Beyond safety: adverse events and unanticipated advantages of SGLT2 inhibitors

Abstract

Background: Sodium-glucose transporter 2 inhibitors (SGLT2i) are widely used for diabetes management and have demonstrated benefits in treating acute and chronic heart failure (HF) and chronic kidney disease (CKD). Their increasing application has revealed various side effects, although only a few are currently recognized as drug-related adverse events, based on ongoing observations. Aims: This review synthesizes positive and negative side effects linked to SGLT2i and proposes management strategies. Methods: A literature search of PubMed/EMBASE, Web of Science, and Google Scholar from the past 10 years identified randomized trials, meta-analyses, observational cohorts, and pharmacovigilance studies reporting SGLT2i-related events across genitourinary, endocrine, metabolic, hematologic, skeletal, and vascular domains. Results: Data indicate an increased incidence of genital infections (GIs) in diabetic subjects, while associations with urinary tract infections (UTIs) are less consistent. Non-diabetic HF/CKD patients show modest increases in GIs and UTIs. SGLT2i modestly increase hematocrit and may reveal clonal erythrocytosis. Rare conditions like Fournier’s gangrene have been reported, though without a clearly increased risk in clinical trials: all the reported cases led to drug discontinuation. There is no conclusive evidence linking SGLT2i to fractures or osteoporosis, and risk of lower-limb amputation appears comparable to DPP-4 inhibitors, with some trend compared to GLP-1 receptor agonists, suggesting caution in patients with peripheral artery disease. Observational data suggest SGLT2i may protect against syncope and reduce acute kidney injury. Conclusions: Overall, SGLT2i are safe, with manageable adverse events such as GIs and UTIs. A thorough understanding of potential complications is essential for clinicians to optimize patients’ management.