For millions of adults managing cardiovascular disease, heart failure, or chronic kidney disease alongside diabetes, SGLT2 inhibitors have become cornerstone therapy — yet a poorly understood metabolic complication continues to limit their broader adoption. Understanding when this risk is real versus overstated may determine whether patients receive a drug class with documented mortality benefits.
This narrative review, drawing on randomized controlled trials, retrospective studies, systematic reviews, and meta-analyses published between 2014 and 2024 across PubMed, Web of Science, and Scopus, examines the full risk-benefit profile of sodium-glucose co-transporter 2 (SGLT2) inhibitors. Originally approved as glucose-lowering agents, these drugs have since demonstrated cardio-renal protective effects independent of glycemic control — earning first-line status in clinical guidelines for patients with established cardiovascular disease, heart failure with reduced or preserved ejection fraction, and chronic kidney disease. The review then focuses specifically on euglycemic diabetic ketoacidosis (EDKA), a paradoxical and potentially life-threatening condition in which ketoacidosis develops despite near-normal blood glucose levels — a presentation that routinely delays diagnosis and appropriate treatment.
The SGLT2 inhibitor class — including empagliflozin, dapagliflozin, and canagliflozin — has accumulated some of the strongest cardiovascular outcome trial data in pharmacology over the past decade, with landmark trials such as EMPA-REG OUTCOME, DAPA-HF, and CREDENCE establishing survival and hospitalization benefits. EDKA, while real, appears to cluster around identifiable precipitating factors: prolonged fasting, surgical procedures, low-carbohydrate diets, insulin omission, and alcohol use. The contradictory prevalence data the review highlights reflects genuine methodological inconsistency across studies, not necessarily true biological variability. From a population-level standpoint, the net benefit calculation almost certainly favors SGLT2 inhibitor use in high-risk patients when clinicians are equipped to recognize EDKA's atypical presentation. The review's primary contribution is framing EDKA as a manageable, trigger-dependent risk rather than an inherent class liability — a reframing that could meaningfully reduce prescribing hesitancy.