Benefit-Risk Assessment of GLP-1 Receptor Agonists: Implications for Dermatologists and Plastic Surgeons

Abstract

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have gained prominence for their efficacy in treating type 2 diabetes and obesity. Recent evidence suggests that their pleiotropic effects—beyond glycemic control and weight loss—include anti-inflammatory, immunomodulatory, and antioxidative effects, which may beneficially support various dermatologic conditions such as psoriasis, hidradenitis suppurativa, acanthosis nigricans, and Hailey-Hailey disease. However, GLP-1 RAs are also associated with emerging cutaneous adverse drug reactions, including bullous, exanthematous and vasculitic manifestations, and other rare side effects. In aesthetic and reconstructive surgery, rapid weight loss induced by these agents has raised concerns regarding facial volume depletion, skin laxity, and impaired wound healing. In addition, perioperative management of patients on GLP-1 RAs requires careful assessment as a result of delayed gastric emptying and the associated potential risk of pulmonary aspiration. This narrative review summarizes current knowledge on the benefit/risk profile of GLP-1 RAs, highlighting their impact for dermatologists and plastic surgeons in relevant contexts.

Key Summary Points

GLP-1 receptor agonists (GLP-1 RAs), initially approved for type 2 diabetes and obesity, exhibit anti-inflammatory and immunomodulatory effects that may benefit dermatologic conditions.

These agents are linked to various cutaneous adverse reactions, and may influence perioperative risk and outcome in plastic surgery.

Safety issues such as gastrointestinal side effects, pancreatitis, gallbladder disease, thyroid cancer, and psychiatric risks remain under investigation, warranting cautious patient selection and monitoring.

Dermatologists and plastic surgeons are advised to weigh the therapeutic benefits of GLP-1 RAs against their risks to optimize patient outcomes.

Introduction

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have revolutionized the treatment landscape for type 2 diabetes mellitus (T2DM) and obesity, offering significant benefits in glycemic control, weight reduction, and cardiometabolic protection. Beyond these established indications, accumulating evidence suggests that GLP-1 RAs exert pleiotropic effects on immune regulation, inflammation, and tissue remodeling—pathways highly relevant to dermatological and surgical disciplines [1–5].

A structured narrative literature review was conducted by five authors using MEDLINE/PubMed as the primary database, covering publications in English from January 2005 to January 2025. The review aimed to address two major clinical domains: (1) the emerging therapeutic potential of GLP-1 RAs in dermatology and aesthetic medicine; and (2) the incidence and pathophysiology of cutaneous adverse events associated with their use. Secondary searches were performed using Google Scholar and regulatory sources, e.g., US Food and Drug Administration (FDA) labels and European Medicines Agency (EMA) reports, to capture gray literature and pharmacovigilance data. Search terms included combinations of “GLP-1 receptor agonist,” “semaglutide,” “liraglutide,” “tirzepatide,” “cutaneous side effects,” “dermatology,” “hidradenitis,” “psoriasis,” “bullous pemphigoid,” “facial aging,” and “plastic surgery.” Of 260 articles initially identified, 155 were included on the basis of predefined eligibility criteria prioritizing randomized controlled trials, observational studies, systematic reviews, regulatory reports, and clinically relevant case series in adult populations. Articles focusing exclusively on non-dermatologic or non-cutaneous outcomes without translational relevance were excluded. The final selection of references reflects a comprehensive and multidisciplinary synthesis to inform both dermatologic and surgical practice. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Clinical Pharmacology of GLP-1 RAs

The approval of the first GLP-1 RA, exenatide, by the FDA in 2005 marked a significant advancement in treating diabetes and obesity. Since then, several human GLP-1 RAs, such as liraglutide, dulaglutide, semaglutide, and tirzepatide, have been developed, offering enhanced pharmacokinetic properties for more convenient administration [1]. This review focuses principally on GLP-1 RAs approved for treating both T2DM and obesity: liraglutide, semaglutide, and tirzepatide. Their most important pharmacological features are reported in Table 1. Notably, semaglutide emerged as the second best-selling drug in 2024, and in the same year, sales of tirzepatide increased 124% from the previous year [2].

Table 1.

Comparative pharmacological aspects of GLP-1 agonists approved for diabetes and obesity

