How GLP-1 Receptor Activators May Influence Immune and Metabolic Processes in Long-Term Inflammatory Skin Diseases

Emerging evidence suggests that GLP-1R is expressed in several components of the skin, as illustrated in Figure 2, indicating that GLP-1 signalling may exert direct local effects within the cutaneous microenvironment [10,11,37,38].

Experimental studies investigating GLP-1R distribution in murine skin demonstrated receptor expression using RT-PCR, Western blotting, and in situ immunocytochemistry, with localization predominantly within specific regions of hair follicles [39]. In the same study, proglucagon expression was also detected in skin tissue, and GLP-1 stimulation activated MAPK/ERK signalling in cultured skin-derived cells, suggesting the existence of a local GLP-1 signalling axis in the skin [39,40]. Mechanistically, GLP-1 has also been shown to transactivate the epidermal growth factor receptor (EGFR), potentially via c-Src activation and the release of endogenous EGF-like ligands, linking GLP-1 signalling with pathways involved in epithelial growth and tissue remodelling [41,42]. Additionally, cultured skin-derived cells exposed to GLP-1 express the neural stem cell marker nestin, a feature associated with dedifferentiated epithelial cells and epithelial–mesenchymal transition processes [43,44]. Together, these observations support the hypothesis that GLP-1 may function through autocrine or paracrine mechanisms regulating skin development and folliculogenesis [39].

Further evidence indicates that keratinocytes themselves may represent functional targets of GLP-1 receptor signalling. In cultured keratinocytes, GLP-1R mRNA and protein expression have been confirmed, and stimulation with the GLP-1 analogue liraglutide was shown to enhance keratinocyte migration through activation of the PI3K/Akt pathway. In vivo experiments in murine models further demonstrated that liraglutide administration facilitated wound healing, supporting a direct role for GLP-1R signalling in epidermal repair processes [12]. Activation of the GLP-1R/PI3K/Akt pathway has also been related to cytoprotective effects in other tissues, which include the inhibition of cell death programs such as necroptosis, and therefore it is possible that similar pathways could be involved in the increased cell survival and regeneration observed during cutaneous wound healing [45]. Moreover, the activation of the PI3K/Akt/mTOR pathway, which is a downstream target of the GLP-1R pathway, has been correlated with increased cell proliferation and differentiation. This implies a broader role for the GLP-1R pathway in the context of tissue remodelling and repair, which is important in the context of wound healing [46]. Additionally, the activation of the GLP-1R pathway has been correlated with the normalization of abnormal cell migration, proliferation, and apoptosis under stressful conditions via the modulation of the PI3K/Akt and ERK1/2 pathways. This implies a broader role for the GLP-1R pathway in the restoration of normal cellular homeostasis in the context of wound healing [28].

GLP-1R expression has also been observed in immune cells infiltrating the skin, which may be particularly relevant in inflammatory dermatoses. In a study in which skin biopsies of patients with plaque psoriasis were examined, the expression of GLP-1R was observed in five of six affected skin samples, whereas it was only rarely observed in unaffected psoriatic skin or in healthy skin [9]. Importantly, cultured keratinocytes stimulated with pro-inflammatory cytokines such as tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) did not demonstrate GLP-1R expression, suggesting that receptor detection in psoriatic plaques likely reflects infiltration by GLP-1R-expressing immune cells rather than constitutive expression by keratinocytes [47,48]. These findings highlight a potential immunomodulatory role of GLP-1 signalling within inflamed skin.

Clinical observations further support the possibility of direct cutaneous actions of GLP-1RAs. A case report described by Faurschou et al. marked improvement of long-standing psoriasis shortly after initiation of liraglutide therapy for T2DM, with reduction in scaling and pruritus occurring before significant weight loss or metabolic improvement, suggesting a potential direct anti-inflammatory effect of GLP-1R activation in the skin [26,49,50,51,52].

Beyond their metabolic actions, GLP-1RAs exert important immunomodulatory and anti-inflammatory effects through several intracellular signalling pathways relevant to inflammatory skin diseases. One key mechanism involves modulation of innate immune cells such as invariant natural killer T (iNKT) cells, which play an important role in psoriasis pathogenesis [53]. iNKT cells recognize lipid antigens presented by CD1d molecules and rapidly produce cytokines including IFN-γ, IL-4, IL-17, TNF-α, and GM-CSF, thereby shaping inflammatory responses in the skin [54,55].

GLP-1 receptors are expressed on iNKT cells, and stimulation with GLP-1 or its analogues can modulate their activity and distribution [52]. In patients with psoriasis treated with GLP-1RAs, circulating iNKT cell numbers increase while their accumulation within psoriatic plaques decreases, suggesting redistribution of these cells away from inflamed skin [26,52].

At the molecular level, GLP-1R activation stimulates adenylate cyclase through G-protein coupling, leading to increased intracellular cAMP and activation of PKA. PKA subsequently phosphorylates the transcription factor cAMP response element-binding protein (CREB) [56]. CREB activation can inhibit the NF-κB signalling pathway and suppress transcription of pro-inflammatory mediators, thereby attenuating inflammatory cytokine production and potentially promoting anti-inflammatory responses such as IL-10 induction [26,56,57].

