Course of the effects of LDL-cholesterol reduction on cardiovascular risk over time: A meta-analysis of 60 randomized controlled trials

• Published in: Atherosclerosis 2024-09, Vol.396, p.118540, Article 118540
• Main Authors: Burger, Pascal M., Dorresteijn, Jannick A.N., Koudstaal, Stefan, Holtrop, Joris, Kastelein, John J.P., Jukema, J. Wouter, Ridker, Paul M., Mosterd, Arend, Visseren, Frank L.J.
• Format: Article
• Language: English
• Subjects: Aged; Anticholesteremic Agents - therapeutic use; Biomarkers - blood; Cardiovascular Diseases - blood; Cardiovascular Diseases - mortality; Cardiovascular Diseases - prevention & control; Cholesterol, LDL - blood; Female; Heart Disease Risk Factors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Male; Middle Aged; PCSK9 Inhibitors - therapeutic use; Randomized Controlled Trials as Topic; Risk Assessment; Time Factors; Treatment Outcome
• ISSN: 0021-9150; 1879-1484; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2024.118540

Individuals with or at high risk of cardiovascular disease (CVD) often receive long-term treatment with low-density lipoprotein cholesterol (LDL-C) lowering therapies, but whether the effects of LDL-C reduction remain stable over time is uncertain. This study aimed to establish the course of the effects of LDL-C reduction on cardiovascular risk over time. Randomized controlled trials (RCTs) of LDL-C lowering therapies were identified through a search in MEDLINE and EMBASE (1966–January 2023). The primary analyses were restricted to statins, ezetimibe, and proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors, with other therapies included in sensitivity analyses. Random-effects meta-analyses were performed to establish the hazard ratio (HR) for major vascular events (cardiovascular death, myocardial infarction, unstable angina, 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 HR for major vascular events per 1 mmol/L LDL-C reduction. Additionally, treatment-by-time interactions were evaluated in an individual participant data meta-analysis of six atorvastatin trials. A total of 60 RCTs were identified (408,959 participants, 51,425 major vascular events). The HR for major vascular events per 1 mmol/L LDL-C reduction was 0.78 (95 % confidence interval [CI] 0.75–0.81). Follow-up duration was not associated with a change in the HR for major vascular events (HR for change per year 0.994; 95 % CI 0.970–1.020; p = 0.66). The HR attenuated with increasing age in primary prevention (HR for change per 5 years 1.097; 95 % CI 1.031–1.168; p = 0.003), but not secondary prevention (HR for change per 5 years 0.987; 95 % CI 0.936–1.040; p = 0.63). Consistent results were found for statin trials only, and all trials combined. In the individual participant data meta-analysis (31,310 participants, 6734 major vascular events), the HR for major vascular events did not significantly change over follow-up time (HR for change per year 0.983; 95 % CI 0.943–1.025; p = 0.42), or age (HR for change per 5 years 1.022; 95 % CI 0.990–1.055; p = 0.18). Based on available RCT data with limited follow-up duration, the relative treatment effects of LDL-C reduction are stable over time in secondary prevention, but may attenuate with higher age in primary prevention. [Display omitted] •Based on all relevant RCTs