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).


CONCLUSIONS
DPP-4 inhibitors were not associated with an undue increase in bleeding AERs in the FAERS database.
1 Auburn University, Auburn, AL, USA.
Md Motiur
MM
Rahman
2 Auburn University, Mobile, AL, USA.
Michael J
MJ
Scalese
1 Auburn University, Auburn, AL, USA.
Richard A
RA
Hansen
D016907:Adverse Drug Reaction Reporting Systems; D001241:Aspirin / Q000009:adverse effects; D000077144:Clopidogrel; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects*; D006470:Hemorrhage / Q000139:chemically induced*; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D008687:Metformin / Q000009:adverse effects; D016017:Odds Ratio; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects; D012189:Retrospective Studies; D012306:Risk; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives
D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D010975:Platelet Aggregation Inhibitors; D008687:Metformin; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin
DPP-4 inhibitors; MedWatch; adverse event reporting; antiplatelet; bleeding; linagliptin; saxagliptin; sitagliptin