706894000 + +SNOMED + +NO + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +NO + +YES + +NO +
+45768456 + +Neuropathy due to unstable diabetes mellitus type 1 + +706891008 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +NO + +YES + +NO +
+4128019 + +Brittle type 1 diabetes mellitus + +290002008 + +SNOMED + +NO + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.12.14 Concept: Type 2 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+443238 + +Diabetic - poor control + +268519009 + +SNOMED + +NO + +YES + +NO +
+201820 + +Diabetes mellitus + +73211009 + +SNOMED + +NO + +YES + +NO +
+442793 + +Complication due to diabetes mellitus + +74627003 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +YES + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +YES + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +YES + +YES + +NO +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +YES + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +YES + +YES + +NO +
+4016045 + +Diabetic - good control + +170763003 + +SNOMED + +NO + +YES + +NO +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +YES + +YES + +NO +
+43531009 + +Pregnancy and type 1 diabetes mellitus + +609566000 + +SNOMED + +YES + +YES + +NO +
+4024659 + +Gestational diabetes mellitus + +11687002 + +SNOMED + +YES + +YES + +NO +
+
+
+

A.12.15 Concept: GLP-1 receptor agonists

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774435 + +dulaglutide + +1551291 + +RxNorm + +NO + +YES + +NO +
+1583722 + +exenatide + +60548 + +RxNorm + +NO + +YES + +NO +
+40170911 + +liraglutide + +475968 + +RxNorm + +NO + +YES + +NO +
+44506754 + +lixisenatide + +1440051 + +RxNorm + +NO + +YES + +NO +
+793143 + +semaglutide + +1991302 + +RxNorm + +NO + +YES + +NO +
+44816332 + +albiglutide + +1534763 + +RxNorm + +NO + +YES + +NO +
+
+ +
+
+
+

A.13 New user of empagliflozin as 2nd-line treatment with prior T2DM Feb2020-Jun2021

+
+

A.13.1 Cohort Entry Events

+

People with continuous observation of 365 days before event may enter the cohort when observing any of the following:

+
    +
  1. drug exposure of ‘empagliflozin’ for the first time in the person’s history.
    2. +
+

Limit cohort entry events to the earliest event per person.

+

Restrict entry events to with all of the following criteria:

+
    +
  1. with the following event criteria: who are >= 18 years old.
    2. +
  2. having at least 1 condition occurrence of ‘Type 2 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
  3. having no condition occurrences of ‘Type 1 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    4. +
  4. having no condition occurrences of ‘Secondary diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    5. +
+
+
+

A.13.2 Additional Inclusion Criteria

+
+

I. Prior metformin use

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 drug era of ‘Metformin’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period; with era length >= 90 days.
    2. +
  2. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

II. No prior GLP-1 RA exposure

+

Entry events having no drug exposures of ‘GLP-1 receptor agonists’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

III. No prior DPP4 inhibitor exposure

+

Entry events having no drug exposures of ‘DPP4 inhibitors’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

IV. No prior SGLT-2 inhibitor exposure

+

Entry events having no drug exposures of ‘SGLT2 inhibitors except empagliflozin’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

V. No prior SU exposure

+

Entry events having no drug exposures of ‘Sulfonylureas’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VI. No prior other anti-diabetic exposure

+

Entry events having no drug exposures of ‘Other anti-diabetics’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VII. No prior insulin use or combo initiation: Proxy for < 30 days drug era anytime before index and no combination use on index

+

Entry events with all of the following criteria:

+
    +
  1. having no drug eras of ‘Insulin’, starting anytime up to 30 days before cohort entry start date; allow events outside observation period; with era length > 30 days.
    2. +
  2. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.
    3. +
+
+
+

VIII. index date between 1Feb2020 and 30Jun2021

+

Entry events with the following event criteria: starting between February 1, 2020 and June 30, 2021.

+
+
+
+

A.13.3 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘empagliflozin’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

A.13.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

A.13.5 Concept: DPP4 inhibitors

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43013884 + +alogliptin + +1368001 + +RxNorm + +NO + +YES + +NO +
+40239216 + +linagliptin + +1100699 + +RxNorm + +NO + +YES + +NO +
+40166035 + +saxagliptin + +857974 + +RxNorm + +NO + +YES + +NO +
+1580747 + +sitagliptin + +593411 + +RxNorm + +NO + +YES + +NO +
+19122137 + +vildagliptin + +596554 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.13.6 Concept: empagliflozin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774751 + +empagliflozin + +1545653 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.13.7 Concept: SGLT2 inhibitors except empagliflozin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43526465 + +canagliflozin + +1373458 + +RxNorm + +NO + +YES + +NO +
+44785829 + +dapagliflozin + +1488564 + +RxNorm + +NO + +YES + +NO +
+45774751 + +empagliflozin + +1545653 + +RxNorm + +YES + +YES + +NO +
+793293 + +ertugliflozin + +1992672 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.13.8 Concept: Sulfonylureas

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1594973 + +chlorpropamide + +2404 + +RxNorm + +NO + +YES + +NO +
+1597756 + +glimepiride + +25789 + +RxNorm + +NO + +YES + +NO +
+1560171 + +glipizide + +4821 + +RxNorm + +NO + +YES + +NO +
+19097821 + +gliquidone + +25793 + +RxNorm + +NO + +YES + +NO +
+1559684 + +glyburide + +4815 + +RxNorm + +NO + +YES + +NO +
+1502809 + +tolazamide + +10633 + +RxNorm + +NO + +YES + +NO +
+1502855 + +tolbutamide + +10635 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.13.9 Concept: Other anti-diabetics

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1529331 + +acarbose + +16681 + +RxNorm + +NO + +YES + +NO +
+1530014 + +acetohexamide + +173 + +RxNorm + +NO + +YES + +NO +
+730548 + +bromocriptine + +1760 + +RxNorm + +NO + +YES + +NO +
+19033498 + +carbutamide + +2068 + +RxNorm + +NO + +YES + +NO +
+19001409 + +glibornuride + +102846 + +RxNorm + +NO + +YES + +NO +
+19059796 + +gliclazide + +4816 + +RxNorm + +NO + +YES + +NO +
+19001441 + +glymidine + +102848 + +RxNorm + +NO + +YES + +NO +
+1510202 + +miglitol + +30009 + +RxNorm + +NO + +YES + +NO +
+1502826 + +nateglinide + +274332 + +RxNorm + +NO + +YES + +NO +
+1525215 + +pioglitazone + +33738 + +RxNorm + +NO + +YES + +NO +
+1516766 + +repaglinide + +73044 + +RxNorm + +NO + +YES + +NO +
+1547504 + +rosiglitazone + +84108 + +RxNorm + +NO + +YES + +NO +
+1515249 + +troglitazone + +72610 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.13.10 Concept: Insulin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1596977 + +insulin, regular, human + +253182 + +RxNorm + +NO + +YES + +NO +
+1550023 + +insulin lispro + +86009 + +RxNorm + +NO + +YES + +NO +
+1567198 + +insulin aspart, human + +51428 + +RxNorm + +NO + +YES + +NO +
+1502905 + +insulin glargine + +274783 + +RxNorm + +NO + +YES + +NO +
+1513876 + +insulin lispro protamine, human + +314684 + +RxNorm + +NO + +YES + +NO +
+1531601 + +insulin aspart protamine, human + +352385 + +RxNorm + +NO + +YES + +NO +
+1586346 + +insulin, regular, pork + +221109 + +RxNorm + +NO + +YES + +NO +
+1544838 + +insulin glulisine, human + +400008 + +RxNorm + +NO + +YES + +NO +
+1516976 + +insulin detemir + +139825 + +RxNorm + +NO + +YES + +NO +
+1590165 + +insulin, regular, beef-pork + +235275 + +RxNorm + +NO + +YES + +NO +
+1513849 + +lente insulin, human + +314683 + +RxNorm + +NO + +YES + +NO +
+1562586 + +lente insulin, pork + +93108 + +RxNorm + +NO + +YES + +NO +
+1588986 + +insulin human, rDNA origin + +631657 + +RxNorm + +NO + +YES + +NO +
+1513843 + +lente insulin, beef-pork + +314682 + +RxNorm + +NO + +YES + +NO +
+1586369 + +ultralente insulin, human + +221110 + +RxNorm + +NO + +YES + +NO +
+35605670 + +insulin argine + +1740938 + +RxNorm + +NO + +YES + +NO +
+35602717 + +insulin degludec + +1670007 + +RxNorm + +NO + +YES + +NO +
+21600713 + +INSULINS AND ANALOGUES + +A10A + +ATC + +NO + +YES + +NO +
+19078608 + +insulin, protamine zinc, beef-pork 100 UNT/ML Injectable Suspension + +311053 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.13.11 Concept: Metformin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1503297 + +metformin + +6809 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.13.12 Concept: Secondary diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +NO + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.13.13 Concept: Type 1 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +NO + +YES + +NO +
+42689695 + +Eating disorder co-occurrent with diabetes mellitus type 1 + +1067201000000106 + +SNOMED + +NO + +YES + +NO +
+765533 + +Glaucoma due to diabetes mellitus type 1 + +60981000119103 + +SNOMED + +NO + +YES + +NO +
+43531006 + +Maturity onset diabetes of the young, type 1 + +609562003 + +SNOMED + +NO + +YES + +NO +
+765650 + +Cranial nerve palsy due to diabetes mellitus type 1 + +82561000119101 + +SNOMED + +NO + +YES + +NO +
+45770986 + +Retinopathy due to unstable diabetes mellitus type 1 + +706894000 + +SNOMED + +NO + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +NO + +YES + +NO +
+45768456 + +Neuropathy due to unstable diabetes mellitus type 1 + +706891008 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +NO + +YES + +NO +
+4128019 + +Brittle type 1 diabetes mellitus + +290002008 + +SNOMED + +NO + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.13.14 Concept: Type 2 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+443238 + +Diabetic - poor control + +268519009 + +SNOMED + +NO + +YES + +NO +
+201820 + +Diabetes mellitus + +73211009 + +SNOMED + +NO + +YES + +NO +
+442793 + +Complication due to diabetes mellitus + +74627003 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +YES + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +YES + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +YES + +YES + +NO +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +YES + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +YES + +YES + +NO +
+4016045 + +Diabetic - good control + +170763003 + +SNOMED + +NO + +YES + +NO +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +YES + +YES + +NO +
+43531009 + +Pregnancy and type 1 diabetes mellitus + +609566000 + +SNOMED + +YES + +YES + +NO +
+4024659 + +Gestational diabetes mellitus + +11687002 + +SNOMED + +YES + +YES + +NO +
+
+
+

A.13.15 Concept: GLP-1 receptor agonists

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774435 + +dulaglutide + +1551291 + +RxNorm + +NO + +YES + +NO +
+1583722 + +exenatide + +60548 + +RxNorm + +NO + +YES + +NO +
+40170911 + +liraglutide + +475968 + +RxNorm + +NO + +YES + +NO +
+44506754 + +lixisenatide + +1440051 + +RxNorm + +NO + +YES + +NO +
+793143 + +semaglutide + +1991302 + +RxNorm + +NO + +YES + +NO +
+44816332 + +albiglutide + +1534763 + +RxNorm + +NO + +YES + +NO +
+
+ +
+
+
+

A.14 New user of empagliflozin as 2nd-line treatment with prior T2DM Jul2021-Dec2023

+
+

A.14.1 Cohort Entry Events

+

People with continuous observation of 365 days before event may enter the cohort when observing any of the following:

+
    +
  1. drug exposure of ‘empagliflozin’ for the first time in the person’s history.
    2. +
+

Limit cohort entry events to the earliest event per person.

