Liraglutide vs Semaglutide vs Dulaglutide in Veterans With Type 2 Diabetes

Importance The head-to-head comparative effectiveness and safety of individual glucagon-like peptide-1 receptor agonists (GLP-1RAs) are not well understood. Objective To compare risks of kidney, cardiovascular, and death outcomes among patients with type 2 diabetes initiating GLP-1RAs in the Department of Veterans Affairs (VA) health system. Design, Setting, and Participants This comparative effectiveness study used an active-comparator, new-user target trial–emulation design with national data linked among the VA, Medicare, and US Renal Data System. Participants were GLP-1RA–naive veterans with type 2 diabetes and without end-stage kidney disease treated with metformin who started liraglutide, semaglutide, or dulaglutide between January 1, 2018, and December 31, 2021. Data were analyzed from September 2024 to June 2025. Exposure Liraglutide, semaglutide, or dulaglutide. Main Outcomes and Measures Kidney failure (sustained estimated glomerular filtration rate <15 mL/min/1.73 m 2 or initiation of kidney replacement therapy), composite cardiovascular and kidney metabolic (CKM) events (kidney failure or major adverse cardiovascular events [MACE]; myocardial infarction, heart failure, or stroke/transient ischemic attack), MACE, all-cause death, and adverse gastrointestinal events (gastroparesis, intestinal obstruction, gallstones, acute cholecystitis, acute pancreatitis) were evaluated separately through March 31, 2023. Results Of 21 790 included veterans (mean [SD] age, 63.5 [10.8] years, 19 823 [91.0%] male), 5425 (24.9%), 10 838 (49.7%), and 5527 (24.9%) initiated liraglutide, semaglutide, and dulaglutide, respectively. In weighted Cox regression models, compared with initiation of semaglutide, liraglutide initiation had similar hazards for kidney failure (hazard ratio [HR], 0.93; 95% CI, 0.60-1.44), the CKM composite outcome (HR, 0.96; 95% CI, 0.84-1.10), and MACE (HR, 0.95; 95% CI, 0.83-1.09). Results were similar with liraglutide vs dulaglutide and dulaglutide vs semaglutide comparisons. Liraglutide had significantly lower hazard of all-cause death compared with semaglutide under intent-to-treat analyses (HR, 0.83; 95% CI, 0.69-0.99), which lost significance in per-protocol models. Compared with dulaglutide, liraglutide was associated with a lower risk of all-cause mortality in both the intent-to-treat (HR, 0.69; 95% CI, 0.58-0.83) and per-protocol (HR, 0.50; 95% CI, 0.31-0.82) analyses, but compared with semaglutide, dulaglutide had higher hazard of mortality only in the per-protocol model (HR, 1.72; 95% CI, 1.20-2.47). The only observed difference for the gastrointestinal adverse events was a decreased risk for gallstones and acute cholecystitis with dulaglutide vs semaglutide (gallstones: HR, 0.72; 95% CI, 0.54-0.95; acute cholecystitis: HR, 0.62; 95% CI, 0.39-0.99). Conclusions and Relevance In this comparative effectiveness study in veterans with diabetes, liraglutide, semaglutide, and dulaglutide initiators had similar risks for kidney and cardiovascular outcomes. Head-to-head randomized trials are needed to confirm these findings.