RESEARCH PROTOCOL

Estimating the risk of non-arteritic ischemic optic neuropathy (NAION) and diabetic retinopathy (DR) progression associated with semaglutide exposure in patients with diabetes mellitus

Version: 1

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, ccai6@jhmi.edu
Michelle Hribar, PhD	Oregon Health & Science University, hribarm@ohsu.edu
	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 GLP-1 RAs (dulaglutide, and exenatide), and non-GLP-1 RA medications (including empagliflozin, sitagliptin, and glipizide) among adults with type 2 diabetes mellitus. To estimate the relative incidence rate of NAION and DR worsening associated with with GLP-1 RAs and non-GLP-1 RAs exposure compared with non-exposure.

Design: Retrospective study employing 1) an active comparator, new-user cohort design, 2) self-controlled case series.

Subjects: Adults (≥ 18 years) with type 2 diabetes mellitus who are 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: 1) New-User active Comparator Cohort Design: Patients who are new-users of 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 (dulaglutide and exenatide) with each of the comparators. 2) Self-Controlled Case Series: the incidence rate of NAION during periods of exposure with each of the T2DM medications will be compared to the incidence rate of NAION during control periods of non-exposure using Poisson regression models.

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. 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?

8 Research Methods

8.1 Study Design/Data Source(s)

This will be a retrospective cohort study employing 2 study designs: 1) 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, and 2) a self-controlled case-series. 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) For the new-user active comparator cohort design, 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. 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)

We will use the OHDSI open-source tool PheValuator to estimate the performance characteristics i.e., sensitivity, specificity, and positive (PPV) and negative (NPV) predictive value, of the two rule-based consortium developed definitions of NAION. PheValuator was designed to estimate the performance characteristics of phenotypes without the need for medical chart reviews. [12,13] The tool uses mathematical models to estimate the probability that a subject has the outcome of interest, in this case, NAION. The model is trained by comparing the characteristics, e.g., diagnosis codes, laboratory measurements, and drug prescriptions, of subjects with a high probability of having NAION to those with a low probability of having NAION. For example, subjects with 2 or more diagnosis codes for NAION on the same day have a high probability of having NAION and subjects with no diagnosis codes for NAION have a low probability of having NAION. The model was developed using three prediction windows after the index (diagnosis) event: 1-10 days, 11-20 days, and 21-30 days post-index. After the probabilistic model was developed, we applied the model to a large, randomly selected group of subjects from each database. Using these probabilities, we estimated the performance of the phenotype algorithms.

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.[14]

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

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).[15,16] The R package versioning history will be recorded using the renv file and stored in the study Github repository.

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.

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.

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.[17]

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.[18] 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.[16] Patients with T2DM and NAION diagnosed after the first year in the observation period will be included in the analysis. We will use Poisson regression models to compare the incidence rates of NAION while on-treatment with a T2DM medication relative to control time during the observation period. Control time will include periods during the study period when the patient had diagnosed T2DM and excludes the first 365 days of the observation period. Models will have separate adjustments for the pre-exposure time window and potential effects of seasonality and calendar time. Diagnostics will be run to evaluate whether this was an appropriate analysis.

10 Study Diagnostics

Residual bias can still remain in observational studies even after PS adjustment is applied to control for measured confounding.[19,20] To address this, we conduct negative control (falsification) outcome experiments for each comparison and outcome, assuming the null hypothesis of no differential effect (i.e., risk ratio (RR) = 1) is true for each negative control outcome. We identified 96 negative controls using a data-driven algorithm that selects OMOP condition concept occurrences with similar prevalence to the outcomes of interest but lacking evidence of association with exposures in published literature, drug product labels, and spontaneous reports.[21] These were then verified through expert review. The list of negative controls is provided below. From these experiments, we derive an empirical null distribution to account for residual study bias. Using this empirical null, we calibrate each RR estimate, its 95% confidence interval (CI), and the p-value to test for the null hypothesis. We consider an RR significantly different from the null if the calibrated p-value is below 0.05, without adjusting for multiple testing.