+

Restrict entry events to with all of the following criteria:

+
    +
  1. with the following event criteria: who are >= 18 years old.
    2. +
  2. having at least 1 condition occurrence of ‘Type 2 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
  3. having no condition occurrences of ‘Type 1 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    4. +
  4. having no condition occurrences of ‘Secondary diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    5. +
+
+
+

A.14.2 Additional Inclusion Criteria

+
+

I. Prior metformin use

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 drug era of ‘Metformin’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period; with era length >= 90 days.
    2. +
  2. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

II. No prior GLP-1 RA exposure

+

Entry events having no drug exposures of ‘GLP-1 receptor agonists’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

III. No prior DPP4 inhibitor exposure

+

Entry events having no drug exposures of ‘DPP4 inhibitors’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

IV. No prior SGLT-2 inhibitor exposure

+

Entry events having no drug exposures of ‘SGLT2 inhibitors except empagliflozin’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

V. No prior SU exposure

+

Entry events having no drug exposures of ‘Sulfonylureas’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VI. No prior other anti-diabetic exposure

+

Entry events having no drug exposures of ‘Other anti-diabetics’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VII. No prior insulin use or combo initiation: Proxy for < 30 days drug era anytime before index and no combination use on index

+

Entry events with all of the following criteria:

+
    +
  1. having no drug eras of ‘Insulin’, starting anytime up to 30 days before cohort entry start date; allow events outside observation period; with era length > 30 days.
    2. +
  2. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.
    3. +
+
+
+

VIII. index date between 1Jul2021 and 31Dec2023

+

Entry events with the following event criteria: starting between July 1, 2021 and December 31, 2023.

+
+
+
+

A.14.3 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘empagliflozin’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

A.14.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

A.14.5 Concept: DPP4 inhibitors

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43013884 + +alogliptin + +1368001 + +RxNorm + +NO + +YES + +NO +
+40239216 + +linagliptin + +1100699 + +RxNorm + +NO + +YES + +NO +
+40166035 + +saxagliptin + +857974 + +RxNorm + +NO + +YES + +NO +
+1580747 + +sitagliptin + +593411 + +RxNorm + +NO + +YES + +NO +
+19122137 + +vildagliptin + +596554 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.14.6 Concept: empagliflozin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774751 + +empagliflozin + +1545653 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.14.7 Concept: SGLT2 inhibitors except empagliflozin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43526465 + +canagliflozin + +1373458 + +RxNorm + +NO + +YES + +NO +
+44785829 + +dapagliflozin + +1488564 + +RxNorm + +NO + +YES + +NO +
+45774751 + +empagliflozin + +1545653 + +RxNorm + +YES + +YES + +NO +
+793293 + +ertugliflozin + +1992672 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.14.8 Concept: Sulfonylureas

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1594973 + +chlorpropamide + +2404 + +RxNorm + +NO + +YES + +NO +
+1597756 + +glimepiride + +25789 + +RxNorm + +NO + +YES + +NO +
+1560171 + +glipizide + +4821 + +RxNorm + +NO + +YES + +NO +
+19097821 + +gliquidone + +25793 + +RxNorm + +NO + +YES + +NO +
+1559684 + +glyburide + +4815 + +RxNorm + +NO + +YES + +NO +
+1502809 + +tolazamide + +10633 + +RxNorm + +NO + +YES + +NO +
+1502855 + +tolbutamide + +10635 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.14.9 Concept: Other anti-diabetics

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1529331 + +acarbose + +16681 + +RxNorm + +NO + +YES + +NO +
+1530014 + +acetohexamide + +173 + +RxNorm + +NO + +YES + +NO +
+730548 + +bromocriptine + +1760 + +RxNorm + +NO + +YES + +NO +
+19033498 + +carbutamide + +2068 + +RxNorm + +NO + +YES + +NO +
+19001409 + +glibornuride + +102846 + +RxNorm + +NO + +YES + +NO +
+19059796 + +gliclazide + +4816 + +RxNorm + +NO + +YES + +NO +
+19001441 + +glymidine + +102848 + +RxNorm + +NO + +YES + +NO +
+1510202 + +miglitol + +30009 + +RxNorm + +NO + +YES + +NO +
+1502826 + +nateglinide + +274332 + +RxNorm + +NO + +YES + +NO +
+1525215 + +pioglitazone + +33738 + +RxNorm + +NO + +YES + +NO +
+1516766 + +repaglinide + +73044 + +RxNorm + +NO + +YES + +NO +
+1547504 + +rosiglitazone + +84108 + +RxNorm + +NO + +YES + +NO +
+1515249 + +troglitazone + +72610 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.14.10 Concept: Insulin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1596977 + +insulin, regular, human + +253182 + +RxNorm + +NO + +YES + +NO +
+1550023 + +insulin lispro + +86009 + +RxNorm + +NO + +YES + +NO +
+1567198 + +insulin aspart, human + +51428 + +RxNorm + +NO + +YES + +NO +
+1502905 + +insulin glargine + +274783 + +RxNorm + +NO + +YES + +NO +
+1513876 + +insulin lispro protamine, human + +314684 + +RxNorm + +NO + +YES + +NO +
+1531601 + +insulin aspart protamine, human + +352385 + +RxNorm + +NO + +YES + +NO +
+1586346 + +insulin, regular, pork + +221109 + +RxNorm + +NO + +YES + +NO +
+1544838 + +insulin glulisine, human + +400008 + +RxNorm + +NO + +YES + +NO +
+1516976 + +insulin detemir + +139825 + +RxNorm + +NO + +YES + +NO +
+1590165 + +insulin, regular, beef-pork + +235275 + +RxNorm + +NO + +YES + +NO +
+1513849 + +lente insulin, human + +314683 + +RxNorm + +NO + +YES + +NO +
+1562586 + +lente insulin, pork + +93108 + +RxNorm + +NO + +YES + +NO +
+1588986 + +insulin human, rDNA origin + +631657 + +RxNorm + +NO + +YES + +NO +
+1513843 + +lente insulin, beef-pork + +314682 + +RxNorm + +NO + +YES + +NO +
+1586369 + +ultralente insulin, human + +221110 + +RxNorm + +NO + +YES + +NO +
+35605670 + +insulin argine + +1740938 + +RxNorm + +NO + +YES + +NO +
+35602717 + +insulin degludec + +1670007 + +RxNorm + +NO + +YES + +NO +
+21600713 + +INSULINS AND ANALOGUES + +A10A + +ATC + +NO + +YES + +NO +
+19078608 + +insulin, protamine zinc, beef-pork 100 UNT/ML Injectable Suspension + +311053 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.14.11 Concept: Metformin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1503297 + +metformin + +6809 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.14.12 Concept: Secondary diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +NO + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.14.13 Concept: Type 1 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +NO + +YES + +NO +
+42689695 + +Eating disorder co-occurrent with diabetes mellitus type 1 + +1067201000000106 + +SNOMED + +NO + +YES + +NO +
+765533 + +Glaucoma due to diabetes mellitus type 1 + +60981000119103 + +SNOMED + +NO + +YES + +NO +
+43531006 + +Maturity onset diabetes of the young, type 1 + +609562003 + +SNOMED + +NO + +YES + +NO +
+765650 + +Cranial nerve palsy due to diabetes mellitus type 1 + +82561000119101 + +SNOMED + +NO + +YES + +NO +
+45770986 + +Retinopathy due to unstable diabetes mellitus type 1 + +706894000 + +SNOMED + +NO + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +NO + +YES + +NO +
+45768456 + +Neuropathy due to unstable diabetes mellitus type 1 + +706891008 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +NO + +YES + +NO +
+4128019 + +Brittle type 1 diabetes mellitus + +290002008 + +SNOMED + +NO + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.14.14 Concept: Type 2 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+443238 + +Diabetic - poor control + +268519009 + +SNOMED + +NO + +YES + +NO +
+201820 + +Diabetes mellitus + +73211009 + +SNOMED + +NO + +YES + +NO +
+442793 + +Complication due to diabetes mellitus + +74627003 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +YES + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +YES + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +YES + +YES + +NO +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +YES + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +YES + +YES + +NO +
+4016045 + +Diabetic - good control + +170763003 + +SNOMED + +NO + +YES + +NO +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +YES + +YES + +NO +
+43531009 + +Pregnancy and type 1 diabetes mellitus + +609566000 + +SNOMED + +YES + +YES + +NO +
+4024659 + +Gestational diabetes mellitus + +11687002 + +SNOMED + +YES + +YES + +NO +
+
+
+

A.14.15 Concept: GLP-1 receptor agonists

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774435 + +dulaglutide + +1551291 + +RxNorm + +NO + +YES + +NO +
+1583722 + +exenatide + +60548 + +RxNorm + +NO + +YES + +NO +
+40170911 + +liraglutide + +475968 + +RxNorm + +NO + +YES + +NO +
+44506754 + +lixisenatide + +1440051 + +RxNorm + +NO + +YES + +NO +
+793143 + +semaglutide + +1991302 + +RxNorm + +NO + +YES + +NO +
+44816332 + +albiglutide + +1534763 + +RxNorm + +NO + +YES + +NO +
+
+ +
+
+
+

A.15 New user of empagliflozin with prior T2DM and prior metformin and no insulin

+
+

A.15.1 Cohort Entry Events

+

People with continuous observation of 365 days before event may enter the cohort when observing any of the following:

+
    +
  1. drug exposure of ‘empagliflozin’ for the first time in the person’s history.
    2. +
+

Limit cohort entry events to the earliest event per person.

