Evaluating the Impact of SGLT-2 Inhibitors on Frailty in Older Adults: A Clinical Review

Background: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, including empagliflozin, canagliflozin, and dapagliflozin, have demonstrated significant cardiovascular and renal benefits in managing type 2 diabetes mellitus (T2DM). However, their impact on frailty in older adults remains a subject of debate, given their associations with weight loss, fluid depletion, and potential reductions in muscle mass, which could contribute to sarcopenia and frailty-related complications. Objectives: This narrative review evaluates the effects of SGLT-2 inhibitors on frailty in older adults with T2DM by analyzing their influence on body composition, muscle mass, and overall functional status. It further examines the balance between their benefits and risks in frail populations, emphasizing the need for appropriate patient selection and monitoring strategies. Methods: A comprehensive review of systematic reviews, meta-analyses, randomized controlled trials (RCTs), and real-world observational studies was conducted. Data were obtained from major medical databases, including PubMed, Embase, Cochrane Library, and Web of Science. Studies focusing on body composition changes, cardiovascular outcomes, frailty-related events, and mortality in older adults using SGLT-2 inhibitors were analyzed. Results: Findings indicate that SGLT-2 inhibitors significantly reduce body weight, visceral fat, and cardiovascular events while preserving renal function. However, multiple studies report reductions in lean body mass and skeletal muscle index, raising concerns about sarcopenia, particularly in frail individuals. Meta-analyses of RCTs reveal that SGLT-2 inhibitors may decrease skeletal muscle mass while promoting lipolysis and gluconeogenesis, potentially exacerbating frailty in high-risk populations. Despite these concerns, retrospective cohort studies and real-world evidence suggest that SGLT-2 inhibitors are associated with lower mortality and reduced frailty-related events in individuals with T2DM and heart failure. Comparative studies highlight that SGLT-2 inhibitors provide superior cardiovascular protection over dipeptidyl peptidase-4 inhibitors (DPP- 4is) and comparable benefits to glucagon-like peptide-1 receptor agonists (GLP-1RAs), albeit with an increased risk of DKA and genital infections. Conclusion: While SGLT-2 inhibitors offer significant cardiometabolic and renal benefits, their effects on muscle mass and frailty warrant further investigation. Individualized treatment approaches— including nutritional support, exercise interventions, and close monitoring—are essential to mitigate potential risks in frail older adults. Updated clinical guidelines should address the appropriate use of SGLT-2 inhibitors in frail populations, considering both their benefits and risks. Future research should focus on elucidating the biological mechanisms underlying the relationship between SGLT-2 inhibitors and frailty, as well as developing strategies to prevent muscle loss in at-risk individuals.