The three GLP-1 receptor agonist (RA) drugs liraglutide (Victoza), semaglutide (Ozempic), and dulaglutide (Trulicity) provided similar cardiovascular and kidney benefits in people with type 2 diabetes (T2D) although liraglutide was associated with lower mortality than dulaglutide, a new comparative effectiveness study found.

The three drugs also produced similar gastrointestinal outcomes. Given that liraglutide has recently come off patent and a generic is available, the findings have potentially important clinical implications despite some methodology limitations of the study, the authors said.

These results support “choosing an initial GLP-1 RA that patients can afford, access, and adhere to without compromising risk,” first author Catherine Derington, MD, assistant professor of medicine at the University of Colorado Anschutz School of Medicine, Aurora, Colorado, and lead author Srinivasan Beddhu, MD, professor of internal medicine and scientific director of the Cardio-Renal and Metabolism Center, The University of Utah, Salt Lake City, Utah, told Medscape Medical News in a joint email.

“Overall safety was comparable across the three agents, with a very small increased risk of gallbladder events with semaglutide,” they added.

However, “an important caveat is that these are observational analyses and despite advanced statistical methods, there will always be concern for residual confounding. We believe randomized controlled trials are warranted to definitively address these questions,” Derrington and Beddhu noted.

Few Differences in Cardiorenal Benefits

The study, involving 21,790 US veterans, used an active-comparator, new-user target trial-emulation design with data from national linked databases. The participants all had T2D with or without end-stage kidney disease treated with metformin who initiated either liraglutide (25.4%), dulaglutide (24.9%), or semaglutide (49.7%) between January 1, 2018, and December 31, 2021, with data analyzed from September 2024 to June 2025. The results were published online in JAMA Network Open.

“Of note, tirzepatide was not included in this study as it was approved after the study inclusion period,” the authors said.

To account for baseline differences between groups, propensity scoring was used to estimate the probability of initiating each medication based on 56 baseline variables and inverse probability of treatment weighting applied.

In the intent-to-treat model (irrespective of adherence or treatment switches), weighted models showed that compared with initiating semaglutide, liraglutide initiation had a similar risk for kidney failure (hazard ratio [HR], 0.93) and the composite outcome of kidney failure or the major adverse cardiovascular events (MACEs), myocardial infarction, heart failure, or stroke/transient ischemic attack (HR, 0.96), neither differing significantly.

But those initiating liraglutide had a significantly lower risk for all-cause death than those initiating semaglutide (HR, 0.83; 95% CI, 0.69-0.99) and dulaglutide (HR, 0.69; 95% CI, 0.58-0.83). There were no differences in the risks for kidney failure, the cardio-kidney composite, MACE, or all-cause death between dulaglutide and semaglutide.

For the per-protocol model, the proportions of those still alive and taking their medication at month 12 was 60.9% for liraglutide, 67.2% for semaglutide, and 72.1% for dulaglutide. Less than 10% in each group switched to another GLP-1 RA within the first year (8.4%, 1.3%, and 8.4% of liraglutide, semaglutide, and dulaglutide initiators, respectively)

As in the intent-to-treat analysis, in the per-protocol model HRs were similar across the three GLP-1 RAs for kidney failure, the cardio-kidney composite, and MACE for liraglutide vs semaglutide. The difference in overall mortality was no longer significant for liraglutide vs semaglutide, but liraglutide was again associated with lower all-cause death than dulaglutide (HR, 0.50; 95% CI, 0.31-0.82).

Dulaglutide had similar hazards for kidney failure, the cardio-kidney composite, and MACE compared with liraglutide and semaglutide, but here dulaglutide had a higher hazard of mortality than semaglutide (HR, 1.72; 95% CI, 1.20-2.47).

“It is important to note that dulaglutide confers a lower risk of mortality in placebo-controlled trials, and should a clinician choose to use it, they should not expect an increased risk of mortality in their patient,” Derington and Beddhu told Medscape Medical News.

Gastrointestinal adverse events were similar in the weighted models for both the intent-to-treat and per-protocol analyses, except that dulaglutide was associated with a lower risk for both gallstones and acute cholecystitis than semaglutide (HRs, 0.72 and 0.62, respectively).

Mean weight changes at month 24 were losses of 9.7 lb in the liraglutide group, 12.2 lb in the semaglutide group, and 9.8 lb in the dulaglutide group. The differences were significant for liraglutide vs semaglutide (P < .001) and dulaglutide vs semaglutide (P < .001) but not for liraglutide vs dulaglutide (P = .86).

Conclusions Require Confirmation

In an accompanying editorial, Patrick J. O’Connor, MD, of HealthPartners Institute, Minneapolis, and Romain Neugebauer, PhD, of Kaiser Permanente Division of Research, Pleasanton, California, wrote that “the story is far from over,” despite the finding of similar cardiorenal and overall mortality outcomes, citing methodological issues such as not fully addressing attrition bias in the study’s intent-to-treat analysis and possible residual confounding.

“Comparative effectiveness studies using causal inference frameworks are becoming more common, and to properly interpret their findings and assess their rigor, we clinicians need to provide vitally important clinical context and perspective,” they wrote.

“Keep in mind how comparative effectiveness studies differ from traditional randomized trials in design, analysis, and interpretation and partner with methodologists trained in causal inference to reliably guide our patients through the rapidly changing clinical landscape of diabetes care,” they added.

“Due to the methodological limitations of the study under discussion, its conclusions require confirmation,” O’Connor told Medscape Medical News.

Derrington and Beddhu agreed, but added, “Nonetheless, these results suggest that within these three GLP-1 RA, the choice for CV [cardiovascular] and kidney protection could be based on cost, coverage, and patient choice.”

This study was supported by grants from the National Institutes of Health (NIH) and the Department of Veterans Affairs. Derington and Beddhu had no further disclosures. O’Connor reported receiving grants from the NIH and the Patient-Centered Outcomes Research Institute. Neugebauer had no disclosures.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X @MiriamETucker and BlueSky @miriametucker.bsky.social.