SGLT2 Inhibitors After Myocardial Infarction: Evidence, Mechanisms and Gaps in Knowledge

Sodium–glucose cotransporter 2 inhibitors (SGLT2is) have revolutionized the treatment of heart failure and are now established as disease-modifying therapies across the spectrum of left ventricular ejection fraction. More recently, these agents have been evaluated in the early post-acute myocardial infarction (AMI) setting, raising interest in their potential role beyond heart failure prevention. Evidence from post-AMI randomized trials and contemporary meta-analyses consistently shows neutral effects on ischemic coronary outcomes, despite favorable effects on heart failure-related endpoints, ventricular remodeling, and cardiometabolic parameters. At the same time, data from experimental and translational research provide a biological framework in which SGLT2i exert anti-atherogenic effects through multiple complementary mechanisms, including improvement of cardiometabolic risk factors, attenuation of vascular and systemic inflammation, modulation of endothelial function, regulation of vascular smooth muscle cell behavior, macrophage inflammatory polarization, inhibition of inflammasome signaling, and modulation of the perivascular adipose tissue–vascular interface. Taken together, the available evidence highlights a dissociation between clinical trial outcomes in the early post-AMI phase and the underlying vascular biology associated with SGLT2 inhibition. While the dominant early clinical effects of SGLT2i appear to relate to hemodynamic and heart failure-preventive mechanisms, their potential impact on atherosclerotic disease may be more gradual and context-dependent. This review summarizes current clinical and mechanistic evidence supporting this interpretation and discusses the implications for understanding the role of SGLT2i in patients after AMI.