The ketogenic diet (KD) has emerged as a widely adopted metabolic intervention for weight loss, glycemic control, and management of metabolic syndrome. In clinical practice, KD is frequently associated with improvements in insulin resistance, triglyceride levels, and body weight. However, a subset of individuals develops marked elevations in low-density lipoprotein cholesterol (LDL-C), sometimes exceeding traditional high-risk thresholds, raising concerns regarding its potential impact on atherosclerotic cardiovascular disease (ASCVD).

This paradox has led to renewed interest in the heterogeneity of lipid responses to carbohydrate restriction. Notably, the lean mass hyper-responder (LMHR) phenotype—characterized by elevated LDL-C, high high-density lipoprotein cholesterol (HDL-C), and low triglycerides—illustrates that KD does not uniformly induce hypercholesterolemia. These observations challenge the conventional lipid-centric model and suggest that metabolic context, genetic predisposition, and dietary composition play critical roles in modulating cardiovascular risk. Importantly, animal-based fats are not equivalent to saturated fatty acids, and saturated fat intake alone does not necessarily translate directly into atherosclerotic disease.
In parallel, emerging evidence highlights the role of ketone metabolism in cardiac energetics. In heart failure with reduced ejection fraction (HFrEF), the failing myocardium demonstrates increased reliance on ketone bodies as an efficient energy substrate. Clinical studies have shown that β-hydroxybutyrate infusion can improve cardiac output and myocardial perfusion. Furthermore, the benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) may be partially mediated through enhanced ketone availability and utilization.
Recent updates in U.S. dietary policy have also acknowledged the limitations of long-standing low-fat, high-carbohydrate recommendations, which have not effectively curbed the rising prevalence of metabolic syndrome. Collectively, these findings suggest that the relationship between KD and cardiovascular risk extends beyond LDL-C alone and reflects a complex interplay between lipid metabolism, energy metabolism, and individual variability. A precision medicine approach is therefore essential for individualized risk assessment and clinical decision-making.