Anti-inflammatory effects of GLP-1RAs have also been demonstrated in skin-resident cells. In lipopolysaccharide-stimulated HaCaT keratinocytes, liraglutide reduced activation of inflammatory pathways including NF-κB, JAK2/STAT3, and SOCS3 signalling while decreasing secretion of pro-inflammatory cytokines such as TNF-α and IL-6 [38,58]. These effects were mediated through activation of AMP-activated protein kinase (AMPK), as pharmacological inhibition of AMPK reversed the anti-inflammatory activity of liraglutide [38].

Evidence from tissue injury models further supports cytoprotective and anti-inflammatory actions of GLP-1RAs in the skin. In a murine random-pattern skin flap model, the GLP-1 analogue exenatide significantly improved flap survival by enhancing angiogenesis, reducing oxidative stress, and attenuating pyroptosis. These effects were mediated through activation of autophagy via TFE3 nuclear translocation and AMPK-dependent pathways, including AMPK–SKP2–CARM1 and AMPK–mTOR signalling [59]. The consistent anti-inflammatory and anti-angiogenic effects have also been reported in ocular inflammatory models. Liraglutide was found to reduce pathological angiogenesis and the expression of inflammatory mediators, including NLRP3 inflammasome, IL-1β, IL-6, and TNF-α, in a laser-induced choroidal neovascularization model [60]. These findings suggest that GLP-1R signalling inhibits inflammatory pathways through cAMP/PKA pathways in immune cells and through the regulation of inflammatory pathways by AMPK in keratinocytes [58,60].

Together, these mechanisms highlight the multifaceted anti-inflammatory actions of GLP-1R activation across both immune and skin-resident cells, supporting its potential relevance in chronic inflammatory dermatoses (Figure 3).

The IL-23/Th17/IL-17 axis represents a central inflammatory pathway in several chronic skin diseases, particularly psoriasis. IL-17 acts as a key effector cytokine that promotes keratinocyte activation, neutrophil recruitment, and amplification of inflammatory signalling within the skin [61,62].

Evidence suggests that GLP-1RAs may influence this pathway through modulation of IL-17-producing immune cells. Dermal γδ T cells constitute an important source of IL-17 in psoriatic lesions and play a significant role in disease pathogenesis [37]. Treatment with GLP-1 analogues such as exenatide or liraglutide has been associated with reduced numbers of dermal γδ T cells and decreased IL-17 expression in psoriatic skin, accompanied by improvement in clinical disease severity [50]. Furthermore, GLP-1 signalling may inhibit TNF-α–driven inflammatory cascades and reduce lymphocyte recruitment by decreasing stromal cell-derived factor-1 (SDF-1)-mediated chemotaxis [50,63,64]. In a prospective case-series study, reductions in Psoriasis Area and Severity Index (PASI) scores correlated with decreases in dermal γδ T-cell percentages and IL-17 expression following GLP-1 analogue therapy, suggesting that modulation of IL-17-producing immune populations may contribute to the observed clinical effects [50].

Microbial dysbiosis has emerged as a key mediator of inflammation in AD. Patients suffering from AD have low microbial diversity as well as increased microbial colonization, which is strongly correlated with disease severity as well as exacerbations [65]. Bacterial components such as lipopolysaccharide (LPS) act as potent activators of innate immune responses by triggering inflammatory signalling pathways including NF-κB activation in macrophages and other immune cells [66].

Experimental models of AD demonstrate that LPS-driven inflammatory signalling contributes to increased production of nitric oxide and pro-inflammatory mediators through activation of NF-κB and MAPK pathways. In macrophage models, LPS stimulation induces overexpression of inflammatory mediators such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2, further amplifying cutaneous inflammation [67,68].

These microbial-driven inflammatory pathways are particularly relevant in AD, where impaired skin barrier function facilitates microbial colonization and promotes chronic immune activation. As GLP-1R signalling has been shown to suppress key inflammatory pathways such as NF-κB and MAPK signalling in immune and skin-resident cells, modulation of LPS-induced inflammatory responses may represent another mechanism through which GLP-1RAs could influence inflammatory skin diseases [38].

Accumulating evidence suggests that GLP-1RAs exert pro-regenerative effects in cutaneous wound healing through coordinated modulation of immune responses, angiogenesis, and keratinocyte function. Chronic wounds are characterized by persistent inflammation, impaired macrophage polarization, defective angiogenesis, and delayed re-epithelialization [69]. GLP-1RA signalling appears to address several of these pathophysiological barriers by regulating inflammatory pathways and promoting tissue repair processes [10].

One important mechanism involves direct stimulation of keratinocyte migration and proliferation. Experimental studies have demonstrated that keratinocytes express GLP-1Rs, and activation of this pathway by liraglutide significantly enhances keratinocyte migration through activation of the PI3K/Akt signalling pathway, thereby accelerating re-epithelialization in experimental wound models [12]. More recent mechanistic studies further revealed that liraglutide can regulate cytoskeletal and adhesion signalling in keratinocytes through stabilization of unconventional myosin-1c (Myo1c), which enhances interaction with dedicator of cytokinesis-5 (Dock5). Activation of the Myo1c/Dock5 axis promotes keratinocyte proliferation, migration, and adhesion, ultimately improving collagen deposition, extracellular matrix remodelling, and wound closure in diabetic mouse models [70].

