A Review of Glucagon-like Peptide-1 in Dermatology

J Clin Aesthet Dermatol. 2025;18(3):42–50.

by Willmar Patino, MD; Amanda Thomas, BS; Sanjana Jain, BS; James Q. Del Rosso, DO; and Naiem T. Issa, MD, PhD

Dr. Patino is with Forefront Dermatology in Manitowoc, Wisconsin. Ms. Thomas is with the Creighton University School of Medicine in Phoenix, Arizona. Ms. Jain is with Indiana University in Bloomington, Indiana. Dr. Del Rosso is with JDR Dermatology Research in Las Vegas, Nevada. Dr. Issa is with Forefront Dermatology in Vienna, Virginia, Issa Research and Consulting, LLC in Springfield, Virginia, the Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery at the University of Miami Miller School of Medicine in Miami, Florida, and the George Washington University School of Medicine and Health Science in Washington, District of Columbia.

FUNDING: No funding was provided for this article.

DISCLOSURES: Dr. Issa has served as a consultant and advisor for Eli Lilly and Company. Dr. Del Rosso has served as an investigator, consultant, advisor, and/or speaker for Galderma, Abbvie, Aclaris, Almirall, Amgen, Anaptys Bio, Arcutis, Athenex, Bausch, Biofrontera, Biopharmx, Biorasi, Blue Creek, Botanix, Brickell, Bristol Meyers Squibb, Cara Therapeutics, Cassiopea, Dermata, Dermavant, Encore, Epi Health, Evommune, Ferndale, Genentech, Incyte, JEM Health, Leo Pharma, La Roche Posay, Lilly, MC2, Novan, Pfizer, Ralexar, Regeneron, Sanofi-Genzyme, Sente, SolGel, Sonoma, Sun Pharma, Trevi, UCB, Verrica, and Vyne.

ABSTRACT: Objective: Glucagon-like peptide-1 (GLP-1) is a hormone produced in response to meal intake by endocrine intestinal cells. GLP-1 binds to its receptors which are expressed on various cells throughout the body. GLP-1 receptors (GLP-1R) have become a target for the treatment of diabetes mellitus and weight loss, and GLP-1 receptor agonist (GLP-1RA) use has become more common among patients. In addition to the anti-hyperglycemic effects, recent studies have exhibited anti-inflammatory effects of GLP-1RAs. Current research surrounding GLP-1Rs and GLP-1R agonism in dermatology is limited. This review aims to describe the current knowledge of GLP-1Rs and GLP-1RA use in dermatology and suggest future directions. Methods: A literature search focused on GLP-1RAs and their effect on cutaneous disease processes was performed across various databases. The databases were searched through May 2024. Results: The use of GLP-1RAs have shown promising anti-inflammatory effects and improvement in wound healing, psoriasis, and hidradenitis suppurativa. Several cutaneous adverse reactions to GLP-1RAs were also identified with injection site pruritus, erythema, and rash being the most commonly reported. Limitations: Current literature is limited to case reports and small-scale studies. Conclusion: The literature suggests anti-inflammatory effects of GLP-1RAs may provide direct benefit in the treatment of dermatologic conditions independent of glucose control in addition to indirect improvement via modulation of blood glucose and weight loss. Further studies investigating the implications of GLP-1RA use and the possible therapeutic potential of GLP-1RAs in inflammatory skin conditions are warranted.

Keywords: GLP-1 receptor agonists, psoriasis, wound healing, hidradenitis suppurativa, cutaneous adverse effects

Introduction

Glucagon-like peptide-1 (GLP-1) is an incretin hormone produced in the intestinal epithelial endocrine L-cells following meal intake.¹ GLP-1 is formed by posttranslational proteolytic cleavage of the proglucagon gene product and is degraded by dipeptidyl peptidase-4 (DPP-4).^2,3 GLP-1 controls blood glucose by stimulating insulin secretion, inhibiting glucagon secretion, stimulating beta-cell proliferation and differentiation, decreasing beta-cell apoptosis, delaying gastric emptying, and reducing food intake.² GLP-1 has also been shown to possess anti-inflammatory effects on pancreatic islets and adipose tissue.² 

GLP-1 binds to glucagon-like peptide-1 receptors (GLP-1R) which are class II G protein-coupled receptors.¹ GLP-1Rs are found on a variety of cells including those of the endocrine pancreas, keratinocytes, endothelial cells, neurons, astrocytes, microglia, pancreatic beta-cells, intraepithelial lymphocytes, neutrophils, and eosinophils.^4,5 GLP-1Rs are also expressed in various locations including the kidney, lung, heart, and hypothalamus.^2,4,6 The wide expression of these receptors suggests possible roles beyond glucose-lowering.²

