GLP-1 Agonists: Implications for Dermatology

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Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially developed to treat type 2 diabetes mellitus, have become increasingly popular, particularly for weight management. Today, an estimated 6% of Americans are on one of these medications. While lifestyle modification is still the gold standard for managing obesity, GLP-1 RAs have dramatically impacted care for patients with obesity.¹ More recently, there has been increased exploration of their possible role in treating inflammatory conditions, such as psoriasis, hidradenitis suppurativa (HS), and atopic dermatitis (AD).² With more dermatologists encountering patients on GLP-1 RAs and as evidence grows for their off-label use, understanding these medications can help us care for our patients.^1-4

Pharmacology of GLP-1 RAs

A GLP-1 RA is an incretin—a peptide secreted by enteroendocrine cells in response to nutrient intake. GLP-1 RAs increase insulin secretion and inhibit glucagon in a glucose-dependent manner.⁵ Additionally, GLP-1 RAs promote the proliferation of pancreatic beta cells while also decreasing their rate of apoptosis, further contributing to the increase of insulin.^1,6

GLP-1 RAs bind to receptors located not only in the pancreas and gastrointestinal tract, but also in the brain, heart, liver, kidneys, and immune tissues such as macrophages and T cells.^1,7,8 This diverse distribution explains their broad metabolic and immunologic effects. Activation of hypothalamic GLP-1 receptors contributes to reduced appetite and increased satiety, which supports weight loss. Delayed gastric emptying and improved food control further reinforce these effects. The most common negative side effects include nausea, vomiting, and diarrhea, which tend to be mild and transient. These effects can be minimized by initiating therapy at a low dose and gradually titrating up.^1,4,7,8

Unlike endogenous GLP-1, synthetic analogs, such as liraglutide, semaglutide, and dulaglutide, are resistant to dipeptidyl peptidase 4 degradation, resulting in longer half-lives. Liraglutide requires daily injection, whereas semaglutide and tirzepatide are longer acting and can be dosed on a weekly or biweekly basis.⁹ Semaglutide is also available in an oral formulation, which has increased adherence in comparison to other glucose-lowering agents.¹

The 3 major GLP-1 class medications that are US Food and Drug Administration approved for obesity and can be used as a primary treatment are semaglutide, liraglutide, and the dual GLP-1 and gastric inhibitory peptide co-agonist tirzepatide.¹ Semaglutide stands out within this class, as it is the first drug in the United States approved to reduce cardiovascular comorbidities, such as risk of cardiovascular death, heart attack, and stroke, in patients with obesity. This indication will allow for increased coverage under Medicare part D plans, which can now add semaglutide to their formulary.⁹

Beyond obesity and diabetes, GLP-1 RAs are being investigated for their role in various conditions, such as metabolic liver disease, neurodegenerative disease, and systemic inflammatory conditions.^4,8

Although generally well tolerated, there are some important contraindications and precautions to keep in mind when considering GLP-1 RAs. These agents should not be used in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 due to findings from rodent studies.^1,10 A history of pancreatitis is another consideration, as there have been rare reports of acute pancreatitis associated with GLP-1 RA use.^1,3 In patients with significant gastrointestinal disorders, particularly gastroparesis, caution is advised given the delayed gastric emptying effects of these medications. Additionally, cases of gallbladder disease and acute kidney injury have been reported, albeit infrequently. While overall safety profiles are favorable, clinicians should review each patient’s medical history and monitor for adverse effects during initiation and dose escalation.^1,3,10

Impact on Obesity and Dermatologic Relevance

GLP-1 RAs are now widely used in the treatment of obesity, with several agents approved specifically for weight loss in patients with or without diabetes. Semaglutide and tirzepatide are among the most effective options, with consistent weight loss ranging from 10% to over 20%.¹

Obesity affects the skin through metabolic, mechanical, and immunologic mechanisms, with nearly 60% to 70% of individuals with obesity experiencing some form of skin involvement.²

