Comparing Liraglutide, Semaglutide, and Dulaglutide in Veterans With Type 2 Diabetes: Which GLP-1 Drug Performs Best?

This was a comparative effectiveness study using a target trial-emulation design, linking national data from the VA health system, Medicare, and the US Renal Data System. Researchers identified veterans with type 2 diabetes who were new users of liraglutide, semaglutide, or dulaglutide between 2018 and 2021, all of whom were already on metformin and did not have end-stage kidney disease. They used weighted Cox regression models to compare outcomes including kidney failure, cardiovascular events, death, and gastrointestinal adverse events through March 2023.

GLP-1 receptor agonists have become a cornerstone of type 2 diabetes treatment, but most evidence comes from placebo-controlled trials rather than head-to-head comparisons. Clinicians and patients need to know whether one GLP-1RA offers meaningful advantages over another. This large real-world study provides reassurance that the three most commonly used GLP-1RAs are broadly comparable for heart and kidney protection, while flagging potential mortality differences that warrant confirmation in randomized trials.

As GLP-1 receptor agonists see rapidly expanding use for diabetes, obesity, and cardiorenal protection, understanding which agent to choose matters for individualized care. This study adds to a growing body of real-world evidence suggesting the class effect is largely consistent across agents for cardiovascular and kidney outcomes. The mortality signal favoring liraglutide is intriguing but could reflect residual confounding in observational data — the authors themselves call for head-to-head randomized trials to settle the question.

As an observational study, even with careful statistical adjustments, residual confounding cannot be ruled out — differences in why doctors prescribed one drug over another could influence outcomes. The study population was predominantly male veterans (91%), which limits generalizability to women and non-veteran populations. The mortality advantage for liraglutide lost significance in some per-protocol analyses, suggesting the finding may not be robust. Additionally, the study period (2018–2021) included the early COVID-19 pandemic, which may have affected outcomes in ways that are difficult to account for.