Abstract 4365430: Cumulative exposure to low-density lipoprotein cholesterol levels explains the cardiovascular benefit over time in randomized clinical trials

Introduction: It is well-established that lowering low-density lipoprotein cholesterol (LDL-C) levels is associated with cardiovascular risk reduction, with clinical benefits increasing over time; however, previous analyses may have underestimated the real treatment effect by not accounting for yearly changes in LDL-C levels. Research Question: The aim of this study was to assess the reduction in major cardiovascular event (MCE) risk after each year of statin therapy, considering the actual LDL-C reduction achieved annually. Methods: We included statin randomized controlled trials (RCTs) from the Cholesterol Treatment Trialists' Collaboration meta-analyses that reported the Kaplan-Meyer curve for MCE (defined as a composite of acute myocardial infarction, non-hemorrhagic stroke, cardiac death, and ischemia-driven revascularization) and LDL-C change after each year of follow-up. We used an online image-processing tool ( WebPlotDigitizer 4.5 ) to extract trial-level data from event curves and LDL-C graphs, to estimate hazard ratios (HRs) with 95% confidence intervals (95% CI) for therapy-outcome associations and to track LDL-C changes after each year of follow-up. HRs for MCE and LDL-C measurement after each year of treatment were then scaled to a 1 mmol/L reduction. For each year of follow-up, HRs standardized for 1 mmol/L were pooled through a random-effects meta-analysis. Results: We included a total of 13 RCTs with statins enrolling 99,360 participants. A 1 mmol/L reduction in LDL-C was associated with increasing cardiovascular benefit over time, with a consistent trend across trials lasting up-to 3, 4 and 5 years ( Figure ). In the latter case, the pooled data from 9 RCTs with data available up to 5 years showed a risk reduction per 1 mmol/L ranging from 13% after one year (HR: 0.87; 95% CI: 0.73-1.04) to a 22% reduction after 5 years (HR: 0.78; 95% CI: 0.71-0.86). Conclusions: Our findings reinforce the notion that prolonged exposure to lower LDL-C levels translates into greater cardiovascular risk reduction over time, even for the same reduction in LDL-C levels, thus highlighting the need for timely and persistent management of hypercholesterolemia. These insights should be integrated into clinical guidelines to further optimize long-term cardiovascular prevention strategies.