Commercially available GLP-1 receptor agonists (GLP-1RA) include dulaglutide, exenatide, semaglutide, the dual GLP-1 and gastric inhibitory polypeptide receptor agonist tirzepatide, and combined liraglutide/insulin degludec and lixisenatide/insulin glargine.⁷ GLP1-RAs have become increasingly more utilized medications for the treatment of diabetes mellitus and weight loss, with recent studies demonstrating possible anti-inflammatory and immunomodulatory effects as well. Though research is limited, in vitro and in vivo studies have alluded to the potential of semaglutide exerting anti-inflammatory effects by decreasing glucotoxicity, immune cell recruitment, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and various pro-inflammatory cytokine expression, lipotoxicity, and oxidative stress.⁸ Direct action on the skin is a possible mechanism, as GLP-1Rs have been shown to be expressed in the skin of newborn mice and cultured skin cells.⁹ 

This review aims to summarize the available research pertaining to GLP-1Rs and GLP- 1RAs in the field of dermatology, including wound healing and the treatment of psoriasis and hidradenitis suppurativa. We also suggest other potential therapeutic applications of GLP-1RAs in inflammatory cutaneous conditions.

GLP-1 Receptors in the Skin 

Though GLP-1Rs have been found to be expressed in skin, their role is still not fully understood (Figure 1).⁵ In a study investigating the expression of GLP-1Rs in the skin of newborn mice and cultured skin cells, GLP-1Rs were detected by RT-PCR, Western immunoblot analysis, and in situ immunocytochemistry.¹⁰ The presence of GLP-1Rs in mouse skin was found in localized regions of the hair follicle.¹⁰ Another study assessing the presence of GLP-1Rs in cultured keratinocytes demonstrated that GLP-1R mRNA was present and Western blot confirmed protein expression of GLP-1Rs.⁵ With the addition of GLP-1 to the skin-derived cells, phosphorylation of ERK1/2 was noted and consistent with active protein kinase/phosphatase signaling.¹⁰ 

GLP-1Rs were also found in immune cells that can infiltrate the skin. In a study assessing the presence of GLP-1Rs in keratinocytes or immune cells, punch biopsies were obtained from the skin of healthy volunteers and patients with plaque psoriasis. GLP-1Rs were expressed in five of six skin biopsies from psoriasis plaques, in one of six biopsies from unaffected psoriatic skin, and in one of six biopsies from healthy skin.¹¹ When cultured keratinocytes were stimulated with tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), no GLP-1 expression was detected.¹¹ This suggested the presence of GLP-1Rs demonstrated in the biopsies of psoriasis patients was likely due to immune cell infiltration rather than GLP-1Rs located in the skin.¹¹

GLP-1 Receptor Agonists and Wound Healing

Wound healing is a process that consists of four phases, including hemostasis, inflammation, proliferation, and remodeling/maturation. During hemostasis, von Willebrand factor is released by endothelial cells, which leads to platelet adhesion and release of mediators resulting in the formation of a fibrin clot. Vessels also constrict and blood flow is reduced. The inflammatory phase involves vasodilation due to histamine and serotonin release from mast cells as well as granulocyte and monocyte migration. The leukocytes secrete cytokines and growth factors and keratinocytes secrete inflammatory cytokines. The inflammatory phase is directed by cytokines, matrix proteins, and enzymes. The proliferative phase is characterized by fibroblast-driven formation of granulation tissue and keratinocyte migration and proliferation. The final phase consists of the remodeling of granulation tissue directed by matrix metalloproteins (MMPs) and tissue inhibitor of metalloproteinases (TIMPs). Type I collagen is replaced by type III collagen and elastin reappears.¹²

In vitro studies have shown that liraglutide, a GLP-1RA, can increase keratinocyte migration.⁵ GLP-1R activation can reduce the inflammatory response and augment angiogenesis as well as transforming growth factor-β/matrix metalloproteinase-mediated regeneration.¹³ Liraglutide has also been shown to accelerate wound healing in vivo. This is demonstrated by accelerated wound closure of punch excisions seen in mice treated with topical liraglutide when compared to control.⁵

Wound healing is also mediated by the PI3K/Akt pathway.⁵ Increased keratinocyte migration via the activation of PI3K/Akt has been demonstrated as the addition of liraglutide further augmented the scratch-induced phosphorylation of Akt.⁵ Scratch-injury has already been reported as an essential step in keratinocyte migration.⁵

Another study investigated the rate of excisional wound healing in diabetic rats treated with exendin-4, a GLP-1RA, and placebo.¹³ This study found that rats treated with exendin-4 had increased endothelial progenitor cells and protein levels of vascular endothelial growth factor receptor-2 (VEGF R2), phosphorylated endothelial nitric oxide synthase (eNOS), matrix metalloproteinase-2 (MMP-2), and transforming growth factor-β (TGF-β).¹³ This caused increased vascularity, dermal regeneration, and epidermal regeneration leading to overall faster wound healing.¹³ 

