The Use of GLP-1 Agonists in the Management of Cutaneous Disease

J Clin Aesthet Dermatol. 2024;17(9):34–37.

by Karan Lal, DO, and Emilee Herringshaw, MD, MBA

Dr. Lal is with Affiliated Dermatology in Scottsdale, Arizona, and Northwell Dermatology in Lake Success, New York. Dr. Herringshaw is with the University of Massachusetts Chan Medical School in Worcester, Massachusetts.

FUNDING: No funding was provided for this article.

DISCLOSURES: Dr. Lal is a speaker with Incyte, Sanofi, Pfizer, Abbvie, Boehringer Ingelheim, Sun Pharma, and Galderma.

ABSTRACT: Glucagon-like peptide-1 (GLP-1) agonists are a class of medications indicated for type 2 diabetes and obesity that may play a role in the management of cutaneous disease, in part due to their anti-inflammatory effects. These molecules interact with cytokines critical to the development and persistence of skin disease, such as TNF-α, IL-23, IL-17 and IL-22. Correspondingly, immunologic pathways that are downregulated by GLP-1 agonists may serve as a target for various skin conditions that are worsened by inflammation. Furthermore, the known benefit of weight loss for certain skin conditions may be further potentiated by GLP-1 agonists. In this brief report, the authors describe multiple cases of patients with psoriasis, hidradenitis suppurativa, acanthosis nigricans, and Hailey-Hailey disease for which patients experienced improvement subsequent to treatment with GLP-1 therapy. These cases demonstrate the utility of GLP-1 agonists in treating dermatologic conditions that are refractory to other therapies and further highlight the potential of GLP-1 agonists in treating skin disease.

Keywords: Psoriasis, hidradenitis suppurativa, Hailey-Hailey disease, medical dermatology, immunology, acanthosis nigricans 

Introduction

Glucagon-like peptide-1 (GLP-1) agonists are a class of medications that mimic GLP-1, a hormone which belongs to the incretin family.^1–3 GLP-1 agonists suppress appetite, delay gastric emptying and regulate glucose homeostasis.^2–4 They are prescribed for type 2 diabetes mellitus (T2DM) and obesity, for which they currently have approval from the United States (US) Food and Drug Administration (FDA).⁵ In addition to approved indications, GLP-1 agonists may have a role in the management of cutaneous disease, as demonstrated through off-label treatment in the literature (Table 1). 

GLP-1 agonists play an important role in immunoregulatory pathways and the development of cutaneous disorders. GLP-1 agonists inhibit TNF-α and nuclear factor-kappa B (NF-κB), thereby reducing pro-inflammatory cytokines.^1,6 The receptors of GLP-1 agonists are also expressed in activated T cells, which can enhance anti-inflammatory effects.⁷ In addition, they inhibit IL-23, IL-17, and IL-22, key drivers in the development of psoriasis and hidradenitis suprrativa (HS).^8,9 GLP-1 agonists also upregulate keratinocyte migration due to P13K/Akt activation, which is pertinent to wound healing.¹⁰ Thus, GLP-1 agonists may play a larger role in the management of skin disease given their interaction with immune mediators.¹¹ 

Despite the promise of these medications, they are accompanied by significant risks, including gastrointestinal issues, pancreatitis, kidney failure, gallbladder disease, and thyroid cancer.² Of these adverse effects, gastrointestinal effects are most commonly reported.² In addition, patients can experience unwanted cosmetic effects from rapid weight loss, such as sagging facial skin.² To mitigate side effects, these medications are started at a low dose and increased over time.²

Recently, the potential applications of GLP-1 agonists beyond obesity and T2DM has garnered attention, with focus on their anti-inflammatory properties and pleotropic potential.^1,2 Our interest is examining the utility of GLP-1 agonists for skin conditions exacerbated by excess weight and inflammation through a review of the literature. 

Methods

We conducted a search with PubMed, Medline, Clinicaltrials.gov, and Google scholar using the search terms Dermatology, GLP-1, skin, semaglutide, liraglutide, dulaglutide, albiglutide, exenatide, lixisenatide, tirzepatide from 2005 to 2023. Articles discussing the use of GLP-1 agonists  for indications other than skin conditions were excluded. 

Results

The FDA approved GLP-1 agonists in 2005. They are currently indicated for T2DM and obesity.⁵ Off label uses for psoriasis, hidradenitis suppurativa, acanthosis nigricans (AN), and Hailey-Hailey disease (HDD) have been reported. 

