Type 2 Diabetes Drugs Linked to Huge Blisters (Bullous Pemphigoid)


August 08, 2018

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.

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


What is Bullous Pemphigoid?










Bullous pemphigoid (BUL-us PEM-fih-goid) is a rare skin condition that causes large, fluid-filled blisters. The blisters develop on areas of skin that often flex, such as the lower abdomen, upper thighs or armpits. Bullous pemphigoid is most common in people older than age 60.

Bullous pemphigoid occurs when your immune system attacks a thin layer of tissue below your outer layer of skin. The reason for this abnormal immune response is unknown, although it sometimes can be triggered by taking certain medications.

Treatment usually includes medications, such as prednisone, and other drugs that suppress the immune system. Bullous pemphigoid can be life-threatening, especially for older people who are already in poor health.


The primary feature of bullous pemphigoid is the appearance of large blisters that don’t easily rupture when touched. The fluid inside the blisters is usually clear but may contain some blood. The skin around the blisters may appear normal, reddish or darker than usual. Some people with bullous pemphigoid develop an eczema or hive-like rash rather than blisters.

In most cases, the blisters appear on the lower abdomen, groin, upper thighs and arms. Blisters are often located along creases or folds in the skin, such as the skin on the inner side of a joint.

The affected areas of skin can be very itchy. You might also develop blisters or sores in your mouth. If the mucous membranes of your eyes and mouth are primarily where your blisters are concentrated, this type of condition is called mucous membrane pemphigoid. If you develop blisters on your eyes, you’re more likely to have scarring. This condition requires prompt diagnosis and treatment.

When to see a doctor

If you develop unexplained blistering — a condition not caused, for example, by a known skin allergy or contact with poison ivy — see your doctor.


The cause of bullous pemphigoid is not well-understood. The blisters occur because of a malfunction in your immune system.

Your body’s immune system normally produces antibodies to fight bacteria, viruses or other potentially harmful foreign substances. For reasons that are not clear, the body may develop an antibody to a particular tissue in your body.

In bullous pemphigoid, the immune system produces antibodies to the fibers that connect the outer layer of skin (epidermis) and the next layer of skin (dermis). These antibodies trigger inflammation that produces the blisters and itching of bullous pemphigoid.

Contributing factors

Bullous pemphigoid usually appears randomly with no clear factors contributing to the onset of disease. A small percentage of cases may be triggered by certain medical treatments, such as:

Medications. Prescription drugs that may cause bullous pemphigoid include penicillin, etanercept (Enbrel), sulfasalazine (Azulfidine) and furosemide (Lasix). AND NOW CERTAIN TYPE 2 DIABETES MEDCATIONS

Light and radiation. Ultraviolet light therapy to treat certain skin conditions may trigger bullous pemphigoid, as can radiation therapy to treat cancer.

Risk factors

Bullous pemphigoid most commonly occurs in people older than age 60, and the risk increases with age.


If ruptured blisters become infected, this can lead to sepsis — a potentially life-threatening blood infection that affects your entire body. Sepsis is more likely to occur in older adults who are in generally poor health.

Rare forms of bullous pemphigoid involving the mucous membranes of the mouth or eye can lead to scarring.



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