To ensure the reliability and generalizability of all comparisons, we evaluate study diagnostics while blinded to the results, and only present estimates that successfully pass these diagnostics.[22,23] For the primary analysis using the active comparator new-user cohort design, our diagnostics include: (1) preference score distributions between the target and comparator cohorts to evaluate empirical equipoise and population generalizability; (2) cohort balance before and after PS adjustment, defined by the absolute standardized mean differences (SMDs) on extensive patient characteristics for each target-comparator-analysis; (3) negative control calibration plots to assess residual bias, quantified by the Expected Absolute Systematic Error (EASE) derived from the empirical null distribution; and for the primary analysis (Cox PH model), (4) Kaplan-Meier plots to visually examine hazard ratio proportionality assumptions. A study passes diagnostics and contributes to the meta analysis if more than 10% of patients have preference scores between 0.3 and 0.7 on both arms, maximum SMD < 0.1 after PS adjustment, and EASE < 0.25. For the self-controlled case-series analysis, study diagnostics include (1) time trend check that tests for stable background hazards over time periods after PS adjustment, and (2) pre-exposure check to ensure comparative effects in 30 days pre-exposure do not significantly differ from the null to rule out reverse causality; a study passes diagnostics if the p-values for both checks are > 0.05. For both analyses we further evaluate the meta-analytic minimally detectable risk ratio (MDRR) as a proxy of statistical power and only admit a meta-analytic RR estimate if meta-analytic MDRR < 10.

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)	>0

10.2 Diagnostic Thresholds for Self-Controlled Case-Series

Study Diagnostics	Threshold
Pre-exposure	>0.05
Time Trend	>0.05
Residual Bias (Expected Absolute Systematic Error (EASE))	<0.25
Meta-analysis Minimum Detectable Relative Risk (MDRR)	>0

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

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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

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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

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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

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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

Swerdel JN, Hripcsak G, Ryan PB. PheValuator: Development and evaluation of a phenotype algorithm evaluator. Journal of Biomedical Informatics 2019;97:103258. doi:10.1016/j.jbi.2019.103258

13

Swerdel JN, Schuemie M, Murray G, et al. PheValuator 2.0: Methodological improvements for the PheValuator approach to semi-automated phenotype algorithm evaluation. Journal of Biomedical Informatics 2022;135:104177. doi:10.1016/j.jbi.2022.104177

14

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

15

OHDSI/Strategus. 2024.https://github.com/OHDSI/Strategus (accessed 29 Apr 2023).

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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

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Reps JM, Schuemie MJ, Suchard MA, et al. Design and implementation of a standardized framework to generate and evaluate patient-level prediction models using observational healthcare data. Journal of the American Medical Informatics Association: JAMIA 2018;25:969–75. doi:10.1093/jamia/ocy032

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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

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Schuemie MJ, Hripcsak G, Ryan PB, et al. Empirical confidence interval calibration for population-level effect estimation studies in observational healthcare data. Proceedings of the National Academy of Sciences of the United States of America 2018;115:2571–7. doi:10.1073/pnas.1708282114

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Schuemie MJ, Hripcsak G, Ryan PB, et al. Robust empirical calibration of p‐values using observational data. Statistics in Medicine 2016;35:3883–8. doi:10.1002/sim.6977

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Voss EA, Boyce RD, Ryan PB, et al. Accuracy of an automated knowledge base for identifying drug adverse reactions. Journal of Biomedical Informatics 2017;66:72–81. doi:10.1016/j.jbi.2016.12.005

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Schuemie MJ, Cepeda MS, Suchard MA, et al. How Confident Are We about Observational Findings in Healthcare: A Benchmark Study. Harvard Data Science Review 2020;2. doi:10.1162/99608f92.147cc28e

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Schuemie MJ, Ryan PB, Hripcsak G, et al. Improving reproducibility by using high-throughput observational studies with empirical calibration. Philosophical Transactions Series A, Mathematical, Physical, and Engineering Sciences 2018;376:20170356. doi:10.1098/rsta.2017.0356

Appendix

A Indication Cohort

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’.

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

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

---

B Exposure Cohorts for Cohort Design

B.1 New user of semaglutide as 2nd-line treatment with prior T2DM and prior metformin

B.1.1 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.