Metabolically, obesity is closely tied to insulin resistance and hyperinsulinemia, which can contribute to the development of acanthosis nigricans and skin tags. Moreover, obesity is an independent risk factor for a variety of inflammatory skin conditions, including psoriasis, HS, and AD.^2,11,12 Obesity may create low-grade systemic inflammation that increases the release of pro-inflammatory cytokines and adipokines, such as tumor necrosis factor alpha (TNF-α), IL-6, and leptin.^12,13 AD severity, for example, positively correlates with body mass index (BMI) and expression of inflammatory cytokines such as leptin.¹³

Mechanically, obesity leads to increased skin folds, friction, and moisture accumulation, which predispose individuals to impaired skin barrier function, delayed wound healing, and overgrowth of bacteria or yeast. These factors make it more likely for patients with obesity to develop conditions such as intertrigo, folliculitis, and candidal infections.^2,12

Moreover, obesity influences how patients with psoriasis respond to systemic therapies like methotrexate, cyclosporine, and biologics.^2,12 Obesity reduces the efficacy of psoriatic treatment and increases the risk of adverse events. Patients with obesity and psoriasis are more prone to having higher serum cyclosporine levels and nephrotoxic effects than patients with psoriasis who are a normal weight.^12,14

In addition to mechanical and inflammatory drivers, the microbiome may play a role in linking obesity to skin conditions like AD and psoriasis. Obesity is linked to dysbiosis of the gut and skin microbiome. An increased abundance of Corynebacterium has been observed on the skin of individuals with a higher BMI. In the gut, children with obesity and AD often show an increase in inflammatory microbes, such as Faecalibacterium and Oscillospira, and a reduction in beneficial bacteria like Bifidobacterium and Eubacterium. These microbial imbalances may influence skin inflammation through immune and epithelial signaling pathways.^12,13

Impact on Inflammatory Skin Disease

GLP-1 RAs can improve inflammatory skin conditions primarily through the systemic changes that accompany weight loss. Beyond their metabolic benefits, these agents exert direct effects on immune pathways relevant to skin inflammation.

Indirect Effects via Weight Loss and Metabolic Improvement

In psoriasis, weight reduction has been associated with lower disease severity, improved responses to systemic therapies, and reduced circulating inflammatory markers.^9,12 Liraglutide 1.8 mg and 3 mg improved Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) scores in patients with type 2 diabetes and obesity. Liraglutide also reduced C-reactive protein, plasma cortisol, IL-23, IL-17, and IL-17-producing T cells.^8,9,12,15 Moreover, patients with psoriasis and a BMI below 30 treated with biologics in a trial were more likely to reach almost complete resolution when compared to patients with a BMI above 30 (4.9% vs 43% at week 12 and 67% vs 56% at week 24).¹²

Patients with HS, a condition strongly associated with obesity and mechanical stress in intertriginous areas, frequently report reductions in flare frequency and lesion count following weight loss.^2,9 In a large Danish cohort, a decrease in BMI was associated with self-reported remission of HS, particularly for female patients.^2,9,16 While weight loss in HS is associated with disease improvement, bariatric surgery has worsened or induced de novo HS in some studies, and exercise remains a painful challenge for patients with HS.^2,9 In case reports and proof of concept studies, liraglutide 3 mg for 3 months improved Hurley stage, DLQI, and Beck Depression Inventory scores. Furthermore, patients who received semaglutide 0.8 mg for 8 months experienced fewer flares and had improved DLQI scores.⁹

Similarly, individuals with AD often have improvement in symptoms and Eczema Area and Severity Index scores after weight reduction, potentially due to improvements in hormone balance, skin barrier function, and decreased systemic inflammation.¹⁶ Weight loss can also induce favorable shifts in the skin and gut microbiome, which are thought to further modulate immune responses in inflammatory dermatoses.¹³

Taken together, these indirect effects of GLP-1 RAs through metabolic normalization and weight reduction play a key role in inflammatory skin disease improvement. While all GLP-1 RAs induce weight loss and modulate immune tissue to varying degrees, semaglutide remains the most utilized agent.^1,7,12 However, choosing the right medication requires individualized consideration of comorbidities, contraindications, costs, and patient preferences.¹⁰

