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Investigators are building an empirical evidence base for real world data through large-scale emulation of randomized controlled trials. The investigators' goal is to understand for what types of clinical questions real world data analyses can be conducted with confidence and how to implement such studies.
This is a non-randomized, non-interventional study that is part of the Randomized Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology (RCT-DUPLICATE) initiative (www.rctduplicate.org) of the Brigham and Women's Hospital, Harvard Medical School. Randomized controlled trials (RCTs) have demonstrated cardiovascular benefits of the modern incretin therapies semaglutide and tirzepatide in selected populations. SUSTAIN-6 (NCT01720446) and SURPASS-CVOT (NCT04255433) showed reductions in cardiovascular events with semaglutide and tirzepatide among patients with T2DM at high cardiovascular risk, findings that were also replicated in clinical practice settings (NCT06659744, NCT07088718). The REWIND trial (NCT01394952) demonstrated similar cardiovascular efficacy for dulaglutide and suggested benefit in both patients with and without prior cardiovascular disease.4 These findings raise the broader question of whether cardiovascular benefits of modern incretin therapies extend to individuals without established atherosclerotic cardiovascular disease (ASCVD) when used in routine clinical practice.
To address this question, this comparative effectiveness study using a target trial emulation framework will assess the incretin therapies dulaglutide, semaglutide, and tirzepatide vs sitagliptin (used as an active comparator placebo proxy) on major adverse cardiovascular events (MACE) among individuals with type 2 diabetes (T2DM) and overweight with or without ASCVD.
Although many features of the target trial cannot be directly replicated in healthcare claims, measurements of key design features, including outcomes, exposures, and inclusion/exclusion criteria, were designed to proxy those features from the target trial. Randomization cannot be achieved in healthcare claims data but was proxied through a statistical balancing of measured covariates according to standard practice.
The database analyses will be new-user active-comparative studies, conducted using 3 national United States claims databases, where we compare the effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on preventing atherosclerotic cardiovascular events.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Initiation of dulaglutide, semaglutide or tirzepatide | Exposure group. |
| |
| Initiation of sitagliptin | Reference group. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dulaglutide | Drug | Initiation of dulaglutide dispensing claim is used as the exposure. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Composite of myocardial infarction, stroke, or all-cause mortality (with ASCVD) | Hazard ratio of the composite of myocardial infarction, stroke, or all-cause mortality in individuals with T2DM and overweight with ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Composite of myocardial infarction, or stroke (with ASCVD) | Hazard ratio of the composite of myocardial infarction or stroke in individuals with T2DM and overweight with ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Composite of myocardial infarction, stroke, or all-cause mortality (without ASCVD) | Hazard ratio of the composite of myocardial infarction, stroke, or all-cause mortality in individuals with T2DM and overweight without ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Composite of myocardial infarction, or stroke (without ASCVD) | Hazard ratio of the composite of myocardial infarction or stroke in individuals with T2DM and overweight without ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Measure | Description | Time Frame |
|---|---|---|
| Myocardial infarction (with ASCVD) | Hazard ratio of the occurrence of myocardial infarction in individuals with T2DM and overweight with ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Measure | Description | Time Frame |
|---|---|---|
| Hernia (with ASCVD) | Hazard ratio of negative control outcome hernia in individuals with T2DM and overweight with ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
The database analyses will be new-user active-comparative studies, conducted using 3 national United States claims databases, where we compare the effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on preventing atherosclerotic cardiovascular events.
Optum: Eligible cohort entry period from September 18, 2014 to August 31, 2025. Marketscan: Eligible cohort entry from October 1, 2016 to October 31, 2023. Medicare: Eligible cohort entry from September 18, 2014 to October 31, 2020.
POPULATION WITH ASCVD
Inclusion Criteria:
Exclusion Criteria:
POPULATION WITHOUT ASCVD
Inclusion Criteria:
Exclusion Criteria:
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Individuals with T2DM and overweight with (or without) ASCVD.
