A quarter-century of progress: innovations in lipid medicine that transformed cardiovascular prevention

This TimeCapsule reviews the major transformations in lipid metabolism and cardiovascular disease prevention during the first quarter of the 21st century and their impact on clinical practice. From late 20^th century paradigms to current state-of-the-art strategies, the field has consolidated statins as foundational therapy while establishing the clinical benefit of non-statin agents and introducing biological therapies into cardiovascular disease prevention. These developments support the paradigm that lowering LDL-cholesterol levels earlier and sustaining this over time translates to greater reductions in cardiovascular risk. More recently, RNA-targeted and DNA-targeted approaches have enabled the modulation of proteins, such as PCSK9, lipoprotein(a), apolipoprotein C-III, and ANGPTL3. The traditional concept of HDL-cholesterol being considered a good cholesterol has been challenged, whereas the causal relevance of lipoprotein(a) has gained recognition. New metrics-including non-HDL-cholesterol, apolipoprotein B, triglyceride-rich remnants, or remnant cholesterol-are increasingly integrated into residual risk assessment. A growing sex-specific perspective has refined cardiovascular research and care. Despite robust evidence, the proportion of patients meeting their recommended targets remains unacceptably low. Implementation science seeks to address this persistent evidence-practice gap. In parallel, artificial intelligence is reshaping scientific methodologies and is poised to transform the understanding and management of lipid-related cardiometabolic disease.