Despite similar kidney and cardiovascular protection across glucagon-like peptide-1 drugs, subtle differences in mortality and gastrointestinal safety may influence individualized treatment choices for patients with type 2 diabetes, according to a recent study published in JAMA Network Open.
In an active-comparator, new-user, target trial–emulation study using US Department of Veterans Affairs national data linked with Medicare and the US Renal Data System, researchers found that the glucagon-like peptide-1 receptor agonists (GLP-1RAs) liraglutide, semaglutide, and dulaglutide demonstrated similar effectiveness for kidney and cardiovascular outcomes in veterans with type 2 diabetes. The study also reported modest differences in mortality, with liraglutide associated with a lower risk of death compared with dulaglutide, and comparable gastrointestinal safety among all three agents.
The analysis compared liraglutide, semaglutide, and dulaglutide in 21,790 GLP-1RA–naive veterans with type 2 diabetes who were receiving metformin and did not have end-stage kidney disease. Between January 2018 and December 2021, 5,425 initiated liraglutide, 10,838 initiated semaglutide, and 5,527 initiated dulaglutide. Participants were followed through March 2023 (mean age 63.5 years; 91% male). Propensity scores were generated from 56 baseline variables, and inverse probability of treatment weighting was applied to balance covariates across treatment groups.
Primary outcomes included kidney failure, major adverse cardiovascular events—defined as myocardial infarction, heart failure, or stroke/transient ischemic attack—and a composite kidney–cardiovascular–metabolic outcome. Secondary outcomes included all-cause death and gastrointestinal adverse events. Median follow-up ranged from 2.7 to 3.0 years.
In weighted Cox regression analyses, there were no significant differences found among the GLP-1RAs for kidney failure, major adverse cardiovascular events, or composite kidney–cardiovascular–metabolic composite outcomes. Liraglutide was associated with a lower risk of all-cause death compared with semaglutide (hazard ratio [HR], 0.83) in intent-to-treat analysis and with dulaglutide in both intent-to-treat (HR, 0.69) and per-protocol (HR, 0.50) analyses. Dulaglutide had a higher mortality risk compared with semaglutide only in per-protocol analysis (HR, 1.72). Gastrointestinal adverse events were rare, though dulaglutide showed a reduced risk of gallstones (HR, 0.72) and acute cholecystitis (HR, 0.62) relative to semaglutide. Mean weight loss at 24 months was 9.7 pounds with liraglutide, 12.2 pounds with semaglutide, and 9.8 pounds with dulaglutide.
“These findings support the need for a future head-to-head randomized clinical trial comparing liraglutide vs semaglutide, particularly given that the GLP-1RAs will lose patent exclusivity and become more widely accessible,” noted lead author Catherine G. Derington, PharmD, MS, of the Department of Medicine, Division of Cardiology, University of Colorado School of Medicine, Aurora, and Adult & Child Center for Outcomes Research & Delivery Science, University of Colorado Anschutz Medical Campus, Aurora, and colleagues.
In an invited commentary, publihsed in JAMA Network Open, Patrick J. O’Connor, MD, MA, MPH, of HealthPartners Institute, Minneapolis, Minnesota, and Romain Neugebauer, PhD, of Kaiser Permanente Division of Research, Pleasanton, California, noted that incretin mimetics have transformed diabetes care and are increasingly used for patients with high cardiovascular risk. They observed that Derington et al’s analysis adds important real-world evidence, showing liraglutide and semaglutide provide comparable cardiorenal benefits, while dulaglutide may confer higher mortality risk. The commentators emphasized that comparative-effectiveness designs such as this emulate randomized trials at lower cost and with broader generalizability, but interpretation must consider residual confounding and analytic assumptions. “Although Derington et al provide evidence suggesting similar impact of liraglutide and semaglutide on a range of cardiorenal outcomes and overall mortality, the story is far from over,” they concluded.
Sydney E. Hartsell, MD, MPH, received grants from the National Kidney Foundation, Bayer, and Women in Nephrology; Stavros G. Drakos, MD, PhD, received personal fees from Abbott and Novartis; and Tom Greene, PhD, received research funding from the National Kidney Foundation, the Collaborative Study Group, the NIH, and the Patient-Centered Outcomes Research Institute; study funding was provided by the NIH, the Department of Veterans Affairs, and related institutional grants.
Patrick J. O’Connor, MD, MA, MPH, reported research support from multiple NIH institutes, the Agency for Healthcare Research and Quality, and the Patient-Centered Outcomes Research Institute outside the submitted work; no other disclosures were reported.
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