GLP-1RA-mediated wound repair is also closely linked to modulation of innate immune responses. Experimental studies demonstrate that liraglutide promotes polarization of macrophages from pro-inflammatory M1 phenotypes toward reparative M2 macrophages during wound healing [71]. This shift enhances the production of pro-repair mediators and angiogenic factors, including vascular endothelial growth factor (VEGF), thereby promoting neovascularization and tissue regeneration [7,71,72]. Additional immunometabolic mechanisms involve the regulation of oxidative stress and cell death pathways. In diabetic wound models, dulaglutide has been shown to activate the Nrf2 antioxidant signalling pathway, increasing expression of glutathione peroxidase (GPX4) and SLC7A11 while reducing lipid peroxidation and ferroptosis. These effects restore redox balance and improve keratinocyte viability, contributing to enhanced wound closure [73].

In addition, the activation of the GLP-1R has been shown to stimulate angiogenesis and endothelial repair. In diabetic animal models, the administration of the GLP-1RA, exendin-4, has been shown to increase the number of endothelial progenitor cells and the expression of vascular remodelling mediators, such as VEGFR-2, phosphorylated endothelial nitric oxide synthase, transforming growth factor-beta, and matrix metalloproteinase-2. These processes play critical roles in the proliferative and remodelling phases of wound healing [74,75]. The GLP-1RA-based approach may be beneficial for the enhancement of antimicrobial defense and vascularization in infected wounds. Biomaterial-based delivery systems that combine liraglutide and zinc oxide nanoparticles have been shown to have synergistic antibacterial activities against Staphylococcus aureus and Escherichia coli, and promote endothelial cell migration, tubule formation, and wound healing [76,77].

These studies indicate that GLP-1RAs enhance wound healing through multiple complementary mechanisms, including activation of PI3K/Akt signalling in keratinocytes, regulation of cytoskeletal migration pathways, modulation of macrophage polarization, suppression of oxidative stress and ferroptosis, and stimulation of angiogenesis [10,12,28]. These pleiotropic immunometabolic effects suggest that GLP-1R signalling may represent a promising therapeutic target for chronic and diabetes-associated cutaneous wounds.

The diverse mechanisms through which GLP-1RAs promote wound healing including keratinocyte activation, immune modulation, reduction in oxidative stress, stimulation of angiogenesis, and antimicrobial effects are summarized in Figure 4 [10,12,28,70,71,72,73,74,76,77,78,79].

Modern medicine is redefining psoriasis not merely as an isolated cutaneous disorder, but as a critical component of a broader metabolic “comorbidome”. This shift necessitates an evolution in therapeutic strategies toward agents capable of modulating systemic inflammation. At the core of this relationship lies a bidirectional link between psoriasis and T2DM, where chronic immune activation drives escalating IR, leading to progressive vascular damage [26,80,81]. Genetic studies further highlight a shared pathogenic foundation, identifying susceptibility genes such as PTPN22, ST6GAL1, and JAZF1, which participate in inflammatory pathways mediated by T-cells [82].

Population-based analyses utilizing the AoUDB and TriNetX databases demonstrate that the use of GLP-1RAs is associated with a reduced risk (approximately 40–60%) of developing psoriasis and psoriatic arthritis (PsA) [5,83]. This effect has been reported as statistically significant in observational datasets, regardless of the degree of weight loss or the patient’s glycaemic status, although causal relationships cannot be firmly established, pointing toward a potential extra-metabolic immunomodulatory action of these molecules [83]. Furthermore, recent biomarker research indicates that incretin dysregulation and shifts in GIP-1 and leptin levels manifest in the serum long before the onset of clinical joint symptoms, suggesting that GLP-1RAs may represent a potential tool to influence the ‘’psoriatic march” [84]. The clinical response to GLP-1 RA therapy has been reported as relatively rapid in some cases. Patients may report a substantial reduction in pruritus and improved sleep quality within the first 48 h of administration, significantly predating any measurable changes in body mass. Although these observations are primarily derived from limited clinical reports [26]. Direct evidence of these phenomena is found in the case of a 59-year-old male with T2DM [49], where the initiation of liraglutide triggered an immediate dampening of cutaneous inflammation (PGA score drop from 3 to 1) despite a baseline Body Mass Index (BMI) of 29.3 kg/m². The fact that previous glycaemic control had been intermittently achieved without skin improvement may suggests that the drug’s direct anti-inflammatory properties, rather than simple metabolic stabilization, initiated the healing process [49]. These findings are supported by small prospective data, including a cohort study in which T2DM patients saw their mean PASI score drop from 15.7 to 2.0 after 12 weeks of liraglutide therapy [82]. A unique contribution of this study is the histopathological evidence: skin biopsies revealed reduced epidermal thickness, the total disappearance of Munro’s microabscesses, and the resolution of neutrophilic infiltrates, objectively suggesting the drug’s potent anti-inflammatory action within the skin tissue itself. Concurrently, significant improvements in pancreatic function and a reduction in IR, measured by the HOMA-IR index, were observed [82]. However, results from the first randomized placebo-controlled trial (RCT) shed new light on this drug class in obese patients without diabetes. Within a short 8-week observation period window, liraglutide induced a 2.6-point drop in PASI, which did not reach statistical significance compared to placebo. This suggests that in normoglycemic individuals, immunomodulatory mechanisms may require longer exposure times or more potent molecules, such as semaglutide, to overcome epidermal tissue resistance [85].