A similar study described improved wound healing in normoglycemic mice treated with exendin-4 when compared to exendin 4(9-39) and saline.¹⁴ Exendin 4(9-39) is a peptide modified from exendin-4 that acts as an antagonist at GLP-1 receptors.¹⁴ Wound sizes were measured at the time of abrasion and after 144 hours by ruler and software.¹⁴ In mice treated with exendin-4, the wounds were 92-percent healed at 144 hours, compared to 53-percent, 68-percent, and 79-percent healed for saline, exendin-4(9–39), and exendin-4(9–39)+exendin-4, respectively.¹⁴ The extent of inflammatory infiltrate observed in hematoxylin and eosin-stained sections was similar among all treatment groups and the control group.¹⁴ The number of fibroblasts measured by HSP47 expression were highest in exendin-4 treated mice as was the number of differentiated myofibroblasts which were characterized by the presence of Acta2+ cells by immunohistochemical analysis.¹⁴ Western-blot analysis showed active ERK1/2 in exendin-4 treatment mice, but not in the control or combined exendin-4(9-39) and exendin-4 mice.¹⁴ CD31+ cells were also increased in the exendin-4 mice which suggested enhanced endothelial cell proliferation.¹⁴ Overall, this study demonstrated enhanced wound healing with increased fibroblasts, myofibroblasts, and vessel density in normoglycemic mice suggesting a role independent of hyperglycemia. 

Exendin-4 was also shown to have beneficial effects on fibroblast function, metabolic, inflammatory, and healing markers in diabetic rat models.¹⁵ Zucker diabetic fatty rats were injected with saline or varying doses of exendin-4. After three weeks, the fibroblasts and myofibroblasts were isolated and demonstrated decreased C-reactive protein (CRP) and matrix metalloprotease-9/tissue matrix metalloproteinase inhibitor-1 (MMP-9/TIMP-1) ratio in rats treated with exendin-4. This suggests increased anti-inflammatory and pro-healing effects. A similar study with a long-acting exendin-4 analog also demonstrated accelerated wound healing of foot ulcers in diabetic rat models.¹⁶ 

The GLP-1RA liraglutide was found in one study to synergistically improve healing with zinc oxide (ZnO) in nanofibrous dressings while preventing infection and promoting vascularization.¹⁷ Electrospinning allowed for the fabrication of Poly(l-lactide-co-glycolide) (PLGA)/Gel membranes and encapsulation of liraglutide and ZnO nanoparticle (ZnO-NPs).¹⁷ In vitro scratch wound healing assays were performed and demonstrated increased migration and formation of tubule networks of human umbilical vein endothelial cells (HUVECs) when liraglutide was added.¹⁷ 

Additionally, activation of AMP-activated protein kinase (AMPK) by liraglutide leads to endothelial protection and angiogenesis regulated by the hypoxia inducible factor-1α–heme oxygenase-1 (Hif-1α HO-1) axis.¹⁸ Liraglutide has been shown to activate AMPK in rat vascular smooth muscle cells.¹⁹ AMPK activation has been shown to play a role in angiogenesis and diabetic wound healing by reducing inflammation and promoting re-epithelization.²⁰

In diabetic mice models, liraglutide treatment reduced oxidative stress and endothelial apoptosis relative to the untreated mice. HUVECs treated with liraglutide also had decreased endothelial impairment. In endothelial cell cultures, liraglutide increased AMPK activity, which is downregulated by hyperglycemia, illustrating the role of liraglutide in AMPK activation. siRNA transfection that interfered with AMPKα1/2 expression in HUVECs resulted in increased apoptosis and a lack of previously observed protective effects. That finding suggested AMPK activation was the mechanism by which liraglutide exerted its protective effects. Downstream of AMKPK, Hif-1α was demonstrated to play a role in the endothelial protective effects of liraglutide which promoted diabetic wound healing.¹⁸ 

There are many mechanisms by which GLP-1RAs may act to improve wound healing (Figure 2) and the findings of these studies suggest that treatment with GLP-1RAs could have significant applications in wound healing. Improvement in wound healing were seen in normoglycemic mice, suggesting a role independent of glucose control and in-vitro studies have shown that GLP-1RAs may directly improve wound healing, independent of blood glucose control, through the reduction of CRP and MMP-9/TIMP-1 ratio, endothelial protection and angiogenesis secondary to increased AMPK, increased endothelial cell proliferation due to stimulation of CD31+ cells, P13/AKT induced keratinocyte migration, increased vascularity and dermal and epidermal regeneration due to increased phosphorylated eNOS and VEGF R2, as well as increased endothelial progenitor cells, fibroblasts, and myofibroblasts. 

