Comparative safety of imeglimin versus sitagliptin in Japanese patients with type 2 diabetes: A pharmacy-based retrospective cohort study.

Clinical evidence supports the safety and efficacy of imeglimin, a new oral antidiabetic medication that increases insulin secretion and reduces insulin resistance. However, comparative real-world safety data with dipeptidyl peptidase-4 inhibitors, widely used in Japan, remain limited. This retrospective, pharmacy-based cohort study compared the incidence of adverse events (gastrointestinal events and hypoglycemia) among patients newly prescribed imeglimin or sitagliptin in real-world settings. Using a new-user design, we analyzed the 2022-2024 community pharmacy data across Japan, including 1,140 and 990 new imeglimin and sitagliptin users, respectively. Primary outcome (incidence of treatment-related events classified using Medical Dictionary for Regulatory Activities terminology) was evaluated using Cox proportional hazards models. Unadjusted and multivariable-adjusted hazard ratios (aHRs) for events during a 4-month follow-up were estimated. At least one adverse event was reported among 31% of imeglimin users versus 22% of sitagliptin users. Hypoglycemia risk differed non-significantly between groups (aHR: 0.66; 95% confidence interval [CI]: 0.20-2.22). However, imeglimin was associated with substantially higher risks of gastrointestinal events than sitagliptin (aHR: 5.44; 95% CI: 3.44-8.61), particularly nausea (aHR: 15.34; 95% CI: 3.50-67.23), diarrhea (aHR: 7.90; 95% CI: 2.54-24.62), and abdominal discomfort (aHR: 6.02; 95% CI: 1.47-24.58). Sensitivity analyses in patients receiving monotherapy yielded increased risk (hazard ratio (HR): 5.36; 95% CI: 2.63-10.92). Imeglimin use was associated with a higher incidence of gastrointestinal events than sitagliptin in Japanese clinical practice, closely approaching our prespecified threshold for clinical significance. Conversely, no significant difference was observed in hypoglycemia risk, although this finding should be interpreted with caution owing to the limited number of events. Involving community pharmacists allowed for active monitoring and identification of events that are often underreported in large-scale claims databases. Clinicians should prioritize gastrointestinal monitoring during initial stages of imeglimin therapy, particularly in older patients with complex treatment regimens.