Assessing the Association Between GLP-1 Receptor Agonists and Diabetic Foot Complications Using Real-World Pharmacovigilance Database and Mendelian Randomization

Background Limited studies to date have yielded inconsistent results regarding the association between glucagon-like peptide-1 receptor agonist (GLP-1RA) use and diabetic foot complications. We conducted a comprehensive analysis of the FDA Adverse Event Reporting System (FAERS) database and performed drug target Mendelian randomization (MR) studies to explore the association between GLP-1RAs and diabetic foot complications. Methods We mined the FAERS database from 2005q2 to 2024q2 using AERSMine. Additionally, a two-sample MR analysis was conducted to investigate the causal relationship between GLP-1R agonism and diabetic foot complications. Results A total of 1819 adverse event reports were recorded for GLP-1RAs, compared to 17,206 reports for other ATC-A10 class drugs. The frequency of diabetic foot reports in the GLP-1RA group was significantly lower than in the control group (6.38 vs 11.31/1000 reports), with a proportional reporting ratio (PRR) of 0.56 (95% confidence interval [CI], 0.54 to 0.59; P < 0.001). This trend was consistently observed across individual GLP-1RA molecules, including semaglutide (PRR, 0.45; 95% CI, 0.39 to 0.51), dulaglutide (PRR, 0.49; 95% CI, 0.45 to 0.54), and liraglutide (PRR, 0.30; 95% CI, 0.26 to 0.35). These results remained robust after conducting secondary and sensitivity analyses, further supporting their consistency and reliability. MR results generally corroborated the findings from the retrospective analyses of the AE records in the FAERS database. Conclusions Pharmacovigilance and drug target MR suggested a potential association between GLP-1RA use and diabetic foot complications, but the evidence is preliminary and requires further real-world prospective validation.