Feature	Liraglutide	Semaglutide	Tirzepatide
Therapeutic Indications	T2DM, OB, OW	T2DM, OB, OW	T2DM, OB, OW
Administration and posology	SC: 1.2 mg–1.8 mg once daily (T2DM); 3.0 mg once daily (OB, OW)	SC: 0.5–2 mg once weekly (T2DM); 2.4 mg once weekly (OB, OW) OU: 4–50 mg daily (T2DM)	SC: 5–15 mg once weekly (T2DM, OB, OW)
Selectivity (GLP-1/GIP)	GLP-1	GLP-1	GLP-1/GIP
Contraindications	None (apart from hypersensitivity)
Bioavailability	55%	89% (SC); 1–2% (OU)	80%
Volume of distribution	11–17 L	12.5 L (SC); 8 L (OU)	10.3 L and 9.7 L in patients with obesity
Protein bound	> 98%	> 99%	99%
Metabolism and transporters	DPP4 and NEP to various smaller polypeptides	Proteolytic cleavage of the peptide backbone, sequential beta-oxidation of the fatty acid side chain. The enzyme NEP is involved	Metabolized by proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty diacid moiety, and amide hydrolysis
Elimination	Metabolites in urine (6%) or feces (5%)	3% via urine as intact semaglutide	Via urine and feces
t1/2	13 h	1 week (168 h)	120 h
Use in pregnancy	Should not be used	Should not be used	Not recommended during pregnancy
Use in renal impairment	Mild, moderate: no dose adjustment (T2DM, OB, OW) Severe: no dose adjustment (T2DM); not recommended (OB, OW) End-stage renal disease: not recommended (T2DM, OB, OW)	Mild, moderate: no dose adjustment (T2DM, OB, OW) Severe: no dose adjustment (T2DM); not recommended (OB, OW) End-stage renal disease: not recommended (T2DM, OB, OW)	Mild or moderate: no dose adjustment (T2DM, OB, OW) Severe: caution (T2DM)
Use in hepatic impairment	Mild or moderate: no dose adjustment (T2DM, OB, OW); should be used cautiously (OB, OW) Severe: not recommended (T2DM, OB, OW)	Mild or moderate: no dose adjustment (T2DM, OB, OW); should be used cautiously (OB, OW) Severe: caution (T2DM); not recommended (OB, OW)	Mild or moderate: no dose adjustment (T2DM, OB, OW) Severe: caution (T2DM)
Pharmacokinetic drug—interactions [8]	Delay of gastric emptying may influence the absorption of concomitantly administered oral medicinal products. Interaction studies (with warfarin, oral contraceptive, acetaminophen, angiotensin-converting enzyme inhibitors, statins, digoxin) did not show any clinically relevant delay of absorption and therefore, no dose adjustment is required
Ecotoxicity/environmental risk assessment (ERA)	Not expected to pose a risk to the environment

Beinaglutide is not shown because marketing approval is restricted to China. Data were obtained from Summaries of Product Characteristics

T2DM type 2 diabetes mellitus, OB obesity, OW overweight, SC subcutaneous, OS oral use, GLP-1 glucagon-like peptide 1, GIP gastric inhibitory polypeptide, DPP4 dipeptidyl peptidase 4, NEP enzyme neutral endopeptidase

GLP-1 RAs mimic the action of the endogenous incretin hormone GLP-1 by activating GLP-1 receptors in pancreatic β-cells; this promotes glucose homeostasis, through glucose-dependent insulin secretion and suppression of glucagon release [1]. Additionally, by binding to GLP-1 receptors in enteric neurons and endocrine cells, these agents slow gastric motility, reduce acid secretion, and modulate appetite through satiety signaling to the hypothalamus [3]. Preclinical and clinical studies have demonstrated that GLP-1 receptors expressed in myocardial and vascular endothelium tissue play a fundamental role in the cardioprotective effect of GLP-1 RAs, lowering the risk of major cardiovascular events, heart failure, and kidney complications in adults with and without diabetes [4]. Furthermore, as a result of their pleiotropic effect on multiple organ systems, these agents are emerging as potential therapy for metabolic dysfunction-associated steatotic liver disease, neurodegenerative conditions, and behavioral health disorders [5, 6].

From a safety perspective, gastrointestinal adverse effects are the most commonly reported for GLP-1 RAs, with nausea, vomiting, and diarrhea remaining the leading causes of treatment discontinuation [7]. Further studies are needed to clarify potential associations between GLP-1 RAs and some recent concerns related to their safety. Figure 1 shows the most relevant aspects of the benefits/risks profile of GLP-1 RAs.

Fig. 1.

Benefits/risks balance of GLP-1 receptor agonists and future perspectives. NAION non-arteritic anterior ischemic optic neuropathy, T2DM type 2 diabetes mellitus, OSAS obstructive sleep apnea syndrome, OA osteoarthritis, MASLD metabolic associated steatotic liver disease, HF heart failure, CKD chronic kidney disease

Emerging Uses of GLP-1 RAs in Dermatology

GLP-1 RAs also possess anti-inflammatory, immunomodulatory, and antioxidant effects. In dermatology, these properties are particularly relevant for treating chronic inflammatory diseases such as psoriasis, hidradenitis suppurativa (HS), acanthosis nigricans (AN), and Hailey-Hailey disease (HHD). The use of GLP-1 RAs for these conditions is still off-label, and the literature lacks clear guidelines on the appropriate drug management in these clinical uses [8]. Therefore, randomized controlled trials (RCTs) and consensus statements are needed to establish standardized recommendations.

Psoriasis

Psoriasis is an immune-mediated skin disease associated with an increased risk of metabolic disorders, including T2DM and obesity. These conditions are linked to chronic systemic inflammation and cardiovascular complications, which in turn increase morbidity and mortality [9]. Several trials involving psoriatic patients treated with GLP-1 RAs for approved indications have shown beneficial effects in improving psoriasis severity [10]. Additionally, case reports and prospective cohort studies of patients treated with GLP-1 RAs have demonstrated reductions in the Psoriasis Area and Severity Index (PASI) score, Physician’s Global Assessment (PGA), and Dermatology Life Quality Index (DLQI) after 2–12 months of treatment [11–16]. Furthermore, temporary discontinuation of the drug led to the recurrence of psoriatic lesions, with subsequent improvement in the PASI score upon reintroduction [13]. One RCT examined the efficacy of liraglutide (up to 1.8 mg daily) in patients with psoriasis and T2DM over 12 weeks. This treatment resulted in a significant reduction in mean PASI and DLQI scores, improved skin lesions, and reduced levels of interleukin (IL)−17, IL-23, and tumor necrosis factor alpha (TNFα). Metabolic benefits, such as weight loss and low-density lipoprotein (LDL) reduction, were also observed, with good tolerability [17]. In contrast, another RCT found no significant differences in PASI or DLQI scores after 8 weeks of liraglutide treatment compared to placebo [18].