GLP-1 Receptor Agonists and Psoriasis

Psoriasis is a common dermatologic disorder that has a high comorbidity with metabolic syndrome and cardiovascular disease. Patients with diabetes are at higher risk of developing psoriasis.²¹ The pathogenesis of psoriasis is an immune mediated process. The proinflammatory effects of TNF-α released by dendritic cells and others trigger inflammation in macrophages, lymphocytes, keratinocytes, and endothelial cells. Interleukin (IL)-23 and Th17 activation also induce keratinocyte proliferation and further release of pro-inflammatory cytokines in a positive feedback loop. Psoriasis has also been associated with βdefensin, the Th2 pathway involving IL-4 and IL-13, and adaptive immunity involving CD8 T cells.²² Additionally, keratinocytes secrete antimicrobial peptides, cytokines, and chemokines that cause immune cell infiltration. The combined inflammatory effects cause vascular endothelial cells to activate pro-angiogenic factors including vascular endothelial growth factor (VEGF). Current treatment consists of topical or systemic immunomodulators and biologics.²³

Some studies demonstrated possible anti-inflammatory benefits from semaglutide use in patients with insulin resistance and psoriasis.²⁴ Published case reports showed improvement of psoriatic lesions after initiation of GLP-1RAs. One case published in 2012 described a 61-year-old male with a history of type 2 diabetes mellitus (T2DM) and psoriasis. His initial Psoriasis Area and Sensitivity Index (PASI) score was 11. The patient’s diabetes was initially treated with metformin and sulfonylureas and treatment was intensified with exenatide to improve glycemic control. One month after the addition of exenatide, the patient reported improvement, and at one year, his PASI was estimated to be 3 to 4. Exenatide was discontinued and psoriatic lesions worsened, with a PASI >10, but improved promptly to 3.1 after exenatide re-initiation. During this time, there were no other changes made to his treatment plan.²⁵ 

A similar case report details a 73-year-old male patient with T2DM, treated with metformin, as well as severe psoriasis, refractory to adalimumab, who was treated with semaglutide. PASI was initially 33.2, and Dermatology Life Quality Index (DLQI) was 26.0 indicative of severe disease and poor quality of life, respectively. After four months, PASI decreased to 8.0 and DLQI improved to 3 with improved diabetes control. At 10 months, the patient continued to improve with a PASI of 2.6 and DLQI of 0.²⁶ Another report described a 59-year-old male patient with a history of moderate psoriasis and inadequately controlled diabetes. Upon initiation of liraglutide, he was not receiving treatment for psoriasis. After initiation of liraglutide, he noted improvement in pruritis within days and a rapid decrease in scaling. Over three months, his psoriasis continued to improve, along with improvement in glycemic control and weight loss. Given his history of previously controlled diabetes without improvement of psoriasis and improvement of psoriatic lesions prior to weight loss while being treated with liraglutide, the improvement in his psoriasis was likely due to a mechanism other than weight reduction or glycemic control.²⁷

A case published in the literature also showed improvement of psoriasis when treated with liraglutide combined with acitretin. A 54-year-old male patient with obesity and recalcitrant psoriasis previously trialed etanercept, efalizumab, narrowband UVB, psoralen-UVA, ciclosporin, methotrexate, acitretin, and fumaric acid without response. He began adalimumab therapy, but it was discontinued after the diagnosis of amelanotic malignant melanoma was made. He was started on acitretin 50mg daily, and liraglutide was added due to lack of response. After one year of combined treatment, PASI and DLQI improved significantly.²⁸ The improvement in psoriasis after the addition of liraglutide suggests the role of liraglutide in improvement.

A systematic review and meta-analysis of prospective cohort studies and before–after studies prior to June 20, 2020, sought to analyze the efficacy of liraglutide in treatment of plaque psoriasis. The review analyzed four trials that included a total of 32 patients. Patients who were treated with liraglutide showed significantly lower PASI and fasting plasma glucose, whereas there was no significant difference in body mass index (BMI), DLQI, and hemoglobin A1C. This suggested that the role of GLP-1RAs in improvement of psoriasis was independent of weight loss or diabetic control.²⁹

A prospective cohort study assessed changes in PASI, DLQI, tissue and pathologic analysis of psoriasis, BMI, waist circumference, fasting blood glucose, fasting C-peptide, hemoglobin A1C, blood lipid levels, and CRP after 12 weeks of treatment of liraglutide 1.8mg. After 12 weeks, the mean PASI and DLQI had a statistically significant reduction. Epidermal thickness after liraglutide treatment was also significantly decreased. In addition to the clinical and histologic improvement of psoriasis, there were significant improvements in hemoglobin A1C, BMI, waist circumference and fasting C-peptide levels. Liraglutide was shown to improve psoriasis, suggesting possible mechanisms related to inflammation, blood glucose control, and weight reduction.³⁰ We are unable to determine through this study if improvement in psoriasis is due to mechanisms directly related to GLP-1RAs or through improved blood glucose management and weight loss.

