Course of the effects of LDL-cholesterol reduction on cardiovascular risk over time: a meta-analysis of 59 trials

Abstract Background Therapies lowering low-density lipoprotein cholesterol (LDL-c) are widely used to reduce cardiovascular disease (CVD) risk in patients with or at high risk of CVD. Therapy is usually continued lifelong, but whether the effects of LDL-c reduction remain stable over time is uncertain. This study aimed to establish the course of the relative treatment effects of LDL-c reduction on cardiovascular risk over time, i.e. treatment duration and age. Methods Randomized controlled trials (RCTs) of LDL-c lowering therapies were identified through a search in MEDLINE and EMBASE (1966-January 2023). RCTs of guideline-recommended therapies (i.e. statins, ezetimibe, and proprotein convertase subtilisin–kexin type 9 inhibitors [PCSK9i]) were selected for the primary analyses, with RCTs of other therapies included in sensitivity analyses. Random-effects meta-analyses were performed to establish the average relative risk (RR) for major vascular events (cardiovascular death, myocardial infarction or other acute coronary syndrome, coronary revascularization, or stroke) per 1 mmol/L LDL-c reduction. Course of the effects over time was assessed using random-effects meta-regression analyses for the association between follow-up duration, age, and the RR for major vascular events per 1 mmol/L LDL-c reduction. Analyses were also stratified for primary and secondary prevention. Results A total of 59 trials (26 statin trials, 2 ezetimibe trials, 3 statin/ezetimibe combination trials, 7 PCSK9i trials, and 21 other trials) were selected, including 394,989 participants and 49,642 major vascular events. Mean follow-up was 3.9 years (range 0.9-9.7), and age was 63.8 years (range 48.0-77.0). The average RR for major vascular events per 1 mmol/L LDL-c reduction was 0.78 (95% confidence interval [CI] 0.75-0.81), with slightly larger risk reductions in primary (RR 0.74; 95% CI 0.68-0.81) as compared to secondary prevention (RR 0.80; 95% CI 0.77-0.83). Follow-up duration was not associated with the RR for major vascular events (p = 0.615), with the meta-regression line showing a stable RR over follow-up time (RR for change per year 0.994; 95% CI 0.971-1.017). The RR for major vascular events increased (i.e. risk reduction decreased) with age in primary prevention (RR for change per 5 years 1.094; 95% CI 1.028-1.165; p = 0.018), but remained largely unchanged in secondary prevention (RR for change per 5 years 0.986; 95% CI 0.943-1.031; p = 0.533). Consistent results were fou