The anti-inflammatory properties of GLP-1 RAs may be relevant for managing T2DM, obesity, and psoriatic lesions, all of which are associated with chronic inflammation [15, 17, 19, 20]. The pathogenesis can be explained by the fact that the number of circulating invariant natural killer T cells (iNKTs), a subset of innate T cells, is lower in individuals with diseases characterized by autoreactive tissue inflammation, such as psoriasis. Since the GLP-1 receptor is expressed on iNKT cells, GLP-1 RAs could induce a dose-dependent inhibition of cytokine secretion by these cells, resulting in improved psoriatic disease [11, 12, 21, 22].

GLP-1 RAs may also reduce the number of dermal γδ-T cells and IL-17 mRNA expression in psoriasis plaques in patients with diabetes [13, 22]. Additionally, it is important to note that weight reduction and improved glycemic control resulting from GLP-1 RA therapy may contribute to the reduction in psoriasis severity [12, 23, 24]. Only a case report has described the worsening of psoriasis following the introduction of liraglutide [25]. The authors hypothesize that this paradoxical worsening is due to a cytokine imbalance, similar to what is seen with the exacerbation of disease after administration of biological treatments like anti-TNFα, which increases interferon (IFN)-α release and leukocyte chemotaxis [25].

In conclusion, GLP-1 RAs may have a beneficial effect on psoriasis, but further randomized studies are needed to confirm these findings [10, 22].

Hidradenitis Suppurativa

HS is a chronic and debilitating inflammatory skin disorder characterized by deep, painful nodules, abscesses, fistulas, sinus tracts, and scarring in the intertriginous areas, significantly impacting quality of life [26, 27]. Its pathogenesis is multifactorial, beginning with follicular occlusion of the pilosebaceous unit, followed by follicular rupture and subsequent immune responses. Pro-inflammatory cytokines (e.g., IL-1β and TNFα), mediators of Th1 and Th17 cells (e.g., IFNγ and IL-17), and effector mechanisms involving neutrophils, macrophages, and plasma cells are all implicated in the disease process [28, 29]. Obesity and HS are closely linked: the prevalence of obesity is higher in patients with HS, and conversely, obesity may predispose individuals to develop HS. Weight loss has been associated with improvement in HS symptoms [30–32].

Liraglutide and semaglutide are the only GLP-1 RAs currently used, even if not approved, in the treatment of HS [31]. The proposed mechanism for the benefits of GLP-1 RAs in HS appears to involve both weight reduction and direct effects on the immune system [33]. A recent prospective study evaluated the use of 3 mg liraglutide for 3 months in 14 patients with HS, excluding those with T2DM. The results showed significant improvements in Hurley stage scores, DLQI, and the Beck Depression Inventory (BDI). Interestingly, weight changes were not correlated with changes in Hurley stage, BDI, or inflammatory markers [34]. In a retrospective study of 30 patients with HS treated with semaglutide at an average weekly dose of 0.8 mg, there was a reduction in patient-reported flare-ups and a significant improvement in mean DLQI scores. Notably, the average dose used was lower than the FDA-approved 2.4 mg per week for weight control [35].

In summary, GLP-1 RAs, through weight loss and the reduction of pro-inflammatory cytokines [31, 33], could provide a complementary approach to standard therapies for HS, especially in patients with obesity [36].

Acanthosis Nigricans

AN is a skin disorder characterized by symmetrical, velvety, hyperpigmented plaques in intertriginous areas. There are several types of AN, including benign, obesity-associated, syndromic, malignant, acral, unilateral, medication-induced, and mixed forms [37]. The prevalence of AN is increasing, largely as a result of the rise in obesity and T2DM, with obesity-associated AN being the most common phenotype [37]. Insulin and insulin-like growth factor 1 (IGF-1) are thought to play a role in promoting this condition, as their receptors are present on keratinocytes and fibroblasts. These hormones are typically elevated in patients with diabetes and obesity [38]. Only case reports report that GLP-1 RAs may improve glucose homeostasis and reduce circulating insulin levels, leading to a gradual improvement in skin manifestations of AN [39]. Similar to other antidiabetic medications, such as metformin [40], and in combination with diet and exercise, the reduction in insulin resistance induced by GLP-1 RAs may help reduce or resolve AN.

Hailey-Hailey Disease

HHD, also known as benign familial pemphigus, is a rare autosomal dominant disorder that affects keratinocyte adhesion. It is characterized by painful intraepidermal vesicles, erosion, maceration, and frequent secondary infections, primarily in the flexural areas. HHD is a chronic condition marked by recurrent flare-ups and limited treatment options [41]. Only one case in the literature reports the use of liraglutide to treat T2DM in a patient with HHD. This patient experienced significant improvement with subcutaneous injections of 1.8 mg daily of liraglutide, resulting in nearly complete resolution of HHD manifestations in the neck, armpits, and inguinal and abdominal folds [42]. It has been hypothesized that reduced IL-17 expression may contribute to this improvement. Indeed, patients with HHD show a five- to seven-fold increase in IL-17 levels in the dermal inflammatory infiltrates of affected skin [42].

