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Cardiovascular disease (CVD) has long been the leading cause of death globally, often accompanied by comorbidities like obesity, abnormal lipid profiles, and insulin resistance. Insulin, a key regulator of cellular metabolism, is impaired in insulin resistance, characterized by defects in glucose uptake, oxidation, and glycogen synthesis, with a lesser effect on lipid oxidation. While free fatty acids are the primary substrate for ATP production in the myocardium, other substrates, such as glucose and lactate, can also be used. Insulin resistance induces metabolic alterations that contribute to CVD, including chronic hyperglycemia, oxidative stress, and inflammation. Additionally, insulin resistance disrupts lipid metabolism, leading to dyslipidemia and the lipid triad: elevated plasma triglycerides, low HDL, and small dense LDL, which together, along with endothelial dysfunction, promote atherosclerotic plaque formation. Insulin resistance in the myocardium generates damage through three mechanisms: altered signal transduction, impaired substrate metabolism regulation, and disrupted substrate delivery to the heart. This review aims to explore the mechanisms linking insulin resistance to CVD, highlighting the potential for therapies targeting insulin resistance to reduce CVD and atherosclerotic plaque formation.