Type 2 Diabetes Drugs Linked to Bullous Pemphigoid

Use of certain dipeptidyl peptidase 4 (DPP-4) inhibitors appears to be associated with a small but significantly elevated risk for developing the chronic blistering skin condition bullous pemphigoid, new research suggests.

Findings from a retrospective case-control study were published online August 8 in JAMA Dermatology by Khalaf Kridin, MD, PhD, and Reuven Bergman, MD, both of the department of dermatology, Rambam Health Care Campus, Haifa, Israel.

The new data join an emerging literature linking the increased incidence of bullous pemphigoid in recent years with certain medications, and specifically, DPP-4 inhibitors, a class of type 2 diabetes drug.

Another study, published online July 12 in Diabetes Care, also found an association between DPP4 inhibitors and bullous pemphigoid in adverse event reporting data from Japan.

Both that study and the current one point specifically to a greater risk of bullous pemphigoid for patients with type 2 diabetes taking vildagliptin (Galvus, Novartis) and linagliptin (Tradjenta, Lilly/Boehringer Ingelheim), but not sitagliptin (Januvia, Merck).

Clinicians prescribing DPP4 inhibitors should be aware of the association and stop the medication if bullous pemphigoid develops, Kridin told Medscape Medical News.

"The small sample size of our study may interfere with drawing general conclusions, but our recommendation is to withdraw DPP4 inhibitors whenever a diagnosis of bullous pemphigoid is confirmed. DPP4 inhibitor withdrawal led to prominently better clinical outcomes," he noted.

Kridin also advised that DPP4 inhibitors be "used cautiously in patients with initial high risk for bullous pemphigoid, namely elderly patents and those with disabling neurological diseases."

However, he pointed out that although the absolute risk for bullous pemphigoid among people with type 2 diabetes taking DPP4 inhibitors couldn't be determined from the current case-control study, other data suggest it's probably low. In another recent Japanese study of 9304 people taking DPP4 inhibitors between 2009 and 2017, only eight developed bullous pemphigoid. Although the rate (0.0859%) in that study was higher than in the general population, it "may indicate that the absolute risk is not high," Kridin said.

Case-Control Data Show Elevated Bullous Pemphigoid Risk

Bullous pemphigoid is a chronic, inflammatory, subepidermal, blistering disease. If untreated, it can persist for months or years, with periods of spontaneous remissions and exacerbations. The disease can be fatal, particularly in patients who are debilitated.

Kridin and Bergman identified 82 patients with diabetes who received a new diagnosis of bullous pemphigoid during 2011 to 2017 at their tertiary referral institution and matched them by age, sex, and ethnicity to 328 controls with diabetes but without bullous pemphigoid.

Mean age at presentation was 79 years, and 54% of patients were women. At the time of enrolment, 44% of the patients with bullous pemphigoid were treated with DPP4 inhibitors, compared with 22% of controls (P < .001).

Over a median 2 years' follow-up, development of bullous pemphigoid was significantly more likely among those taking DPP4 inhibitors, with an odds ratio (OR) of 2.83. The strongest associations were seen in patients younger than 70 years (OR, 5.59), followed by age 70 to 79 years (OR, 3.20), and 80 years and older (OR, 2.40). The association was stronger in men (OR, 4.46) than women (OR, 1.88).

By individual DPP4 inhibitor, vildagliptin was most strongly linked to bullous pemphigoid (OR, 9.28) followed by linagliptin (OR, 6.61). No significant association was seen with sitagliptin, which actually was used less frequently by patients with bullous pemphigoid versus those without, although that relationship wasn't significant (OR, 0.42).

After controlling for confounding factors such as comorbid neurologic conditions and metformin use, DPP4 inhibitor use appeared to be independently associated with the development of bullous pemphigoid, with adjusted ORs of 3.16 overall, 10.67 for vildagliptin, and 6.65 for linagliptin (all significant).

Compared with the 46 patients with bullous pemphigoid who had not been taking a DPP4 inhibitor, the 36 patients with the DPP4 inhibitor-associated skin condition had greater involvement of mucosal surfaces (22% vs 6.5%; P = .04), but lower circulating eosinophil (P = .01) and platelet counts (P = .02).

Of the 19 patients with DPP4 inhibitor-associated bullous pemphigoid who had their treatment stopped, 15 experienced complete remission and three partial remission. But of 13 patients in whom DPP4 inhibitor treatment wasn't stopped, eight died and only three achieved remission.

The mechanism for the association isn't known, but the inhibition of DPP-4 could lead to alterations in cutaneous antigenicity, the authors postulate.

Supportive Data From Japanese Adverse Drug Event Reports

In the earlier Diabetes Care study, Masanori Arai, MD, of the department of endocrinology and metabolism, Graduate School of Medicine, Yokohama City University, Japan, and colleagues, identified 546 bullous pemphigoid cases from the Japanese Adverse Drug Event Report (JADER) database, of which 392 were associated with DPP4 inhibitor use.

The JADER contains all pharmacovigilance data spontaneously reported to Japan's Pharmaceuticals and Medical Devices Agency since April 2004.

In an adjusted analysis, reported odds ratios for bullous pemphigoid by individual DPP4 inhibitor were 2.67 for linagliptin, 5.52 for teneligliptin (International Nonproprietary Name Tenelia, Mitsubishi Tanabe Pharma/Daiichi Sankyo), and 12.09 for vildagliptin. There were no significant associations for sitagliptin, saxagliptin (Onglyza, AstraZeneca), or alogliptin (Nesina, Takeda).

Arai and colleagues explain that vildagliptin, teneligliptin, and linagliptin have a lower substrate selectivity for DPP-4 or higher volume of distribution, and therefore, "it is possible that the inhibition of DPP-8 or DPP-9, but not that of DPP-4, in the skin evokes immunopathogenic reactions that result in the blister formation in bullous pemphigoid."

Kridin and Arai have reported no relevant financial relationships.

JAMA Dermatology. Published online August 8, 2018. Abstract

Diabetes Care. Published online July 12, 2018. e-Letter

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