Rare Emerging Adverse Cutaneous Reactions

Dermal Hypersensitivity

The most reported cutaneous adverse drug reaction (ADR) occurring during GLP-1 RAs treatment is dermal hypersensitivity (DHS). DHS can be localized, presenting as erythematous, pruritic wheals and plaques at injection sites, or generalized. The underlying pathogenesis is due to an allergic cutaneous manifestation resulting from an exaggerated immune response to external stimuli. Localized reactions have been reported in patients using liraglutide and dulaglutide [43–46], while generalized urticaria and systemic anaphylaxis have been associated with exenatide and tirzepatide [47–51]. Additionally, semaglutide has been associated with generalized cutaneous eruptions without systemic involvement [52]. The onset of reactions varied, occurring between 4 weeks and 3 years after medication initiation. Studies indicate that exenatide is more immunogenic than liraglutide, with anti-exenatide antibodies detected in 41% of patients after 30 weeks [53]. Management ranges from antihistamines for mild cases to hospitalization for severe reactions, with switching to a less immunogenic analogue as an option [54]. Two cases of angioedema were reported right after dulaglutide and exenatide administration [55, 56]; one case of facial edema and necrotic skin lesions was reported after liraglutide use. Treatment with topical and systemic steroids led to recovery [57].

Eosinophilic Panniculitis

Cases of eosinophilic panniculitis have been reported after exenatide extended-release (ER) injections, presenting as skin-colored nodules that develop within days, weeks, or months of starting the medication. The underlying pathogenesis seems to be related to an inflammatory response to foreign microcapsules due to a potential deficiency of enzymes needed to break down the poly-(d,l-lactide-co-glycolide) material into lactic and glycolic acid [58–60].

Morbilliform drug Eruption

Morbilliform drug eruption, appearing as macules and papules, sometimes purpuric, has also been reported in association with dulaglutide [60–62]. It is a type IV immune-mediated reaction mediated by cytotoxic T cells [63]. It usually appears 2–5 weeks after the first administration and resolves with topical and systemic steroids.

Psoriasiform Drug Eruption

Psoriasiform eruption was also described after exenatide ER and liraglutide administration, respectively 4 days and 2 weeks after drug administration. Patients complained of erythematous scaly plaques on the trunk, extremities, face, and scalp. Treatment required topical steroids and acitretin in one case and cyclosporine in another [25, 64].

Fixed Drug Eruption

A fixed drug eruption was reported in one case following semaglutide use, presenting as a persistent, round, hyperpigmented patch on the buttock and abdomen, distant from the injection site [65].

Drug-Induced Leukocytoclastic Vasculitis

Drug-induced leukocytoclastic vasculitis (LCV) has been reported with semaglutide use. A case of skin-limited LCV occurred with weekly subcutaneous semaglutide administration, resolving after drug discontinuation [66].

Allodynia

Four cases of dose-dependent allodynia associated with semaglutide were identified. Symptom resolution varied with discontinuation or continued therapy. The underlying pharmacological mechanism remains unclear [67].

Bullous, Pustular, and Ulcerative Reactions

Bullous pemphigoid (BP) is an autoimmune bullous disorder caused by the production of antibodies against hemidesmosomal proteins, primarily BP180 and BP230, which are essential for the adhesion of the epidermis to the dermis. In the recent past, BP has been associated with other drugs acting on the incretin pathway, namely dipeptidyl peptidase 4 (DPP4) inhibitors (especially linagliptin) [68–71]. Currently, the vast majority of the evidence on GLP-1 RAs stemmed from case reports with dulaglutide, liraglutide, and semaglutide [72–75]. Patients showed pruritic, erythematous lesions evolving into blisters. Symptoms developed after 2 weeks to 2 months after the first administration. The clinical features of GLP-1 RA-associated BP may not always correspond to the characteristic tense blisters of classic BP, and elevated autoantibody levels can persist even as clinical symptoms improve. A case of vesiculopustular eruption occurred 6 weeks after liraglutide use, with non-grouped vesicles and red borders on the thorax, abdomen, face, neck, arms, and lower extremities. Histopathology confirmed vesiculopustular dermatosis with subcorneal bullae [76].

Pyoderma gangrenosum was reported in one case after dulaglutide administration. Biopsy revealed epidermal acanthosis and perivascular neutrophilic infiltrate. After drug discontinuation the patient was treated with adalimumab, cyclosporine, and intralesional steroids [77].

The association between acne vulgaris and the use of GLP-1 RAs is still unclear. A recent meta-analysis of three studies found no direct correlation between acne vulgaris and GLP-1 RAs as a side effect [78]. While a retrospective cohort study concluded that patients treated with GLP-1 RAs had a higher risk of developing acne vulgaris compared to the control group at both 90 days and 1 year. Moreover, women had a significantly increased likelihood of developing acne vulgaris after 1 year [79].

A case of acute photo-distributed exanthematous pustulosis has been reported following liraglutide initiation, presenting as pustules on the chest and arms. Histological findings showed neutrophilic abscesses and eosinophils. The condition resolved after discontinuing liraglutide and using topical triamcinolone, leaving only post-inflammatory hyperpigmentation [60, 80].

Hair Loss

Hair loss is increasingly being linked to GLP-1 RAs, with growing evidence suggesting a possible association. An analysis of the FDA Adverse Event Reporting System (collecting worldwide adverse events) identified an increased reporting odds ratio for alopecia with semaglutide and tirzepatide, while no significant increase was observed for liraglutide, dulaglutide, exenatide, or lixisenatide [81]. Burke et al. conducted a study involving 283 patients receiving GLP-1 RAs treatment, of whom 35 reported experiencing hair loss (androgenetic alopecia, telogen effluvium, unspecified hair loss). The analysis found no significant association between specific GLP-1 RAs and androgenetic alopecia, though semaglutide showed a potential trend toward increased hair loss. For telogen effluvium, tirzepatide exhibited a borderline association [82].