A breakthrough came with a 2024 cohort study involving 43 patients treated with semaglutide (1.6 mg/week) over six months [86]. The study demonstrated a significant reduction in PASI and skin pain (VAS pain). Utilizing nutritional ultrasound, researchers proved that dermatological improvement correlates with the selective reduction in metabolically active preperitoneal fat. Crucially, the impact on PASI, Dermatology Life Quality Index (DLQI), and mood (BDI scale) remained statistically significant even after adjusting for percentage weight loss, confirming a mechanism of action independent of weight reduction, although these findings require confirmation in larger controlled trials [86].

Further evidence is provided by clinical cases of patients with atypical metabolic profiles or resistance to standard care. One report described a non-obese male (BMI 25.5 kg/m²) whose psoriasis went into remission following exenatide therapy; a “re-challenge” effect (relapse after discontinuation and improvement upon reintroduction) supports a possible association [87]. Similarly, the case of a 73-year-old patient with morbid obesity showed that semaglutide may represent an alternative therapeutic option even after the failure of biological therapy (adalimumab), leading to a PASI reduction of over 92% [88]. The molecular model of GLP-1RA action is based on precise intracellular regulation. These agents activate the cAMP/CREB pathway and stimulate AMPK kinase in the epidermis, leading to the suppression of critical inflammatory pathways, including NF-κB and the JAK2/STAT3 axis [84]. Inhibiting STAT3 phosphorylation may contribute to limiting the pathological hyperproliferation of keratinocytes and dampens their ability to recruit macrophages, effectively silencing psoriatic plaque activity [38,88]. A vital link in this response is the effect on iNKT cells. In psoriatic patients, the number of circulating iNKT cells is naturally diminished as they sequester in the skin. GLP-1RA therapy has been shown to increase circulating iNKT levels by nearly 38%, suggesting a migration from inflammatory tissues back into the systemic circulation [52,82]. It has even been hypothesized that the dramatic improvement of psoriasis following bariatric surgery is largely due to the postoperative spike in endogenous GLP-1 levels modulating these specific cells [87].

The drug’s target was confirmed by the detection of GLP-1R mRNA directly in biopsies of active psoriatic plaques, while it was absent in healthy skin [9]. This suggests that the primary therapeutic target within the skin is the immune infiltrate. Although a recent epidemiological analysis [89] indicated a rare 17% increase in the risk of de novo psoriasis (possibly due to gut microbiota modulation), systemic anti-inflammatory resolution- evidenced by falling levels of CRP, ferritin, and homocysteine- remains the dominant clinical outcome of therapy [80,86,89]. Despite the overwhelming evidence of therapeutic efficacy, the first case of paradoxical reaction recently appeared in the literature [90]. It concerns a 34-year-old female patient who experienced a sudden exacerbation of skin lesions only two weeks after starting liraglutide. The authors propose a “cytokine imbalance” hypothesis, suggesting that in rare individuals, the rapid inhibition of the IL-23/IL-17 axis may lead to a compensatory surge of interferon-alpha (IFN-α). While isolated, this report serves as a reminder of the need for individualized patient monitoring, particularly in those predisposed to volatile immune responses [90].

In conclusion, current evidence suggests that GLP-1RAs may represent a promising adjunctive approach in metabolic dermatology, particularly in patients with coexisting metabolic disorders. While available data indicate potential benefits in reducing psoriatic disease activity, improving DLQI, and modulating systemic inflammation, the overall level of clinical evidence remains limited and is largely based on case reports, small observational studies, and relatively short-term trials. Therefore, well-designed, large-scale randomized controlled studies are needed to confirm the magnitude, consistency, and long-term clinical relevance of these effects [5,9,15,38,49,52,82,83,84,85,86,87,88,90,91].

Table 1 summarizes the current clinical and mechanistic evidence regarding the use of GLP-1RAs in psoriasis. It includes data from clinical trials, cohort studies, and case reports, highlighting their effects on disease severity (PASI), DLQI, metabolic parameters, and key inflammatory pathways.

HS is a chronic inflammatory dermatosis in which pilosebaceous unit dysfunction plays a pivotal role in the underlying pathogenesis [93]. The condition is clinically characterized by the presence of painful nodules, abscesses, and fistulae, predominantly localized within intertriginous areas and regions abundant in apocrine glands, such as the axillae and inguinal folds [94]. This disorder exhibits a robust correlation with metabolic disturbances; an excess of adipose tissue triggers a decline in anti-inflammatory adiponectin levels while simultaneously serving as a primary source for the overproduction of pro-inflammatory adipokines and cytokines, including IL-1β, TNF- α, and IL-6 [94,95]. The systemic circulation of these mediators not only exacerbates the dermatological progression but also induces systemic IR and a proatherogenic state [93].