Some reports also described psoriasis remission after gastric bypass surgery. These cases contributed to the hypothesis of GLP-1 mediated improvement in psoriasis since GLP-1 was demonstrated to be elevated following gastric bypass surgery.³¹ One case demonstrated long-term remission of severe psoriasis and significant weight loss two years after laparoscopic gastric bypass surgery.³² Another case demonstrated immediate improvement in psoriasis in a 56-year-old male patient with obesity after open gastric bypass surgery. At four months post-operative follow-up, his psoriasis was in remission, and he lost 34.8 percent of excess body weight, although improvement in psoriasis was noted prior to weight loss.³³ The temporal relationship between improvement in psoriasis prior to weight loss suggested a mechanism of disease improvement independent of weight loss.

GLP-1 receptors have been shown to be increased in psoriasis plaques compared to skin of healthy individuals. One study obtained punch biopsies from healthy volunteers and affected and unaffected skin of psoriasis patients as well as blood samples. Psoriasis plaques had higher levels of GLP-1R expression than unaffected skin by real-time PCR. Both patients with psoriasis and the healthy controls expressed GLP1- receptors in the blood. Additionally, human keratinocytes were not found to express GLP-1 receptors even when cultured with TNF-α, IFN-γ, or a combination. These findings suggest that the expression of GLP-1Rs in psoriatic plaques is due to immune cell infiltration.¹¹ 

Modulation of invariant natural killer T (iNKT) cells by GLP-1RAs was another mechanism demonstrated to improve psoriasis. Hogan and colleagues started two obese patients with psoriasis on liraglutide after observation of psoriasis improvement with exenatide and liraglutide treatment in the index patient.³⁴ The index patient was a 60-year-old female patient with extensive psoriasis and a PASI greater than 15, who reported improvement of psoriasis severity within two days of exenatide initiation.³⁴ She experienced nausea on exenatide and it was discontinued, with subsequent worsening of psoriasis, and was started on liraglutide with improvement within three weeks to a PASI of 10.2 that remained stable nine months after initiation of liraglutide.³⁴ Two additional patients with obesity and psoriasis were started on liraglutide, and the levels of iNKT cells were measured at baseline and after six weeks of treatment.³⁴ Both patients saw clinical improvement in psoriasis following liraglutide therapy.³⁴ After six weeks, the iNKT cells in circulation increased while the number of iNKT cells in psoriatic plaques decreased. The change in distribution of iNKT cells was further evaluated by confirming the production of GLP-1Rs that responded to GLP-1 and reduced iNKT cell cytokine production.³⁴ In patients with plaque psoriasis treated with liraglutide, iNKT cells in psoriatic plaques decreased while circulating iNKT cells increased, likely because of the immunoregulatory action of GLP-1 on iNKT cells.³⁵ A prospective cohort study by Ahern et al³⁶ showed the same pattern of iNKT cell distribution and improvement in psoriasis. Ten weeks of liraglutide therapy significantly improved PASI and DLQI in seven patients with psoriasis and diabetes. After 10 weeks, the number of circulating iNKT cells was also increased.

Another mechanism by which GLP-1RAs may exert their effects is through activation of AMPK. One study showed that the introduction of liraglutide increased AMPK phosphorylation and reduced phospho-IKKα/β S176/S180, phospho-NF-κB p65, phospho-JAK2, phospho-STAT3, SOCS3, TNF-α, and IL-6 levels. Additionally, liraglutide prevented macrophage migration. This demonstrated a pathway by which liraglutide regulated inflammation.³⁷

Regulation of the IL-23/Th17 pathway is another possible mechanism of the anti-inflammatory effects of GLP-1RAs. Diabetic mice models treated with liraglutide were shown to have improved glucose metabolism and insulin resistance, reduced PASI, and decreased expression of IL-23, IL-17, IL-22, and TNF-α in skin tissue. This suggests that liraglutide works to reduce severity of psoriasis through anti-inflammatory effects.³⁸

γδ T cells are a subset of T cells that reside in the dermis. After stimulation by IL-23, γδ T cells release IL-17. In addition to the previously described involvement of Th1 and Th17 cells in the development of psoriasis, γδ T cells have also been shown to play a role.³⁹ A prospective study of patients with moderate-to-severe plaque psoriasis showed a higher percentage of dermal γδ T cells in psoriatic plaques when compared to control. After treatment with exenatide or liraglutide, six of seven patients enrolled in the study saw either an improvement or lack of change in PASI. The same patients also saw a reduction in γδ T cells. PASI and γδ T cell percentage had a significant correlation (r=0.894, p=0.007). Additionally, reduction in IL-17 was seen in the patients who had an improvement in PASI. This study demonstrated a correlation between clinical improvement of psoriasis with reduction in γδ T cell number and expression of IL-17, suggesting another possible mechanism by which GLP-1RAs improve psoriasis.⁴⁰

