Comparable Cardiorenal Outcomes Among Three GLP-1 Receptor Agonists in Veterans with Type 2 Diabetes: JAMA
USA: A retrospective comparative effectiveness study among veterans with type 2 diabetes found that three GLP-1 receptor agonists-semaglutide, liraglutide, and dulaglutide—showed similar risks for kidney failure and major cardiovascular events. However, mortality risks and some adverse events varied between agents. In the absence of head-to-head trials, these observational findings may help clinicians select appropriate GLP-1 therapies.
Published in JAMA Network Open, the study was led by Dr. Catherine G. Derington from the Department of Medicine, Division of Cardiology, University of Colorado School of Medicine, Aurora, and colleagues. The research aimed to evaluate whether individual GLP-1 receptor agonists differ in their effects on kidney, cardiovascular, and mortality outcomes among veterans with type 2 diabetes.
The study employed an active-comparator, new-user target trial–emulation design, utilizing national data from the U.S. Department of Veterans Affairs, Medicare, and the U.S. Renal Data System. It included 21,790 GLP-1RA–naive veterans with type 2 diabetes who were treated with metformin and initiated either liraglutide, semaglutide, or dulaglutide between January 2018 and December 2021. The participants, mostly male (91%) with a mean age of 63.5 years, were followed through March 2023 to assess outcomes including kidney failure, major adverse cardiovascular events (MACE), all-cause mortality, and gastrointestinal side effects.
The analysis revealed the following findings:
- No significant differences were observed among liraglutide, semaglutide, and dulaglutide in terms of kidney failure, composite kidney-cardiovascular-metabolic (CKM) events, or major adverse cardiovascular events (MACE).
- The hazard ratios for kidney failure, CKM outcomes, and MACE were comparable across all three drug groups.
- Liraglutide users showed a lower risk of all-cause mortality compared with dulaglutide users in both intent-to-treat and per-protocol analyses.
- Compared with semaglutide, liraglutide demonstrated a modest reduction in mortality risk in intent-to-treat analyses, though this finding was not statistically significant after further adjustment.
- Dulaglutide users had a higher risk of mortality compared with semaglutide users in per-protocol models.
- All three GLP-1 receptor agonists exhibited similar safety profiles for gastrointestinal adverse events.
- The only notable difference was a reduced risk of gallstones and acute cholecystitis in dulaglutide users compared with semaglutide users.
The authors highlighted that while the results indicate comparable kidney and cardiovascular benefits among the three agents, variations in mortality and certain adverse events warrant further exploration. Given the growing clinical use of GLP-1 receptor agonists for diabetes and obesity management, as well as their anticipated wider availability following patent expirations, these findings carry practical significance for clinicians.
Dr. Derington and colleagues concluded that although all three GLP-1 receptor agonists demonstrated similar overall effectiveness for kidney and cardiovascular outcomes, future head-to-head randomized clinical trials are essential to confirm these observational results and clarify potential differences in mortality and safety outcomes.
Reference:
Derington CG, Sarwal A, Wei G, et al. Liraglutide vs Semaglutide vs Dulaglutide in Veterans With Type 2 Diabetes. JAMA Netw Open. 2025;8(10):e2537297. doi:10.1001/jamanetworkopen.2025.37297
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