+

Restrict entry events to with all of the following criteria:

+
    +
  1. with the following event criteria: who are >= 18 years old.
    2. +
  2. having at least 1 condition occurrence of ‘Type 2 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
  3. having no condition occurrences of ‘Type 1 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    4. +
  4. having no condition occurrences of ‘Secondary diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    5. +
+
+
+

A.15.2 Additional Inclusion Criteria

+
+

I. Prior metformin use

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 drug era of ‘Metformin’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period; with era length >= 90 days.
    2. +
  2. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

II. No prior insulin use or combo initiation: Proxy for < 30 days drug era anytime before index and no combination use on index

+

Entry events with all of the following criteria:

+
    +
  1. having no drug eras of ‘Insulin’, starting anytime up to 30 days before cohort entry start date; allow events outside observation period; with era length > 30 days.
    2. +
  2. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.
    3. +
+
+
+
+

A.15.3 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘empagliflozin’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

A.15.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

A.15.5 Concept: empagliflozin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774751 + +empagliflozin + +1545653 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.15.6 Concept: Insulin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1596977 + +insulin, regular, human + +253182 + +RxNorm + +NO + +YES + +NO +
+1550023 + +insulin lispro + +86009 + +RxNorm + +NO + +YES + +NO +
+1567198 + +insulin aspart, human + +51428 + +RxNorm + +NO + +YES + +NO +
+1502905 + +insulin glargine + +274783 + +RxNorm + +NO + +YES + +NO +
+1513876 + +insulin lispro protamine, human + +314684 + +RxNorm + +NO + +YES + +NO +
+1531601 + +insulin aspart protamine, human + +352385 + +RxNorm + +NO + +YES + +NO +
+1586346 + +insulin, regular, pork + +221109 + +RxNorm + +NO + +YES + +NO +
+1544838 + +insulin glulisine, human + +400008 + +RxNorm + +NO + +YES + +NO +
+1516976 + +insulin detemir + +139825 + +RxNorm + +NO + +YES + +NO +
+1590165 + +insulin, regular, beef-pork + +235275 + +RxNorm + +NO + +YES + +NO +
+1513849 + +lente insulin, human + +314683 + +RxNorm + +NO + +YES + +NO +
+1562586 + +lente insulin, pork + +93108 + +RxNorm + +NO + +YES + +NO +
+1588986 + +insulin human, rDNA origin + +631657 + +RxNorm + +NO + +YES + +NO +
+1513843 + +lente insulin, beef-pork + +314682 + +RxNorm + +NO + +YES + +NO +
+1586369 + +ultralente insulin, human + +221110 + +RxNorm + +NO + +YES + +NO +
+35605670 + +insulin argine + +1740938 + +RxNorm + +NO + +YES + +NO +
+35602717 + +insulin degludec + +1670007 + +RxNorm + +NO + +YES + +NO +
+21600713 + +INSULINS AND ANALOGUES + +A10A + +ATC + +NO + +YES + +NO +
+19078608 + +insulin, protamine zinc, beef-pork 100 UNT/ML Injectable Suspension + +311053 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.15.7 Concept: Metformin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1503297 + +metformin + +6809 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.15.8 Concept: Secondary diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +NO + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.15.9 Concept: Type 1 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +NO + +YES + +NO +
+42689695 + +Eating disorder co-occurrent with diabetes mellitus type 1 + +1067201000000106 + +SNOMED + +NO + +YES + +NO +
+765533 + +Glaucoma due to diabetes mellitus type 1 + +60981000119103 + +SNOMED + +NO + +YES + +NO +
+43531006 + +Maturity onset diabetes of the young, type 1 + +609562003 + +SNOMED + +NO + +YES + +NO +
+765650 + +Cranial nerve palsy due to diabetes mellitus type 1 + +82561000119101 + +SNOMED + +NO + +YES + +NO +
+45770986 + +Retinopathy due to unstable diabetes mellitus type 1 + +706894000 + +SNOMED + +NO + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +NO + +YES + +NO +
+45768456 + +Neuropathy due to unstable diabetes mellitus type 1 + +706891008 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +NO + +YES + +NO +
+4128019 + +Brittle type 1 diabetes mellitus + +290002008 + +SNOMED + +NO + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.15.10 Concept: Type 2 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+443238 + +Diabetic - poor control + +268519009 + +SNOMED + +NO + +YES + +NO +
+201820 + +Diabetes mellitus + +73211009 + +SNOMED + +NO + +YES + +NO +
+442793 + +Complication due to diabetes mellitus + +74627003 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +YES + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +YES + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +YES + +YES + +NO +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +YES + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +YES + +YES + +NO +
+4016045 + +Diabetic - good control + +170763003 + +SNOMED + +NO + +YES + +NO +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +YES + +YES + +NO +
+43531009 + +Pregnancy and type 1 diabetes mellitus + +609566000 + +SNOMED + +YES + +YES + +NO +
+4024659 + +Gestational diabetes mellitus + +11687002 + +SNOMED + +YES + +YES + +NO +
+
+ +
+
+
+

A.16 New user of sitagliptin as 2nd-line treatment with prior T2DM and prior metformin

+
+

A.16.1 Cohort Entry Events

+

People with continuous observation of 365 days before event may enter the cohort when observing any of the following:

+
    +
  1. drug exposure of ‘sitagliptin’ for the first time in the person’s history.
    2. +
+

Limit cohort entry events to the earliest event per person.

+

Restrict entry events to with all of the following criteria:

+
    +
  1. with the following event criteria: who are >= 18 years old.
    2. +
  2. having at least 1 condition occurrence of ‘Type 2 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
  3. having no condition occurrences of ‘Type 1 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    4. +
  4. having no condition occurrences of ‘Secondary diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    5. +
+
+
+

A.16.2 Additional Inclusion Criteria

+
+

I. Prior metformin use

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 drug era of ‘Metformin’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period; with era length >= 90 days.
    2. +
  2. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

II. No prior GLP-1 RA exposure

+

Entry events having no drug exposures of ‘GLP-1 receptor agonists’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

III. No prior DPP4 inhibitor exposure

+

Entry events having no drug exposures of ‘DPP4 inhibitors except sitagliptin’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

IV. No prior SGLT-2 inhibitor exposure

+

Entry events having no drug exposures of ‘SGLT2 inhibitors’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

V. No prior SU exposure

+

Entry events having no drug exposures of ‘Sulfonylureas’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VI. No prior other anti-diabetic exposure

+

Entry events having no drug exposures of ‘Other anti-diabetics’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VII. No prior insulin use or combo initiation: Proxy for < 30 days drug era anytime before index and no combination use on index

+

Entry events with all of the following criteria:

+
    +
  1. having no drug eras of ‘Insulin’, starting anytime up to 30 days before cohort entry start date; allow events outside observation period; with era length > 30 days.
    2. +
  2. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.
    3. +
+
+
+
+

A.16.3 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘sitagliptin’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

A.16.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

A.16.5 Concept: DPP4 inhibitors except sitagliptin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43013884 + +alogliptin + +1368001 + +RxNorm + +NO + +YES + +NO +
+40239216 + +linagliptin + +1100699 + +RxNorm + +NO + +YES + +NO +
+40166035 + +saxagliptin + +857974 + +RxNorm + +NO + +YES + +NO +
+1580747 + +sitagliptin + +593411 + +RxNorm + +YES + +YES + +NO +
+19122137 + +vildagliptin + +596554 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.16.6 Concept: sitagliptin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1580747 + +sitagliptin + +593411 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.16.7 Concept: SGLT2 inhibitors

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43526465 + +canagliflozin + +1373458 + +RxNorm + +NO + +YES + +NO +
+44785829 + +dapagliflozin + +1488564 + +RxNorm + +NO + +YES + +NO +
+45774751 + +empagliflozin + +1545653 + +RxNorm + +NO + +YES + +NO +
+793293 + +ertugliflozin + +1992672 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.16.8 Concept: Sulfonylureas

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1594973 + +chlorpropamide + +2404 + +RxNorm + +NO + +YES + +NO +
+1597756 + +glimepiride + +25789 + +RxNorm + +NO + +YES + +NO +
+1560171 + +glipizide + +4821 + +RxNorm + +NO + +YES + +NO +
+19097821 + +gliquidone + +25793 + +RxNorm + +NO + +YES + +NO +
+1559684 + +glyburide + +4815 + +RxNorm + +NO + +YES + +NO +
+1502809 + +tolazamide + +10633 + +RxNorm + +NO + +YES + +NO +
+1502855 + +tolbutamide + +10635 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.16.9 Concept: Other anti-diabetics

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1529331 + +acarbose + +16681 + +RxNorm + +NO + +YES + +NO +
+1530014 + +acetohexamide + +173 + +RxNorm + +NO + +YES + +NO +
+730548 + +bromocriptine + +1760 + +RxNorm + +NO + +YES + +NO +
+19033498 + +carbutamide + +2068 + +RxNorm + +NO + +YES + +NO +
+19001409 + +glibornuride + +102846 + +RxNorm + +NO + +YES + +NO +
+19059796 + +gliclazide + +4816 + +RxNorm + +NO + +YES + +NO +
+19001441 + +glymidine + +102848 + +RxNorm + +NO + +YES + +NO +
+1510202 + +miglitol + +30009 + +RxNorm + +NO + +YES + +NO +
+1502826 + +nateglinide + +274332 + +RxNorm + +NO + +YES + +NO +
+1525215 + +pioglitazone + +33738 + +RxNorm + +NO + +YES + +NO +
+1516766 + +repaglinide + +73044 + +RxNorm + +NO + +YES + +NO +
+1547504 + +rosiglitazone + +84108 + +RxNorm + +NO + +YES + +NO +
+1515249 + +troglitazone + +72610 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.16.10 Concept: Insulin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1596977 + +insulin, regular, human + +253182 + +RxNorm + +NO + +YES + +NO +
+1550023 + +insulin lispro + +86009 + +RxNorm + +NO + +YES + +NO +
+1567198 + +insulin aspart, human + +51428 + +RxNorm + +NO + +YES + +NO +
+1502905 + +insulin glargine + +274783 + +RxNorm + +NO + +YES + +NO +
+1513876 + +insulin lispro protamine, human + +314684 + +RxNorm + +NO + +YES + +NO +
+1531601 + +insulin aspart protamine, human + +352385 + +RxNorm + +NO + +YES + +NO +
+1586346 + +insulin, regular, pork + +221109 + +RxNorm + +NO + +YES + +NO +
+1544838 + +insulin glulisine, human + +400008 + +RxNorm + +NO + +YES + +NO +
+1516976 + +insulin detemir + +139825 + +RxNorm + +NO + +YES + +NO +
+1590165 + +insulin, regular, beef-pork + +235275 + +RxNorm + +NO + +YES + +NO +
+1513849 + +lente insulin, human + +314683 + +RxNorm + +NO + +YES + +NO +
+1562586 + +lente insulin, pork + +93108 + +RxNorm + +NO + +YES + +NO +
+1588986 + +insulin human, rDNA origin + +631657 + +RxNorm + +NO + +YES + +NO +
+1513843 + +lente insulin, beef-pork + +314682 + +RxNorm + +NO + +YES + +NO +
+1586369 + +ultralente insulin, human + +221110 + +RxNorm + +NO + +YES + +NO +
+35605670 + +insulin argine + +1740938 + +RxNorm + +NO + +YES + +NO +
+35602717 + +insulin degludec + +1670007 + +RxNorm + +NO + +YES + +NO +
+21600713 + +INSULINS AND ANALOGUES + +A10A + +ATC + +NO + +YES + +NO +
+19078608 + +insulin, protamine zinc, beef-pork 100 UNT/ML Injectable Suspension + +311053 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.16.11 Concept: Metformin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1503297 + +metformin + +6809 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.16.12 Concept: Secondary diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +NO + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.16.13 Concept: Type 1 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +NO + +YES + +NO +
+42689695 + +Eating disorder co-occurrent with diabetes mellitus type 1 + +1067201000000106 + +SNOMED + +NO + +YES + +NO +
+765533 + +Glaucoma due to diabetes mellitus type 1 + +60981000119103 + +SNOMED + +NO + +YES + +NO +
+43531006 + +Maturity onset diabetes of the young, type 1 + +609562003 + +SNOMED + +NO + +YES + +NO +
+765650 + +Cranial nerve palsy due to diabetes mellitus type 1 + +82561000119101 + +SNOMED + +NO + +YES + +NO +
+45770986 + +Retinopathy due to unstable diabetes mellitus type 1 + +706894000 + +SNOMED + +NO + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +NO + +YES + +NO +
+45768456 + +Neuropathy due to unstable diabetes mellitus type 1 + +706891008 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +NO + +YES + +NO +
+4128019 + +Brittle type 1 diabetes mellitus + +290002008 + +SNOMED + +NO + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.16.14 Concept: Type 2 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+443238 + +Diabetic - poor control + +268519009 + +SNOMED + +NO + +YES + +NO +
+201820 + +Diabetes mellitus + +73211009 + +SNOMED + +NO + +YES + +NO +
+442793 + +Complication due to diabetes mellitus + +74627003 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +YES + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +YES + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +YES + +YES + +NO +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +YES + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +YES + +YES + +NO +
+4016045 + +Diabetic - good control + +170763003 + +SNOMED + +NO + +YES + +NO +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +YES + +YES + +NO +
+43531009 + +Pregnancy and type 1 diabetes mellitus + +609566000 + +SNOMED + +YES + +YES + +NO +
+4024659 + +Gestational diabetes mellitus + +11687002 + +SNOMED + +YES + +YES + +NO +
+
+
+

