Weighing in on glucagon-like peptide-1 receptor agonists in dermatology

By Warren R. Heymann, MD, FAAD
April 17, 2024
Vol. 6, No. 16

Glucagon-like peptide-1 (GLP-1) receptor agonists — your patients are on them, and perhaps you are too (or at least have thought about it). In 2023, more than 500 million people worldwide were afflicted with obesity and type 2 diabetes mellitus. According to Sabina and Alsamman, GLP-1 receptor agonists (GLP1RA) offer a beacon of hope for these patients. GLP1RA promotes delayed gastric emptying; the drugs also increase insulin secretion while inhibiting glucagon release, but only when glucose levels are elevated via the incretin effect, thus reducing the likelihood of hypoglycemia. (1) (The incretin effect in healthy individuals is when oral glucose elicits higher insulin secretory responses than does intravenous glucose, despite inducing similar levels of glycemia.) (2) These agents are proven to provide glycemic and weight loss benefits translating into potential cardiovascular benefits. (1) Obesity plays a significant role in dermatology, notably for patients with psoriasis, hidradenitis suppurativa (HS), polycystic ovary disease (PCOS), and other diseases. What role do GLP1RA have in managing these disorders?

GLP1RA include semaglutide (Ozempic, Rybelsus, Wegovy), exenatide (Bydureon BCise, Byetta), liraglutide (Victoza, Saxenda), dulaglutide (Trulicity), and others that are no longer available in the United States. Tirzepatide (Mounjaro, Zepbound) is a dual GLP-1 and GIP (glucose-dependent insulinotropic polypeptide) agonist. (1) Semaglutide and tirzepatide are utilized for weight loss — demand for these drugs has limited their supply (notably for Wegovy and Mounjaro). (3) As of today (April 5, 2024), only Wegovy (which has a higher dose of semaglutide than Ozempic) and Zepbound are FDA-approved for chronic weight management, according to ePocrates. (I have no conflicts of interest related to drugs mentioned in this commentary.)

Patients lose weight on either semaglutide or tirzepatide because they feel satiated after eating “normal” amounts of food. My patients on GLP1RA for weight loss have been pleased with the results without any significant side effects. Of course, such an impression is skewed. Many common (nausea, vomiting, others) and severe adverse reactions (hypersensitivity reactions, pancreatitis, gastroparesis, acute kidney injury, others) have been reported and should be discussed with patients before their administration. (ePocrates, 4)

Jennings et al. reported the case of a 31-year-old woman with recalcitrant HS who lost 6.5 kg over eight weeks on liraglutide. Her HS and Dermatology Life Quality Index (DLQI) improved significantly. Aside from weight loss itself, the authors note that liraglutide may be anti-inflammatory by decreasing cytokines such as IL-17, TNF-a, and NFkB. (5) Although there are FDA-approved GLP1RA for weight loss, Gu and Sabaratnam raise ethical concerns about using agents only approved for diabetes for weight loss that could exacerbate drug shortages for diabetic patients. (4)

Hogan et al. detail the case of a 60-year-old woman with type 2 diabetes and a BMI of 37 kg/m2. She experienced improved sleep and decreased pruritus of her psoriasis within two days of receiving exenatide. She was switched to liraglutide because of nausea; she remained stable for nine months. The authors observed increased invariant natural killer T (iNKT) cells in the circulation and a corresponding reduction of iNKT cells in psoriatic plaques, suggesting that such immunological changes could have contributed to improvement in psoriasis. (6,7) Just as paradoxical reactions to TNF-a inhibitors may exacerbate psoriasis, such reactions may occur with GLP1RA. A 34-year-old woman with a history of mild psoriasis and insulin-resistant diabetes demonstrated a flare of her psoriasis with new lesions appearing two weeks after the administration of liraglutide. (8)

Theoretically, GLP1RA may be a helpful adjunct in any dermatosis where being overweight is an exacerbating factor. A meta-analysis demonstrated that liraglutide and semaglutide (in addition to orlistat — an inhibitor of gastric and pancreatic lipases) were superior to placebo for anthropometric outcomes in PCOS. (9) A 60-year-old diabetic woman with recalcitrant Hailey-Hailey disease demonstrated near-complete resolution of her skin disease after losing 10 kg after starting liraglutide. (10)