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

B.1.2 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. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.

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. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.

B.1.3 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.

B.1.4 Cohort Eras

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

B.1.5 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

B.1.6 Concept: semaglutide

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

B.1.7 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

B.1.8 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

B.1.9 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

B.1.10 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

B.1.11 Concept: Metformin

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

B.1.12 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

B.1.13 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

B.1.14 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

B.1.15 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

---

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

B.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 ‘dulaglutide’ for the first time in the person’s history.

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

B.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. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.

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. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.

B.2.3 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.

B.2.4 Cohort Eras

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

B.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

B.2.6 Concept: dulaglutide

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

B.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

B.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

B.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

B.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

B.2.11 Concept: Metformin

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

B.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

B.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

B.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

B.2.15 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

---

B.3 New user of exenatide as 2nd-line treatment with prior T2DM and prior metformin

B.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 ‘exenatide’ for the first time in the person’s history.

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

B.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. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.

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. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.

B.3.3 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.

B.3.4 Cohort Eras

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

B.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

B.3.6 Concept: exenatide

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

B.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

B.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

B.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

B.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

B.3.11 Concept: Metformin

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

B.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

B.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

B.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

B.3.15 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

---

B.4 New user of empagliflozin as 2nd-line treatment with prior T2DM and p

B.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 ‘empagliflozin’ for the first time in the person’s history.

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

B.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. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.

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. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.

B.4.3 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.

B.4.4 Cohort Eras

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

B.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

B.4.6 Concept: empagliflozin

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

B.4.7 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

B.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

B.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

B.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

B.4.11 Concept: Metformin

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

B.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

B.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

B.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

B.4.15 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

---

B.5 New user of sitagliptin as 2nd-line treatment with prior T2DM and prior metformin

B.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 ‘sitagliptin’ for the first time in the person’s history.

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

B.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. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.

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. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.

B.5.3 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.

B.5.4 Cohort Eras

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

B.5.5 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

B.5.6 Concept: sitagliptin

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

B.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

B.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

B.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

B.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

B.5.11 Concept: Metformin

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

B.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

B.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

B.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

B.5.15 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

---

B.6 New user of glipizide as 2nd-line treatment with prior T2DM and prior metformin

B.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 ‘glipizide’ for the first time in the person’s history.

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

B.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. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.

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. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.

B.6.3 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.

B.6.4 Cohort Eras

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

B.6.5 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

B.6.6 Concept: glipizide

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

B.6.7 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

B.6.8 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

B.6.9 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

B.6.10 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

B.6.11 Concept: Metformin

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

B.6.12 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

B.6.13 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

B.6.14 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

B.6.15 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

---

B.7 New user of semaglutide with prior T2DM and prior metformin and no insulin

B.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 ‘semaglutide’ for the first time in the person’s history.

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

B.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. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.

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. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.

B.7.3 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.

B.7.4 Cohort Eras

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

B.7.5 Concept: semaglutide

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

B.7.6 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

B.7.7 Concept: Metformin

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

B.7.8 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

B.7.9 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

B.7.10 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.8 New user of empagliflozin with prior T2DM and prior metformin and no insulin

B.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 ‘empagliflozin’ for the first time in the person’s history.

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

B.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. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.

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. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.

B.8.3 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.

B.8.4 Cohort Eras

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

B.8.5 Concept: empagliflozin

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

B.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

B.8.7 Concept: Metformin

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

B.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

B.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

B.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

---

B.9 New user of sitagliptin with prior T2DM and prior metformin and no insulin

B.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 ‘sitagliptin’ for the first time in the person’s history.

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

B.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. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.

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. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.

B.9.3 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.

B.9.4 Cohort Eras

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

B.9.5 Concept: sitagliptin

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

B.9.6 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

B.9.7 Concept: Metformin

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

B.9.8 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

B.9.9 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

B.9.10 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.10 New user of glipizide with prior T2DM and prior metformin and no insulin

B.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 ‘glipizide’ for the first time in the person’s history.

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

B.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. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.

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. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.

B.10.3 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.

