Safety and Tolerability of SGLT2 Inhibitors

The advent of sodium-glucose co-transporter (SGLT) inhibitors - including selective SGLT2 and dual SGLT1/2 agents - has redefined cardiorenometabolic therapy, markedly reducing cardiovascular events, heart failure hospitalizations, and kidney disease progression in patients with and without diabetes. Despite their robust and well-documented benefits, uptake is sometimes limited in specific patient groups, often reflecting concerns about adverse effects. Traditionally reported risks - including hypoglycemia, euglycemic diabetic ketoacidosis, volume depletion, acute kidney injury, genital and urinary tract infections, bone fractures, and lower limb amputations - exhibit heterogeneous clinical relevance; some are not consistently reproduced or are of uncertain clinical significance, whereas others are rare but clinically meaningful and modulated by patient phenotype, comorbidities, and concomitant therapies. Drawing on large cardiovascular and renal outcome trials, supplemented by real-world evidence, which provide estimates of both absolute and relative risks, this chapter offers an evidence-based framework to anticipate, recognize, and mitigate complications, supporting the safe and effective integration of SGLT inhibitors across diverse clinical populations.