Sodium-Glucose Cotransporter-2 Inhibitors and Cutaneous Adverse Reactions: A Systematic Review of Clinical Phenotypes, Time-to- Onset Profiles, and Management Strategies (2020–2026)

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are widely prescribed for type 2 diabetes mellitus, cardiovascular protection, and renal outcomes. However, accumulating real-world and clinical trial data have identified a diverse spectrum of cutaneous adverse reactions (CARs) associated with their use. The clinical phenotypes range from mild pruritus and maculopapular eruptions to severe bullous pemphigoid (BP), Fournier's gangrene (FG), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Despite increasing recognition, systematic characterization of SGLT2i-induced CARs with respect to phenotype-specific time-to-onset profiles and evidence-based management strategies remains limited. This systematic review was conducted following PRISMA 2020 guidelines. PubMed, EMBASE, Scopus, and Google Scholar were searched from January 1, 2020, to January 31, 2026. Studies reporting SGLT2i-associated CARs in patients with type 2 diabetes were included. Eligibility followed the PICOS framework: patients receiving SGLT2i, any cutaneous adverse reaction, comparison with other antidiabetic agents or placebo, and outcomes including phenotype, time-to-onset, management, and resolution. Two reviewers independently performed study selection, data extraction, and risk of bias assessment using Cochrane RoB 2 for randomized controlled trials (RCTs), the Newcastle-Ottawa Scale for cohort studies, and JBI checklists for case series. Narrative synthesis was performed due to clinical heterogeneity precluding meta-analysis. Of 847 records screened, 42 studies met inclusion criteria, comprising 9 RCTs, 11 cohort studies, and 22 case series/reports, encompassing 18,432 patients. Mild-to-moderate CARs (pruritus, maculopapular rash, urticaria, eczema) were the most frequently reported, with onset typically within days to weeks of drug initiation, and resolved with topical corticosteroids or antihistamines without SGLT2i discontinuation in most cases. Bullous pemphigoid was the most frequently reported severe phenotype, with a delayed onset of several months to years following SGLT2i exposure. Management typically required SGLT2i withdrawal and immunomodulatory therapy including topical or systemic corticosteroids, and doxycycline with niacinamide. Fournier's gangrene was reported with a median time-to-onset of approximately 8 months and a mortality rate of 11.8%, requiring surgical debridement and intravenous antibiotics. SJS and TEN were reported with a median onset of approximately 18 days, requiring intensive care, intravenous immunoglobulin, and corticosteroids, with high mortality. Risk of bias was low for RCTs and good-to-excellent for cohort studies. SGLT2i-induced cutaneous adverse reactions encompass a broad phenotypic spectrum with distinct time-to-onset profiles: early-onset (days to weeks) mild reactions amenable to symptomatic management, and delayed-onset (months) immune-mediated bullous pemphigoid requiring drug withdrawal and targeted therapy. Rare but severe emergencies, including Fournier's gangrene and SJS/TEN, mandate prompt recognition and multidisciplinary intervention. Clinicians should maintain vigilance for cutaneous events throughout SGLT2i therapy, with phenotype-guided management strategies. Prospective pharmacovigilance and mechanistic studies are warranted to refine risk stratification.