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Dermatologic adverse events with DLP1RA are not rare. A delayed hypersensitivity injection site reaction to liraglutide in a 39-year-old man was reported. He was able to continue his injections by using topical steroids (clobetasol initially, then mometasone). A vesiculopustular rash, acute exanthematous pustulosis, and generalized erythematous eruption have been described with liraglutide use. (11) A nodule demonstrating eosinophilic panniculitis has been reported at the injection site of exenatide extended-release. (12) Semaglutide has been associated with bullous pemphigoid in a 61-year-old woman. (13) In a scoping review encompassing 22 articles describing dermatologic adverse reactions of semaglutide in 255 patients, alopecia was reported in 6.9% of patients taking the oral medication but only 0.2% of patients using the subcutaneous injection (compared to 0.3% and 0.2% of patients on placebo, respectively). The authors also noted isolated cases of angioedema, eosinophilic fasciitis, and leukocytoclastic vasculitis.

In conclusion, GLP1RA medications are in vogue and may be valuable adjunctive agents for any dermatosis where excess weight may be an aggravating factor. There is a commercial for a semaglutide using the 1975 Pilot song “Magic.” Several patients would consider their experience of losing weight with these agents magical. While encouraging, from a dermatologic perspective, more long-term studies are needed for both efficacy and safety.

Point to Remember: Glucagon-like peptide-1 (GLP-1) receptor agonists are now approved for weight loss, which may benefit dermatoses associated with excess weight. Dermatologists should be familiar with the potential adverse effects and benefits of these drugs.

Our expert’s viewpoint

David A. Wetter, MD, FAAD
Professor of Dermatology
Mayo Clinic
Rochester, Minnesota

During the coronavirus disease 2019 (COVID-19) pandemic, our patients routinely wondered whether their skin eruptions could be due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection — or an adverse reaction to the SARS-CoV-2 vaccine. In an analogous way, given the widespread and increasing use of GLP-1 receptor agonists (GLP1RA) for weight loss and type 2 diabetes mellitus, patients may inquire if various skin eruptions could be related to their GLP1RA medications. During residency, our mentors advised us to learn not only the side effects (systemic and dermatologic) of medications used to treat dermatologic conditions, but also the uncommon (but serious) side effects of systemic medications used to treat non-dermatologic conditions. Dr. Heymann’s insightful commentary highlights how GLP1RA medications fall into both categories, with reports of uncommon (but important to recognize) dermatologic adverse events, and studies exploring their potential benefits in treating dermatologic diseases associated with excess weight.

Given the variety of dermatologic diseases that are aggravated by obesity (15, 16), it was illuminating to learn how GLP1RA medications may benefit skin conditions (such as hidradenitis suppurativa) through weight loss and possibly immunologic changes. Having previously published case series regarding paradoxical autoimmune dermatologic adverse reactions to biologics (particularly tumor necrosis factor-alpha inhibitors) (17, 18, 19), with subsequent reports expanding upon the knowledge gleaned from our studies, it was encouraging to see several recent dermatologic publications describing rare (but important) dermatologic adverse reactions to GLP1RA medications, alerting the dermatologic community about these findings. I look forward to the emergence of additional insights, related to both dermatologic benefits and adverse effects of GLP1RA medications, in the upcoming years to further optimize the care of our dermatology patients.

1. Sabina M, Alsamman MM. Pulse of Progress: A Systematic Review of Glucagon-Like Peptide-1 Receptor Agonists in Cardiovascular Health. Cardiol Res. 2024 Feb;15(1):1-11. doi: 10.14740/cr1600. Epub 2024 Jan 10. PMID: 38464707; PMCID: PMC10923257.

2. Nauck MA, Meier JJ. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol. 2016 Jun;4(6):525-36. doi: 10.1016/S2213-8587(15)00482-9. Epub 2016 Feb 12. PMID: 26876794.

3. https://www.epocrates.com/online/article/fda-reports-limited-availability-of-tirzepatide-semaglutide-injections

4. Gu Y, Sebaratnam DF. GLP-1 receptor agonists for hidradenitis suppurativa: Navigating benefits, risks, and ethical considerations. Int J Dermatol. 2024 Feb 28. doi: 10.1111/ijd.17108. Epub ahead of print. PMID: 38415751.

5. Jennings L, Nestor L, Molloy O, Hughes R, Moriarty B, Kirby B. The treatment of hidradenitis suppurativa with the glucagon-like peptide-1 agonist liraglutide. Br J Dermatol. 2017 Sep;177(3):858-859. doi: 10.1111/bjd.15233. Epub 2017 Jul 14. PMID: 27943236.