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| Name | Affiliation | Role |
|---|---|---|
| Shirley Wang, PhD, ScM | Brigham and Women's Hospital | Principal Investigator |
| Nils Krüger, MD | Brigham and Women's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Brigham and Women's Hospital | Boston | Massachusetts | 02120 | United States |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan: Study Protocol | May 7, 2026 | May 8, 2026 | Prot_SAP_000.pdf |
| Prot | Yes | No | No | Study Protocol: Study Protocol Amendment | Jun 5, 2026 | Jun 16, 2026 | Prot_001.pdf |
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D050177 | Overweight |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| C555680 | dulaglutide |
| C000591245 | semaglutide |
| D000098860 | Tirzepatide |
| D000068900 | Sitagliptin Phosphate |
| ID | Term |
|---|---|
| D000067757 | Glucagon-Like Peptide-1 Receptor |
| D000067756 | Glucagon-Like Peptide Receptors |
| D043562 | Receptors, G-Protein-Coupled |
| D011956 | Receptors, Cell Surface |
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| Semaglutide | Drug | Initiation of semaglutide dispensing claim is used as the exposure. |
|
| Tirzepatide | Drug | Initiation of tirzepatide dispensing claim is used as the exposure. |
|
| Sitagliptin | Drug | Initiation of sitagliptin dispensing claim is used as the reference. |
|
| Stroke (with ASCVD) | Hazard ratio of the occurrence of stroke in individuals with T2DM and overweight with ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| All-cause mortality (with ASCVD) | Hazard ratio of the occurrence of all-cause mortality in individuals with T2DM and overweight with ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Composite of myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization (with ASCVD) | Hazard ratio of the composite of myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization in individuals with T2DM and overweight with ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Composite of myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or hospitalization for heart failure (with ASCVD) | Hazard ratio of the composite of myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or hospitalization for heart failure in individuals with T2DM and overweight with ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Unstable angina (with ASCVD) | Hazard ratio of the occurrence of unstable angina in individuals with T2DM and overweight with ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Coronary revascularization (with ASCVD) | Hazard ratio of the occurrence of coronary revascularization in individuals with T2DM and overweight with ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Hospitalization for heart failure (with ASCVD) | Hazard ratio of the occurrence of hospitalization for heart failure in individuals with T2DM and overweight with ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Time to first hospitalization for any cause (with ASCVD) | Hazard ratio of time to first hospitalization for any cause in individuals with T2DM and overweight with ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Myocardial infarction (without ASCVD) | Hazard ratio of the occurrence of myocardial infarction in individuals with T2DM and overweight without ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Stroke (without ASCVD) | Hazard ratio of the occurrence of stroke in individuals with T2DM and overweight without ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| All-cause mortality (without ASCVD) | Hazard ratio of the occurrence of all-cause mortality in individuals with T2DM and overweight without ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Composite of myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization (without ASCVD) | Hazard ratio of the composite of myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization in individuals with T2DM and overweight without ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Composite of myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or hospitalization for heart failure (without ASCVD). | Hazard ratio of the composite of myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or hospitalization for heart failure in individuals with T2DM and overweight without ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Unstable angina (without ASCVD) | Hazard ratio of the occurrence of unstable angina in individuals with T2DM and overweight without ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Coronary revascularization (without ASCVD) | Hazard ratio of the occurrence of coronary revascularization in individuals with T2DM and overweight without ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Hospitalization for heart failure (without ASCVD) | Hazard ratio of the occurrence of hospitalization for heart failure in individuals with T2DM and overweight without ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Time to first hospitalization for any cause (without ASCVD) | Hazard ratio of time to first hospitalization for any cause in individuals with T2DM and overweight without ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Urinary tract infections (with ASCVD) | Hazard ratio of the safety outcome of urinary tract infections in individuals with T2DM and overweight with ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Serious infections (with ASCVD) | Hazard ratio of the safety outcome of serious infections in individuals with T2DM and overweight with ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Gastrointestinal adverse events (with ASCVD) | Hazard ratio of the safety outcome of gastrointestinal adverse events in individuals with T2DM and overweight with ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Urinary tract infections (without ASCVD) | Hazard ratio of the safety outcome of urinary tract infections in individuals with T2DM and overweight without ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Serious infections (without ASCVD) | Hazard ratio of the safety outcome of serious infections in individuals with T2DM and overweight without ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Gastrointestinal adverse events (without ASCVD) | Hazard ratio of the safety outcome of gastrointestinal adverse events in individuals with T2DM and overweight without ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Lumbar radiculopathy (with ASCVD) | Hazard ratio of negative control outcome lumbar radiculopathy in individuals with T2DM and overweight with ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Hernia (without ASCVD) | Hazard ratio of negative control outcomes hernia in individuals with T2DM and overweight without ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| Lumbar radiculopathy (without ASCVD) | Hazard ratio of negative control outcomes lumbar radiculopathy in individuals with T2DM and overweight without ASCVD, comparing dulaglutide, semaglutide, and tirzepatide vs sitagliptin. | Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i |
| D004700 | Endocrine System Diseases |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D008565 | Membrane Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D011964 | Receptors, Gastrointestinal Hormone |
| D018000 | Receptors, Peptide |
| D014230 | Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011719 | Pyrazines |