Considering these associations, GLP-1RAs are being increasingly considered as a potential adjunctive option to traditional therapeutic regimens, although a definitive characterization of their impact on HS remains limited and requires further investigation. Multicenter data and proof-of concept analyses suggest that the implementation of these agents may be associated with a clinical response in approximately 60–62% of patients, although these findings are derived primarily from observational data [93,95,96,97]. Particularly noteworthy are observations of patients who, despite no modification to their primary dermatological treatment, experienced a reduction in purulent discharge, fewer exacerbations, and substantial pain relief following the introduction of GLP-1 analogues (such as liraglutide or semaglutide). In the case of liraglutide, the mean Visual Analogue Scale (VAS) score for pain decreased from 5.6 to 3.2 [93]. Studies on this agent also recorded an improvement in Hurley staging, descending from a mean of 2.6 to 1.1, while observations of patients on semaglutide revealed a progressive decline in disease activity as measured by the HASI-R scale (from 11.34 to 7.45) [98] and the HS-PGA, particularly in moderate to severe cases [99]. These findings suggest a potential adjuvant benefit of this drug class, although confirmation in controlled studies is warranted.

The therapeutic benefit of GLP-1RAs in HS is likely multifactorial and extends beyond the secondary effects of weight loss. A critical aspect highlighted in recent reports is the direct influence of semaglutide on sebaceous gland function. The expression of GLP-1Rs within tissues associated with the pilosebaceous apparatus allows for the direct inhibition of lipogenesis and a reduction in sebum secretory activity [98]. Prospective studies have demonstrated that a 24-month course of semaglutide therapy leads to a significant decrease in sebumetry parameters, falling from 186.45 µg/cm² to 138.56 µg/cm² [98]. Concurrently, essential immunomodulation occurs via the NF-κB pathway, resulting in the suppression of key mediators such as IL-17, IL-22, IL-23 and TNF-α [99]. This process encompasses the dampening of the systemic inflammatory axis (indicated by reductions in hs-CRP, leukocytosis, and ESR) and the modulation of Toll-like receptors (TLRs), which may contribute to a diminished inflammatory response to the bacterial flora residing within hair follicles. Furthermore, the inhibition of matrix metalloproteinases (specifically MMP-9) may support cutaneous healing and tissue remodelling [93,95,99].

While a reduction in BMI mitigates mechanical epidermal maceration and the risk of the Koebner phenomenon, clinical evidence suggests that dermatological improvement can occur in some patients independently of significant weight loss. This is evidenced by favourable clinical outcomes observed even with low-dose oral semaglutide (3 mg daily) [99]. Nevertheless, retrospective analyses confirm that patients achieving the most substantial BMI reduction (averaging −6.2 kg) frequently exhibit superior clinical responses [96]. Furthermore, long-term administration of GLP-1RAs appears to function as a biologic-sparing therapy. Data indicate that patients exposed to semaglutide or tirzepatide have a 51% lower probability of requiring the initiation of advanced biologic agents, such as adalimumab or secukinumab [100].

The convergence of these metabolic and immunological mechanisms facilitates the interruption of the “therapeutic vicious cycle” characterized of HS. Conventional weight loss through physical exertion is often contraindicated in HS patients due to friction-induced pain and subsequent maceration within skin folds. The implementation of GLP-1RAs addresses these mechanical provocateurs while simultaneously providing systemic modulation of the immune response. Consequently, this therapeutic approach leads not only to the remission of cutaneous lesions but also to significant enhancements in psychological well-being, as evidenced by improved DLQI scores and mood stabilization measured by the Beck Depression Inventory (BDI) [93,96,98].

To comprehensively evaluate the real-world efficacy of GLP-1 analogues, objective clinical parameters must be supplemented by Patient-Reported Outcomes (PROs). A cross-sectional survey conducted at the University of Pennsylvania [97] provides pivotal evidence of high patient satisfaction regarding the integration of GLP-1RAs into established treatment regimens. Although agents such as semaglutide, tirzepatide, or liraglutide were primarily prescribed for weight management or glycaemic control, 68.2% of respondents reported a distinct and palpable improvement in their HS-specific skin condition [97]. These subjective patient perceptions align closely with objective clinical data: 61.9% of participants reported a significant decrease in the frequency of painful flares, while 66.7% noted a cessation in the formation of new inflammatory lesions. The impact on daily functioning was primarily manifested through the alleviation of chronic pain (52.4%) and the mitigation of highly stigmatizing symptoms, including purulent discharge (62%), persistent pruritus (47.6%), and the malodor associated with active fistulae (42.9%) [97]. Overall, nearly 60% of surveyed patients confirmed that GLP-1RA therapy substantially reduced the extent to which the disease dictated their social and life activities.