6. Hogan AE, Tobin AM, Ahern T, Corrigan MA, Gaoatswe G, Jackson R, O'Reilly V, Lynch L, Doherty DG, Moynagh PN, Kirby B, O'Connell J, O'Shea D. Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis. Diabetologia. 2011 Nov;54(11):2745-54. doi: 10.1007/s00125-011-2232-3. Epub 2011 Jul 9. PMID: 21744074; PMCID: PMC3188710.

7. Drucker DJ, Rosen CF. Glucagon-like peptide-1 (GLP-1) receptor agonists, obesity and psoriasis: diabetes meets dermatology. Diabetologia. 2011 Nov;54(11):2741-4. doi: 10.1007/s00125-011-2297-z. Epub 2011 Sep 3. PMID: 21892687.

8. Nowowiejska J, Baran A, Flisiak I. The first case of psoriatic skin lesions exacerbation after liraglutide. Pol Arch Intern Med. 2023 Aug 30;133(7-8):16527. doi: 10.20452/pamw.16527. Epub 2023 Jul 6. PMID: 37415553.

9. Goldberg A, Graca S, Liu J, Rao V, Witchel SF, Pena A, Li R, Mousa A, Tay CT, Pattuwage L, Teede H, Yildiz BO, Ee C. Anti-obesity pharmacological agents for polycystic ovary syndrome: A systematic review and meta-analysis to inform the 2023 international evidence-based guideline. Obes Rev. 2024 Feb 14:e13704. doi: 10.1111/obr.13704. Epub ahead of print. PMID: 38355887.

10. Barry R, Murray G, Hellen R, Ní Raghallaigh S. Liraglutide, a GLP-1 agonist, as a new adjunct treatment in Hailey-Hailey disease: a case report. Clin Exp Dermatol. 2024 Mar 21;49(4):409-411. doi: 10.1093/ced/llad429. PMID: 38039150.

11. Yaneva M, Handjieva-Darlenska T, Kazandjieva J, Darlenski R. Delayed type hypersensitivity injection site reaction and tolerance induction to liraglutide for the treatment of obesity. JAAD Case Rep. 2023 Jun 17;38:100-101. doi: 10.1016/j.jdcr.2023.06.010. PMID: 37600731; PMCID: PMC10433277.

12. Ko JW, Park KD, Lee Y, Lee JH, Hong DK. Eosinophilic Panniculitis Following the Subcutaneous Injection of Exenatide Extended-Release. Ann Dermatol. 2020 Jun;32(3):230-232. doi: 10.5021/ad.2020.32.3.230. Epub 2020 Apr 24. PMID: 33911742; PMCID: PMC7992610.

13. Burruss CP, Jones JM, Burruss JB. Semaglutide-associated bullous pemphigoid. JAAD Case Rep. 2021 Aug 5;15:107-109. doi: 10.1016/j.jdcr.2021.07.027. PMID: 34466645; PMCID: PMC8385392.

14. Tran MM, Mirza FN, Lee AC, Goldbach H, Libby TJ, Wisco OJ. Dermatologic findings associated with semaglutide use: a scoping review. J Am Acad Dermatol. 2024 Mar 28:S0190-9622(24)00532-2. doi: 10.1016/j.jaad.2024.03.021. Epub ahead of print. PMID: 38554940.

15. Hirt PA, Castillo DE, Yosipovitch G, Keri JE. Skin changes in the obese patient. J Am Acad Dermatol. 2019 Nov;81(5):1037-1057.

16. Rosen J, Darwin E, Tuchayi SM, Garibyan L, Yosipovitch G. Skin changes and manifestations associated with the treatment of obesity. J Am Acad Dermatol. 2019 Nov;81(5):1059-1069.

17. Wetter DA, Davis MD. Lupus-like syndrome attributable to anti-tumor necrosis factor alpha therapy in 14 patients during an 8-year period at Mayo Clinic. Mayo Clin Proc. 2009 Nov;84(11):979-84.

18. Shmidt E, Wetter DA, Ferguson SB, Pittelkow MR. Psoriasis and palmoplantar pustulosis associated with tumor necrosis factor-alpha inhibitors: the Mayo Clinic experience, 1998-2010. J Am Acad Dermatol. 2012 Nov;67(5):e179-85.

19. Sokumbi O, Wetter DA, Makol A, Warrington KJ. Vasculitis associated with tumor necrosis factor-alpha inhibitors. Mayo Clin Proc. 2012 Aug;87(8):739-45.

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