Psoriasis. The success of treating psoriasis with GLP-1 agonists has been documented in case reports and a prospective cohort study performed in 2019.^12–15 The earliest reported patient that we identified in the literature was a 59-year-old male with inadequately controlled diabetes who lived with moderate and stable psoriasis for 15 years.¹² He had failed topical corticosteroids, narrowband UVB therapy, and vitamin D analogs. He was prescribed liraglutide (0.6mg daily for one week, then 1.2mg daily for five weeks) given concomitant challenges with glucose control. Within a few days of starting liraglutide, his psoriasis improved, itching stopped, and scaling was reduced. Over 12 weeks, he experienced a reduction in his hemoglobin A1c (hbA1c), weight, and Physician Global Assessment (PGA) scale. Changes with psoriasis occurred before he lost any weight. Previous periods of euglycemia were not reported to improve his psoriasis. Thus, the anti-inflammatory effects of therapy were considered to be a key contributor to his improvement.¹² 

An additional case of a 73-year-old male patient with chronic obstructive pulmonary disease (COPD), Class III obesity and T2DM demonstrated rapid resolution of severe psoriasis with improved glycemic control and reduced body weight.¹³ This patient had psoriasis plaques that were refractory to topical therapies and adalimumab, as well as T2DM that was poorly controlled with metformin therapy. He had severe psoriasis (Psoriasis Area and Severity Index [PASI] score of 33.2) which had an extremely negative impact on his quality of life (Dermatology Quality of Life Index [DLQI] score of 26.0). He was started on semaglutide (0.25mg per week x 4 weeks, then 0.5mg per week x 12 weeks, maintained at 1mg per week) which decreased the severity of his psoriasis and improved his quality of life. His PASI score was reduced to 2.6 (-92.2%) and DLQI to 0. This patient experienced long-lasting improvement of psoriasis that was previously refractory to biologics, suggesting that severe, resistant lesions may benefit from GLP-1 agonist therapy.¹³ 

In a third case, a 50-year-old female patient with obesity and T2DM was started on semaglutide (0.25mg per week x 4 weeks, then 0.5mg per week x 12 weeks, maintained on 1mg per week) and evaluated for changes in adipose tissue depots surrounding the heart and coronary arteries.¹⁴ The patient underwent computed tomography (CT) to assess epicardial adipose tissue (EAT) attenuation and peri coronary adipose tissue (PCAT) attenuation, measures indicative of cardiac risk. Over the duration of 10 months, attenuation signals, markers related to obesity (weight, body mass index (BMI), waist circumference), lipids (LDL, triglycerides), inflammation (CRP, IL-6, ESR) and glycemic control (hbA1C) were reduced. Her psoriasis was also improved and had less of an impact on her quality of life. This case demonstrated how semaglutide has the potential to improve psoriasis outcomes involving both the cutaneous presentation and associated comorbidities such as cardiovascular risk.¹⁴ 

Finally, a prospective cohort study of seven patients with T2DM and psoriasis demonstrated improvement in psoriasis treated with GLP-1 agonists through the reduction of inflammation, blood sugar improvement, and weight loss.¹⁵ Patients were administered liraglutide for 12 weeks and underwent assessment before and after therapy. At the end of treatment, there was improvement in psoriasis severity and quality of life.¹⁵ HbA1C, BMI, and waist circumference decreased. Fasting C-peptide levels increased while the Homeostatic Model Assessment for Insulin Resistance (HOMA – IR) decreased.¹⁵ Samples evaluated with histology showed decreased epidermal thickness subsequent to treatment. This study showed how liraglutide can serve as an effective therapy for severe psoriasis through multiple pathways pertaining to inflammation, blood glucose levels, and obesity.¹⁵

These studies demonstrate that GLP-1 agonists are a potential alternative for patients with obesity or T2DM who develop psoriasis and are resistant to biologic therapies.^13,14 In these patients, the potential of GLP-1 agonists not only can deliver improvement for the targeted conditions, but can reduce comorbidities, such as obesity, dyslipidemia, and cardiovascular disease.¹⁶ 

Hidradenitis suppurativa. GLP-1 agonists have also been used for HS, a condition that is associated with metabolic syndrome, obesity, and systemic inflammation, which currently has limited treatment modalities.¹⁷ GLP-1 agonists may offer benefits related to weight loss and anti-inflammatory effects^.17 The case of a 31-year-old female patient with Hurley Stage II HS demonstrated a significant improvement in cutaneous presentation and pain level after treatment with liraglutide. Prior to starting therapy, she was assessed to have severe disease by the HS-Physician’s Global Assessment (PGA) with a score of 4. She started on liraglutide (0.6 mg daily, increased to 1.8 for maintenance) which reduced disease severity to minimal (PGA score of 1). Over a period of four weeks, her DLQI reduced (24 to 14), weight decreased (by 4.5 kg) and she required less analgesia to manage her pain. The improvement of this case is suggested to be related to pathways known to HS, including those involving  IL-17 and other cytokines associated with TNF-α and NF-κB.¹⁷ Compared to alternative immunosuppressives used in the management of HS, this can serve as a viable alternative that also assists with weight loss and targets inflammatory pathways that promote disease progression.    