Several theories have been proposed regarding the impact of GLP-1 RAs on hair health. On the one hand, some suggest that these medications may disrupt hair growth cycles or accelerate androgenetic alopecia in predisposed individuals; in contrast, others highlight potential benefits, such as improved insulin sensitivity and enhanced blood circulation to the scalp. Previous research has demonstrated the presence of GLP-1 receptors in murine hair follicles, although their precise role in the hair growth cycle remains undefined. This indicates a possible effect of GLP-1 RAs on hair growth, but the lack of human data underscores the need for further research [83]. On the other hand, another theory is that the rapid weight loss caused by these agents may trigger telogen effluvium, a type of non-scarring alopecia characterized by widespread hair shedding, typically seen after metabolic stress. Telogen effluvium is frequently observed in patients undergoing significant weight loss, such as following metabolic or bariatric surgery [84, 85].

Implications for Plastic Surgery

The growing use of GLP-1 RAs for the management of T2DM and weight loss is giving rise to a new patient population with distinct clinical needs. Plastic surgery is increasingly involved in addressing these needs across regenerative, aesthetic, and reconstructive domains.

GLP-1 RA-Related Facial Aging

The rapid and significant weight loss induced by GLP-1 RAs often leads to a noticeable reduction in facial fat pad volume, along with a decline in skin collagen, elastin, and essential nutrients. Additionally, the loss of fatty acids compromises the skin barrier, resulting in dryness. These changes have important aesthetic implications, including soft tissue ptosis due to a mismatch between skin envelope and underlying volume, particularly evident as sagging along the jawline. Volume loss is most pronounced in the upper cheeks—leading to an inversion of the “triangle of beauty”—as well as in the lips and chin. These alterations contribute to the deepening of wrinkles such as the nasolabial folds and marionette lines, culminating in an overall appearance of sudden facial aging. The effects are more pronounced in older patients, who already experience age-related collagen and elastin depletion. Colloquially, these changes are referred to on social media as “semaglutide face” or “Ozempic face,” based on the commercial names of semaglutide. In 2023, Humphrey and Lawrence emphasized the importance for plastic surgeons to recognize these potential effects, counsel patients before initiating therapy, and consider both surgical and non-surgical interventions to mitigate facial volume loss, sagging, and premature aging [86]. Hansen et al., in their commentary on Humphrey and Lawrence’s paper [87], emphasized that several studies have demonstrated improvements in quality of life associated with GLP-1 RA-induced weight loss, along with health-related benefits such as enhanced cardiovascular outcomes that outweigh the impact of facial aging. In addition, as semaglutide is not officially approved for chronic weight management, changes in facial appearance are not listed in the FDA label as adverse events [88]. However, accelerated facial aging is a well-documented consequence of rapid weight loss, previously described in the context of bariatric surgery, primarily due to fat volume depletion and reduced skin elasticity. In a 2024 study, Mansour et al. [89] analyzed Google Trends data related to the term “Ozempic face.” Their findings revealed that searches for “Ozempic face” nearly matched those for general “Ozempic side effects,” suggesting that this undesirable aesthetic outcome is a significant concern among patients treated with GLP-1 RAs. The skin-related effects of these drugs have been further reviewed by Haykal et al. in a 2025 narrative review [90]. Several therapeutic strategies have been proposed to address facial volume loss and skin laxity. Non-surgical interventions include injectable treatments such as dermal fillers, biostimulatory fillers, and autologous fat grafting (lipofilling), as well as energy-based devices like radiofrequency (RF), high-intensity focused ultrasound (HIFU), and fractional lasers. In selected patients, surgical options used in post-bariatric contexts—such as facelifts and neck lifts—may be appropriate. The primary goals of treatment are restoration of facial volume, stimulation of collagen production, regenerative enhancement, and management of excess skin. Although injectable fillers are often considered the most accessible solution for volume restoration, treating large-volume deficits with fillers alone may lead to an unnatural appearance and the so-called overfilled syndrome, characterized by impaired facial expression [91]. Furthermore, de Oliveira et al. [92] reported a case of delayed-onset facial edema and an inflammatory reaction 3 months after hyaluronic acid filler injections to the lips and infraorbital area, which occurred following initiation of semaglutide. The authors hypothesized that the medication may trigger immune responses, as the inflammation resolved after intralesional hyaluronidase administration. Notably, GLP-1 RAs have been shown to modulate immune activity by enhancing NK cell cytotoxicity. In 2024, O’Neill et al. [93] advocated for a multimodal approach that includes nutritional optimization, volume restoration, skin resurfacing, and surgical intervention when indicated. Among volume restoration techniques, lipofilling appears particularly promising owing to its dual volumizing and regenerative effects. Additional regenerative options such as platelet-rich plasma (PRP), microneedling, RF, HIFU, and fractional lasers may support collagen synthesis and skin quality. Regarding timing, regenerative treatments can be initiated in the early stages, even during ongoing weight loss. However, candidates for surgical procedures such as facelift, neck lift, or brow lift should ideally wait until their weight stabilizes [93]. In post-bariatric surgery, this plateau typically occurs between 12 and 18 months postoperatively, while in patients on GLP-1 RAs, the timing of weight stabilization is less predictable. In our view, surgical interventions should be postponed until weight has remained stable for a sufficient period to avoid complications related to malnutrition and to ensure durable aesthetic outcomes.

