Dipeptidyl Peptidase-4 Inhibitor-Associated Risk of Bleeding: An Evaluation of Reported Adverse Events.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control, and sitagliptin has been associated with a reduction in cardiovascular events. In vivo data suggest reduced platelet activation, and aggregation may play a role, and therefore, increased bleeding risk is possible.

OBJECTIVE: Comparatively assess bleeding risks associated with DPP-4 inhibitors against standard treatment.

METHODS: Exploratory analyses of adverse event reports (AERs) from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database (2004-2012 periods) were conducted. DPP-4 inhibitor-related bleeding was assessed with metformin as negative control, and aspirin, clopidogrel, and prasugrel illustrated positive comparators. Reporting odds ratios (RORs) and 95% CIs were calculated as a measure of disproportionality of reporting, and RORs were compared across drugs with the Breslow-Day statistics.

RESULTS: From 2004 to 2012, 36 298, 4288, and 1202 AERs were found for sitagliptin, saxagliptin, and linagliptin, respectively, with 863, 102, and 14 bleeding complications. The relative reporting rate was not elevated with any DPP-4 inhibitor (sitagliptin: ROR = 0.71, 95% CI = 0.67-0.76; saxagliptin: ROR = 0.72, 95% CI = 0.59-0.87; linagliptin: ROR = 0.35, 95% CI = 0.20-0.59) or with metformin (ROR = 0.77; 95% CI = 0.75-0.78). Sitagliptin showed relatively higher reporting as compared with linagliptin ( P = 0.006) but not with saxagliptin ( P = 0.98). As positive references, antiplatelet drugs demonstrated relatively higher reporting compared with metformin (aspirin: ROR = 1.50, 95% CI = 1.48-1.51; clopidogrel: ROR = 2.28, 95% CI = 2.23-2.33; prasugrel: ROR = 5.09, 95% CI = 4.57-5.67).

CONCLUSION: DPP-4 inhibitors were not associated with an undue increase in bleeding AERs in the FAERS database.