Dermatologic Implications of Glucagon-Like Peptide-1 Receptor Agonist Medications

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are becoming increasingly common medications with over 1.1 million patients receiving prescriptions between January 2018 and June 2024 [1]. This is because GLP-1RAs have emerged as a transformative class of medications in the management of type 2 diabetes and obesity [2]. Initially developed to enhance glycemic control by mimicking the body’s natural incretin hormone GLP-1, these agents have now extended their reach, demonstrating significant efficacy in promoting weight loss [3, 4]. With the FDAs recent approval of GLP-1RAs for treatment of obesity in patients with a body mass index (BMI) ≥30 or ≥27 with weight-related comorbidities (e.g., hypertension and type 2 diabetes), their use has expanded rapidly [5]. Clinical trials and real-world data highlight the ability of GLP-1RAs to facilitate weight reductions of up to 15% over one to 2 years, a notable achievement in the pharmacologic treatment of obesity [5]. Consequently, at this time, a majority of these prescriptions (approximately 83%) are written for antidiabetic treatment, while 17% are for anti-obesity purposes [1].

Beyond weight loss, GLP-1RAs offer additional therapeutic benefits. For example, liraglutide and semaglutide have demonstrated cardiovascular protective effects, particularly in patients with established cardiovascular disease and type 2 diabetes [6]. More recently, the use of GLP-1RAs in the treatment of addiction appears promising [7, 8].

As their use increases, attention has also turned to the broader range of effects these agents may have. While gastrointestinal side effects such as nausea and diarrhea remain the most reported adverse events, recent observations suggest that GLP-1RAs also have implications for the skin [9]. Ranging from mild injection site reactions to more complex immune-mediated responses, a variety of cutaneous effects have been noted in the growing population of patients using these therapies [10]. Furthermore, emerging research indicates that GLP-1 receptor activation may influence processes such as wound healing and keratinocyte function, sparking interest in their potential therapeutic applications in dermatology [11]. This review aimed to explore the dermatologic effects associated with GLP-1RA use, examining both adverse reactions and potential benefits.

GLP-1RAs mimic and enhance the activity of GLP-1, an endogenous incretin hormone. Incretins are hormones secreted by gut enteroendocrine cells in response to food intake [12, 13]. They play a crucial role in lowering blood glucose levels by regulating glucose metabolism and suppressing appetite [13]. GLP-1RAs enhance glycemic control and promote weight loss through four primary mechanisms: (1) stimulating glucose-dependent insulin secretion; (2) inhibiting glucagon release, which decreases postprandial hepatic glucose production; (3) slowing gastric emptying, which reduces the rate of glucose absorption through the intestines and promotes a feeling of satiety by prolonging gastric distention; and (4) modulating central nervous system pathways, which helps decrease the perception of appetite [12, 13].

GLP-1Rs are expressed across various tissues, including the skin, where they are thought to play a role in keratinocyte proliferation, differentiation, and cytoprotection to maintain the skin barrier [14]. In keratinocytes, GLP-1Rs, such as liraglutide, have been shown to enhance migration through activation of the PI3K/Akt pathway and accelerate wound healing in animal models [15]. Additionally, GLP-1R activation has been implicated in promoting growth factor activity, further supporting a possible role in wound repair and tissue regeneration [15, 16]. Given these findings, GLP-1RAs receptor agonists are being explored for therapeutic potential in dermatologic conditions such as psoriasis and wound healing [16‒19].

The role of GLP-1Rs in hair follicles has not been extensively studied in humans, but evidence from mouse models suggests that GLP-1 and proglucagon receptors are highly expressed around hair follicles [20]. In these models, activation of the GLP-1 receptor has been shown to stimulate the MAPK/ERK signaling pathway, which is involved in cellular proliferation, differentiation, and cytoprotection processes critical for hair follicle growth and maintenance. This pathway may enhance the resilience of hair follicles against stressors [20].