Most cases in the literature demonstrate improvement of psoriasis after the initiation of GLP-1RAs, but one report described a patient with an exacerbation of psoriatic lesions after the initiation of liraglutide. A 34-year-old female patient with a history of mild psoriasis for which she was not receiving treatment was started on liraglutide for insulin resistance. After two weeks of treatment with liraglutide, the patient noted the appearance of new psoriatic lesions that continued to progress over two months. Liraglutide was discontinued, topical agents were initiated, but she failed to respond. The patient was treated with cyclosporin A with a gradual improvement in lesions. The unexpected paradoxical worsening of psoriatic lesions after treatment with liraglutide was hypothesized to be due to cytokine imbalance with the release of IFN-α and leukocyte chemotaxis after liraglutide-induced inhibition of TNF-α, IL‑17, and IL‑23.⁴¹

Although most literature demonstrates improvement of psoriatic lesions with GLP-1RA therapy, a randomized placebo-controlled trial showed lack of improvement with liraglutide in glucose-tolerant patients. Twenty, glucose-tolerant patients with obesity and psoriasis were enrolled in the study for eight weeks. There was not a significant difference in PASI, DLQI, or CRP in patients treated with liraglutide compared to controls. Liraglutide did significantly increase weight loss and lower total cholesterol.⁴² Given the lack of response in glucose-tolerant patients, this study suggests that the mechanism by which GLP-1RAs improve psoriasis is indirect and mediated by glycemic control. 

Although there is some conflicting data, in most studies GLP-1RAs have demonstrated anti-inflammatory effects in psoriasis (Figure 3) and several studies suggest that these medications could be associated with significant improvement of psoriatic lesions. Larger randomized placebo-controlled trials including a variety of patient populations (ie, those with metabolic syndrome versus those without) are needed to confirm efficacy of GLP-1RAs according to patient type. This is akin to the post-hoc analysis of tildrakizumab (anti-IL-23) which showed comparable efficacy in patients with and without metabolic syndrome.⁴³ The data regarding improvement of psoriasis following the initiation on GLP-1RAs is mixed and much of the data is limited to case reports. In some cases, the improvement in psoriasis coincided with weight loss and improved glycemic control but in others improvement was seen prior to weight loss. A randomized controlled trial showed no improvement in psoriatic lesions in patients who were glucose tolerant. Therefore, the improvement in psoriasis is likely indirect through improved glucose control, although specific anti-inflammatory processes have been identified.

GLP-1 Receptor Agonists and Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that presents most commonly in intertriginous areas as nodules, abscesses, draining sinus tracts, and scarring. The pathophysiology of HS is complex but involves follicular hyperkeratosis/occlusion, sweat gland dysfunction, immune dysregulation, bacterial infections, and chronic local and systemic inflammation. Chronic inflammation is sustained by a lack of Notch signaling leading to toll-like receptor stimulation with subsequent TNF-α and IL-1β secretion causing dendritic cell activation and IL-23 release which polarizes Th17 cells and leads to increased IL-17. Current treatments for HS include topical clindamycin, erythromycin, and gentamicin, oral antibiotics including tetracyclines, clindamycin, combined clindamycin and rifampicin, combined clindamycin and ofloxacin, biologics such as adalimumab, infliximab, secukinumab and off-label ustekinumab and brodalumab.⁴⁴ Current research on the potential of GLP-1RAs in the management of HS is limited.

There is one case reported in the literature that demonstrated improvement in HS after initiation of liraglutide; a 31-year-old female patient with obesity, a history of smoking, and a HS-Physician’s Global Assessment (HS-PGA) of 4, indicative of severe disease. Her HS was not responsive to rifampicin-clindamycin, metformin, spironolactone, adalimumab, etanercept, and dapsone. She had a Dermatology Life Quality Index (DLQI) of 24, which is indicative of a large negative impact on her life, and she required daily narcotic analgesia for HS-related pain management. After four weeks of treatment with liraglutide, her HS improved significantly to a HS-PGA of 1 significant for minimal disease. Her DLQI improved to 14 and she required less analgesia. Additionally, the liraglutide was well tolerated. The improvement in both HS-PGA and DLQI was possibly due to combined actions of weight loss and GLP-1 receptor activation. Liraglutide has been shown to decrease IL-17 and cytokines induced by TNF-α which play a role in the pathogenesis of HS.⁴⁵ This case suggested the possible therapeutic potential of GLP-1RAs in refractory HS, but the mechanism by which it acts is unknown and we are unable to state if it is due to direct anti-inflammatory effects of liraglutide or indirect effects secondary to weight loss.