A.16.15 Concept: GLP-1 receptor agonists

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774435 + +dulaglutide + +1551291 + +RxNorm + +NO + +YES + +NO +
+1583722 + +exenatide + +60548 + +RxNorm + +NO + +YES + +NO +
+40170911 + +liraglutide + +475968 + +RxNorm + +NO + +YES + +NO +
+44506754 + +lixisenatide + +1440051 + +RxNorm + +NO + +YES + +NO +
+793143 + +semaglutide + +1991302 + +RxNorm + +NO + +YES + +NO +
+44816332 + +albiglutide + +1534763 + +RxNorm + +NO + +YES + +NO +
+
+ +
+
+
+

A.17 New user of sitagliptin with prior T2DM and prior metformin and no insulin

+
+

A.17.1 Cohort Entry Events

+

People with continuous observation of 365 days before event may enter the cohort when observing any of the following:

+
    +
  1. drug exposure of ‘sitagliptin’ for the first time in the person’s history.
    2. +
+

Limit cohort entry events to the earliest event per person.

+

Restrict entry events to with all of the following criteria:

+
    +
  1. with the following event criteria: who are >= 18 years old.
    2. +
  2. having at least 1 condition occurrence of ‘Type 2 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
  3. having no condition occurrences of ‘Type 1 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    4. +
  4. having no condition occurrences of ‘Secondary diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    5. +
+
+
+

A.17.2 Additional Inclusion Criteria

+
+

I. Prior metformin use

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 drug era of ‘Metformin’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period; with era length >= 90 days.
    2. +
  2. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

II. No prior insulin use or combo initiation: Proxy for < 30 days drug era anytime before index and no combination use on index

+

Entry events with all of the following criteria:

+
    +
  1. having no drug eras of ‘Insulin’, starting anytime up to 30 days before cohort entry start date; allow events outside observation period; with era length > 30 days.
    2. +
  2. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.
    3. +
+
+
+
+

A.17.3 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘sitagliptin’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

A.17.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

A.17.5 Concept: sitagliptin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1580747 + +sitagliptin + +593411 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.17.6 Concept: Insulin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1596977 + +insulin, regular, human + +253182 + +RxNorm + +NO + +YES + +NO +
+1550023 + +insulin lispro + +86009 + +RxNorm + +NO + +YES + +NO +
+1567198 + +insulin aspart, human + +51428 + +RxNorm + +NO + +YES + +NO +
+1502905 + +insulin glargine + +274783 + +RxNorm + +NO + +YES + +NO +
+1513876 + +insulin lispro protamine, human + +314684 + +RxNorm + +NO + +YES + +NO +
+1531601 + +insulin aspart protamine, human + +352385 + +RxNorm + +NO + +YES + +NO +
+1586346 + +insulin, regular, pork + +221109 + +RxNorm + +NO + +YES + +NO +
+1544838 + +insulin glulisine, human + +400008 + +RxNorm + +NO + +YES + +NO +
+1516976 + +insulin detemir + +139825 + +RxNorm + +NO + +YES + +NO +
+1590165 + +insulin, regular, beef-pork + +235275 + +RxNorm + +NO + +YES + +NO +
+1513849 + +lente insulin, human + +314683 + +RxNorm + +NO + +YES + +NO +
+1562586 + +lente insulin, pork + +93108 + +RxNorm + +NO + +YES + +NO +
+1588986 + +insulin human, rDNA origin + +631657 + +RxNorm + +NO + +YES + +NO +
+1513843 + +lente insulin, beef-pork + +314682 + +RxNorm + +NO + +YES + +NO +
+1586369 + +ultralente insulin, human + +221110 + +RxNorm + +NO + +YES + +NO +
+35605670 + +insulin argine + +1740938 + +RxNorm + +NO + +YES + +NO +
+35602717 + +insulin degludec + +1670007 + +RxNorm + +NO + +YES + +NO +
+21600713 + +INSULINS AND ANALOGUES + +A10A + +ATC + +NO + +YES + +NO +
+19078608 + +insulin, protamine zinc, beef-pork 100 UNT/ML Injectable Suspension + +311053 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.17.7 Concept: Metformin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1503297 + +metformin + +6809 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.17.8 Concept: Secondary diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +NO + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.17.9 Concept: Type 1 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +NO + +YES + +NO +
+42689695 + +Eating disorder co-occurrent with diabetes mellitus type 1 + +1067201000000106 + +SNOMED + +NO + +YES + +NO +
+765533 + +Glaucoma due to diabetes mellitus type 1 + +60981000119103 + +SNOMED + +NO + +YES + +NO +
+43531006 + +Maturity onset diabetes of the young, type 1 + +609562003 + +SNOMED + +NO + +YES + +NO +
+765650 + +Cranial nerve palsy due to diabetes mellitus type 1 + +82561000119101 + +SNOMED + +NO + +YES + +NO +
+45770986 + +Retinopathy due to unstable diabetes mellitus type 1 + +706894000 + +SNOMED + +NO + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +NO + +YES + +NO +
+45768456 + +Neuropathy due to unstable diabetes mellitus type 1 + +706891008 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +NO + +YES + +NO +
+4128019 + +Brittle type 1 diabetes mellitus + +290002008 + +SNOMED + +NO + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.17.10 Concept: Type 2 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+443238 + +Diabetic - poor control + +268519009 + +SNOMED + +NO + +YES + +NO +
+201820 + +Diabetes mellitus + +73211009 + +SNOMED + +NO + +YES + +NO +
+442793 + +Complication due to diabetes mellitus + +74627003 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +YES + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +YES + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +YES + +YES + +NO +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +YES + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +YES + +YES + +NO +
+4016045 + +Diabetic - good control + +170763003 + +SNOMED + +NO + +YES + +NO +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +YES + +YES + +NO +
+43531009 + +Pregnancy and type 1 diabetes mellitus + +609566000 + +SNOMED + +YES + +YES + +NO +
+4024659 + +Gestational diabetes mellitus + +11687002 + +SNOMED + +YES + +YES + +NO +
+
+ +
+
+
+

A.18 New user of glipizide as 2nd-line treatment with prior T2DM and prior metformin

+
+

A.18.1 Cohort Entry Events

+

People with continuous observation of 365 days before event may enter the cohort when observing any of the following:

+
    +
  1. drug exposure of ‘glipizide’ for the first time in the person’s history.
    2. +
+

Limit cohort entry events to the earliest event per person.

+

Restrict entry events to with all of the following criteria:

+
    +
  1. with the following event criteria: who are >= 18 years old.
    2. +
  2. having at least 1 condition occurrence of ‘Type 2 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
  3. having no condition occurrences of ‘Type 1 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    4. +
  4. having no condition occurrences of ‘Secondary diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    5. +
+
+
+

A.18.2 Additional Inclusion Criteria

+
+

I. Prior metformin use

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 drug era of ‘Metformin’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period; with era length >= 90 days.
    2. +
  2. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

II. No prior GLP-1 RA exposure

+

Entry events having no drug exposures of ‘GLP-1 receptor agonists’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

III. No prior DPP4 inhibitor exposure

+

Entry events having no drug exposures of ‘DPP4 inhibitors’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

IV. No prior SGLT-2 inhibitor exposure

+

Entry events having no drug exposures of ‘SGLT2 inhibitors’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

V. No prior SU exposure

+

Entry events having no drug exposures of ‘Sulfonylureas except glipizide’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VI. No prior other anti-diabetic exposure

+

Entry events having no drug exposures of ‘Other anti-diabetics’, starting anytime on or before cohort entry start date; allow events outside observation period.

