Cardiovascular Outcomes and Safety of Semaglutide in Non-Overweight Populations with Type 2 Diabetes: A Comparison with Dipeptidyl Peptidase 4 Inhibitors

Abstract Aims The effects of semaglutide on non-overweight patients with type 2 diabetes (T2D) remain unclear. We retrospectively compared all-cause mortality, cardiovascular outcomes, and adverse events in patients with T2D with a body mass index (BMI) < 25 kg/m² who received semaglutide or dipeptidyl peptidase 4 (DPP-4) inhibitors. Methods and results Based on the TriNetX database of electronic medical records between 2018 and 2020, we identified 340 721 patients with T2D with a BMI <25 kg/m². Of the 6789 patients who received semaglutide, 2454 who received DPP-4 inhibitors after diagnosis were excluded. Of the 41 141 patients who received DPP-4 inhibitors, 5252 patients who received GLP-1 receptor agonists after diagnosis were excluded. After propensity score matching, 4194 patients were included in each group. The primary outcome was the 3-year cumulative incidence of all-cause mortality; the secondary outcomes were acute myocardial infarction (AMI) and stroke. The adverse events included nausea, vomiting, diarrhoea, and hypoglycaemia. The semaglutide group had a significantly lower risk of all-cause mortality compared to the DPP-4 inhibitor group [6.1% vs. 10.7%, P < 0.001; hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.45–0.65]. Semaglutide was not associated with the incidence of AMI (6.1% vs. 7.1%, P = 0.173; HR 0.87, 95% CI 0.72–1.06) or stroke (8.4% vs. 7.7%, P = 0.220; HR 1.11, 95% CI 0.94–1.32). Adverse events, including nausea and vomiting, diarrhoea, and hypoglycaemia, were not significantly different between the groups. Conclusion In patients with T2D and BMI <25 kg/m2, semaglutide was associated with a lower 3-year risk of all-cause mortality than DPP-4 inhibitors.