GLP-1 Receptor Agonists Related to Body Contouring Surgery

The rapid and significant weight loss induced by GLP-1 RAs results in substantial depletion of subcutaneous fat and loss of skin elasticity, leading to pronounced skin laxity and body contour deformities. These changes carry not only aesthetic implications but also functional concerns. In selected patients, the same body contouring surgical procedures commonly performed in post-bariatric patients—such as abdominoplasty, mastopexy, thigh lift, and brachioplasty—may be indicated [90]. In 2024, Toms et al. published a retrospective study demonstrating a dose-dependent relationship between the use of GLP-1 RAs and an increased demand for aesthetic body contouring surgeries [94]. However, appropriate surgical planning requires a deeper understanding of how GLP-1 RAs-induced rapid weight loss affects collagen and elastin synthesis, the extracellular matrix, and wound healing dynamics. Recently, Taraschi et al. [95] reported wound healing complications in two patients undergoing breast surgery while receiving GLP-1 RAs. Despite adherence to standard surgical techniques and postoperative care, both patients experienced delayed healing, fat necrosis, and tissue fragility. These complications may be attributed to nutritional deficiencies frequently observed during rapid weight loss, including depletion of iron, vitamin B₁₂, fat-soluble vitamins, and proteins. Therefore, surgical intervention should be deferred until the patient has achieved weight stability and optimized nutritional status. Preoperative and postoperative nutritional support is essential, particularly ensuring adequate weight-based protein intake for 2–4 weeks before surgery and continuing for at least 4 weeks postoperatively to support optimal healing [93]. As with facial rejuvenation procedures, body contouring surgery should only be considered after a sustained period of weight stability, not only to minimize the risk of healing complications due to malnutrition but also to ensure long-term surgical results. Additionally, regenerative approaches such as lipofilling and platelet-rich plasma may have a potential role in improving outcomes in body contouring surgery, although their efficacy in this context has yet to be conclusively demonstrated.

GLP-1 Receptor Agonists and Reconstructive Surgery Procedures

In 2024, Stanton et al. published a comprehensive review on the use of GLP-1 RAs in plastic surgery, focusing for the first time primarily on their potential benefits and practical considerations in reconstructive procedures [96]. Preclinical studies have suggested that GLP-1 RAs may enhance vascularization in reconstructive flaps. In particular, animal models have shown that GLP-1 RAs can reduce necrosis in random-pattern skin flaps [97]. Furthermore, in rat models, the GLP-1 RA exendin-4 was found to alleviate ischemia–reperfusion injury in skin flaps by upregulating Gpx4 expression, thereby inhibiting ferroptosis [73]. Clinical evidence also suggests potential advantages in wound healing. A nationwide Danish retrospective cohort study indicated that GLP-1 RAs may offer protection against lower extremity amputations in patients with T2DM, compared to sulfonylureas [98]. In patients with burns, however, the impact of GLP-1 RAs remains uncertain. As noted by Manasyan et al., while these agents reduce insulin requirements and maintain adequate glucose control with fewer hypoglycemic events, they may simultaneously impede adequate nutrition as a result of delayed gastric emptying and present a risk of aspiration. Nevertheless, they could still support healing via mechanisms such as enhanced angiogenesis and keratinocyte migration [99]. In the context of breast reconstruction, GLP-1 RAs may help broaden eligibility for autologous procedures such as DIEP flap reconstruction. Patterson et al. found that patients with class III obesity (BMI > 40) had significantly higher risks of abdominal donor site complications and microsurgical failure, highlighting the importance of preoperative weight optimization and the potential need to delay reconstruction until target BMI thresholds are reached [100]. Borab et al. outlined several systemic advantages of GLP-1 RAs, including weight loss, glycemic control, cardiovascular protection (e.g., reduced incidence of myocardial infarction and stroke), and their role as a non-surgical alternative to bariatric procedures. These benefits also translate into improved eligibility and reduced risk profiles for plastic surgery patients [101]. High BMI is associated with increased complications and prolonged wound healing in procedures such as abdominoplasty and breast reduction; thus, GLP-1 RAs may serve as valuable tools in preoperative risk reduction [102, 103]. Additionally, BMI reduction through GLP-1 RAs may lower the risk of perioperative venous thromboembolism (VTE), although it remains unclear whether these agents exert direct effects on coagulation pathways [104]. Emerging hypotheses also suggest a possible role in reducing lymphedema risk in breast surgery patients undergoing axillary lymph node dissection, with or without immediate lymphatic reconstruction, by preventing obesity-induced mechanical pressure on lymphatic vessels [105].

Perioperative Management and Potential Drug Discontinuation to Avoid Aspiration Pneumonia

GLP-1 RAs are increasingly used in patients undergoing elective or urgent surgeries, including facial and body plastic surgery. In addition, their impact on gastric motility has raised perioperative concerns, particularly related to delayed gastric emptying, which increases the risk of vomiting and aspiration during induction of general anesthesia. Therefore, if and how GLP-1 RAs should be discontinued before surgery is a matter of debate.

