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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. It is intended to assess the comparative effectiveness of tirzepatide vs semaglutide on cardiovascular outcomes among patients at cardiovascular risk with overweight or obesity but without diabetes treated in clinical practice.
The SELECT trial (NCT03574597) demonstrated that semaglutide reduces major adverse cardiovascular events in individuals with established cardiovascular disease and overweight or obesity but without diabetes. Whether tirzepatide provides similar cardiovascular benefit in patients without diabetes is being evaluated in the ongoing placebo-controlled SURMOUNT-MMO trial (NCT05556512), with results expected in late 2027. Although SURMOUNT-MMO will assess the cardiovascular efficacy of tirzepatide in individuals without diabetes, evidence to inform treatment choices among available incretin-based therapies in clinical practice is urgently needed. Therefore, this study examines the comparative effectiveness of tirzepatide vs semaglutide among patients at cardiovascular risk with overweight or obesity but without diabetes in clinical practice.
Although many features of the target trial cannot be directly replicated in healthcare claims, key design features, including outcomes, exposures, and inclusion/exclusion criteria, were selected 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 study will be a new-user active-comparative study, conducted using 3 national United States claims databases, where we compare the effect of tirzepatide vs semaglutide on the composite end point of all-cause mortality, myocardial infarction, or stroke. Clinical guidelines during the study period recommended both tirzepatide and semaglutide for the same indications of glucose lowering and weight reduction.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tirzepatide | Exposure group |
| |
| Injectable semaglutide | Reference group |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tirzepatide | Drug | Initiation of tirzepatide described in electronic health records is used as the exposure. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Composite of all-cause mortality, myocardial infarction, or stroke. | To evaluate the comparative effect of tirzepatide vs injectable semaglutide on the composite of death, myocardial infarction, or stroke in patients at cardiovascular risk with overweight or obesity but without diabetes treated in clinical practice. | 1 day after prescription fill of exposure or comparator until outcome, end of data, end of study period, death, discontinuation (45 day grace, risk-window), nursing home admission, augmentation/additional exposure or switch to comparator or other GLP1-RA |
| Measure | Description | Time Frame |
|---|---|---|
| Individual components of the primary endpoint, i.e., all-cause mortality, myocardial infarction, or stroke | To evaluate the comparative effect of tirzepatide vs injectable semaglutide on the individual components of the primary endpoint, i.e., death, myocardial infarction, or stroke in patients at cardiovascular risk with overweight or obesity but without diabetes treated in clinical practice. | 1 day after prescription fill of exposure or comparator until outcome, end of data, end of study period, death, discontinuation (45 day grace, risk-window), nursing home admission, augmentation/additional exposure or switch to comparator or other GLP1-RA |
| Measure | Description | Time Frame |
|---|---|---|
| Urinary tract infections | To evaluate the comparative effect of tirzepatide vs injectable semaglutide on the safety outcome of urinary tract infections in patients at cardiovascular risk with overweight or obesity but without diabetes treated in clinical practice. | 1 day after prescription fill of exposure or comparator until outcome, end of data, end of study period, death, discontinuation (45 day grace, risk-window), nursing home admission, augmentation/additional exposure or switch to comparator or other GLP1-RA |
Study period:
Optum: Eligible cohort entry period between May 13, 2022 to November 30, 2025. MarketScan: Eligible cohort entry period between May 13, 2022 to September 30, 2023.
Medicare: Eligible cohort entry period between May 13, 2022 to September 30, 2024.
Inclusion Criteria:
Exclusion Criteria:
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Individuals aged 18 years or older at cardiovascular risk with overweight or obesity but without diabetes treated in clinical practice
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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 | Yes | No | No | Study Protocol | May 21, 2026 | Jun 4, 2026 | Prot_000.pdf |
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| ID | Term |
|---|---|
| D009765 | Obesity |
| D050177 | Overweight |
| ID | Term |
|---|---|
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
| D001835 | Body Weight |
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| ID | Term |
|---|---|
| D000098860 | Tirzepatide |
| C000591245 | semaglutide |
| 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 injectable semaglutide described in electronic health records is used as the reference. |
|
| Composite of myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or hospitalization for heart failure | To evaluate the comparative effect of tirzepatide vs injectable semaglutide on the composite of myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or hospitalization for heart failure in patients at cardiovascular risk with overweight or obesity but without diabetes treated in clinical practice. | 1 day after prescription fill of exposure or comparator until outcome, end of data, end of study period, death, discontinuation (45 day grace, risk-window), nursing home admission, augmentation/additional exposure or switch to comparator or other GLP1-RA |
| Hospitalization for heart failure | To evaluate the comparative effect of tirzepatide vs injectable semaglutide on the occurrence of heart failure hospitalizations in patients at cardiovascular risk with overweight or obesity but without diabetes treated in clinical practice. | 1 day after prescription fill of exposure or comparator until outcome, end of data, end of study period, death, discontinuation (45 day grace, risk-window), nursing home admission, augmentation/additional exposure or switch to comparator or other GLP1-RA |
| Hospitalization for unstable angina | To evaluate the comparative effect of tirzepatide vs injectable semaglutide on the occurrence of hospitalizations for unstable angina in patients at cardiovascular risk with overweight or obesity but without diabetes treated in clinical practice. | 1 day after prescription fill of exposure or comparator until outcome, end of data, end of study period, death, discontinuation (45 day grace, risk-window), nursing home admission, augmentation/additional exposure or switch to comparator or other GLP1-RA |
| Coronary revascularization | To evaluate the comparative effect of tirzepatide vs injectable semaglutide on the occurrence of coronary revascularization in patients at cardiovascular risk with overweight or obesity but without diabetes treated in clinical practice. | 1 day after prescription fill of exposure or comparator until outcome, end of data, end of study period, death, discontinuation (45 day grace, risk-window), nursing home admission, augmentation/additional exposure or switch to comparator or other GLP1-RA |
| Serious infections | To evaluate the comparative effect of tirzepatide vs injectable semaglutide on the safety outcome of serious infections in patients at cardiovascular risk with overweight or obesity but without diabetes treated in clinical practice. | 1 day after prescription fill of exposure or comparator until outcome, end of data, end of study period, death, discontinuation (45 day grace, risk-window), nursing home admission, augmentation/additional exposure or switch to comparator or other GLP1-RA |
| Gastrointestinal adverse events | To evaluate the comparative effect of tirzepatide vs injectable semaglutide on the safety outcome of gastrointestinal adverse events in patients at cardiovascular risk with overweight or obesity but without diabetes treated in clinical practice. | 1 day after prescription fill of exposure or comparator until outcome, end of data, end of study period, death, discontinuation (45 day grace, risk-window), nursing home admission, augmentation/additional exposure or switch to comparator or other GLP1-RA |
| Hernia | To evaluate the comparative effect of tirzepatide vs injectable semaglutide on the negative control outcome of hernia in patients at cardiovascular risk with overweight or obesity but without diabetes treated in clinical practice. | 1 day after prescription fill of exposure or comparator until outcome, end of data, end of study period, death, discontinuation (45 day grace, risk-window), nursing home admission, augmentation/additional exposure or switch to comparator or other GLP1-RA |
| Lumbar radiculopathy | To evaluate the comparative effect of tirzepatide vs injectable semaglutide on the negative control outcome of lumbar radiculopathy in patients at cardiovascular risk with overweight or obesity but without diabetes treated in clinical practice. | 1 day after prescription fill of exposure or comparator until outcome, end of data, end of study period, death, discontinuation (45 day grace, risk-window), nursing home admission, augmentation/additional exposure or switch to comparator or other GLP1-RA |
| 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 |