This improvement in quality of life may translate into a measurable reduction in the burden on the healthcare system. A detailed analysis of healthcare utilization conducted in Miami demonstrated that a one-year exposure to GLP-1 agonists results in a dramatic decline in the requirement for high-acuity care. Specifically, there was a reduction in the frequency of emergency department visits and hospitalization, falling from 11.9% to a mere 3.7%, whereas these metrics remained consistently elevated (approx. 18.8%) in the matched control group [101]. Crucially, investigators emphasize the necessity of rigorous metabolic vigilance. Within the HS population, often characterized by an advanced metabolic age and compromised body composition, the aggressive use of weight-reduction dosages carries an inherent risk of lean muscle mass depletion, or sarcopenia. Consequently, an integrated therapeutic model is advocated, wherein GLP-1RA pharmacotherapy is administered alongside optimized protein intake and resistance training. Such a multi-faceted approach maximizes dermatological benefits while simultaneously safeguarding the patient’s overall metabolic integrity [101].

The most compelling evidence supporting the disease-modifying potential of this drug class stems from large-scale population analyses utilizing the TriNetX network. A landmark study involving over 13,000 patients with a 10-year longitudinal perspective demonstrated that systemic GLP-1 agonist utilization correlates with a nearly 18% reduction in the requirement for invasive and traumatizing surgical interventions, such as incision and drainage (I&D) procedures (RR = 0.821) [102]. Furthermore, users of these agents required significantly fewer systemic antibiotic courses (mean 2.78 vs. 4.11 prescriptions) and exhibited a reduced reliance on analgesics (RR = 0.843). However, these findings are observational and should be interpreted with caution, as causality cannot be established. The same cohort also demonstrated lower mortality rates and reduced progression to severe disease stages [102].

In the context of health economics and treatment escalation, GLP-1RAs emerge as a highly effective “biologic-sparing therapy”. According to cohort analysis data [100], patients with obesity and HS receiving semaglutide or tirzepatide had 51% lower odds of requiring the initiation of costly TNF-α or IL-17 inhibitors compared to matched controls. The synergy of metabolic, immunomodulatory, and systemic benefits positions this pharmacological group as a cornerstone—albeit an underutilized one—of the modern, interdisciplinary paradigm for managing HS.

Despite the documented, pleiotropic impact of GLP-1RAs on reducing HS severity, current data highlight substantial barriers to the widespread clinical adoption of this modality. It is estimated that nearly 60% of patients with inflammatory skin disease meet the eligibility criteria for GLP-1 analogue therapy, with this figure reaching a peak of 72.3% within the HS population. Regrettably, a significant therapeutic gap persists in clinical practice: only 36.4% of eligible patients receive appropriate medical counselling, and a mere one in five (22.1%) is ultimately prescribed the medication [103]. This discrepancy is particularly concerning given the proven role of these agents in arresting cutaneous disease progression [95]. The fact that nearly 25% of patients requiring metabolic intervention remain under the exclusive care of dermatological clinics imposes a new clinical responsibility upon specialists in this field [103]. Proactive identification of indications for GLP-1RA therapy in the dermatological setting is not merely an obesity intervention; it represents a critical component of a holistic therapeutic strategy aimed at modifying the natural history of HS through the systemic attenuation of inflammation [93,95,99,103].

Table 2 presents a comprehensive summary of the existing data with regard to GLP-1RAs in the management of HS. The importance of this table lies in its ability to show the multifaceted effects of GLP-1RAs on dermatological parameters, as well as their effects on various aspects of the pathophysiology of HS.

AD is a chronic inflammatory disease of the skin characterized by periods of relapse and remission, persistent itching, typical lesion localization and early onset. Its pathogenesis involved complex interactions between genetically determined impairments in epidermal barrier structure and function, dysregulated immune and inflammatory responses, as well as infectious and environmental factors [104]. Despite a growing understanding of the pathogenesis of AD and increasing interest in the role of GLP-1RAs in inflammatory conditions, the current literature regarding their specific impact on AD remains sparse. To date, evidence is primarily limited to small cohort studies and individual case reports, and robust clinical data are lacking [102,105,106].

GLP-1RAs appear to exert a dual therapeutic effect, addressing both metabolic and immunological drivers of the disease. On a metabolic level, they significantly mitigate IR. Simultaneously, they modulate immune dysregulation by attenuating Th2 and Th-17-mediated inflammation, which are predominantly responsible for pruritus and erythema [107,108]. Molecular mechanisms underlying these effects include the inhibition of the NF-κB pathway, a reduction in reactive oxygen species (ROS) production, the promotion of Treg expansion, and a decrease in systemic pro-inflammatory cytokines such as IL-6 and TNF-α [108,109]. Furthermore, preliminary data suggest that GLP-1R activation on eosinophils may lead to downregulation of interleukin-4 (IL-4) and interleukin-13 (IL-13), cytokines that are typically elevated in AD patients. Consequently, these AD-related biomarkers may serve as predictors for the clinical efficacy of GLP-1RA therapy [105].