Perioperative management guidelines have evolved in recent years. In 2021, the Society for Perioperative Assessment and Quality Improvement recommended discontinuing GLP-1 RAs on the day of surgery [106], whereas the British Centre for Perioperative Care advised continuing the medication perioperatively [107]. In 2023, the American Society of Anesthesiologists issued more specific recommendations: discontinuation 1 day prior to surgery for patients using daily formulations, and 1 week prior for weekly formulations. In addition, if a patient presents with nausea, vomiting, or abdominal pain, surgery should be postponed. For patients who did not discontinue GLP-1 RAs, gastric ultrasound may be used to assess residual gastric contents [108].

Recent evidence offers contrasting perspectives. A 2024 comparative cohort study by Alkabbani et al. [109] found no increased risk of pulmonary aspiration during upper gastrointestinal endoscopy in GLP-1 RA users versus those on sodium-glucose co-transporter 2 (SGLT2) inhibitors. However, retained gastric content was more frequent, often necessitating cancellation or postponement of endoscopy. Conversely, Yeo et al. reported a significantly increased risk of aspiration pneumonia in GLP-1 RA users undergoing gastrointestinal endoscopy, especially with propofol sedation, likely due to impaired airway protection reflexes [110]. Gastric motility may take up to 4 weeks to normalize following GLP-1 RA withdrawal, yet discontinuation for such an extended period could compromise glycemic control and cardiovascular benefits. Thus, shared decision-making between surgical, anesthetic, and medical teams is essential to balance risks and benefits [111]. In 2024, a multi-society clinical practice guideline was issued jointly by the American Gastroenterological Association, the American Society for Metabolic and Bariatric Surgery, the American Society of Anesthesiologists (ASA), the International Society of Perioperative Care of Patients with Obesity, and the Society of American Gastrointestinal and Endoscopic Surgeons [112]. Recommendation 1 emphasizes shared decision-making before surgery to determine whether GLP-1 RA should be continued or withheld. Key risk factors for delayed gastric emptying and aspiration include escalation phase vs. maintenance phase of therapy; high dosage; weekly vs. daily dosing; presence of gastrointestinal symptoms; comorbidities such as bowel dysmotility, gastroparesis, or Parkinson’s disease. If these factors are absent, continuation may be appropriate. If present, discontinuation should be considered, following the ASA guidance: withholding on the day of surgery for daily formulations and 1 week prior for weekly ones. All patients should still be evaluated on the day of the procedure for symptoms of delayed gastric emptying. Recommendation 2 advises proactive measures to reduce aspiration risk: preoperative liquid diet for at least 24 h; use of gastric ultrasound to assess residual volume before surgery; and a discussion with the patient regarding the potential need for rapid sequence induction (RSI) to minimize aspiration risk, versus postponement of the procedure.

Systemic Side Effects

Gastrointestinal Side Effects

The most commonly reported side effects of GLP-1 RAs are gastrointestinal, including nausea, vomiting, diarrhea, constipation, abdominal pain, and dyspepsia [113–115]. The mechanisms are not fully understood but may involve delayed gastric emptying, activation of the area postrema in the central nervous system, changes in nutrient absorption, and altered intestinal motility [116–118]. These effects tend to be dose-dependent, class-dependent, and are more frequent during the initial stages of treatment [114, 118]. Nausea may diminish over the course of therapy and can be managed by gradually increasing the dose [119, 120]. In general, gastrointestinal side effects, especially constipation, may persist even as other symptoms diminish over time and appear to occur less frequently with long-acting GLP-1 RAs [118]. Patients with gastrointestinal side effects can be advised to eat slowly, consume smaller meal portions, avoid high-fat foods, and consider using antiemetic therapy if necessary [118]. GLP-1-based therapies have also been linked to more severe, albeit rare, gastrointestinal side effects, including intestinal obstruction and symptomatic gastroparesis [121].

Pancreatic Side Effects

GLP-1 receptors are found not only in pancreatic islet cells but also in the exocrine duct cells of the pancreas [122]. It is hypothesized that incretin therapies stimulate these receptors, potentially leading to the overgrowth of cells lining the smaller ducts [122]. This overgrowth may result in hyperplasia and chronic low-grade or acute inflammation, which could contribute to the development of acute pancreatitis [122]. Additionally, GLP-1 suppresses pancreatic exocrine secretion, a proposed mechanism linked to the development of pancreatitis [123]. Acute pancreatitis has been reported in connection with GLP-1 RAs use [121, 124–126], though the data are insufficient to establish a causal relationship. Indeed, a meta-analysis by Nreu et al. demonstrated that GLP-1 RAs showed no association with pancreatitis (MH-OR 1.24 [0.94, 1.64]; P = 0.13) and pancreatic cancer (MH-OR 1.28 [0.87, 1.89]; P = 0.20) [127] (the authors note that data regarding pancreatic cancer are too limited to draw any firm conclusions). Pancreatitis should be suspected in patients experiencing persistent, severe abdominal pain, with or without nausea, and GLP-1 RAs should be discontinued if this occurs [128]. If pancreatitis is confirmed, the treatment should not be resumed, and GLP-1 RAs should not be started in patients with a history of pancreatitis [128].

Gallbladder Side Effects

Finally, a systematic review and meta-analysis by He et al. found that GLP-1 RAs are associated with an increased risk of gallbladder and biliary diseases (including cholelithiasis and cholecystitis), particularly at higher doses, longer treatment durations, and when used for weight loss [129]. These findings highlight the need for cautious use and thorough reporting of gallbladder-related adverse events in future trials and in the post-marketing setting.