B.10.4 Cohort Eras

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

B.10.5 Concept: glipizide

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

B.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

B.10.7 Concept: Metformin

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

B.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

B.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

B.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

---

B.11 New user of dulaglutide with prior T2DM and prior metformin and no insulin

B.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 ‘dulaglutide’ for the first time in the person’s history.

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

B.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. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.

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. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.

B.11.3 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.

B.11.4 Cohort Eras

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

B.11.5 Concept: dulaglutide

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

B.11.6 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

B.11.7 Concept: Metformin

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

B.11.8 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

B.11.9 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

B.11.10 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.12 New user of exenatide with prior T2DM and prior metformin and no insulin

B.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 ‘exenatide’ for the first time in the person’s history.

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

B.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. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.

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. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.

B.12.3 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.

B.12.4 Cohort Eras

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

B.12.5 Concept: exenatide

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

B.12.6 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

B.12.7 Concept: Metformin

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

B.12.8 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

B.12.9 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

B.12.10 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.13 New user of semaglutide as 2nd-line treatment with prior T2DM Dec2017-Jan2020

B.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 ‘semaglutide’ for the first time in the person’s history.

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

B.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. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.

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. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.

VIII. index date between 1Dec2017 and 31Jan2020

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

B.13.3 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.

B.13.4 Cohort Eras

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

B.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

B.13.6 Concept: semaglutide

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

B.13.7 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

B.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

B.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

B.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

B.13.11 Concept: Metformin

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

B.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

B.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

B.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

B.13.15 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

---

B.14 New user of semaglutide as 2nd-line treatment with prior T2DM Feb2020-Jun2021

B.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 ‘semaglutide’ for the first time in the person’s history.

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

B.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. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.

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. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.

VIII. index date between 1Feb2020 and 30Jun2021

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

B.14.3 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.

B.14.4 Cohort Eras

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

B.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

B.14.6 Concept: semaglutide

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

B.14.7 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

B.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

B.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

B.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

B.14.11 Concept: Metformin

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

B.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

B.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

B.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

B.14.15 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

---

B.15 New user of semaglutide as 2nd-line treatment with prior T2DM Jul2021-Dec2023

B.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 ‘semaglutide’ for the first time in the person’s history.

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

B.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. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.

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. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.

VIII. index date between 1Jul2021 and 31Dec2023

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

B.15.3 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.

B.15.4 Cohort Eras

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

B.15.5 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

B.15.6 Concept: semaglutide

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

B.15.7 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

B.15.8 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

B.15.9 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

B.15.10 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

B.15.11 Concept: Metformin

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

B.15.12 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

B.15.13 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

B.15.14 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

B.15.15 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

---

B.16 New user of empagliflozin as 2nd-line treatment with prior T2DM Dec2017-Jan2020

B.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 ‘empagliflozin’ for the first time in the person’s history.

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

B.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. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.

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. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.

VIII. index date between 1Dec2017 and 31Jan2020

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

B.16.3 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.

B.16.4 Cohort Eras

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

B.16.5 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

B.16.6 Concept: empagliflozin

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

B.16.7 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

B.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

B.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

B.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

B.16.11 Concept: Metformin

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

B.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

B.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

B.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

B.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

---

B.17 New user of empagliflozin as 2nd-line treatment with prior T2DM Feb2020-Jun2021

B.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 ‘empagliflozin’ for the first time in the person’s history.

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

B.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. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.

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. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.

VIII. index date between 1Feb2020 and 30Jun2021

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

B.17.3 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.

B.17.4 Cohort Eras

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

B.17.5 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

B.17.6 Concept: empagliflozin

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

B.17.7 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

B.17.8 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

B.17.9 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

B.17.10 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

B.17.11 Concept: Metformin

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

B.17.12 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

B.17.13 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

B.17.14 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

B.17.15 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

---

B.18 New user of empagliflozin as 2nd-line treatment with prior T2DM Jul2021-Dec2023

B.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 ‘empagliflozin’ for the first time in the person’s history.

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

B.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. having at least 3 drug exposures of ‘Metformin’, starting anytime on or before cohort entry start date; allow events outside observation period.

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. having no drug eras of ‘Insulin’, starting between 30 days before and 0 days after cohort entry start date; allow events outside observation period.

