Sodium-Glucose Cotransporter-2 Inhibitors Across the Glycemic Spectrum: Cardiovascular and Renal Outcomes With Mechanistic Insights

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were initially developed as glucose-lowering agents for type 2 diabetes mellitus (T2DM) by reducing proximal tubular glucose reabsorption and promoting glucosuria. Subsequent cardiovascular and renal outcome trials established that these agents provide clinically meaningful benefits that extend beyond glycemic control, including reductions in heart failure (HF) events and slowing of chronic kidney disease (CKD) progression in patients with and without diabetes. We conducted a narrative literature review using PubMed and Google Scholar to identify English-language studies published between January 2019 and December 2025 evaluating SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin) across cardiovascular and renal outcomes. Eligible evidence included randomized controlled trials, large observational studies, systematic reviews/meta-analyses, guidelines, post‑hoc exploratory analyses, secondary analyses, and mechanistic/preclinical studies. Mechanistic data support benefits through natriuresis and osmotic diuresis with favorable ventricular loading, restoration of tubuloglomerular feedback and reduced intraglomerular pressure, improved myocardial energetics, and attenuation of oxidative stress and inflammation. Clinically, SGLT2 inhibitors consistently reduce HF hospitalizations and composite cardiorenal endpoints in diabetic and non-diabetic populations across CKD stages studied and heart conditions, with a generally favorable safety profile; genital mycotic infections are most common, while diabetic ketoacidosis and volume depletion are uncommon with appropriate patient selection and counselling. Evidence gaps remain for stage 5 CKD and dialysis populations and for defining outcomes in lower-risk post-myocardial infarction cohorts. Overall, current data support SGLT2 inhibitors as foundational therapy for eligible patients with HF and/or CKD irrespective of diabetes status.