Debated Unsettled Safety Issues

Cancer

Concerns about a possible connection between GLP-1 RAs and the development of neoplasms have spurred several investigations, especially on thyroid and pancreatic cancers due to a plausible mechanism and a large number of reports in the post-marketing phase [118, 128, 130].

For what concerns pancreatic cancer, a recent historical cohort study of adults with T2DM observed no increased incidence of pancreatic cancer within 7 years of starting GLP-1 RAs treatment. However, extended monitoring beyond this period is recommended to assess long-term risks [131].

The potential link between GLP-1 RAs and thyroid cancer has been a topic of growing research interest, with mixed findings. Nagendra et al. conducted a systematic review and meta-analysis involving 37 RCTs and 19 real-world studies to assess the safety of semaglutide [132]. Their analysis found no statistically significant increase in thyroid cancer risk in patients treated with semaglutide compared to those receiving placebo or other anti-diabetes medications. Furthermore, in the real-world studies reviewed, no cases of thyroid cancer, including medullary thyroid carcinoma, were observed [132]. However, the authors noted prior evidence from studies like Bezin et al. which reported a heightened risk of thyroid cancer, particularly medullary thyroid cancer, associated with other GLP-1 RAs such as liraglutide and exenatide [133].

In contrast, a meta-analysis by Silverii et al. provided evidence suggesting a moderate increase in the relative risk of thyroid cancer with GLP-1 RAs treatment. This association was particularly pronounced in RCTs lasting more than 104 weeks, where the odds ratio for thyroid cancer increased to 1.76. Despite this, the analysis did not find a statistically significant link between GLP-1 RAs and specific thyroid cancer subtypes, such as papillary or medullary thyroid cancer [134]. Silverii et al. also discussed the biological plausibility of GLP-1 RAs influencing thyroid cells, citing preclinical evidence of GLP-1 receptors in thyroid tissue. However, they highlighted the limited evidence of similar effects in humans and called for longer-term trials to clarify the potential risks [134]. In summary, the potential impact of long-acting GLP-1 RAs on human thyroid C cells needs further study. FDA has issued a box warning of the risk of thyroid cancers and are contraindicated liraglutide, exenatide (once weekly), and semaglutide (both oral and injectable) in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia types 2 A or 2B [135, 136].

Pregnancy

There are several considerations when deciding to treat reproductive-aged women with GLP-1 RAs [137]. Anecdotal evidence is emerging on the plausible contribution of GLP-1 RAs to unplanned pregnancies by regularizing ovulation in subjects with obesity and polycystic ovarian syndrome. In addition, the known delayed gastric emptying may impair the absorption of oral medications, including oral contraceptive pills, thus underscoring the importance of counselling patients and educating prescribers for concerted multiprofessional management [138]. If possible, GLP-1 RAs should not be used during pregnancy because of observed reproductive toxicity in animals. For semaglutide, discontinuation is required at least 2 months before a planned pregnancy as a result of its long half-life. Reassuring clinical data are starting to accrue: two multinational population-based cohort studies found no increased risk of major congenital malformations, live births, pregnancy losses, and pregnancy terminations during the periconceptional period with GLP-1 RAs [139]. As a result of the expected increasing use in reproductive-aged women, close monitoring and proactive pharmacovigilance are warranted [140].

Suicidal Ideation and Other Rare Undesirable Effects

With the expanding role in diabetes and obesity, as well as potential extending therapeutic uses in the neurological area (e.g., stroke, neurodegenerative disorders, alcohol- and substance-use disorders), rare side effects have recently emerged. In particular, semaglutide was specifically under investigation by regulators, including the EMA and the FDA, because of a series of reports and pharmacovigilance studies on suicidal or self-harming thoughts [141, 142]. Although no firm causality was demonstrated, and recent observational data are reassuring, it seems prudent to screen for depression and anxiety as common comorbidities in clinical practice [133, 143–147]. On January 17, 2025, the EMA also started a review on the potential association between semaglutide and non-arteritic anterior ischemic optic neuropathy [148].

Conclusion

GLP-1 RAs are transforming metabolic care and expanding their clinical footprint into dermatological and aesthetic practice. Their pleiotropic effects beyond glycemic control offer promising therapeutic opportunities in chronic skin diseases and plastic surgery, but also introduce unique challenges related to cutaneous adverse reactions, facial aging, surgical outcomes, and perioperative safety. As their use becomes increasingly common, dermatologists and plastic surgeons must remain vigilant in assessing both the potential benefits and risks to ensure optimized, multidisciplinary patient care.

Author Contributions

Stephano Cedirian, Michela Starace, Emanuel Raschi, Francesca Pampaloni, Monia Donati, Rossella Sgarzani, Luca Negosanti, Luca Rapparini and Michelangelo La Placa conceptualized and designed the study, conducted data collection and analysis, and wrote the initial draft of the manuscript. Rossella Sgarzani and Michelangelo La Placa. Michela Starace and Emanuel Raschi contributed to data interpretation, provided critical revisions, and approved the final version of the manuscript. Stephano Cedirian, Luca Rapparini, Francesca Pampaloni, Monia Donati, Luca Negosanti assisted in study design, literature review, and editing of the manuscript. All authors read and approved the final manuscript.

Funding

No funding or sponsorship was received for this study or the publication of this article.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Stephano Cedirian, Monia Donati, Luca Rapparini, Francesca Pampaloni, Michelangelo La Placa, Rossella Sgarzani, Luca Negosanti, Emanuel Raschi and Michela Starace is an Editorial Board member of Dermatology and Therapy. Michela Starace was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.