The impact of GLP-1 receptor agonists (GLP-1RAs) on hair health is a growing area of interest, particularly in the context of alopecia associated with significant weight loss. While some studies speculate that GLP-1RA therapy may contribute to enhanced hair quality and reduced hair loss via improved insulin sensitivity or improved blood flow, others propose potential risks of GLP-1RA therapy on hair health including disrupted hair growth cycles from the biologic stress of weight loss or nutritional deficiencies from dietary changes [21].

To date, no research has specifically investigated the presence or role of GLP-1 receptors in human nail biology. However, given the effects of GLP-1RAs on other keratinized structures like hair, this remains an area for potential future investigation.

As of September 1, 2024, an estimated 6.08% of adverse effects reported to the FDA were dermatologic in nature, but this figure may underestimate the true prevalence due to underreporting [22].

Popularized by the general media, the term “Ozempic face” was coined to describe a gaunt, aged appearance resulting from the loss of facial fat due to rapid weight loss associated with the use of semaglutide, a GLP-1 receptor agonist [23, 24]. Patients experiencing “Ozempic face” commonly report hollowing of the cheeks, sunken eyes, sagging jowls, and increased prominence of wrinkles.

It is thought that the primary pathophysiological mechanism behind “Ozempic face” is the nonselective fat loss that occurs during rapid weight reduction. While GLP-1RAs, including Ozempic, target overall body fat reduction, they also affect the subcutaneous fat in the face, leading to the characteristic facial volume loss. The skin, already prone to decreased collagen and elastin with age, becomes more susceptible to sagging when facial fat diminishes, contributing to the appearance of wrinkles and jowling [23, 24].

Physicians should counsel patients about the potential cosmetic impacts of using Ozempic and the available treatment options including fillers and autologous fat grafting for volume restoration. Additionally, microneedling and lasers may help improve skin texture and elasticity after addressing volume loss. It is important to manage patient expectations, especially for those who discontinue Ozempic and experience weight regain, which won’t necessarily lead to return of facial fat volume or may necessitate the removal or adjustment of previously administered fillers [23, 24].

Injection site reactions are common adverse effects observed in patients using GLP-1RAs like semaglutide, liraglutide, and tirzepatide usually presenting with localized redness, swelling, pain, or pruritus at the site of injection. The prevalence of these reactions has been reported in up to 20% of patients using these medications [25, 26]. Urticaria has also been documented [27].

Delayed hypersensitivity reactions have been reported in some cases. These reactions may present 24–48 h after administration, with symptoms including erythematous plaques, itching, and, in rare cases, systemic symptoms like respiratory distress or gastrointestinal issues [27]. Urticarial reactions can occur independently or as part of a hypersensitivity response, complicating the clinical picture.

The pathophysiology of injection site reactions is thought to be related to both the drug formulation and individual patient factors. GLP-1RAs, such as semaglutide and liraglutide, may induce localized immune responses due to their protein-based nature, which can trigger an inflammatory reaction at the injection site [25]. Delayed hypersensitivity reactions, such as those observed with liraglutide, are T-cell mediated and may involve perivascular infiltrates of lymphocytes and eosinophils in the skin [27].

Urticarial reactions, often linked to histamine release, are generally mediated by mast cell degranulation and can result from drug-specific IgE antibodies or non-IgE-mediated pathways [27]. The specific immunogenic potential of GLP-1RAs, while low, is sufficient to elicit these immune responses in a subset of patients [25].

The management of injection site reactions involves symptomatic relief and, in some cases, discontinuation of the offending drug. Mild injection site reactions can be managed with topical corticosteroids or antihistamines [26]. Patients are also advised to rotate injection sites [25].

For delayed hypersensitivity reactions, discontinuation of the drug is often required. If hypersensitivity is confirmed, switching from liraglutide to semaglutide, may be considered, as cross-reactivity is not always present [27].

Altered skin sensations, including dysesthesia, paresthesia, hyperesthesia, and burning sensations, are among the most common dermatologic side effects reported, particularly with semaglutide [28]. A scoping review of semaglutide use revealed that dysesthesia, paresthesia, and skin burning sensations were experienced by approximately 2–3% of patients on oral semaglutide [29]. In addition, hyperesthesia and neuralgia were reported in smaller subsets, affecting between 1 and 2% of patients [29]. Notably, these more frequently occurred in association with oral semaglutide than with subcutaneous formulations.

