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Incretin-based therapy for diabetes and dermatology: Promise and peril


DII small banner By Warren R. Heymann, MD
Oct. 23, 2017


In a given day, how many of your patients are diabetic? According to the American Diabetes Association, in 2015, 9.4% of the US population (30.3 million) were diabetic; 29 million of this group had type 2 diabetes.

Incretin hormones refer to the synthesis and secretion of gut-derived factors released after oral nutrient intake with pancreatic islet cell hormone secretion and glucose homeostasis. (1)
 
Incretin-based therapies are effective glucose-lowering drugs that have an increasing role in the treatment of type 2 diabetes, due to their efficacy, safety, and ease of use. Both glucagon-like peptide-1 receptor agonists (GLP-1Ra, albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide) and dipeptidyl peptidase-4 inhibitors (DPP-4i, alogliptin, linagliptin, saxagliptin, sitagliptin) are commonly used for glycemic control as adjuncts to metformin, other oral antiglycemic agents, or insulin. GLP-1Ra may have additional effects, such as weight loss, that may be advantageous in obese patients. (2)

A constellation of comorbidities of the metabolic syndrome (insulin resistance, obesity, hyperlipidemia, and hypertension) has been associated with psoriasis; these same comorbidities are now also associated with hidradenitis suppurativa (HS). (3)
 
GLP-1Ra drugs have been used successfully to treat psoriasis in obese patients with type 2 diabetes. The cutaneous inflammation was believed to be due to decreased lymphocyte migration, decreased cytokine production, increased regulatory T cells, decreased invariant natural killer T cells in psoriatic plaques, decreased macrophage activation, diminished body weight, and decreased adipokines. (4)

Jennings et al reported the case of a 31 year-old obese woman with recalcitrant HS, even with when treated with adalimumab, Administration of liraglutide led to significant improvement, based on Physician’s Global and the Dermatology Quality Life Index (DQLI). Although this may be due to the patient’s weight loss, the improvement may also be related to decreased levels of IL-17, tumor necrosis factor-alpha, and NF-kappa B. The authors suggest that GLP-1Ra drugs may be a viable treatment for HS. (5) In an accompanying editorial, it is noted that GLP-1Ra analogues act by potentiating glucose-dependent insulin secretion, reducing insulin resistance, inhibiting glucagon production, and inducing satiety. The authors acknowledge that this is only a solitary case report — albeit an exciting one — and conclude that the next logical step is a Phase I clinical trial. (6).
 
Unfortunately, for the DPP-4i drugs, there have been several recent reports of their inducing bullous pemphigoid (BP) – ten for vildagliptin; four for sitagliptin, and three for linagliptin. (7,8) In the cases presented by Haber et al (7) both cases of BP resolved with discontinuing linagliptin and utilizing topical clobetasol. The mechanism by which these drugs induce bullous pemphigoid is unknown.

The incretin story and dermatology in in its initial chapters — the protagonists may be heroes or villains. This will be an ongoing saga.

1. Lovshin JA. Glucagon-like peptide-1 receptor agonists: A class update for treating type 2 diabetes. Can J Diabetes. 2017;41:524-535.
2. Waldrop G, et al. Incretin-based therapy for diabetes: What a cardiologist needs to know. J Am Coll Cardiol 2016; 67: 1488-96.
3. Lim ZV, Oon HH. Management of hidradenitis suppurativa in patients with metabolic comorbidities. Ann Dermatol 2016; 28: 147-51.
4. Drucker DJ, Rosen CF. Glucagon-like peptide-1 (GLP-1) receptor agonists, obesity and psoriasis: diabetes meets dermatology. Diabetologia 2011; 54: 2741-44.
5. Jennings L, et al. The treatment of hidradenitis suppurativa with the glucagon-like peptide-1 agonist liraglutide. Br J Dermatol 2017; 177;858-9.
6. Emtestam L, Sartorius K. Glucagon-like peptide agonists for treatment of hidradenitis suppurativa. Br J Dermatol 2017; 177: 625-7.
7. Haber R, et al. Bullous pemphigoid associated with linagliptin treatment. JAMA Dermatol 2016; 152: 224-5.
8.Mendonça FM, et al. Three cases of bullous pemphigoid associated with dipeptidyl peptidase-4 inhibitors – one due to linagliptin. Dermatology 2016; 232; 249-53.

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