Are we underestimating the benefits of lipid-lowering therapies?

Cardiovascular disease remains the leading cause of morbidity and mortality worldwide, with elevated low-density lipoprotein cholesterol (LDL-C) recognized as a causal factor and the primary target for the prevention of atherosclerotic cardiovascular disease (ASCVD). Currently available lipid-lowering agents, including statins, ezetimibe, bempedoic acid, and proprotein convertase subtilisin/kexin type 9 inhibitors, can significantly reduce the risk of cardiovascular events across a broad range of patient populations. New oral therapies with novel mechanisms of action and potentially lower costs compared with biologics (including oral proprotein convertase subtilisin/kexin type 9 inhibitors and a new cholesteryl ester transfer protein inhibitor) are under investigation to expand the armamentarium of lipid-lowering drugs and increase the number of patients who can be treated if they prove clinically beneficial. To fully understand the potential health benefits of lipid-lowering therapies, it is essential to consider the concept of cumulative LDL-C exposure and its lifelong impact on ASCVD risk. Genetic studies, Mendelian randomization, and clinical trials consistently demonstrate the cardiovascular benefits of early reduction in LDL-C. However, despite this evidence, treatment gaps, inadequate prescribing, and suboptimal treatment adherence are widespread. The cost-benefit ratio and public health impact emphasize the potential of LDL-C lowering to prevent cardiovascular events and reduce the health care burden. In addition to LDL-C, other risk factors such as lipoprotein(a), triglyceride-rich lipoproteins, and apolipoprotein B must be considered, whereas nonlipid-based mechanisms of atheroprotection, such as inflammation modulation and thrombogenic risk reduction, are also being explored. The future of lipid-lowering and ASCVD prevention requires a more individualized lipid management strategy to optimize cardiovascular outcomes across the lifespan. SIGNIFICANCE STATEMENT: Early and sustained low-density lipoprotein cholesterol reduction dramatically reduces lifelong cardiovascular risk; however, the adoption of lipid-lowering strategies in clinical practice remains suboptimal. Bridging this gap by understanding the true potential of lipid-lowering therapies could significantly reduce the global burden of atherosclerotic disease.