Low-density lipoprotein cholesterol and cardiovascular risk: a necessary causal agent but an insufficient predictor.

Atherosclerosis, the primary underlying cause of cardiovascular morbidity and mortality, is a complex disease of multifactorial aetiology that starts early in life and in which plaque accumulates in the subintimal area of the arterial wall. Atherosclerosis naturally slowly develops unnoticed for many years until clinical complications arise, usually within decades. Dependent on the atherosclerotic burden and specific intercurrent systemic conditions, such as consistent hyperinflammatory state, an atherosclerotic-related complication may arise, usually preceded by plaque rupture or erosion. Therefore, cardiovascular prevention strategies primarily focus on the early recognition and treatment of populations at risk for accelerated atherosclerosis and atherosclerosis-related complications. Low-density lipoprotein cholesterol (LDL-c) plays a pivotal role in the process of atherogenesis. The causal association between increased LDL-c levels and the development of clinically significant atherosclerosis is firmly based and repeatedly exampled in largescaled Mendelian randomized studies and randomized clinical studies. While evidence of LDL-c reduction in secondary prevention settings in patients with diagnosed atherosclerosis is compelling, the timing and cut-offs dictating LDL-c reduction in primary prevention settings remain disputable, especially in patients older than 75 years of age. Significant atherosclerosis is an essential infrastructure for cardiovascular disease, but it is not sufficient for a clinical event to occur, and atherosclerotic complications usually arise from provocation plaque-destabilizing situations, such as hyperinflammation. The current European Society of Cardiology guidelines recommends utilizing the SCORE risk stratification model along with specific background conditions, such as diabetes mellitus, to define long-term cardiovascular risk and direct clinical decision-making on pharmaceutical treatment. While LDL-c is not a part of the individual cardiovascular risk stratification, it remains the major target for treatment in primary prevention due to its strong association with atherosclerotic burden and high availability of efficient pharmacological therapies to reduce LDL-c levels, mostly with statins. Notably, the use of statin therapy in primary prevention settings has been proven to reduce cardiovascular risk in two contemporary pivotal randomized studies. However, the benefits of LDL-c reduction in primary prevention should not be confused with the use of LDL-c levels for risk stratification, which remains debatable. In this regard, and underlining the discrepancy between the impact of LDL-c reduction and its use as a marker for cardiovascular risk prediction, in the JUPITER study, no association was found between baseline LDL-c levels and cardiovascular risk among participants in the placebo arm. Also, longitudinal cohort studies have shown inconsistent associations between LDL-c levels and cardiovascular risk as some show strong associations and some weak or no associations. Thus, the debate on incorporating LDL-c into clinical decision-making algorithms in primary prevention settings remains debatable. In light of the inconsistent reports regarding the role of LDL-c as a predictive marker for cardiovascular risk, especially in older-aged patients, Hilvo et al. have utilized data from three prospective longitudinal cohorts from Europe, including nearly 18 000 participants, to address this question. In their study, now published in the Journal, the investigators aimed to define the predictive role of baseline LDLc levels across the spectrum of age, including patients between 25 and 75 years old without previously reported atherosclerosis-related events. Overall, the study population ( 50% females) was relatively healthy metabolically as, across the three cohorts included in the analysis, diabetes rates were between 1% and 12%, mean systolic blood