The mechanisms underlying these altered skin sensations remain unclear, but several hypotheses have been proposed. One theory suggests that GLP-1RAs may have indirect effects on nerve function, possibly influencing peripheral nerves through metabolic and vascular pathways. GLP-1 receptors are present in the nervous system, and their activation may alter neuronal signaling, contributing to sensations like dysesthesia or hyperesthesia [29]. Additionally, rapid weight loss induced by GLP-1RAs could lead to shifts in fat distribution, potentially impacting the skin’s sensory nerves, leading to sensations of burning or tingling [29]. Another potential mechanism could involve microvascular changes, as GLP-1RAs are known to impact vascular health [29].

Management of altered skin sensations involves a combination of symptom control and, if necessary, modification of the GLP-1RA regimen. For mild cases of paresthesia or dysesthesia, conservative measures such as topical anesthetics or oral pain relievers may be recommended [29]. In more severe cases, the dose of the GLP-1RA may need to be adjusted, or an alternative medication be considered [29].

GLP-1RAs have been associated with a range of rare but significant dermatologic reactions (shown in Table 1). Pyoderma gangrenosum following GLP-1RAs has been reported [10, 30]. Bullous pemphigoid is a documented reaction to GLP-1RAs, with multiple case reports highlighting this condition [31, 32]. Angioedema, another rare but serious condition, has been reported in patients using GLP-1RAs [33].

Vesiculopustular eruptions have also been noted, such as in a case involving liraglutide, where a patient developed an eruption characterized by pustules and vesicles, which resolved upon drug discontinuation [34]. Psoriasiform reactions, including exacerbations of plaque psoriasis, have been reported, with some patients seeing worsening skin lesions despite treatment [35, 36].

Leukocytoclastic vasculitis has been reported with semaglutide [34]. Eosinophilic fasciitis has also been linked to GLP-1RAs [37, 38].

The exact mechanisms behind these dermatologic adverse effects are not fully understood but are believed to involve immune dysregulation secondary to GLP-1RA therapy. Managing these rare skin conditions typically involves discontinuation of the offending GLP-1RA plus, at times, immunosuppressive therapy. For vesiculopustular eruptions, topical corticosteroids may provide symptomatic relief, though more severe cases may require systemic treatment [34]. Psoriasiform reactions, including flare-ups of plaque psoriasis, may be managed with topical or systemic treatments, such as corticosteroids, retinoids, or phototherapy, depending on the severity [35, 36]. In more resistant cases, switching to a different class of medication may be necessary to prevent recurrence.

Leukocytoclastic vasculitis, although rare, may require careful management with systemic corticosteroids or immunosuppressive agents to reduce vessel inflammation [39]. Eosinophilic fasciitis, another uncommon reaction, may also benefit from immunosuppressive therapy [34]. In all cases, early recognition and intervention are crucial to prevent further complications.

Recent investigations have highlighted a potential link between GLP-1RAs and hair loss, prompting interest in their effects on alopecia. A disproportionality analysis using data from the FDA Adverse Event Reporting System (2022–2023) identified a statistically significant association between the use of semaglutide (ROR: 2.46, 95% CI: 2.14–2.83) and tirzepatide (ROR: 1.73, 95% CI: 1.42–2.09) with alopecia [40]. Another study utilized pharmacovigilance databases, including FAERS, DAEN, EudraVigilance, and VigiBase, to conduct a disproportionality analysis of adverse events in diabetes medications, finding that while GLP-1-RAs were the most reported drug class associated with hair loss, no significant disproportionality signals were detected [41]. One case report described a 57-year-old male with AGA who experienced significant hair regrowth after 6 months of tirzepatide, another GLP-1RA, accompanied by improvements in insulin resistance and weight loss [21]. This case study may suggest enhanced metabolic improvements may foster a more favorable environment for hair growth. However, these potential benefits must be weighed against evidence linking GLP-1RA use to hair loss, potentially driven by nutrient deficiencies and the physiological stress of rapid weight loss. These findings underscore the need for further research to clarify the relationship between GLP-1RAs and alopecia, with a particular focus on variations in drug formulations, routes of administration, patterns of weight loss, nutritional status, and the specific types of hair loss affected.

