Semaglutide outperforms other GLP-1 drugs for cardiovascular protection in moderate-risk diabetes patients | Research

The takeaway

Target trial emulation in 81,854 T2D patients at moderate CV risk shows semaglutide reduced MACE by 15% (HR 0.85) and all-cause mortality by 19% (HR 0.81) versus dulaglutide, with liraglutide also showing MACE benefit.

15% MACE reduction at moderate risk
Semaglutide outperformed dulaglutide for cardiovascular protection even in T2D patients at moderate (not just high) cardiovascular risk

What the researchers found

vs Dulaglutide: Semaglutide MACE HR 0.85, mortality HR 0.81, stroke HR 0.82, revascularization HR 0.93. Liraglutide MACE HR 0.84, mortality HR 0.79. Exenatide: no significant differences. 81,854 patients at moderate CV risk.

Why it matters

Most GLP-1 CV outcome data comes from high-risk patients. This study shows semaglutide and liraglutide provide CV protection even in moderate-risk T2D patients, potentially expanding the population that should receive these drugs.

How the study worked

Target trial emulation using claims data (2014-2021). 81,854 patients. Propensity score IPTW Cox models. Compared dulaglutide, exenatide, liraglutide, semaglutide.

What this study cannot tell us

Observational target trial emulation—not a randomized trial. Residual confounding possible. Claims data lacks clinical detail. US-centric.

How to read the evidence

Large target trial emulation with rigorous propensity scoring. Strong observational evidence but not randomized.

When this study was published

Published in 2025; data 2014-2021.

The bigger picture

If GLP-1 drugs provide CV protection at moderate risk levels (not just high risk), the case for broader prescribing strengthens considerably. Semaglutide and liraglutide emerge as the preferred agents.

Questions still open

Should moderate-CV-risk T2D patients preferentially receive semaglutide?
Why does semaglutide outperform dulaglutide despite similar GLP-1R activation?
Would liraglutide 3.0 mg (obesity dose) show even greater CV benefit?

Common questions

Which GLP-1 drug is best for heart protection?

In this large real-world study, semaglutide showed the best cardiovascular outcomes—15% lower risk of heart attacks, strokes, and death compared to dulaglutide. Liraglutide was also beneficial. Exenatide showed no significant difference. This applied to moderate-risk patients, not just high-risk.

Does it matter which GLP-1 drug I take?

Based on this study, yes. Semaglutide and liraglutide both provided heart protection benefits that dulaglutide and exenatide did not match. If cardiovascular protection is a goal beyond blood sugar control, semaglutide appears to be the best choice.

Read the original research

Comparative effectiveness of GLP-1 receptor agonists on cardiovascular outcomes among adults with type 2 diabetes and moderate cardiovascular risk: emulation of a target trial.

Diabetes research and clinical practice, 229, 112910

View on PubMed ↗Publisher’s paper ↗

Citation

Sklepinski, Stacey M; Deng, Yihong; Swarna, Kavya Sindu; Herrin, Jeph; Polley, Eric C; Neumiller, Joshua J; Galindo, Rodolfo J; Umpierrez, Guillermo E; Ross, Joseph S; Borah, Bijan J; Maron, Bradley A; Mickelson, Mindy M; McCoy, Rozalina G. (2025). Comparative effectiveness of GLP-1 receptor agonists on cardiovascular outcomes among adults with type 2 diabetes and moderate cardiovascular risk: emulation of a target trial.. Diabetes research and clinical practice, 229, 112910. https://doi.org/10.1016/j.diabres.2025.112910