GLP-1 receptor agonist and risk of erectile dysfunction in men with type 2 diabetes: a target trial emulation

Background: The association between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and the risk of erectile dysfunction (ED) in men with type 2 diabetes (T2D) remains unclear. This study aimed to evaluate the risk of ED associated with GLP-1RA initiation compared with dipeptidyl peptidase-4 inhibitors (DPP4is) in men with T2D. Methods: We conducted a target trial emulation using electronic health records from a U.S. health system between January 2019 and September 2024. Adult men (>18 years) with T2D initiating either GLP-1RA or DPP4i were included. The primary outcome was incident ED identified using diagnostic codes. Baseline characteristics were balanced using stabilized inverse probability of treatment weighting (sIPTW), and hazard ratios (HRs) were estimated using Cox proportional hazards models. Multiple subgroup analyses, sensitivity analyses (including negative control outcome [NCO] calibration), and external validation were conducted to assess robustness. Findings: After sIPTW, this study included 4910 GLP-1RA initiators and 5524 DPP4i initiators with well-balanced baseline covariates. The incidence rate of ED was higher in the GLP-1RA users (35.2 vs. 28.0 per 1000 person-years) than DPP4i users, with a slightly increased rate (HR, 1.26; 95% CI, 1.08-1.46). Results were generally consistent across sensitivity analyses, subgroups, and an external validation cohort, while the association was attenuated and no longer statistically significant after NCO calibration. Interpretation: In men with T2D, GLP-1RA use was modestly associated with an increased rate of ED. These observational findings may reflect residual or selection bias and do not establish causation. Further studies are warranted to confirm these findings and explore potential underlying mechanisms. Funding: This work was supported in part by National Institutes of Health, United States (RF1AG077820, R01AG073435, R01DK128237).