Evaluation of Risk of Bullous Pemphigoid With Initiation of Dipeptidyl Peptidase-4 Inhibitor vs Second-generation Sulfonylurea

This cohort study analyzed data from 2 large commercial insurance claims databases to characterize the incidence rate of bullous pemphigoid associated with the use of dipeptidyl peptidase-4 inhibitors. Key PointsQuestionWhat is the absolute risk of bullous pemphigoid in patients who initiate use of dipeptidyl peptidase-4 inhibitors and its comparative risk against sulfonylurea use? FindingsIn this cohort study of 1664880 patients with type 2 diabetes, the incidence rate of bullous pemphigoid per 1000 person-years among patients who initiated dipeptidyl peptidase-4 inhibitor therapy was 0.42 compared with 0.31 for sulfonylurea. The risk was 42% higher with dipeptidyl peptidase-4 inhibitors than with sulfonylurea and 62% to 70% higher in subgroups of patients who were 65 years or older, white, and linagliptin users. MeaningThese findings suggest that use of dipeptidyl peptidase-4 inhibitors is associated with higher risk of bullous pemphigoid compared with sulfonylurea, and that clinicians should be aware of this rare adverse effect in subgroups with higher risk. ImportanceDespite several recent reports on the elevated risk of bullous pemphigoid in patients with type 2 diabetes treated with dipeptidyl peptidase-4 (DPP-4) inhibitors, evidence on the absolute risk and comparative safety against other antidiabetics is limited. ObjectiveTo characterize the incidence rate of bullous pemphigoid associated with DPP-4 inhibitor use compared with second-generation sulfonylureas. Design, Setting, and ParticipantsThis cohort study used data from 2 large commercial insurance claims databases (Optum Clinformatics Data Mart from October 17, 2006, to December 31, 2018, and IBM MarketScan Research Database from October 17, 2006, to December 31, 2017) and Medicare data from January 1, 2006, to December 31, 2016. Patients with type 2 diabetes who initiated treatment with DPP-4 inhibitors or second-generation sulfonylurea were included. Main Outcomes and MeasuresThe primary outcome of the study was bullous pemphigoid, identified using diagnosis codes. After 1:1 propensity score matching, the incidence rates of bullous pemphigoid and the hazard ratios (HRs) with 95% CIs comparing patients who initiated DPP-4 inhibitor and second-generation sulfonylurea therapy were estimated. Subgroup analyses by age, sex, race, and individual DPP-4 agents were performed. The results from each database were pooled using inverse-variance fixed-effects meta-analysis. ResultsA total of 1664880 patients who initiated DPP-4 inhibitors (51.0% female; mean [SD] age, 63.9 [9.7] years) and sulfonylurea (50.4% female; mean [SD] age, 63.9 [9.9] years) were included. The incidence rate of bullous pemphigoid per 1000 person-years was 0.42 in the DPP-4 inhibitor group vs 0.31 in the sulfonylurea group (HR, 1.42; 95% CI, 1.17-1.72). Higher rates per 1000 person-years for DPP-4 inhibitor vs sulfonylurea groups were seen in those who were 65 years or older (0.79 vs 0.49; HR, 1.62; 95% CI, 1.32-1.99), white (0.93 vs 0.54; HR, 1.70; 95% CI, 1.30-2.24), and treated with linagliptin (1.20 vs 0.55; HR, 1.68; 95% CI, 1.16-2.43). Conclusions and RelevanceThis study found that patients who initiated DPP-4 inhibitor therapy had higher risk of bullous pemphigoid than those who initiated second-generation sulfonylurea therapy. Clinicians should be aware of this rare adverse effect of DPP-4 inhibitors in subgroups of patients who are older, white, and linagliptin users.