Telogen effluvium (TE), a form of hair loss triggered by physiological stress, may be associated with the use of GLP-1 receptor agonists [41, 42]. Though clinical trials for drugs like semaglutide and liraglutide have not consistently demonstrated a significant increase in hair loss, real-world reports suggest that TE may be more common than initially thought, particularly when these drugs are misused for rapid weight loss [41].

GLP-1RAs, including Exendin-4 and liraglutide, may have therapeutic implications for enhancing wound healing, particularly in diabetic patients [43]. In various animal models, GLP-1R activation has demonstrated improved antibacterial properties, vascularization, enhanced angiogenesis, and promotion of re-epithelization of wounds in diabetic patients [16, 44, 45]. Specifically, diabetic rats treated with GLP-1R agonists exhibited accelerated wound closure, likely due to reduced interleukin-6 levels, increased circulating endothelial progenitor cells, enhanced capillary formation, and upregulation of VEGF, transforming growth factor-β, and matrix metalloproteinase-2 [16, 44, 46, 47]. GLP-1R activation also stimulates epidermal stem cell proliferation in both human and mouse tissues by increasing β-catenin expression, which subsequently upregulates key cell cycle regulators like c-Myc, cyclin D1, and cyclin E1, contributing to enhanced wound healing [48]. Additionally, GLP-1RAs may exert synergistic effects when combined topically with agents such as zinc oxide nanoparticles or adipose-derived stem cells, further improving wound healing outcomes [45, 47]. These findings indicate that GLP-1RAs may play a key role in primary prevention and treatment of diabetic wounds.

GLP-1RAs have also shown promise for therapeutic potential in the management of psoriasis, particularly in patients with comorbid diabetes. Psoriasis plaques demonstrate increased expression GLP-1R compared to healthy tissue [17]. Several studies have demonstrated significant improvements in psoriasis severity, as measured by the Psoriasis Area Severity Index (PASI), along with concurrent reductions in weight and BMI [19, 49]. Notably, the anti-inflammatory effects of GLP-1RAs, such as liraglutide, appear to contribute to psoriasis improvement independently of weight loss or glycemic control [36]. A meta-analysis of 32 patients with psoriasis and type 2 diabetes found that GLP-1RA therapy led to significantly lower PASI scores (SMD: −4.332, 95% CI: −7.611 to −1.053, p = 0.01) [36]. This improvement in psoriasis severity occurred independently of changes in weight and glycemic control, suggesting a direct anti-inflammatory effect of GLP-1RAs. The beneficial effects of GLP-1RAs on psoriasis may be mediated through several mechanisms. First, GLP-1RAs reduce pro-inflammatory cytokines by inhibiting key drivers of psoriasis pathogenesis, including TNF-α, IL-23, IL-17, and IL-22 [50]. Second, they modulate immune cells, as GLP-1 receptors are expressed on activated T cells, enhancing anti-inflammatory effects [51]. Research has demonstrated a decrease in dermal T cells and IL-17 expression following GLP-1RA treatment [51]. Lastly, GLP-1RAs improve metabolic parameters by addressing obesity and insulin resistance, which indirectly alleviates psoriasis severity [50, 51].

Interestingly, studies have observed that GLP-1 levels increase following bariatric surgery and contribute to psoriasis remission before any significant weight loss occurs [52]. This underscores the systemic effects of GLP-1 in reducing inflammation, independent of weight loss. GLP-1RAs have been shown to be effective in patients with refractory psoriasis who failed biologic therapy [53, 54]. These findings suggest that GLP-1RAs hold significant promise as an alternative treatment strategy for psoriasis, particularly in patients with metabolic comorbidities.

GLP-1-RAs have also been proposed as a potential treatment of lichen planopilaris due to their potential antifibrotic, anti-inflammatory, and metabolic regulatory effects. By improving insulin sensitivity, reducing systemic inflammation, and enhancing microvascular function, these medications target key aspects of lichen planopilaris’s pathogenesis [55‒57]. Similarly, GLP-1RAs should be explored in treating scarring alopecia due to their ability to reduce systemic inflammation and improve metabolic health [58‒60].

