Abstract Body: Background: The glucagon-like peptide-1 receptor agonists (GLP-1 RAs) semaglutide (2.4 mg) and liraglutide (3.0 mg) are approved for chronic weight management. Both drugs also have favorable effects on risk of developing diabetes and cardiovascular disease (CVD) compared with placebo, but their comparative effectiveness for these outcomes is unclear. Therefore, we performed a head-to-head comparison of semaglutide and liraglutide, hypothesizing a lower risk associated with semaglutide use because it causes greater weight reduction.
Methods: We employed an active comparator, new user design to emulate a target trial using observational data from MarketScan deidentified administrative claims databases. Enrollees free of diabetes and CVD who were prescribed semaglutide or liraglutide during 2021-2023 were matched 1:1 on age, sex, insurance enrollment date, and GLP-1 RA initiation date. We investigated primary endpoints of incident diabetes and hard CVD (myocardial infarction, heart failure, or stroke), and a secondary endpoint of composite CVD that further included unstable angina and coronary revascularization. We used Cox regression adjusted for a propensity score reflective of comorbidities and medication use.
Results: We matched a total of 57,456 GLP-1 RA users, among whom the mean age was 45 years and 83% were female. Over an average of 1 year of follow-up, we observed 1,104 incident diabetes events, 57 hard CVD events, and 154 composite CVD events. In the adjusted model, semaglutide users had an 11% lower risk of diabetes over follow-up (hazard ratio [HR]: 0.89; 95% CI: 0.79, 1.00; p=.04). For this endpoint, the proportional hazards assumption was violated (p<.0001), so we presented results stratified by follow-up time. During the first 6 months of follow-up, semaglutide use was not associated with risk of diabetes compared with liraglutide use (HR: 1.00 [0.84-1.20]), but a significant association was present thereafter (HR: 0.81 [0.69, 0.94]). We did not detect a difference in risk of hard CVD events (HR: 1.25 [0.74-2.11]) or composite CVD events (HR: 0.89 [0.65-1.23]). Results were unchanged when we applied inverse probability of treatment weighting to compare all eligible GLP-1 RA users.
Conclusion: In this real-world study comparing two GLP-1 RAs head-to-head, semaglutide users were at lower risk of incident diabetes compared with liraglutide users. Additional research is needed to elucidate comparative effects of these drugs on cardiovascular risk.