+
+
+

VII. No prior insulin use or combo initiation: Proxy for < 30 days drug era anytime before index and no combination use on index

+

Entry events with all of the following criteria:

+
    +
  1. having no drug eras of ‘Insulin’, starting anytime up to 30 days before cohort entry start date; allow events outside observation period; with era length > 30 days.
    2. +
  2. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.
    3. +
+
+
+
+

A.18.3 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘glipizide’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

A.18.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

A.18.5 Concept: DPP4 inhibitors

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43013884 + +alogliptin + +1368001 + +RxNorm + +NO + +YES + +NO +
+40239216 + +linagliptin + +1100699 + +RxNorm + +NO + +YES + +NO +
+40166035 + +saxagliptin + +857974 + +RxNorm + +NO + +YES + +NO +
+1580747 + +sitagliptin + +593411 + +RxNorm + +NO + +YES + +NO +
+19122137 + +vildagliptin + +596554 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.18.6 Concept: glipizide

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1560171 + +glipizide + +4821 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.18.7 Concept: SGLT2 inhibitors

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+43526465 + +canagliflozin + +1373458 + +RxNorm + +NO + +YES + +NO +
+44785829 + +dapagliflozin + +1488564 + +RxNorm + +NO + +YES + +NO +
+45774751 + +empagliflozin + +1545653 + +RxNorm + +NO + +YES + +NO +
+793293 + +ertugliflozin + +1992672 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.18.8 Concept: Sulfonylureas except glipizide

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1594973 + +chlorpropamide + +2404 + +RxNorm + +NO + +YES + +NO +
+1597756 + +glimepiride + +25789 + +RxNorm + +NO + +YES + +NO +
+1560171 + +glipizide + +4821 + +RxNorm + +YES + +YES + +NO +
+19097821 + +gliquidone + +25793 + +RxNorm + +NO + +YES + +NO +
+1559684 + +glyburide + +4815 + +RxNorm + +NO + +YES + +NO +
+1502809 + +tolazamide + +10633 + +RxNorm + +NO + +YES + +NO +
+1502855 + +tolbutamide + +10635 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.18.9 Concept: Other anti-diabetics

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1529331 + +acarbose + +16681 + +RxNorm + +NO + +YES + +NO +
+1530014 + +acetohexamide + +173 + +RxNorm + +NO + +YES + +NO +
+730548 + +bromocriptine + +1760 + +RxNorm + +NO + +YES + +NO +
+19033498 + +carbutamide + +2068 + +RxNorm + +NO + +YES + +NO +
+19001409 + +glibornuride + +102846 + +RxNorm + +NO + +YES + +NO +
+19059796 + +gliclazide + +4816 + +RxNorm + +NO + +YES + +NO +
+19001441 + +glymidine + +102848 + +RxNorm + +NO + +YES + +NO +
+1510202 + +miglitol + +30009 + +RxNorm + +NO + +YES + +NO +
+1502826 + +nateglinide + +274332 + +RxNorm + +NO + +YES + +NO +
+1525215 + +pioglitazone + +33738 + +RxNorm + +NO + +YES + +NO +
+1516766 + +repaglinide + +73044 + +RxNorm + +NO + +YES + +NO +
+1547504 + +rosiglitazone + +84108 + +RxNorm + +NO + +YES + +NO +
+1515249 + +troglitazone + +72610 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.18.10 Concept: Insulin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1596977 + +insulin, regular, human + +253182 + +RxNorm + +NO + +YES + +NO +
+1550023 + +insulin lispro + +86009 + +RxNorm + +NO + +YES + +NO +
+1567198 + +insulin aspart, human + +51428 + +RxNorm + +NO + +YES + +NO +
+1502905 + +insulin glargine + +274783 + +RxNorm + +NO + +YES + +NO +
+1513876 + +insulin lispro protamine, human + +314684 + +RxNorm + +NO + +YES + +NO +
+1531601 + +insulin aspart protamine, human + +352385 + +RxNorm + +NO + +YES + +NO +
+1586346 + +insulin, regular, pork + +221109 + +RxNorm + +NO + +YES + +NO +
+1544838 + +insulin glulisine, human + +400008 + +RxNorm + +NO + +YES + +NO +
+1516976 + +insulin detemir + +139825 + +RxNorm + +NO + +YES + +NO +
+1590165 + +insulin, regular, beef-pork + +235275 + +RxNorm + +NO + +YES + +NO +
+1513849 + +lente insulin, human + +314683 + +RxNorm + +NO + +YES + +NO +
+1562586 + +lente insulin, pork + +93108 + +RxNorm + +NO + +YES + +NO +
+1588986 + +insulin human, rDNA origin + +631657 + +RxNorm + +NO + +YES + +NO +
+1513843 + +lente insulin, beef-pork + +314682 + +RxNorm + +NO + +YES + +NO +
+1586369 + +ultralente insulin, human + +221110 + +RxNorm + +NO + +YES + +NO +
+35605670 + +insulin argine + +1740938 + +RxNorm + +NO + +YES + +NO +
+35602717 + +insulin degludec + +1670007 + +RxNorm + +NO + +YES + +NO +
+21600713 + +INSULINS AND ANALOGUES + +A10A + +ATC + +NO + +YES + +NO +
+19078608 + +insulin, protamine zinc, beef-pork 100 UNT/ML Injectable Suspension + +311053 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.18.11 Concept: Metformin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1503297 + +metformin + +6809 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.18.12 Concept: Secondary diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +NO + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.18.13 Concept: Type 1 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +NO + +YES + +NO +
+42689695 + +Eating disorder co-occurrent with diabetes mellitus type 1 + +1067201000000106 + +SNOMED + +NO + +YES + +NO +
+765533 + +Glaucoma due to diabetes mellitus type 1 + +60981000119103 + +SNOMED + +NO + +YES + +NO +
+43531006 + +Maturity onset diabetes of the young, type 1 + +609562003 + +SNOMED + +NO + +YES + +NO +
+765650 + +Cranial nerve palsy due to diabetes mellitus type 1 + +82561000119101 + +SNOMED + +NO + +YES + +NO +
+45770986 + +Retinopathy due to unstable diabetes mellitus type 1 + +706894000 + +SNOMED + +NO + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +NO + +YES + +NO +
+45768456 + +Neuropathy due to unstable diabetes mellitus type 1 + +706891008 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +NO + +YES + +NO +
+4128019 + +Brittle type 1 diabetes mellitus + +290002008 + +SNOMED + +NO + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.18.14 Concept: Type 2 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+443238 + +Diabetic - poor control + +268519009 + +SNOMED + +NO + +YES + +NO +
+201820 + +Diabetes mellitus + +73211009 + +SNOMED + +NO + +YES + +NO +
+442793 + +Complication due to diabetes mellitus + +74627003 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +YES + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +YES + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +YES + +YES + +NO +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +YES + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +YES + +YES + +NO +
+4016045 + +Diabetic - good control + +170763003 + +SNOMED + +NO + +YES + +NO +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +YES + +YES + +NO +
+43531009 + +Pregnancy and type 1 diabetes mellitus + +609566000 + +SNOMED + +YES + +YES + +NO +
+4024659 + +Gestational diabetes mellitus + +11687002 + +SNOMED + +YES + +YES + +NO +
+
+
+

A.18.15 Concept: GLP-1 receptor agonists

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774435 + +dulaglutide + +1551291 + +RxNorm + +NO + +YES + +NO +
+1583722 + +exenatide + +60548 + +RxNorm + +NO + +YES + +NO +
+40170911 + +liraglutide + +475968 + +RxNorm + +NO + +YES + +NO +
+44506754 + +lixisenatide + +1440051 + +RxNorm + +NO + +YES + +NO +
+793143 + +semaglutide + +1991302 + +RxNorm + +NO + +YES + +NO +
+44816332 + +albiglutide + +1534763 + +RxNorm + +NO + +YES + +NO +
+
+ +
+
+
+

A.19 New user of glipizide with prior T2DM and prior metformin and no insulin

+
+

A.19.1 Cohort Entry Events

+

People with continuous observation of 365 days before event may enter the cohort when observing any of the following:

+
    +
  1. drug exposure of ‘glipizide’ for the first time in the person’s history.
    2. +
+

Limit cohort entry events to the earliest event per person.

+

Restrict entry events to with all of the following criteria:

+
    +
  1. with the following event criteria: who are >= 18 years old.
    2. +
  2. having at least 1 condition occurrence of ‘Type 2 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
  3. having no condition occurrences of ‘Type 1 diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    4. +
  4. having no condition occurrences of ‘Secondary diabetes mellitus’, starting anytime on or before cohort entry start date; allow events outside observation period.
    5. +
+
+
+

A.19.2 Additional Inclusion Criteria

+
+

I. Prior metformin use

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 drug era of ‘Metformin’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period; with era length >= 90 days.
    2. +
  2. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

II. No prior insulin use or combo initiation: Proxy for < 30 days drug era anytime before index and no combination use on index

+

Entry events with all of the following criteria:

+
    +
  1. having no drug eras of ‘Insulin’, starting anytime up to 30 days before cohort entry start date; allow events outside observation period; with era length > 30 days.
    2. +
  2. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.
    3. +
+
+
+
+

A.19.3 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘glipizide’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

A.19.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

A.19.5 Concept: glipizide

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1560171 + +glipizide + +4821 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.19.6 Concept: Insulin

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1596977 + +insulin, regular, human + +253182 + +RxNorm + +NO + +YES + +NO +
+1550023 + +insulin lispro + +86009 + +RxNorm + +NO + +YES + +NO +
+1567198 + +insulin aspart, human + +51428 + +RxNorm + +NO + +YES + +NO +
+1502905 + +insulin glargine + +274783 + +RxNorm + +NO + +YES + +NO +
+1513876 + +insulin lispro protamine, human + +314684 + +RxNorm + +NO + +YES + +NO +
+1531601 + +insulin aspart protamine, human + +352385 + +RxNorm + +NO + +YES + +NO +
+1586346 + +insulin, regular, pork + +221109 + +RxNorm + +NO + +YES + +NO +
+1544838 + +insulin glulisine, human + +400008 + +RxNorm + +NO + +YES + +NO +
+1516976 + +insulin detemir + +139825 + +RxNorm + +NO + +YES + +NO +
+1590165 + +insulin, regular, beef-pork + +235275 + +RxNorm + +NO + +YES + +NO +
+1513849 + +lente insulin, human + +314683 + +RxNorm + +NO + +YES + +NO +
+1562586 + +lente insulin, pork + +93108 + +RxNorm + +NO + +YES + +NO +
+1588986 + +insulin human, rDNA origin + +631657 + +RxNorm + +NO + +YES + +NO +
+1513843 + +lente insulin, beef-pork + +314682 + +RxNorm + +NO + +YES + +NO +
+1586369 + +ultralente insulin, human + +221110 + +RxNorm + +NO + +YES + +NO +
+35605670 + +insulin argine + +1740938 + +RxNorm + +NO + +YES + +NO +
+35602717 + +insulin degludec + +1670007 + +RxNorm + +NO + +YES + +NO +
+21600713 + +INSULINS AND ANALOGUES + +A10A + +ATC + +NO + +YES + +NO +
+19078608 + +insulin, protamine zinc, beef-pork 100 UNT/ML Injectable Suspension + +311053 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.19.7 Concept: Metformin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1503297 + +metformin + +6809 + +RxNorm + +NO + +YES + +NO +
+
+
+