VIII. index date between 1Jul2021 and 31Dec2023

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

B.18.3 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.

B.18.4 Cohort Eras

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

B.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

B.18.6 Concept: empagliflozin

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

B.18.7 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

B.18.8 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

B.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

B.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

B.18.11 Concept: Metformin

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

B.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

B.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

B.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

B.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

---

C Exposure Cohorts for SCCS

C.1 semaglutide exposures

C.1.1 Cohort Entry Events

People enter the cohort when observing any of the following:

1. drug exposures of ‘semaglutide’.

C.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.

C.1.3 Cohort Eras

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

C.1.4 Concept: semaglutide

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

---

C.2 dulaglutide exposures

C.2.1 Cohort Entry Events

People enter the cohort when observing any of the following:

1. drug exposures of ‘dulaglutide’.

C.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.

C.2.3 Cohort Eras

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

C.2.4 Concept: dulaglutide

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

---

C.3 exenatide exposures

C.3.1 Cohort Entry Events

People enter the cohort when observing any of the following:

1. drug exposures of ‘exenatide’.

C.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.

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: exenatide

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

---

C.4 empagliflozin exposures

C.4.1 Cohort Entry Events

People enter the cohort when observing any of the following:

1. drug exposures of ‘empagliflozin’.

C.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.

C.4.3 Cohort Eras

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

C.4.4 Concept: empagliflozin

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

---

C.5 sitagliptin exposures

C.5.1 Cohort Entry Events

People enter the cohort when observing any of the following:

1. drug exposures of ‘sitagliptin’.

C.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.

C.5.3 Cohort Eras

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

C.5.4 Concept: sitagliptin

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

---

C.6 glipizide exposures

C.6.1 Cohort Entry Events

People enter the cohort when observing any of the following:

1. drug exposures of ‘glipizide’.

C.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.

C.6.3 Cohort Eras

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

C.6.4 Concept: glipizide

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

---

D Outcome Cohorts

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

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

D.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’.

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.

D.1.3 Cohort Exit

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

D.1.4 Cohort Eras

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

D.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

D.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

D.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

D.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

---

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

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

D.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.

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.

D.2.3 Cohort Exit

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

D.2.4 Cohort Eras

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

D.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

D.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

D.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

D.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

---

D.3 Proliferative diabetic retinopathy

D.3.1 Cohort Entry Events

People enter the cohort when observing any of the following:

1. condition occurrences of ‘Proliferative diabetic retinopathy’.

Limit cohort entry events to the earliest event per person.

D.3.2 Cohort Exit

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

D.3.3 Cohort Eras

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

D.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

---

D.4 Treatment-requiring Diabetic Retinopathy or Macular Edema

D.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. procedure occurrences of ‘focal laser photocoagulation’.

3. procedure occurrences of ‘panretinal photocoagulation’.

Limit cohort entry events to the earliest event per person.

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

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

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

D.4.3 Cohort Exit

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

D.4.4 Cohort Eras

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

D.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

D.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

D.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

D.4.8 Concept: Age-related macular degeneration

Concept ID	Concept Name	Code	Vocabulary	Excluded	Descendants	Mapped
374028	Age related macular degeneration	267718000	SNOMED	NO	YES	NO
4224741	Degenerative disorder of macula	422338006	SNOMED	NO	NO	NO

D.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

D.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

D.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

---

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

D.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. procedure occurrences of ‘focal laser photocoagulation’.

3. procedure occurrences of ‘panretinal photocoagulation’.

4. procedure occurrences of ‘Mechanical vitrectomy’.

Limit cohort entry events to the earliest event per person.

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

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

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

D.5.3 Cohort Exit

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

D.5.4 Cohort Eras

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

D.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

D.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

D.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

D.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

D.5.9 Concept: Age-related macular degeneration

Concept ID	Concept Name	Code	Vocabulary	Excluded	Descendants	Mapped
374028	Age related macular degeneration	267718000	SNOMED	NO	YES	NO
4224741	Degenerative disorder of macula	422338006	SNOMED	NO	NO	NO

D.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

D.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

D.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

D.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

---

E Negative Control Concepts

Table E.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