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Dipeptidyl peptidase 4 (DPP-4) inhibitors were linked with bullous pemphigoid (BP) in male patients with diabetes, according to a population-based study in Korea.

Compared with control patients with diabetes but not on DPP-4 inhibitors, patients prescribed this class of drug had a 58% increase in risk for BP (odds ratio 1.58, 95% CI 1.25-2.00, P<0.001), a condition that causes large, fluid-filled blisters, said Seon Gu Lee, MD, of the CHA University School of Medicine in Seongnam, and colleagues.

A subgroup analysis by sex found that men had nearly twice the risk (OR 1.91, 95% CI 1.39-2.63, P<0.001), while the association was not significant in women (OR 1.24, 95% CI 0.88-1.75, P=0.21), the researchers reported online in .

Of all the DPP-4 inhibitors available in Korea in the study, the association was strongest with vildagliptin (Galvus) with an odds ratio of 1.81 (95% CI 1.31-2.50; P<0.001).

Associations for other drugs were as follows:

• Sitagliptin (Januvia): OR 1.70, 95% CI 1.19-2.43, P=0.004
• Linagliptin (Tradjenta): OR 1.64, 95% CI 1.15-2.33, P=0.006
• All other DPP-4 inhibitors: OR 1.25, 95% CI 0.73-2.14, P=0.41

Patients younger than 75 had more risk compared with those older than that (OR 1.76, 95% CI 1.22-2.55, P=0.003), but the risk was still significant in the older patients (OR 1.50, 95% CI 1.11-2.04, P=0.008), the investigators said.

"Practitioners should consider that DPP-4 inhibitors, particularly vildagliptin, may be associated with the development of BP in patients with diabetes," Lee and colleagues wrote. "Our study also found that the proportion of patients with diabetes among all patients with BP has increased since 2012. According to these results, we hypothesized that the increased proportion of diabetes in patients with BP might be attributable to the use of DPP-4 inhibitors."

Writing in an accompanying , Asli Temel, MD, and Dedee Murrell, FRCP, both of the University of New South Wales in Australia, said the study adds to a growing body of literature emphasizing an association between these antidiabetic agents and drug-induced BP. "If patients with diabetes begin treatment with gliptins and then develop itch, early onset of pemphigoid should be considered... We do not know if ceasing the gliptin therapy will reverse the BP or if, once it develops, it is irreversible."

The retrospective, population-based, case-control study used insurance claims data from 1,340 patients with diabetes in Korea from 2012-2016. Half the patients had BP, and the other half were age- and sex-matched controls with diabetes but not BP. The researchers used univariate and multivariate logistic regression analysis to investigate the association between use of DPP-4 inhibitors and risk of developing BP.

"It is not clear why the use of DPP-4 inhibitors was associated with an increased risk of developing BP in only male patients," the team said. "The exact pathogenesis of how DPP-4 inhibitors might cause BP remains unclear. DPP-4 inhibitors may alter the antigenic properties of the epidermal basement membrane and lead to modifications of the immune response in genetically predisposed patients."

As to why the association was strongest with vildagliptin, Lee and co-authors speculated that it was because vildagliptin has been reported to be the least selective of DPP-4 inhibitors. It has been shown to inhibit the DPP-8 and DPP-9 enzymes as well. "We hypothesized that the inflammasome–caspase-1 pathway was associated with the BP pathogenesis, namely, that unwanted DPP-8 and DPP-9 inhibition induced activation of the caspase-1 pathway because of low selectivity of vildagliptin, which may contribute to an increased risk of developing BP," the investigators said.

They noted that although the nationwide investigation was one of the largest cohort studies of this condition to date, it was limited by the lack of data on the duration of use of DPP-4 inhibitors before the onset of pemphigoid. In addition, the team added, DPP-4 inhibitors are frequently prescribed with metformin, but the study did not consider the effect of metformin because it has not been implicated in the development of pemphigoid.