Cutaneous Side Effects

The most commonly reported adverse effects of GLP-1RAs are nausea, diarrhea, and vomiting.^46,47 Recently, more studies have looked into the injection site related side effects of GLP-1RAs. A review of large clinical trials of GLP-1RAs identified that the most common injection site reactions were rash, erythema, and pruritus.⁴⁷ Injection site reactions occurred more often due to long-acting GLP-1RAs compared to the short-acting formulations.⁴⁷ Another review of Phase III clinical trials reported similar findings and noted that of the long-acting formulations, once-weekly exenatide was shown to cause a greater number of injection-site reactions compared to once-weekly semaglutide and dulaglutide.⁴⁶ Semaglutide and dulaglutide had similar rates of injection-site reactions.⁴⁶ Notably, injection site reactions occur at low rates: 1 to 2 percent with semaglutide, 1 to 3 percent with dulaglutide, and 22 percent with once-weekly exenatide.⁴⁶ Case reports, comparative studies, and small reviews (less than 25 studies included) have reported specific and unique injection site reactions to various GLP-1RAs. A summary of these cutaneous reactions is presented in Table 1. 

A review of cutaneous side effects associated with semaglutide use demonstrated injection site reactions, altered skin sensation, and alopecia were the most common adverse reactions.⁴⁸ The most common altered skin sensations included dysesthesia, hyperesthesia, neuralgia, paresthesia, sensitive skin, and burning sensations.⁴⁸ Alopecia and altered skin sensation were observed more frequently in patients on oral semaglutide.⁴⁸ Isolated case reports have demonstrated bullous pemphigoid, leukocytoclastic vasculitis, and eosinophilic fasciitis as severe adverse cutaneous reactions to semaglutide.^49–51 Bullous pemphigoid has also been reported to be triggered by dulaglutide and liraglutide.^52–54 

Hearn and Sherman⁵⁵ reported the first case of injection-site nodules due to weekly 1mg semaglutide and 0.5mg semaglutide injections. Hard, erythematous, pruritic, raised nodules typically appeared minutes after the injection and resolved within 2 to 4 days for 1mg semaglutide and within 24 hours for 0.5mg semaglutide. This patient had no adverse reactions to dulaglutide.⁵⁵ Another reported side effect to 0.5mg weekly semaglutide was a non-pruritic, non-blanchable, non-raised, painless petechial rash. This rash displayed some features of drug-induced lupus.⁵⁶ Bianchi et al⁵⁷ reported the first case of a delayed urticaria-like rash to dulaglutide. This patient began weekly 0.75mg dulaglutide injections and developed a widespread, itchy, urticaria-like rash following the fourth injection.⁵⁷ A similar delayed reaction occurred with a patient who experienced non-pruritic, red macules and papules two weeks after starting once weekly, 1.5mg dulaglutide injections.⁵⁸ All injection-site reactions typically resolved upon stopping the GLP-1RA and taking anti-allergic medication.^55,57,58 

Notably, cutaneous side effects varied across individuals. In a case study of five patients who were exposed to liraglutide and semaglutide, four patients developed localized pruriginous erythematous infiltrated plaques in reaction to liraglutide injections 1 to 3 months after starting treatment. However, three of these patients were tolerant of semaglutide, while the fourth was diagnosed with allergy to liraglutide and semaglutide. A fifth patient experienced anaphylactic shock, presenting with generalized hives, facial angioedema, dizziness, and hypotension, in response to oral semaglutide. However, this patient had no adverse cutaneous reaction to liraglutide.⁵⁹

Exenatide tended to have a higher frequency of adverse events compared to other GLP-1RAs.⁵⁵ A comparative study that pooled data from two existing studies compared exenatide once weekly to exenatide twice daily.⁶⁰ Patients treated with exenatide once weekly experienced significantly higher rates of injection-site related adverse events (22.0%) compared to patients treated with exenatide twice daily (12.7%). The four most common adverse effects reported in these studies were injection-site erythema, pruritus, urticaria, and rash. Erythema (6.5% vs. 1.1%) and pruritus (11.9% vs 1.1%) were more common in once-weekly users than twice daily users. Urticaria and rash had incidence rates below 1.5 percent for both groups with no significant difference between groups. Notably, the frequency of these adverse events decreased overtime, and none were reported past Week 14.⁶⁰ Similarly, another controlled, randomized trial by Drucker et al⁶¹ compared exenatide once weekly to exenatide twice daily treatments and found that injection-site pruritus was experienced by 17.6 percent of patients on the once weekly regimen and by 1.4 percent of patients on the twice daily regimen. The study noted that reported injection-site pruritus was mild and resolved with continued exenatide administrations.⁶¹

Specific case studies identified additional side effects due to exenatide extended-release injections. Steveling et al⁶² described a rare case of systemic hypersensitivity reaction to exenatide. Previously, this patient tried 5 and 10μg exenatide twice daily and 0.6mg liraglutide with no cutaneous side effects. However, upon starting 2mg exenatide once weekly, the patient experienced urticaria and disseminated pruritus at the injection site hours after the second injection. Hours after the third injection, the patient experienced generalized pruritus and urticarial rash. These adverse effects were resolved with anti-allergic medications.

