HDL Functionality, CETP Inhibitors, and Exercise Training: Where are We?

Exercise training is well established as an effective strategy to increase high-density lipoprotein cholesterol (HDL-C) concentrations, especially in people with high triglycerides and excess visceral adiposity, and is consistently associated with a lower risk of cardiovascular disease (CVD). However, the traditional stratification of CVD risk based solely on HDL-C levels has been increasingly challenged by evidence highlighting the importance of assessing HDL particle functionality rather than HDL-C levels alone. This paradigm shift gained particular attention following clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, in which substantial pharmacologically mediated increases in HDL-C failed to translate into improved cardiovascular outcomes. CETP inhibitor trials reported marked elevations in HDL-C, ranging from approximately 31% to 133%, whereas exercise training typically induces a much more modest increase, on the order of 2% to 5%.^– Despite these quantitative differences, both interventions have been shown to enhance aspects of HDL functionality. In exercise-based interventions, increases in HDL-C are accompanied by improvements in HDL-mediated cholesterol uptake, commonly assessed by cholesterol efflux capacity (CEC), a metric that more accurately reflects reverse cholesterol transport and CVD risk than HDL-C concentration alone.^– Mechanistically, CETP inhibition also enhances HDL cholesterol efflux capacity, indicating that pharmacologically enlarged HDL particles may retain functional properties. Nevertheless, adverse off-target effects and the artificial modulation of lipoprotein metabolism may partly explain the neutral or unfavorable cardiovascular outcomes observed in several CETP inhibitor trials.^,, Together, these findings underscore that, although both exercise training and CETP inhibition substantially increase circulating HDL-C, the biological context, qualitative effects on HDL particles, and clinical implications differ fundamentally between these interventions, reinforcing the need to move beyond HDL-C quantity when evaluating cardiovascular risk and therapeutic strategies.

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