Abstract

Type 2 diabetes mellitus affects over 537 million adults globally and represents the leading cause of cardiovascular 
morbidity and mortality, with diabetic patients experiencing a 2- to 4-fold increased risk of major adverse 
cardiovascular events compared to non-diabetic populations. This narrative review compared the cardiovascular 
protective mechanisms and clinical efficacy of sodium-glucose cotransporter-2 (SGLT2) inhibitors versus metformin 
in type 2 diabetes management. A comprehensive literature search was conducted across PubMed, Embase, and Web 
of Science databases from 2008 to 2024, focusing on cardiovascular outcome trials, mechanistic studies, and 
comparative effectiveness research. SGLT2 inhibitors demonstrated superior cardiovascular protection through 
multiple mechanisms, including osmotic diuresis, cardiac energy metabolism optimization, and direct myocardial 
protective effects, with major trials showing a 13-17% reduction in cardiovascular death compared to placebo. 
Metformin provided cardiovascular benefits primarily through AMP-activated protein kinase activation and 
improved insulin sensitivity, though evidence derives predominantly from observational studies rather than 
dedicated cardiovascular outcome trials. Head-to-head comparisons revealed that SGLT2 inhibitors confer greater 
cardiovascular risk reduction, particularly for heart failure hospitalization (35-39% reduction) and cardiovascular 
mortality, while metformin demonstrates superior glycemic control and metabolic benefits. Both drug classes 
exhibited complementary mechanisms that support combination therapy approaches. The evidence strongly 
supported SGLT2 inhibitors as first-line therapy for diabetic patients with established cardiovascular disease or high 
cardiovascular risk, while metformin remains optimal for metabolic control in lower-risk populations.