DDP-4 Inhibitors Increase Risk of Bullous Pemphigoid

Hemin Lee, MD, MPH

Findings of a recent study demonstrated patients who started dipeptidyl peptidase-4 (DPP-4) inhibitor therapy had a higher risk of bullous pemphigoid than those who initiated second-generation sulfonylurea therapy.

The findings suggested clinicians should be aware of the rare adverse effect in subgroups with higher risk.

Hemin Lee, MD, MPH, and colleagues characterized the incidence rate of bullous pemphigoid associated with DPP-4 inhibitor use compared with second-generation sulfonylureas. The team used data from 3 large US healthcare databases, Optum Clinformatics Data Mart, IBM MarketScan Research Database, and Medicare Parts A, B, and D. The Optum and MarketScan databases included longitudinal medical and pharmacy claims of the commercially insured population in the US.

The investigators created a new-user cohort of patients with a prescription claim for a DPP-4 inhibitor or a second-generation sulfonylurea from the date of the first approval for DPP-4 inhibitors, October 17, 2006, to the end of available data in each database. They applied a washout period of 180 days for both drugs. The date of the first prescription corresponded to the date of cohort entry.

Patients were included if they had at least 180 days of continuous enrollment in commercial insurance and fee-for-service Medicare and at least 1 diagnosis of type 2 diabetes. The team excluded patients younger than 40 years old because bullous pemphigoid is typically seen in older individuals.

The primary outcome was the occurrence of bullous pemphigoid, defined based on ICD-9 or ICD-10 diagnosis codes. Follow-up started 1 day after cohort entry and continued until either the occurrence of bullous pemphigoid, the end of healthcare or pharmacy eligibility, the end of the study period, the switch to a comparator drug, and discontinuation of the index drug.

Overall, the cohort consisted of 870,709 new users of DPP-4 inhibitors, a majority of whom were female (51%) with a mean age of 63.7 years old. There were more than 1.9 million new users of second-generation sulfonylureas, with more than half (51.8%) being male and a mean age of 64.8 years old.

Before matching propensity scores, sulfonylurea users were older than DPP-4 inhibitor users (mean age, 64.8 years old vs 63.7 years old) and had a higher number of antidiabetic drugs prescribed at the index date (mean, 1.26 vs 1.16). After score matching, there were 199,780 pairs of DPP-4 inhibitor or second-generation sulfonylurea users in Optum, 354,759 pairs in MarketScan, and 277,901 pairs in Medicare.

The incidence rates (IRs) per 1000 person-years of bullous pemphigoid for DPP-4 inhibitor versus sulfonylurea groups in each database were .36 vs .27 cases (HR, 1.34; 95% CI, .88-2.04) in Optum; .19 vs .19 cases (HR, 1; 95% CI, .68-1.49) in MarketScan; and .81 vs .48 cases (HR, 1.68; 95% CI, 1.3-2.17) in Medicare. The pooled number in the 3 databases was 247 cases (IR, .42 per 1000 person-years) in the DPP-4 inhibitor group and 184 cases (IR, .31 per 1000 person-years) in the sulfonylurea group. The pooled HR was 1.42 (95% CI, 1.17-1.72).

The team analyzed subgroups of patients in both groups and found there was an increased risk in those who were at least 65 years old (pooled HR, 1.62; 95% CI, 1.32-1.99) and while (pooled HR, 1.7; 95% CI, 1.3-2.24). For DPP-4 inhibitor agents, linagliptin showed the highest risk (pooled HR, 1.68; 95% CI, 1.16-2.43). The risk was less obvious in sitagliptin and saxagliptin compared with sulfonylurea use. Higher risk of bullous pemphigoid in the DPP-4 inhibitor groups was similar between men (pooled HR, 1.38; 95% CI, 1.06-1.79) and women (pooled HR, 1.34; 95% CI, 1.03-1.75).

The results of the study were consistent with other previous studies in reporting a positive association between DPP-4 inhibitors and bullous pemphigoid. Although there was an increased risk of bullous pemphigoid among DPP-4 inhibitor users compared with second-generation sulfonylurea users, the condition is rare and not all cases are associated with morbidity or mortality.

“Therefore, although clinicians should not avoid DPP-4 inhibitors entirely in patients with type 2 diabetes who may be otherwise good candidates for the therapy, they should be aware of the potential risk of bullous pemphigoid in DPP-4 inhibitor use, especially in subgroups of older and white patients and linagliptin users,” Lee and the investigators concluded.

The study, “Evaluation of Risk of Bullous Pemphigoid With Initiation of Dipeptidyl Peptidase-4 Inhibitor vs Second-generation Sulfonylurea,” was published online in JAMA Dermatology.