The role of lipid lowering medications in the primary prevention of cardiovascular disease and mortality: a meta-analysis of randomized controlled trials

Abstract Importance The mortality benefit of lipid-lowering therapies (LLTs) in true primary prevention of cardiovascular disease (CVD) remains uncertain, in part because prior studies frequently included individuals with existing cardiovascular, vascular, or cerebrovascular disease. Objective To evaluate the effect of LLTs on all-cause mortality and major adverse cardiovascular events exclusively in patients without prior CVD. Data sources MEDLINE, EMBASE, and COCHRANE were searched through October 2024 for randomized controlled trials (RCTs) comparing LLTs with control therapy. Study selection RCTs assessing LLTs for primary prevention and reporting mortality or cardiovascular outcomes were included; trials with any participants with prior CVD, vascular disease, or cerebrovascular events were excluded. Results Ten RCTs including 85,829 participants, met criteria. LLTs did not reduce all-cause mortality compared with control (3.9% vs. 3.9%; RR 0.98, 95% CI 0.89–1.07) or cardiac mortality (1.4% vs. 1.5%; RR 0.92, 95% CI 0.82–1.04). However, LLTs—primarily statins—reduced MACE (RR 0.76, 95% CI 0.68–0.84), myocardial infarction (RR 0.64, 95% CI 0.57–0.72), revascularization (RR 0.70, 95% CI 0.57–0.86), stroke/TIA (RR 0.75, 95% CI 0.57–0.98), and cardiovascular hospitalizations (RR 0.75, 95% CI 0.65–0.87). Conclusion Among individuals without prior cardiovascular, vascular, or cerebrovascular disease, LLTs did not reduce all-cause or cardiovascular mortality but were associated with significant reductions in nonfatal cardiovascular events. Additional research is needed to define the benefits of LLTs in true primary prevention.