More cases of injection-site nodules have been reported in response to exenatide extended-release injections compared to other GLP-1RAs.⁶³ A 2015 paper identified 27 cases of injection-site nodules due to exenatide extended-release reported on the FDA Adverse Event Reporting System between January 2012 to December 2013.⁶³ Rare cases of panniculitis associated with exenatide injections have also been reported. Shan and Guo⁶⁴ reported the first case of eosinophilic sclerosing lipogranuloma to exenatide once weekly injections. Notably, this patient had no reaction to daily exenatide.⁶⁴ Another patient who had been receiving weekly exenatide injections for five months noted a slowly enlarging painless, tender, 2cm skin colored nodule on his left thigh. Histopathologic examination confirmed the diagnosis of eosinophilic panniculitis.⁶⁵ Zhu et al⁶⁶ reported a unique case where a patient developed a painful nodule on the left lower quadrant of her abdomen in response to exenatide extended-release injections. In the following months, the previous lesion would resolve, but new lesions would appear at the injection site approximately every week. The lesions were diagnosed as granulomatous panniculitis using a punch biopsy and infrared spectroscopy examination.⁶⁶ Two cases of eosinophil-rich granulomatous panniculitis due to weekly exenatide have also been reported.^67,68

The reported adverse effects are summarized in Table 1. Moving forward, it is important for clinicians to be aware of the possibility of known or novel injection-site reactions in response to GLP-1RAs. 

Major Open Questions

The evidence for improvement of psoriasis, HS, and wound healing following treatment with GLP-1RAs is currently limited to case reports and small-scale studies. Further larger randomized, controlled studies are required to assess the efficacy and long-term benefits of GLP-1RA therapy in these cutaneous conditions. Additionally, these studies can contribute to further elucidating the mechanism by which GLP-1RAs act and if they possess anti-inflammatory effects independent of glycemic control and weight reduction. The anti-inflammatory effects and observed improvement in psoriasis and HS after GLP-1RA treatment opens the possibility of studying their therapeutic potential in other common inflammatory skin conditions such as bullous pemphigoid, lupus erythematosus, and atopic dermatitis.

Conclusion

The use of GLP-1RA therapy for diabetes and weight loss has been increasing significantly.⁶⁹ Wound healing has been an active area of research, and the use of GLP-1RAs has been shown to improve wound healing by increasing keratinocyte migration, PI3K/Akt activation, increasing fibroblasts, myofibroblasts, and vessel density, activation of AMPK, and decreasing CRP and MMP-9/TIMP-1 ratio. Case reports demonstrated a link between the use of GLP-1RAs to clinical and histological improvement in psoriasis and HS. iNKT cell modulation, AMPK phosphorylation, IL-23/Th17 regulation, and reduction of γδ T cells have all shown to be possible mechanisms by which GLP-1RAs exert anti-inflammatory effects. In research pertaining to psoriasis, one case report does exist showing exacerbation of lesions after initiation of liraglutide in addition to a placebo-controlled, randomized study that showed no change in severity of psoriasis in glucose tolerant patients between the group treated with a GLP-1RAs and the control. The literature regarding HS is limited, but a case report has shown improvement in HS after the initiation of liraglutide which is postulated to be because of decreased IL-17 and TNF-α which are known to play a role in the pathogenesis of HS. The most common dermatologic adverse effects of GLP-1RAs are injection site pruritus, erythema, and rash. Case reports have been published highlighting unusual cutaneous side effects of GLP-1RAs, including injection site nodules, alopecia, and altered skin sensations that clinicians should be aware of.

Based on the data presented, GLP-1RAs have potential for improving wound healing, psoriasis, and HS. The mechanism by which GLP-1RAs are thought to impact wound healing is likely through modulating immune effects, and improvement was seen in normoglycemic mice, suggesting a mechanism independent of glucose control. In psoriasis, much of the data is limited to case reports. In some cases, the improvement in psoriasis coincided with weight loss and improved glycemic control but in others improvement was seen prior to weight loss. A randomized, controlled trial showed no improvement in glucose-tolerant patients. Therefore, the improvement in psoriasis is likely secondary to indirect effects of GLP-1RAs, although specific anti-inflammatory processes have been identified. In HS, the data is limited, and we are unable to identify whether liraglutide had direct effects on improving HS versus indirectly improving HS through weight loss. Further studies assessing the temporal relation between glucose control, weight loss, and dermatologic improvement following initiation of GLP-1RAs are needed to determine the efficacy of GLP-1RAs and the mechanism by which they act. The main side effects of GLP-1RAs include nausea, diarrhea, and vomiting with injection site pruritus, erythema, and rash being the most common cutaneous side effects. Given the anti-inflammatory properties of GLP-1RAs, we hypothesize that they may also play a role in the treatment of other inflammatory skin conditions. Further studies assessing the potential for GLP-1RA use in dermatology are warranted.

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