Importantly, treatment with GLP-1 analogues has been associated with changes in gut microbiota composition, including an increased abundance of bacteria producing short-chain fatty acids. This shift is associated with the activation of PPAR-γ and aryl hydrocarbon receptors, which in turn upregulates the expression of filaggrin and tight junction proteins, specifically claudin and occludin. These processes facilitate the restoration of the hydrolipid barrier and a subsequent reduction in transepidermal water loss (TEWL). Moreover, obesity—often the primary indication for initiating GLP-1RA treatment—is a known driver of intestinal permeability. This “leaky gut” allows LPS toxins to enter the bloodstream, thereby exacerbating AD symptoms. By improving intestinal barrier integrity, GLP-1RAs may help reduce systemic inflammation that triggers disease flares [108]. It is therefore vital to emphasize that obese patients with AD may derive benefits from GLP-1RA therapy that exceed those of standard biological treatments, as these agents address the metabolic underpinnings of the disease that conventional dermatological therapies fail to correct [105,107,108,109].

Research involving patients with Class I, II, III obesity indicates that improved glycaemic control, coupled with weight reduction, may decrease the necessity for both systemic and topical glucocorticosteroids, ultimately alleviating the clinical manifestations of AD [109].

Further evidence of this potential is found in a study of patients with chronic spontaneous urticaria (CSU). Following the introduction of GLP-1RA therapy, a rapid and significant decrease in urticarial activity was observed as early as the third week of treatment, occurring alongside weight loss and stabilized glucose levels. Remission was maintained even as standard CSU treatments were tapered [107]. This clinical observation supports the hypothesis that GLP-1 analogues may elevate the mast cell degranulation threshold while inhibiting NF-κB and TNF-α signalling pathways. Given that the restoration of the balance between pro- and anti-inflammatory responses is a fundamental therapeutic goal in both AD and CSU, it stands to reason that these agents could represent a highly effective adjunctive therapy for refractory AD in patients presenting with T2DM and/or metabolic disorders. However, extrapolation of CSU data to AD should be made with caution due to differences in pathophysiology.

Table 3 provides a summary of the clinical evidence for the use of GLP-1RAs in AD and related eosinophil- and mast cell-mediated skin diseases, including CSU. It incorporates large-scale cohort studies and case reports to highlight their effect on proxies of disease severity, cardiovascular risk factors, and symptom control. Furthermore, it also includes proposed immunomodulatory mechanisms of action for these drugs, such as the regulation of Th2 responses (IL-4, IL-13), NF-κB pathways, eosinophils, and mast cells, thereby highlighting the potential role of GLP-1RAs in type 2 inflammatory skin diseases.

Current clinical data regarding the relationship between GLP-1RAs and alopecia remain multifaceted and, at times, contradictory, largely depending on the specific clinical subtype. While some researchers report significant improvements in hair density [110,111,112] and a decreased reliance on conventional hair loss therapies [113], others express concern over a potential risk of hair loss following the initiation of GLP-1RA treatment [114,115,116,117]. Although a hypothesis regarding the risk of hair shedding linked to GLP-1 analogues has been proposed, emerging evidence suggests that the actual clinical significance of this phenomenon remains uncertain and may be less substantial than initially suggested [106].

Central Centrifugal Alopecia (CCCA) is a progressive, scarring form of permanent hair loss that typically originates at the vertex and expands peripherally. Predominantly affecting women of African descent, it is characterized by follicular fibrosis [118]. Interestingly, the severity of T2DM has been mechanistically linked to the pathogenesis of CCCA [110]. Optimal metabolic control, evidenced by a reduction in glycated hemoglobin (HbA1c) alongside standard CCCA treatments, has been associated with improved clinical outcomes. This synergy likely stems from a stabilized metabolic state, which attenuates the pro-inflammatory and fibrotic environment driving follicular destruction [110].

Folliculitis Decalvans (FD) represents another chronic inflammatory alopecia, marked by recurrent flares and scarring [119]. Its pathogenesis involves a complex interplay between immune dysregulation and microbial factors leading to chronic inflammation and irreversible hair loss. A notable case involves a male patient with refractory FD who was treated with tirzepatide while concurrently using topical clobetasol and crisaborole. Although previous topical therapies had proven ineffective, the introduction of tirzepatide led to a significant reduction in pain, exudate, and disease flares. Physical examination revealed a marked decrease in erythema and, crucially, visible hair regrowth- a finding particularly significant in scarring alopecia. During treatment, the patient achieved a weight loss of approximately 22.7 kg (50 lbs), which improved insulin sensitivity and suppressed the chronic inflammatory pathways involved in FD. Notably, tapering the tirzepatide dose led to a resurgence of FD symptoms, suggesting a possible association rather than confirming a direct causal effect [111]. Similarly, a case report of a patient with androgenetic alopecia (AGA) treated with tirzepatide documented a weight loss of 13.6 kg (30 lbs) accompanied by substantial hair thickening [112]. The authors suggest that enhanced insulin sensitivity may contribute to mitigating follicular miniaturization by improving microcirculation and potentially downregulating 5-α-reductase activity.

Despite these promising therapeutic observations, the literature also provides evidence of adverse hair loss events following treatment initiation [114,116]. Retrospective cohort studies utilizing the TriNetX database analysed patients diagnosed with telegenic effluvium (TE), anagen effluvium (AE), alopecia areata (AA), androgenetic alopecia (AGA), and other non-scarring hair loss (ONSH) patterns following semaglutide or tirzepatide use [114,116]. While TE and AE were diagnosed within one year of treatment, AA, AGA, and ONSH were frequently identified as early as six months. Researchers emphasized that BMI changes were relatively modest and comparable across groups, suggesting that these findings cannot be solely attributed to rapid or extreme weight loss [114].