A.19.8 Concept: Secondary diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +NO + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.19.9 Concept: Type 1 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +NO + +YES + +NO +
+42689695 + +Eating disorder co-occurrent with diabetes mellitus type 1 + +1067201000000106 + +SNOMED + +NO + +YES + +NO +
+765533 + +Glaucoma due to diabetes mellitus type 1 + +60981000119103 + +SNOMED + +NO + +YES + +NO +
+43531006 + +Maturity onset diabetes of the young, type 1 + +609562003 + +SNOMED + +NO + +YES + +NO +
+765650 + +Cranial nerve palsy due to diabetes mellitus type 1 + +82561000119101 + +SNOMED + +NO + +YES + +NO +
+45770986 + +Retinopathy due to unstable diabetes mellitus type 1 + +706894000 + +SNOMED + +NO + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +NO + +YES + +NO +
+45768456 + +Neuropathy due to unstable diabetes mellitus type 1 + +706891008 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +NO + +YES + +NO +
+4128019 + +Brittle type 1 diabetes mellitus + +290002008 + +SNOMED + +NO + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +NO + +YES + +NO +
+
+
+

A.19.10 Concept: Type 2 diabetes mellitus

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+443238 + +Diabetic - poor control + +268519009 + +SNOMED + +NO + +YES + +NO +
+201820 + +Diabetes mellitus + +73211009 + +SNOMED + +NO + +YES + +NO +
+442793 + +Complication due to diabetes mellitus + +74627003 + +SNOMED + +NO + +YES + +NO +
+40484648 + +Type 1 diabetes mellitus uncontrolled + +444073006 + +SNOMED + +YES + +YES + +NO +
+201254 + +Type 1 diabetes mellitus + +46635009 + +SNOMED + +YES + +YES + +NO +
+435216 + +Disorder due to type 1 diabetes mellitus + +420868002 + +SNOMED + +YES + +YES + +NO +
+195771 + +Secondary diabetes mellitus + +8801005 + +SNOMED + +YES + +YES + +NO +
+761051 + +Complication due to secondary diabetes mellitus + +138811000119100 + +SNOMED + +YES + +YES + +NO +
+4016045 + +Diabetic - good control + +170763003 + +SNOMED + +NO + +YES + +NO +
+40484649 + +Type 1 diabetes mellitus well controlled + +444074000 + +SNOMED + +YES + +YES + +NO +
+43531009 + +Pregnancy and type 1 diabetes mellitus + +609566000 + +SNOMED + +YES + +YES + +NO +
+4024659 + +Gestational diabetes mellitus + +11687002 + +SNOMED + +YES + +YES + +NO +
+
+ +
+
+
+
+

B Exposure Cohort Definitions

+
+

B.1 Semaglutide (GLP-1RA) exposure

+
+

B.1.1 Cohort Entry Events

+

People enter the cohort when observing any of the following:

+
    +
  1. drug exposures of ‘semaglutide’.
    2. +
+
+
+

B.1.2 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘semaglutide’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

B.1.3 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

B.1.4 Concept: semaglutide

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+793143 + +semaglutide + +1991302 + +RxNorm + +NO + +YES + +NO +
+
+ +
+
+
+

B.2 Dulaglutide (GLP-1RA) exposure

+
+

B.2.1 Cohort Entry Events

+

People enter the cohort when observing any of the following:

+
    +
  1. drug exposures of ‘dulaglutide’.
    2. +
+
+
+

B.2.2 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘dulaglutide’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

B.2.3 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

B.2.4 Concept: dulaglutide

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774435 + +dulaglutide + +1551291 + +RxNorm + +NO + +YES + +NO +
+
+ +
+
+
+

B.3 Exenatide (GLP-1RA) exposure

+
+

B.3.1 Cohort Entry Events

+

People enter the cohort when observing any of the following:

+
    +
  1. drug exposures of ‘exenatide’.
    2. +
+
+
+

B.3.2 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘exenatide’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

B.3.3 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

B.3.4 Concept: exenatide

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1583722 + +exenatide + +60548 + +RxNorm + +NO + +YES + +NO +
+
+ +
+
+
+

B.4 Empagliflozin (SGLT2 inhibitor) exposure

+
+

B.4.1 Cohort Entry Events

+

People enter the cohort when observing any of the following:

+
    +
  1. drug exposures of ‘empagliflozin’.
    2. +
+
+
+

B.4.2 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘empagliflozin’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

B.4.3 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

B.4.4 Concept: empagliflozin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+45774751 + +empagliflozin + +1545653 + +RxNorm + +NO + +YES + +NO +
+
+ +
+
+
+

B.5 Sitagliptin (DPP4 inhibitor) exposure

+
+

B.5.1 Cohort Entry Events

+

People enter the cohort when observing any of the following:

+
    +
  1. drug exposures of ‘sitagliptin’.
    2. +
+
+
+

B.5.2 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘sitagliptin’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

B.5.3 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

B.5.4 Concept: sitagliptin

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1580747 + +sitagliptin + +593411 + +RxNorm + +NO + +YES + +NO +
+
+ +
+
+
+

B.6 Glipizide (Sulfonylurea) exposure

+
+

B.6.1 Cohort Entry Events

+

People enter the cohort when observing any of the following:

+
    +
  1. drug exposures of ‘glipizide’.
    2. +
+
+
+

B.6.2 Cohort Exit

+

The cohort end date will be based on a continuous exposure to ‘glipizide’: +allowing 30 days between exposures, adding 0 days after exposure ends, and using days supply and exposure end date for exposure duration.

+
+
+

B.6.3 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

B.6.4 Concept: glipizide

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+1560171 + +glipizide + +4821 + +RxNorm + +NO + +YES + +NO +
+
+ +
+
+
+
+

C Outcome Cohort Definitions

+
+

C.1 Nonarteric anterior ischemic neuropathy with index date correction and 2dxGCA

+
+

C.1.1 Cohort Entry Events

+

People may enter the cohort when observing any of the following:

+
    +

  1. condition occurrences of ‘Nonarteritic Anterior Ischemic Optic Neuropathy’.

    2. +

  2. condition occurrences of ‘presention conditons for index date correction’.

    3. +
+
+
+

C.1.2 Additional Inclusion Criteria

+
+

I. no giant cell arteritis (defined by 2x diagnosis)

+

Entry events with at most 0 of the following criteria:

+
    +
  1. having at least 2 distinct start dates from condition occurrences of ‘Giant cell arteritis or arteritic ischemic optic neuropathy’.
    2. +
+
+
+

II. has NAION in 60d

+

Entry events having at least 1 condition occurrence of ‘Nonarteritic Anterior Ischemic Optic Neuropathy’, starting between 0 days before and 60 days after cohort entry start date.

+
+
+

III. no traumatic optic nerve injury on or prior

+

Entry events having no condition occurrences of ‘traumatic optic nerve injury’, starting anytime on or before cohort entry start date.

+

Limit qualifying entry events to the earliest event per person.

+
+
+
+

C.1.3 Cohort Exit

+

The person also exists the cohort at the end of continuous observation.

+
+
+

C.1.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

C.1.5 Concept: Nonarteritic Anterior Ischemic Optic Neuropathy

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+373487 + +Ischemic optic neuropathy + +14357004 + +SNOMED + +NO + +YES + +NO +
+4047917 + +Arteritic ischemic optic neuropathy + +230508004 + +SNOMED + +YES + +YES + +NO +
+
+
+

C.1.6 Concept: Giant cell arteritis or arteritic ischemic optic neuropathy

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+4290976 + +Temporal arteritis + +400130008 + +SNOMED + +NO + +YES + +NO +
+37116696 + +Arteritic anterior ischemic optic neuropathy + +733506009 + +SNOMED + +NO + +YES + +NO +
+
+
+

C.1.7 Concept: presention conditons for index date correction

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+4134605 + +Optic disc disorder + +128331005 + +SNOMED + +NO + +YES + +NO +
+374954 + +Optic neuritis + +66760008 + +SNOMED + +NO + +YES + +NO +
+377286 + +Visual field defect + +12184005 + +SNOMED + +NO + +YES + +NO +
+4308632 + +Optic disc edema + +423341008 + +SNOMED + +NO + +YES + +NO +
+
+
+

C.1.8 Concept: traumatic optic nerve injury

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+375428 + +Traumatic optic nerve injury + +48233004 + +SNOMED + +NO + +YES + +NO +
+
+ +
+
+
+

C.2 Nonarteric anterior ischemic neuropathy with index date correction and 2nd dx and 2dxGCA

+
+

C.2.1 Cohort Entry Events

+

People may enter the cohort when observing any of the following:

+
    +

  1. condition occurrences of ‘Nonarteritic Anterior Ischemic Optic Neuropathy’.

    2. +

  2. condition occurrences of ‘presention conditons for index date correction’.

    3. +
+
+
+

C.2.2 Additional Inclusion Criteria

+
+

I. no giant cell arteritis (2dx)

+

Entry events with at most 0 of the following criteria:

+
    +
  1. having at least 2 distinct start dates from condition occurrences of ‘Giant cell arteritis or arteritic ischemic optic neuropathy’, allow events outside observation period.
    2. +
+
+
+

II. has 2+ NAION diagnosis with one in 60d of index and another in 90d

+

Entry events having at least 1 condition occurrence of ‘Nonarteritic Anterior Ischemic Optic Neuropathy’, starting between 0 days before and 60 days after cohort entry start date; having at least 1 condition occurrence of ‘Nonarteritic Anterior Ischemic Optic Neuropathy’, starting between 1 days after and 90 days after ‘Nonarteritic Anterior Ischemic Optic Neuropathy’ start date.

+
+
+

III. no traumatic optic nerve injury on or prior

+

Entry events having no condition occurrences of ‘traumatic optic nerve injury’, starting anytime on or before cohort entry start date; allow events outside observation period.

+

Limit qualifying entry events to the earliest event per person.

+
+
+
+

C.2.3 Cohort Exit

+

The person also exists the cohort at the end of continuous observation.

+
+
+

C.2.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

C.2.5 Concept: Nonarteritic Anterior Ischemic Optic Neuropathy

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+373487 + +Ischemic optic neuropathy + +14357004 + +SNOMED + +NO + +YES + +NO +
+4047917 + +Arteritic ischemic optic neuropathy + +230508004 + +SNOMED + +YES + +YES + +NO +
+
+
+

C.2.6 Concept: Giant cell arteritis or arteritic ischemic optic neuropathy

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+4290976 + +Temporal arteritis + +400130008 + +SNOMED + +NO + +YES + +NO +
+37116696 + +Arteritic anterior ischemic optic neuropathy + +733506009 + +SNOMED + +NO + +YES + +NO +
+
+
+

C.2.7 Concept: presention conditons for index date correction

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+4134605 + +Optic disc disorder + +128331005 + +SNOMED + +NO + +YES + +NO +
+374954 + +Optic neuritis + +66760008 + +SNOMED + +NO + +YES + +NO +
+377286 + +Visual field defect + +12184005 + +SNOMED + +NO + +YES + +NO +
+4308632 + +Optic disc edema + +423341008 + +SNOMED + +NO + +YES + +NO +
+
+
+

C.2.8 Concept: traumatic optic nerve injury

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+375428 + +Traumatic optic nerve injury + +48233004 + +SNOMED + +NO + +YES + +NO +
+
+ +
+
+
+

C.3 Proliferative diabetic retinopathy

+
+

C.3.1 Cohort Entry Events

+

People enter the cohort when observing any of the following:

+
    +
  1. condition occurrences of ‘Proliferative diabetic retinopathy’.
    2. +
+

Limit cohort entry events to the earliest event per person.

