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.

Atherosclerosis is a complex, multifactorial disease that progresses through distinct stages: initiation, progression, and complication, ultimately leading to acute coronary syndromes (ACS). Endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and macrophages are central players in this process, influencing plaque stability and vulnerability. Insulin-Like Growth Factor 1 (IGF-1), soluble-Klotho (S-Klotho), and the Growth Hormone Receptor exon 3 deletion polymorphism (GHRd3) have emerged as key modulators of vascular health, impacting these cellular components through various mechanisms. IGF-1 supports endothelial function, enhances VSMC survival and migration, and mitigates inflammation by inhibiting macrophage recruitment and activation, ultimately reducing the risk of plaque destabilization. S-Klotho, an anti-aging protein with potent anti-inflammatory and antioxidant properties, has been linked to vascular protection, with its deficiency associated with endothelial dysfunction, vascular calcification, and impaired VSMC survival. Evidence suggests that IGF-1 may enhance Klotho shedding, indicating a potential synergistic role in maintaining vascular integrity. This narrative review aims to outline the fundamental stages of atherosclerosis progression, consolidate current evidence on the roles of IGF-1 and S-Klotho in modulating key cellular components of atherosclerosis, and shed light on their potential involvement in plaque healing—an area that remains largely unexplored. By integrating established molecular mechanisms, we explore how these factors may contribute to endothelial integrity, VSMC survival, and macrophage activation and polarization, potentially shaping a more stable plaque phenotype and influencing future therapeutic strategies in cardiovascular disease.