Another TriNetX-based study focused on T2DM patients examined the risk of AGA following therapy with tirzepatide, liraglutide, dulaglutide, and semaglutide. All four agents were associated with an increased risk of AGA, with tirzepatide showing the highest correlation. The risk was progressively lower for semaglutide and dulaglutide, with liraglutide demonstrating the weakest association [116]. Paradoxically, tirzepatide was also linked to the most significant reductions in HbA1c and improvements in insulin sensitivity. This phenomenon has been hypothesized to be related to an increase in insulin-like growth factor-1 (IGF-1) levels, which can enhance androgen receptor activity and accelerate AGA progression. This suggests that rapid metabolic optimization may, in some cases, unmask a genetic predisposition to AGA. However, the risk associated with elevated IGF-1 must be balanced against the systemic benefits of reduced chronic inflammation resulting from improved insulin sensitivity [116].

Data also indicate a significant correlation between hair loss and the diagnosis of T2DM itself. Reports of hair loss were more frequent among patients using GLP-1 analogues for T2DM management compared to those using the same medications solely for weight reduction [115]. This supports the hypothesis that the chronic inflammation and vascular microdamage associated with diabetes serve as predisposing factors for hair loss, which could be influenced by metabolic changes during therapy. Furthermore, the T2DM demographic is generally older, a factor naturally associated with physiological hair thinning and reduced follicular reserve. Consequently, while reporting rates are higher, they do not necessarily exceed statistical expectations or imply a direct toxic effect of the drug on the hair follicle. Instead, this evidence suggests that hair loss may be secondary to metabolic shifts and weight reduction rather than a direct pharmacological effect, although causality cannot be definitively established.

A pronounced female predominance in reporting is also evident, likely due to a higher sensitivity of the female hormonal profile to rapid metabolic changes [120], as well as a greater propensity among women to report adverse dermatological effects (reporting bias) [121].

In conclusion, while current findings are encouraging, most available data are derived from isolated case reports and retrospective database analyses. The overall level of evidence remains limited, and there is a need for longitudinal observation and prospective clinical trials that account for gender differences and specific alopecia phenotypes to further clarify the role of GLP-1RAs in hair disorders.

Table 4 shows an overview of the available literature on the use of GLP-1RAs for hair disorders, including favourable and adverse effects of the therapy on different subtypes of alopecia. It has been compiled by incorporating real-life data, pharmacovigilance studies, and case-based experiences of the therapy by considering the intricate relationship between metabolism, hormonal balance, and pro-inflammatory pathways influencing the therapeutic effects of the therapy.

Current evidence on the use of GLP-1 analogues in skin conditions, including psoriasis, HS, AD, and alopecia, is limited by several methodological constraints. Most studies involved relatively small sample sizes, often encompassing only a few patients or small cohorts (n = 3–24 for psoriasis [9,15,26,52,82,85,87,91], n = 5–20 for HS [21,22,23,24,25,26,27,28,29,30], n = 2–10 for AD [105,109], n = 1–10 for alopecia [106,110,111,112,113,114,115,116,117]), which restricts the generalizability of the results.

A substantial number of studies lacked control groups or randomization. Many were conducted as open-label, retrospective, or single-arm investigations, limiting casual inference and the ability to account for placebo effects [49,86,87,91,92,93,95,96,98,103,106,110,111,112,113,114,115,116,117]. Furthermore, research conducted at single centres may not fully capture the variability present in larger, more diverse patient populations [93,97,99,100,101,102,103,105].

The follow-up periods were often short, ranging from a few weeks to several months, which hampers the assessment of long-term durability of treatment effects and safety in chronic or relapsing disorders [26,52,82,85,95,101,102,112,114]. Many studies also lacked standardized clinical measures and objective markers of disease severity. Instead, outcomes frequently relied on patient-reported assessments, retrospective PASI, Hurley, or EASI scores, diagnostic coding, medical record reviews, prescriptions, or unverified sources [9,26,38,81,87,100,103,105,106,109,110,114,115,117].

Additional limitations included the absence of biological data (e.g., cytokine levels, GLP-1, HbA1c), lack of control over concomitant therapies, inter-center variability, and potential confounding factors such as diet, physical activity, or stress [38,84,92,95,96,106,110,111,112,114,115,116]. In vitro studies, where applied did not always replicate the complex cellular interactions occurring in vivo, and drug concentrations used in laboratory experiments may not correspond to clinically achievable levels [38]. For studies on alopecia, evaluating treatment effects was particularly challenging due to the absence of trichoscopic or clinical assessments of hair loss severity, sex-specific differences in pathophysiology, and potential confounding effects of weight loss [106,110,111,112,113,114,115,116,117].

In summary, while preliminary findings suggest possible therapeutic benefits of GLP-1 analogues in skin disease, the current evidence base remains limited, and there is a need for larger, prospective, RCTs conducted across multiple centers. Such studies should include appropriate control groups, standardized clinical and biomarker assessments, and longer follow-up periods to more accurately evaluate both the efficacy and safety of these therapies.