VANCOUVER, B.C. – Each of the newer classes of antidiabetic medications – the DPP-IV inhibitors, GLP-1 agonists, and SGLT2 inhibitors – has its own characteristic cutaneous side effects, Dr. Justin Endo said at the World Congress of Dermatology.
These drugs aren’t first-line agents for patients with type 2 diabetes, but they have gained solid standing as second-tier medications for the vast number of patients with inadequate glucose control or limiting side effects on first-line therapies, said Dr. Endo of the department of dermatology at the University of Wisconsin–Madison.
DPP-IV inhibitors
The dipeptidyl peptidase–IV inhibitors are the newer drugs linked to the most potentially serious side effects, namely, drug-induced bullous pemphigoid and angioedema.
Investigators at Western Michigan University, Kalamazoo, conducted a literature review and an analysis of the Food and Drug Administration’s Adverse Event Reporting System database and concluded there is a link between DPP-IV inhibitors and the development of bullous pemphigoid, a potentially fatal cutaneous autoimmune blistering disorder. The skin disease appeared after an average of 6 months on DPP-IV inhibitor therapy in their series. In most cases the bullous pemphigoid remitted in response to discontinuation of the drug, often in conjunction with a course of topical or less frequently, oral corticosteroid therapy (J Dermatol Case Rep. 2014 Mar 31;8[1]:24-8).
The mechanism for the development of bullous pemphigoid in patients on a DPP-IV inhibitor is unknown; however, the enzyme DPP-IV is expressed in skin and most other organs.
“I think a key take home is if patients in their 60s or 70s come in with pemphigoid, even though they’re in the usual age group for non–drug-induced pemphigoid, ask whether they are taking a DPP-IV inhibitor. And if they are, get it stopped,” Dr. Endo said.
An initial postmarketing flurry of case reports of angioedema in patients on the then-new DPP-IV inhibitors caused enormous concern until clarification was provided in a study by investigators at Vanderbilt University, Nashville, Tenn., and Novartis. They dove deep into the phase III randomized clinical trial data for one of these agents, vildagliptin (Galvus, manufactured by Novartis), and concluded there was no association between the drug and angioedema, except in patients simultaneously taking an ACE inhibitor, a known risk factor for angioedema. It seems that the dual therapy may cause a double hit, multiplying risk.
The bad news was that patients on an ACE inhibitor and vildagliptin had a 4.57-fold greater risk of angioedema than did those on a non–DPP-IV inhibitor comparator medication. The good news was that the absolute risk was very low: 14 confirmed cases in 2,754 subjects. And most cases of angioedema were of the non–life-threatening variety (Hypertension. 2009 Sep;54[3]:516-23).
“The evidence is really limited, but I have to agree with one expert who said, ‘Hey, if somebody comes into the hospital with angioedema, and they happen to be on a DPP-IV inhibitor and an ACE inhibitor, stop both.’ Whether or not patients can be safely rechallenged with a DPP-IV inhibitor isn’t yet known,” Dr. Endo said.
Another cutaneous side effect associated with DPP-IV inhibitor therapy is peripheral edema. It occurs in 1%-2% of treated patients and could contribute to the refractory nature of some diabetic foot ulcers, according to the dermatologist. Documented cases of photosensitivity, urticaria, and eosinophilic drug rashes have also been reported.
The DPP-IV inhibitors are oral drugs. Those approved in the United States are alogliptin (Nesina), linagliptin (Trajenta), saxagliptin (Onglyza), and sitagliptin (Januvia).
GLP-1 agonists
The chief cutaneous side effects of the glucagonlike peptide–1 receptor agonists are injection site reactions, reported in up to 20% of treated patients in some studies. These reactions are typically mild, itchy, erythematous, and transient.
The GLP-1 agonists are administered subcutaneously once or twice weekly. Those approved in the United States are albiglutide (Tanzeum), dulaglutide (Trulicity), exenatide (Byetta, Bydureon), and liraglutide (Saxenda, Victoza).
SGLT2 inhibitors
The sodium-glucose cotransporter–2 inhibitors are the newest of these three antidiabetic drug classes. They are oral agents. Their most common cutaneous side effect is candidiasis, occurring in about 10% of patients. Women and uncircumcized men are at greatest risk. Fortunately, most cases are mild, episodic, and successfully treated with topical or oral antimycotic therapy, Dr. Endo said.
The SGLT2 inhibitors approved in the United States are canagliflozin (Invokana), dapagliflozin (Farxiga), and enpagliflozin (Jardiance).
Dr. Endo reported having no relevant financial conflicts.