Acanthosis nigricans. The effective treatment of AN with a GLP-1 analog has been demonstrated in a case report. One case in the literature reports improvement in the clinical appearance and epidermal insulin signaling of AN in a 42-year-old woman with obesity and T2DM.¹⁸ She had previously been managed with metformin, pioglitazone, and insulin, then was started on liraglutide (0.6mg/day titrated to 1.2mg/day) in combination with metformin. Over three months, her AN significantly improved and hbA1C decreased to 5.7 (starting value not stated).¹⁸ 

Hailey-Hailey disease.  HHD is a rare condition often refractory to treatment that has been successfully managed with a GLP-1 agonist in one case in the literature. In HHD, blisters form in the intertriginous areas due to mutations in the ATP2C1 gene, a regulator of intracellular calcium.¹⁹ Notably, patients with HHD have a 5 to 7 times increase in IL-17 in affected skin, which is of relevance given the ability of GLP-1 agonists to reduce IL-17 expression.¹⁹ In this case, a 60-year-old woman experienced significant improvement in her HHD after being prescribed liraglutide (1.8mg daily x 6 months). In the past, she had been on many therapies, including topicals, oral antibiotics, naltrexone, and photodynamic therapy and acitretin. Her improvement with a GLP-1 agonist was attributed to anti-inflammatory effects, such as the reduction of IL-17 and IL-6 levels.¹⁹ 

Conclusion

These reports suggest the potential utility of GLP-1 analogs in the treatment of dermatologic disease. GLP-1 analogs demonstrated efficacy in cases refractory to other treatment modalities, often in cases of patients with obesity who would experience additional benefits from starting therapy. The efficacy of GLP-1 agonists was notable for various conditions, including psoriasis, hidradenitis suppurativa, acanthosis nigricans, and Hailey-Hailey disease. Additional studies are needed to evaluate safety, efficacy, and proper use of GLP-1 agonists for dermatologic conditions to consider expanding their approval beyond T2DM and weight loss. 

References 

1. Faurschou A, Pedersen J, Gyldenløve M, et al. Increased expression of glucagon‐like peptide‐1 receptors in psoriasis plaques. Exp Dermatol. 2013;22:150–152.
2. Suran M. As Ozempic’s popularity soars, here’s what to know about semaglutide and weight loss. JAMA. 2023;329(19):1627–1629.
3. Nauck MA, Quast DR, Wefers J, et al. GLP-1 receptor agonists in the treatment of type 2 diabetes– state-of-the-art. Mol Metab. 2021;46:101102. 
4. Holst JJ. The Physiology of Glucagon-like Peptide 1. Physiol Rev. 2007;87:1409–1439.
5. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384: 989–1002.
6. Al-Badri MR, Azar ST. Effect of glucagon-like peptide-1 receptor agonists in patients with psoriasis. Ther Adv Endocrinol Metab. 2014;5:34–38.
7. Rode AKO, Buus TB, Mraz V, et al. Induced human regulatory t cells express the glucagon-like peptide-1 receptor. Cells. 2022;11:2587.
8. Chen P, Lin L, Xu X, et al. Liraglutide improved inflammation via mediating IL-23/Th-17 pathway in obese diabetic mice with psoriasiform skin. J Dermatol Treat. 2021;32:745–751.
9. Scala E, Cacciapuoti S, Garzorz-Stark N, et al. Hidradenitis suppurativa: where we are and where we are going. Cells. 2021;10:2094.
10. Nagae K, Uchi H, Morino-Koga S, et al. Glucagon-like peptide-1 analogue liraglutide facilitates wound healing by activating PI3K/Akt pathway in keratinocytes. Diabetes Res Clin Pract. 2018;146: 155–161.
11. Hogan AE, Tobin AM, Ahern T, et al. Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis. Diabetologia. 2011;54: 2745–2754.
12. Faurschou A, Knop FK, Thyssen JP, et al. Improvement in psoriasis after treatment with the glucagon-like peptide-1 receptor agonist liraglutide. Acta Diabetol. 2014; 51:147–150.
13. Costanzo G, Curatolo S, Busà B, et al. Two birds one stone: semaglutide is highly effective against severe psoriasis in a type 2 diabetic patient. Endocrinol Diabetes Metab Case Rep. Epub ahead of print 1 Aug 2021. 
14. Malavazos AE, Meregalli C, Sorrentino F, et al. Semaglutide therapy decreases epicardial fat inflammation and improves psoriasis severity in patients affected by abdominal obesity and type-2 diabetes. Endocrinol Diabetes Metab Case Rep. 2023;2023(3):23–0017.
15. Xu X, Lin L, Chen P, et al. Treatment with liraglutide, a glucagon-like peptide-1 analogue, improves effectively the skin lesions of psoriasis patients with type 2 diabetes: a prospective cohort study. Diabetes Res Clin Pract. 2019;150: 167–173.
16. Humphrey CD, Lawrence AC. Implications of ozempic and other semaglutide medications for facial plastic surgeons. Facial Plast Surg. 2023;39: 719–721.
17. Jennings L, Nestor L, Molloy O, et al. The treatment of hidradenitis suppurativa with the glucagon‐like peptide‐1 agonist liraglutide. Br J Dermatol. 2017;177: 858–859.
18. Malisiewicz B, Boehncke S, Lang V, et al. Epidermal insulin resistance as a therapeutic target in Acanthosis nigricans? Acta Derm Venereol. 2014; 94: 607–608.
19. Barry R, Murray G, Hellen R, et al. Liraglutide, a GLP-1 agonist, as a new adjunct treatment in Hailey-Hailey disease, a case report. Clin Exp Dermatol. 2024;49(4):409–411.