AMP-activated protein kinase (AMPK) is a central regulator of cellular energy homeostasis, activated in response to increased AMP/ATP ratios during metabolic stress. Its activation has been extensively studied in the context of cardiovascular disease (CVD), and there is strong preclinical and growing clinical evidence supporting its therapeutic potential. AMPK activation promotes beneficial effects on heart and vascular function by enhancing glucose uptake, fatty acid oxidation, and mitochondrial biogenesis, while inhibiting cholesterol and lipid synthesis. These metabolic adaptations are particularly important in the ischemic heart, where energy supply is compromised.

Animal studies have shown that pharmacological activation of AMPK reduces atherosclerotic plaque formation, improves endothelial function, and protects against cardiac hypertrophy and heart failure. Furthermore, several commonly used cardiovascular drugs, such as metformin and statins, exert part of their beneficial effects through AMPK activation. Early-phase clinical trials and observational studies in humans have demonstrated that AMPK activators can improve metabolic risk factors associated with CVD, such as insulin resistance, dyslipidemia, and inflammation.

However, while the mechanistic rationale and preclinical data are robust, large-scale randomized controlled trials specifically targeting AMPK for CVD outcomes are still limited. Therefore, the current evidence rates as a 4: there is solid scientific support and translational promise, but definitive clinical validation is ongoing.