+
+
+

C.3.2 Cohort Exit

+

The person also exists the cohort at the end of continuous observation.

+
+
+

C.3.3 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

C.3.4 Concept: Proliferative diabetic retinopathy

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+380096 + +Proliferative retinopathy due to diabetes mellitus + +59276001 + +SNOMED + +NO + +YES + +NO +
+45763584 + +Proliferative retinopathy due to type 1 diabetes mellitus + +60971000119101 + +SNOMED + +YES + +YES + +NO +
+
+ +
+
+
+

C.4 Treatment-requiring Diabetic Retinopathy or Macular Edema

+
+

C.4.1 Cohort Entry Events

+

People may enter the cohort when observing any of the following:

+
    +

  1. drug exposures of ‘aflibercept ranibizumab and bevacizumab’.

    2. +

  2. procedure occurrences of ‘focal laser photocoagulation’.

    3. +

  3. procedure occurrences of ‘panretinal photocoagulation’.

    4. +
+

Limit cohort entry events to the earliest event per person.

+
+
+

C.4.2 Additional Inclusion Criteria

+
+

I. has DR or ME on or within 90d of treatment

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 condition occurrence of ‘Diabetic retinopathy’, starting between 90 days before and 0 days after cohort entry start date.
    2. +
  2. having at least 1 condition occurrence of ‘Macular edema’, starting between 90 days before and 0 days after cohort entry start date.
    3. +
+
+
+

II. has no AMD or RVO any time prior

+

Entry events with all of the following criteria:

+
    +
  1. having no condition occurrences of ‘Renal vein occlusion’, starting anytime on or before cohort entry start date; allow events outside observation period.
    2. +
  2. having no condition occurrences of ‘Age-related macular degeneration’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

III. has no DR or ME prior to 90d of treatment

+

Entry events with all of the following criteria:

+
    +
  1. having no condition occurrences of ‘Diabetic retinopathy’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period.
    2. +
  2. having no condition occurrences of ‘Macular edema’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period.
    3. +
+
+
+
+

C.4.3 Cohort Exit

+

The person also exists the cohort at the end of continuous observation.

+
+
+

C.4.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

C.4.5 Concept: aflibercept ranibizumab and bevacizumab

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40244266 + +aflibercept + +1232150 + +RxNorm + +NO + +YES + +NO +
+1397141 + +bevacizumab + +253337 + +RxNorm + +NO + +YES + +NO +
+19080982 + +ranibizumab + +595060 + +RxNorm + +NO + +YES + +NO +
+
+
+

C.4.6 Concept: Diabetic retinopathy

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+4174977 + +Retinopathy due to diabetes mellitus + +4855003 + +SNOMED + +NO + +YES + +NO +
+
+
+

C.4.7 Concept: Macular edema

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+4290333 + +Macular retinal edema + +37231002 + +SNOMED + +NO + +YES + +NO +
+4208200 + +Postoperative cystoid macular edema + +312920004 + +SNOMED + +YES + +YES + +NO +
+
+ +
+

C.4.9 Concept: Renal vein occlusion

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+440392 + +Retinal vascular occlusion + +73757007 + +SNOMED + +NO + +YES + +NO +
+4334245 + +Retinal artery occlusion + +232035005 + +SNOMED + +YES + +YES + +NO +
+437544 + +Arterial retinal branch occlusion + +50821009 + +SNOMED + +YES + +YES + +NO +
+4338905 + +Cilioretinal artery occlusion + +232036006 + +SNOMED + +YES + +YES + +NO +
+
+
+

C.4.10 Concept: focal laser photocoagulation

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+4219449 + +Focal laser photocoagulation of retina + +397538008 + +SNOMED + +NO + +YES + +NO +
+2111048 + +Destruction of localized lesion of retina (eg, macular edema, tumors), 1 or more sessions; photocoagulation + +67210 + +CPT4 + +NO + +YES + +NO +
+
+
+

C.4.11 Concept: panretinal photocoagulation

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+2111054 + +Treatment of extensive or progressive retinopathy (eg, diabetic retinopathy), photocoagulation + +67228 + +CPT4 + +NO + +YES + +NO +
+4162096 + +Laser photocoagulation to retina + +399867007 + +SNOMED + +NO + +YES + +NO +
+4013503 + +Repair of retina for retinal tear or defect by laser photocoagulation + +112969004 + +SNOMED + +YES + +YES + +NO +
+4309528 + +Repair of retinal detachment by laser photocoagulation + +85231002 + +SNOMED + +YES + +YES + +NO +
+
+ +
+
+
+

C.5 Treatment-requiring Diabetic Retinopathy or Macular Edema including vitrectomy

+
+

C.5.1 Cohort Entry Events

+

People may enter the cohort when observing any of the following:

+
    +

  1. drug exposures of ‘aflibercept ranibizumab and bevacizumab’.

    2. +

  2. procedure occurrences of ‘focal laser photocoagulation’.

    3. +

  3. procedure occurrences of ‘panretinal photocoagulation’.

    4. +

  4. procedure occurrences of ‘Mechanical vitrectomy’.

    5. +
+

Limit cohort entry events to the earliest event per person.

+
+
+

C.5.2 Additional Inclusion Criteria

+
+

I. has DR or ME on or within 90d of treatment

+

Entry events with any of the following criteria:

+
    +
  1. having at least 1 condition occurrence of ‘Diabetic retinopathy’, starting between 90 days before and 0 days after cohort entry start date.
    2. +
  2. having at least 1 condition occurrence of ‘Macular edema’, starting between 90 days before and 0 days after cohort entry start date.
    3. +
+
+
+

II. has no AMD or RVO any time prior

+

Entry events with all of the following criteria:

+
    +
  1. having no condition occurrences of ‘Renal vein occlusion’, starting anytime on or before cohort entry start date; allow events outside observation period.
    2. +
  2. having no condition occurrences of ‘Age-related macular degeneration’, starting anytime on or before cohort entry start date; allow events outside observation period.
    3. +
+
+
+

III. has no DR or ME prior to 90d of treatment

+

Entry events with all of the following criteria:

+
    +
  1. having no condition occurrences of ‘Diabetic retinopathy’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period.
    2. +
  2. having no condition occurrences of ‘Macular edema’, starting anytime up to 90 days before cohort entry start date; allow events outside observation period.
    3. +
+
+
+
+

C.5.3 Cohort Exit

+

The person also exists the cohort at the end of continuous observation.

+
+
+

C.5.4 Cohort Eras

+

Remaining events will be combined into cohort eras if they are within 0 days of each other.

+
+
+

C.5.5 Concept: Proliferative diabetic retinopathy

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+380096 + +Proliferative retinopathy due to diabetes mellitus + +59276001 + +SNOMED + +NO + +YES + +NO +
+45763584 + +Proliferative retinopathy due to type 1 diabetes mellitus + +60971000119101 + +SNOMED + +YES + +YES + +NO +
+
+
+

C.5.6 Concept: aflibercept ranibizumab and bevacizumab

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+40244266 + +aflibercept + +1232150 + +RxNorm + +NO + +YES + +NO +
+1397141 + +bevacizumab + +253337 + +RxNorm + +NO + +YES + +NO +
+19080982 + +ranibizumab + +595060 + +RxNorm + +NO + +YES + +NO +
+
+
+

C.5.7 Concept: Diabetic retinopathy

+ + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+4174977 + +Retinopathy due to diabetes mellitus + +4855003 + +SNOMED + +NO + +YES + +NO +
+
+
+

C.5.8 Concept: Macular edema

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+4290333 + +Macular retinal edema + +37231002 + +SNOMED + +NO + +YES + +NO +
+4208200 + +Postoperative cystoid macular edema + +312920004 + +SNOMED + +YES + +YES + +NO +
+
+ +
+

C.5.10 Concept: Renal vein occlusion

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+440392 + +Retinal vascular occlusion + +73757007 + +SNOMED + +NO + +YES + +NO +
+4334245 + +Retinal artery occlusion + +232035005 + +SNOMED + +YES + +YES + +NO +
+437544 + +Arterial retinal branch occlusion + +50821009 + +SNOMED + +YES + +YES + +NO +
+4338905 + +Cilioretinal artery occlusion + +232036006 + +SNOMED + +YES + +YES + +NO +
+
+
+

C.5.11 Concept: focal laser photocoagulation

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+4219449 + +Focal laser photocoagulation of retina + +397538008 + +SNOMED + +NO + +YES + +NO +
+2111048 + +Destruction of localized lesion of retina (eg, macular edema, tumors), 1 or more sessions; photocoagulation + +67210 + +CPT4 + +NO + +YES + +NO +
+
+
+

C.5.12 Concept: panretinal photocoagulation

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+2111054 + +Treatment of extensive or progressive retinopathy (eg, diabetic retinopathy), photocoagulation + +67228 + +CPT4 + +NO + +YES + +NO +
+4162096 + +Laser photocoagulation to retina + +399867007 + +SNOMED + +NO + +YES + +NO +
+4013503 + +Repair of retina for retinal tear or defect by laser photocoagulation + +112969004 + +SNOMED + +YES + +YES + +NO +
+4309528 + +Repair of retinal detachment by laser photocoagulation + +85231002 + +SNOMED + +YES + +YES + +NO +
+
+
+

C.5.13 Concept: Mechanical vitrectomy

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Concept ID + +Concept Name + +Code + +Vocabulary + +Excluded + +Descendants + +Mapped +
+4314406 + +Mechanical vitrectomy by pars plana approach + +87021001 + +SNOMED + +NO + +YES + +NO +
+4246506 + +Mechanical vitrectomy + +60177007 + +SNOMED + +NO + +YES + +NO +
+45889738 + +Vitrectomy, mechanical, pars plana approach + +1014238 + +CPT4 + +NO + +YES + +NO +
+2111009 + +Removal of lens material; pars plana approach, with or without vitrectomy + +66852 + +CPT4 + +YES + +NO + +NO +
+
+ +
+
+
+
+

