Tirzepatide vs Semaglutide in Individuals at Cardiovascular Risk But Without Diabetes.

Comparative Effectiveness of Tirzepatide and Semaglutide in Patients at Cardiovascular Risk With Overweight or Obesity But Without Diabetes

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Obesity; Overweight
• Intervention / Treatment: Drug: Tirzepatide; Drug: Semaglutide

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 100000

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02120
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Individuals aged 18 years or older at cardiovascular risk with overweight or obesity but without diabetes treated in clinical practice

Description

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:

• Men or women aged 18 years or older
• History of myocardial infarction, stroke, any surgical or percutaneous revascularization procedure
• Use of antihypertensive or lipid-lowering drugs
• Coronary, carotid, or peripheral artery disease
• BMI greater than or equal to 25.0 mg/m2

Exclusion Criteria:

• Medullary thyroid carcinoma
• MEN syndrome type 2
• Malignancy
• Type 1 diabetes
• Type 2 diabetes
• Secondary diabetes
• End-stage renal disease or dialysis
• Pregnancy
• History of bariatric surgery
• Prior use of pramlintide or any GLP-1-RA, except tirzepatide or semaglutide
• Cardiovascular event or intervention in the last 7 days

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Tirzepatide; Exposure group	Drug: Tirzepatide; Initiation of tirzepatide described in electronic health records is used as the exposure.
Injectable semaglutide; Reference group	Drug: Semaglutide; Initiation of injectable semaglutide described in electronic health records is used as the reference.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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
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

Other Outcome Measures

Outcome Measure	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
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

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Shirley Wang, PhD, ScM, Brigham and Women's Hospital; Principal Investigator: Nils Krüger, MD, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 10, 2026
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: May 23, 2026
• First Submitted That Met QC Criteria: May 23, 2026
• First Posted (Actual): June 2, 2026

Study Record Updates

• Last Update Posted (Actual): June 9, 2026
• Last Update Submitted That Met QC Criteria: June 5, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Overweight; Obesity; Amino Acids, Peptides, and Proteins; Proteins; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide Receptors; Receptors, G-Protein-Coupled; Receptors, Cell Surface; Membrane Proteins; Receptors, Gastrointestinal Hormone; Receptors, Peptide; Tirzepatide; semaglutide
• Other Study ID Numbers: 2018P002966-TIRZSEMA-MMO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No