Risk of Bullous Pemphigoid with Type 2 Diabetes Drugs

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August 12, 2018 – Findings from a retrospective case-control study were published online August 8, 2018, in JAMA Dermatology indicate that the use of certain dipeptidyl peptidase 4 (DPP-4) inhibitor drugs are associated with a small but significantly elevated risk for developing bullous pemphigoid, a chronic blistering skin condition, which, if untreated, it can persist for months or years, with periods of spontaneous remissions and exacerbations, and can be fatal, particularly in patients who are debilitated.

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, 2018, in Diabetes Care, also found an association between DPP-4 inhibitors and bullous pemphigoid in adverse event reporting data from Japan.

Both studies point specifically to a somewhat greater risk of bullous pemphigoid for patients with type 2 diabetes taking Vildagliptin (Galvus) and Linagliptin (Tradjenta), but not Sitagliptin (Januvia). Judging from a second recent Japanese study of 9304 people taking DPP4 inhibitors between 2009 and 2017, where only eight developed bullous pemphigoid and he rate (0.0859%) in that study was higher than in the general population, the absolute risk is not very high. Nevertheless, clinicians prescribing DPP4 inhibitors should be aware of the association and stop the medication if bullous pemphigoid develops. Also DPP4 inhibitors should be used cautiously in patients with initial high risk for bullous pemphigoid, namely elderly patients and those with disabling neurological diseases.

The interesting question is why only Vildagliptin (Galvus) and Linagliptin (Tradjenta), but not Sitagliptin (Januvia), should be associated with development of bullous pemphigoid in some patients, although all three medications are DPP-4 inhibitors? Some insights may come from a study in Japan, where researchers identified 546 bullous pemphigoid cases from the Japanese Adverse Drug Event Report (JADER) database, of which 392 were associated with DPP4 inhibitor use. In an adjusted analysis, reported odds ratios for bullous pemphigoid by individual DPP4 inhibitor were 2.67 for Linagliptin (Tradjenta), 5.52 for Teneligliptin (Tenelia), and 12.09 for Vildagliptin (Galvus). There were no significant associations for Sitagliptin (Januvia), Saxagliptin (Onglyza), or Alogliptin (Nesina). A possible explanation for these different behaviour may be that Vildagliptin (Galvus), Teneligliptin (Tenelia), and Linagliptin (Tradjenta) have a lower substrate selectivity for DPP-4 or higher volume of distribution, and therefore the inhibition of DPP-8 or DPP-9, but not that of DPP-4, in the skin may evoke immunopathogenic reactions that result in the blister formation in bullous pemphigoid.

There remains also the strong possibility of the genetic predisposition of certain patients in the population for the development of  bullous pemphigoid  which may be increased in combination with talking DPP-4 inhibitors. Thus, the HLA-DQB1*03:01 allele has been identified as a biomarker for genetic susceptibility to bullous pemphigoid development under DPP-4 inhibitor treatment (see here for the according study).

 

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About the Author
thassodotcom Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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