Additionally, GLP-1RAs powerful weight loss ability may serve as an adjunctive role in other dermatologic conditions that are exacerbated by excessive weight gain or comorbid metabolic syndrome [54]. Obesity is a significant risk factor for hidradenitis suppurativa, and GLP-1RA-induced weight loss can lead to symptom improvement [54, 61]. By improving insulin sensitivity, GLP-1RAs may help reduce the hyperandrogenism associated with HS [61]. Similar to psoriasis, the anti-inflammatory properties of GLP-1RAs may also contribute to HS improvement [54]. A study that examined 30 obese patients with HS who received semaglutide (mean weekly dose 0.8 mg) for an average of 8.2 months found reduced flare frequency (from once every 8.5 weeks to once every 12 weeks), improved quality of life in 33.3% of patients, and decreased BMI (from 43.07 kg/m² to 41.47 kg/m²) and weight (from 117.7 kg to 111.6 kg) [62]. These findings underscore the promising potential of GLP-1RAs, particularly for those with comorbid obesity, in the treatment of HS. However, more research is needed to explore the efficacy of GLP-1RAs in HS patients without comorbid obesity, as this population remains underrepresented in current studies.

The management of GLP-1RA-related skin reactions must be individualized based on the severity of the presentation and the therapeutic need for glycemic control. In mild cases, such as transient injection-site reactions, continuation of the GLP-1RA with symptomatic treatment (e.g., topical corticosteroids, antihistamines) is typically appropriate. Patients should be reassured that these reactions are usually self-limited.

For patients experiencing moderate-to-severe reactions, such as persistent pruritus or systemic symptoms, dermatologists must weigh the risks and benefits of continued therapy. Systemic immunomodulatory therapy should be considered on a case-by-case basis. In severe cases, dose reduction or switching to an alternative GLP-1RA with a different molecular structure may be considered. If symptoms persist despite modification, discontinuation of the GLP-1RA should be pursued. Collaboration with the prescribing endocrinologist is crucial in these cases to ensure that alternative glycemic management strategies are in place.

Referral to an allergist or immunologist may be necessary for patients with suspected GLP-1RA-induced hypersensitivity reactions, particularly if there is a history of anaphylaxis, angioedema, or other severe immune-mediated responses. Drug-specific immunologic assays may be useful in confirming the diagnosis in complex cases.

While GLP-1RAs have shown efficacy in managing metabolic conditions, there is a need for more robust data on their dermatologic side effects as well their potential to treat some dermatological conditions. Current evidence highlights associations between GLP-1RAs and skin manifestations such as hair loss, but the underlying mechanisms remain poorly understood. Future research should prioritize longitudinal studies with larger sample sizes to examine the long-term dermatologic impacts of these agents, including the role of genetic predispositions, and further elucidate the broader implications of metabolic changes on skin health. Additionally, GLP-1RAs show therapeutic promise in enhancing wound healing and managing psoriasis due to their anti-inflammatory and immunomodulatory effects, independent of weight loss.

Dr. Antonella Tosti has the following conflicts of interest to declare: she serves as a consultant for DS Laboratories, Almirall, Thirty Madison, Eli Lilly, Pfizer, Myovant, Bristol Myers Squibb, Ortho Dermatologics, and Sun Pharmaceuticals LLC. Additionally, she is a principal investigator for Eli Lilly and Concert. Prof. Tosti was a member of the journal’s Editorial Board at the time of submission. The other authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

O.B. conceptualized the review, designed the methodology, performed literature screening and data extraction, drafted the manuscript, and critically revised the work. B.S. conducted literature screening and data extraction and contributed to manuscript drafting. D.A.C. contributed to manuscript drafting and critically reviewed the manuscript. A.T. supervised the study, provided expert insights on dermatology, and performed critical revisions of the manuscript.

Olivia M. Burke and Brianna Sa are co-first authors.