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

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 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