Direct Immunomodulatory Effects of GLP-1 RAs

GLP-1 RAs downregulate proinflammatory cytokines, such as TNF-α, IL-6, IL-17, IL-22, and IL-23, which are key mediators in psoriasis, HS, and AD.^{9,12,13,15,17} GLP-1 receptors are present on activated T cells, macrophages, and dendritic cells, allowing these drugs to influence both innate and adaptive immunity.^18-20 Additionally, the activation of GLP-1 receptors decreases inflammation by protecting chondrocytes against endoplasmic reticulum stress, apoptosis, and inflammation through decreased release of inflammatory signals.¹

In psoriasis, γδ T cells, a subset of T cells located in the dermis, mediate inflammation by producing IL-17. Patients with moderate-to-severe plaque psoriasis exhibit a higher proportion of dermal γδ T cells in psoriatic plaques compared to controls. Liraglutide improved or stabilized PASI scores and reduced γδ T cell levels, with a correlation noted between PASI scores and percentage of γδ T cells (r = 0.894, P = 0.007). Additionally, decreased IL-17 levels were seen in patients who had clinical improvement. These findings suggest that reduction in γδ T cell number and IL-17 expression may be a mechanism by which GLP-1 RAs improve psoriasis.²¹ Furthermore, GLP-1 RA therapy can reverse the invariant natural killer T cell ratio in psoriatic lesions, thereby decreasing the number of these cells within plaques and increasing their numbers in peripheral blood.¹⁷

In HS, GLP-1 RAs may have a direct effect on immune tissues. In preclinical models, these medications act on central neuronal GLP-1 receptors, leading to a reduction in plasma TNF-α, a cytokine involved in the inflammatory environment of lesional skin.⁹ Moreover, in animal models, incretins like GLP-1 RA reduce reactive oxygen species in the vasculature, thereby improving hypertension and cardiac remodeling by decreasing fibroblast and collagen accumulation.⁹ The reduction of matrix metalloproteinases and enhancement of keratinocyte migration with GLP-1 RAs may also improve wound healing through the phosphatidylinositol 3-kinase/Akt signaling pathway.^9,17 These properties suggest potential benefits for conditions involving epidermal disruption or chronic wounds.

A growing number of case reports and small observational studies have described dermatologic improvements in patients receiving GLP-1 RA therapy. Cases include reduced psoriasis severity, attenuation of HS lesions, and improvement in rare disorders such as Hailey-Hailey disease. Notably, some of these outcomes occurred before significant weight loss, reinforcing the possibility of a direct therapeutic role.^9,15 Continued research is needed to establish efficacy, determine optimal patient selection, and explore possible integration with existing dermatologic therapies.

Conclusion

GLP-1 RAs are a promising avenue in both metabolic and inflammatory disease management. They can reduce weight and may modulate immune function and inflammation, including in the context of dermatologic disease. Whether through metabolic rebalancing, microbiome shifts, or direct immunomodulation, GLP-1 RAs may offer a valuable adjunctive approach for managing chronic skin diseases in patients with obesity or metabolic dysfunction.

Serene Majid is a third-year medical student at East Carolina University School of Medicine in North Carolina. She is involved in dermatology research at Wake Forest University School of Medicine, with a focus on psoriasis and autoimmune pathologies, and currently serves as a student coordinator for a free community care clinic. Dr Feldman is a professor of dermatology, pathology, social sciences and health policy, and molecular medicine and translational science and currently leads the Center for Dermatology Research at Wake Forest University School of Medicine in Winston-Salem, NC. He is also the chief medical editor of The Dermatologist.

Disclosure: Dr Feldman has received research, speaking, and/or consulting support from a variety of companies, including Galderma, GlaxoSmithKline/Stiefel, Almirall, Leo Pharma, Boehringer Ingelheim, Mylan, Celgene, Pfizer, Valeant, AbbVie, Samsung, Janssen, Eli Lilly and Company, Menlo, Merck & Co, Novartis, Regeneron, Sanofi,Novan, Qurient, the National Biological Corporation, Caremark, Advance Medical, Sun Pharma, Suncare Research, Informa, UpToDate, and the National Psoriasis Foundation.

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