Cumulative LDL-C exposure strongly influences cardiovascular risk more than later-life levels

Cardiovascular prevention has traditionally focused on achieving progressively lower low-density lipoprotein cholesterol (LDL-C) targets, particularly in individuals classified as high risk. However, accumulating evidence from epidemiological, genetic and clinical studies suggests that cardiovascular risk is strongly influenced by cumulative lifetime exposure to LDL-C rather than by isolated LDL-C levels achieved later in life. From an endocrine perspective, LDL-C should be viewed as a chronic metabolic exposure whose pathogenic impact depends not only on its intensity, but also on its duration over time. This Perspective integrates evidence from longitudinal cohort studies, familial hypercholesterolaemia and Mendelian randomisation analyses, and contrasts current lipid management paradigms with preventive strategies routinely applied to other endocrine–metabolic disorders. While contemporary guidelines recognise the causal role of LDL-C and increasingly acknowledge lifetime risk, this recognition is not always fully translated into operational criteria for early intervention, particularly in younger adults. Within this context, earlier approaches aimed at limiting cumulative LDL-C exposure may offer additional long-term benefit, especially in individuals with long life expectancy. This Perspective, grounded in an endocrine framework, is intended to complement, rather than replace, current guideline-based strategies by highlighting the potential value of incorporating cumulative exposure into preventive decision-making.