D Negative Control Concepts

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+Table D.1: Negative outcome controls specified through condition occurrences that map to (a descendent of) the indicated concept ID +
+ +Concept ID +
+439935 + +Abnormal posture +
+443585 + +Abrasion and/or friction burn of multiple sites +
+199192 + +Abrasion and/or friction burn of trunk without infection +
+4088290 + +Absence of breast +
+4092879 + +Absent kidney +
+75911 + +Acquired hallux valgus +
+137951 + +Acquired keratoderma +
+73241 + +Anal and rectal polyp +
+45757682 + +Anomaly of jaw size +
+81878 + +Benign paroxysmal positional vertigo +
+4216219 + +Bizarre personal appearance +
+133655 + +Burn of forearm +
+134765 + +Cachexia +
+73560 + +Calcaneal spur +
+434327 + +Cannabis abuse +
+140842 + +Changes in skin texture +
+81378 + +Chondromalacia of patella +
+432303 + +Cocaine abuse +
+4201390 + +Colostomy present +
+46269889 + +Complication due to Crohn’s disease +
+434675 + +Complication of gastrostomy +
+134438 + +Contact dermatitis +
+78619 + +Contusion of knee +
+201606 + +Crohn’s disease +
+76786 + +Derangement of knee +
+436077 + +Developmental delay +
+377910 + +Deviated nasal septum +
+4115402 + +Difficulty sleeping +
+45757370 + +Disproportion of reconstructed breast +
+433111 + +Effects of hunger +
+433527 + +Endometriosis +
+4170770 + +Epidermoid cyst +
+437448 + +Exhaustion due to excessive exertion +
+4092896 + +Feces contents abnormal +
+4092896 + +Feces contents abnormal +
+374801 + +Foreign body in ear +
+259995 + +Foreign body in orifice +
+4096540 + +Foreskin deficient +
+439788 + +Galactosemia +
+40481632 + +Ganglion cyst +
+40481632 + +Ganglion cyst +
+4168318 + +Genetic disorder carrier +
+433577 + +Hammer toe +
+4231770 + +Hereditary thrombophilia +
+4012570 + +High risk sexual behavior +
+4012934 + +Homocystinuria +
+374375 + +Impacted cerumen +
+374375 + +Impacted cerumen +
+4344500 + +Impingement syndrome of shoulder region +
+40481897 + +Inadequate sleep hygiene +
+139099 + +Ingrowing nail +
+444132 + +Injury of knee +
+4265896 + +Jellyfish poisoning +
+432593 + +Kwashiorkor +
+434203 + +Late effect of contusion +
+438329 + +Late effect of motor vehicle accident +
+4027782 + +Lipid storage disease +
+433997 + +Lymphangioma +
+4051630 + +Malingering +
+258540 + +Marfan’s syndrome +
+432798 + +Mechanical complication of internal orthopedic device, implant AND/OR graft +
+4103703 + +Melena +
+439795 + +Minimal cognitive impairment +
+4209423 + +Nicotine dependence +
+4209423 + +Nicotine dependence +
+377572 + +Noise effects on inner ear +
+136368 + +Non-toxic multinodular goiter +
+40480893 + +Nonspecific tuberculin test reaction +
+40480893 + +Nonspecific tuberculin test reaction +
+438130 + +Opioid abuse +
+438130 + +Opioid abuse +
+4299094 + +Opioid intoxication +
+4091513 + +Passing flatus +
+437092 + +Physiological development failure +
+433951 + +Poisoning by tranquilizer +
+4202045 + +Postviral fatigue syndrome +
+439790 + +Psychalgia +
+81634 + +Ptotic breast +
+380706 + +Regular astigmatism +
+141932 + +Senile hyperkeratosis +
+4019836 + +Social exclusion +
+36713918 + +Somatic dysfunction of lumbar region +
+443172 + +Splinter of face without major open wound +
+81151 + +Sprain of ankle +
+72748 + +Strain of rotator cuff capsule +
+432436 + +Symbolic dysfunction +
+378427 + +Tear film insufficiency +
+437264 + +Tobacco dependence syndrome +
+433244 + +Tooth loss +
+436876 + +Toxic effect of lead compound +
+440612 + +Toxic effect of tobacco and nicotine +
+4201387 + +Tracheostomy present +
+45757285 + +Unsatisfactory tooth restoration +
+140641 + +Verruca vulgaris +
+4115367 + +Wrist joint pain +
+440193 + +Wristdrop +
+
+ + + +
+
+ +
+ + + + + + + + + + + + + + + + diff --git a/docs/semaglutide-ndp-protocol.Rproj b/docs/semaglutide-ndp-protocol.Rproj new file mode 100644 index 00000000..e83436a3 --- /dev/null +++ b/docs/semaglutide-ndp-protocol.Rproj @@ -0,0 +1,16 @@ +Version: 1.0 + +RestoreWorkspace: Default +SaveWorkspace: Default +AlwaysSaveHistory: Default + +EnableCodeIndexing: Yes +UseSpacesForTab: Yes +NumSpacesForTab: 2 +Encoding: UTF-8 + +RnwWeave: Sweave +LaTeX: pdfLaTeX + +AutoAppendNewline: Yes +StripTrailingWhitespace: Yes diff --git a/docs/style.css b/docs/style.css new file mode 100644 index 00000000..4354b6d4 --- /dev/null +++ b/docs/style.css @@ -0,0 +1,13 @@ +#TOC::before { + content: ""; + display: block; + height: 50px; + margin: 5px 0px 5px 0px; + background-image: url("OHDSI_toc_header.png"); + background-size: contain; + background-position: center center; + background-repeat: no-repeat; +} +h1.title { + text-align: center; +} diff --git a/docs/title.tex b/docs/title.tex new file mode 100644 index 00000000..7561c355 --- /dev/null +++ b/docs/title.tex @@ -0,0 +1 @@ +\thispagestyle{fancy} % from title.tex diff --git a/docs/utils.R b/docs/utils.R new file mode 100644 index 00000000..dbdc589f --- /dev/null +++ b/docs/utils.R @@ -0,0 +1,145 @@ +# Copyright 2021 Observational Health Data Sciences and Informatics +# +# This file is adapted from PrettyOutput.R in LegendT2dm: +# https://github.com/ohdsi-studies/LegendT2dm/blob/master/R/PrettyOutput.R +# +# Licensed under the Apache License, Version 2.0 (the "License"); +# you may not use this file except in compliance with the License. +# You may obtain a copy of the License at +# +# http://www.apache.org/licenses/LICENSE-2.0 +# +# Unless required by applicable law or agreed to in writing, software +# distributed under the License is distributed on an "AS IS" BASIS, +# WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied. +# See the License for the specific language governing permissions and +# limitations under the License. + +#' Print cohort definition with specified name +#' +#' @description +#' Outputs a cohort definition into human-readable \code{markdown} +#' +#' @param name Cohort name listed as section title +#' @param json JSON cohort definition to be printed +#' @param obj Cohort object outputted from \code{CirceR} to be printed; can be \code{NULL} +#' in which case \code{json} is used. +#' @param withConcepts Boolean: Include concept lists in output? +#' @param withClosing Boolean: Add the output from \code{printCohortClose} to end? +#' +#' @export +printCohortDefinitionFromNameAndJson <- function(name, json = NULL, obj = NULL, + withConcepts = TRUE, + withClosing = TRUE) { + + if (is.null(obj)) { + obj <- CirceR::cohortExpressionFromJson(json) + } + + writeLines(paste("##", name, "\n")) + + # Print main definition + markdown <- CirceR::cohortPrintFriendly(obj) + + markdown <- gsub("criteria:\\r\\n ", "criteria:\\\r\\\n\\\r\\\n ", markdown) + markdown <- gsub("old.\\r\\n\\r\\n", "old.\\\r\\\n", markdown) + + markdown <- gsub("The person exits the cohort", "\\\r\\\nThe person also exists the cohort", markdown) + markdown <- gsub("following events:", "following events:\\\r\\\n", markdown) + + markdown <- sub("### Inclusion Criteria", "### Additional Inclusion Criteria\n", markdown) + + markdown <- unnumberAdditionalCriteria(markdown) + markdown <- stringr::str_replace_all( + markdown, "#### (\\d+).", + function(matched_str) { + digit <- stringr::str_extract(matched_str, stringr::regex("\\d+")) + paste0("#### ", utils::as.roman(digit), ".") + } + ) + + rows <- unlist(strsplit(markdown, "\\r\\n")) + rows <- gsub("^ ", "", rows) + markdown <- paste(rows, collapse = "\n") + + writeLines(markdown) + + # Print concept sets + + if (withConcepts) { + lapply(obj$conceptSets, printConceptSet) + } + + if (withClosing) { + printCohortClose() + } +} + + +#' Print concept set +#' +#' @description +#' Outputs a concept set into human-readable \code{markdown} +#' +#' @param conceptSet JSON concept set definition to be printed +#' @param latexTableFontSize Font size to use if output will be converted to PDF via \code{latex} +#' +#' @export +printConceptSet <- function(conceptSet, + latexTableFontSize = 8) { + + markdown <- CirceR::conceptSetPrintFriendly(conceptSet) + rows <- unlist(strsplit(markdown, "\\r\\n")) + rows <- gsub("^\\|", "", rows) + rows <- gsub("\\|$", "", rows) + header <- rows[1] + data <- readr::read_delim(paste(rows[c(2,4:(length(rows)-2))], + collapse = '\n'), + delim = '|', col_types = "ccccccc") + + header <- gsub("###", "### Concept:", header) + + tab <- data %>% mutate_if(is.numeric, format, digits = 10) %>% knitr::kable(linesep = "", booktabs = TRUE, longtable = TRUE) + + if (knitr::is_latex_output()) { + writeLines(header) + + writeLines(tab %>% + kableExtra::kable_styling(latex_options = "striped", font_size = latexTableFontSize) %>% + kableExtra::column_spec(1, width = "5em") %>% + kableExtra::column_spec(2, width = "20em")) + } else if (knitr::is_html_output()) { + writeLines(header) + + writeLines(tab %>% + kableExtra::kable_styling(bootstrap_options = "striped")) + } else { + writeLines(markdown) + } +} + + +#' Print cohort closing line +#' +#' @description +#' Outputs a cohort closing line in \code{markdown} +#' +#' @export +printCohortClose <- function() { + writeLines("") + if (knitr::is_html_output()) { + writeLines("
") + } else { + writeLines("------") + } + writeLines("") +} + +#' Find the subsections corresponding to additional criteria and unnumber them. +unnumberAdditionalCriteria <- function(markdown) { + markdown <- stringr::str_replace_all( + markdown, "#### (\\d+).(.*)", + function(matched_str) { paste(matched_str, "{-}") } + ) + return(markdown) +} From 26a016bec58c55054eca19c10772133eb3db99a4 Mon Sep 17 00:00:00 2001 From: Erik Westlund Date: Mon, 12 Aug 2024 15:30:03 -0400 Subject: [PATCH 2/2] docs: Link to protocol.html from README.md --- README.md | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/README.md b/README.md index 17856700..57379a8f 100644 --- a/README.md +++ b/README.md @@ -10,7 +10,7 @@ Estimation of risk of NAION and other vision disorders from exposure to semaglut - Study lead forums tag: **[[Cindy X. Cai]](https://forums.ohdsi.org/u/cindyxcai)** - Study start date: **-** - Study end date: **-** -- Protocol: **docs/Semaglutide and NAION Research Protocol.pdf** +- Protocol: **