Abstract

Type 2 diabetes mellitus (T2DM) is a major driver of cardiovascular and renal morbidity worldwide. Despite 
advances in glucose-lowering therapies, patients remained at elevated risk for chronic kidney disease (CKD) and 
cardiovascular events, underscoring the need for therapeutic agents that provide benefits beyond glycemic control. 
Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have emerged as disease-modifying agents with renoprotective 
and cardioprotective properties. This review critically evaluated the clinical and mechanistic evidence for SGLT2 
inhibitors in renal protection and cardiovascular outcomes in T2DM. This review synthesized peer-reviewed studies 
from PubMed, Scopus, and Web of Science databases, focusing on preclinical, pharmacokinetic, and randomized 
clinical trial reports published between 2010 and 2025. Large cardiovascular outcome trials such as EMPA-REG 
OUTCOME, CANVAS, DECLARE-TIMI 58, and DAPA-CKD consistently demonstrated significant reductions in 
major adverse cardiovascular events (MACE), hospitalization for heart failure, and progression of kidney disease 
with SGLT2i therapy. Empagliflozin reduced cardiovascular mortality by 38%, while dapagliflozin reduced CKD 
progression risk by 39%. Proposed mechanisms include improved tubuloglomerular feedback, reduced 
intraglomerular pressure, osmotic diuresis, natriuresis, and modulation of inflammatory pathways. Pharmacokinetic 
profiles revealed rapid absorption (tmax 1–2 hours) and half-lives supporting once-daily dosing. Safety profiles were 
favorable, though genital infections and rare diabetic ketoacidosis require monitoring. SGLT2 inhibitors provided 
robust renal and cardiovascular protection in T2DM, shifting treatment paradigms toward cardiorenal risk 
reduction. Future directions emphasized precision medicine, combination therapy, and expanded indications in non
diabetic kidney and heart disease.