Cardiovascular event rate modifies response to pharmacologic LDL-C lowering in primary prevention: implications of a systematic review and meta-analysis for clinical practice.

Background: LDL-C lowering is often delayed in lower-risk primary-prevention settings as absolute benefits appear modest. Trial evidence for greater relative benefits from pharmacologic LDL-C lowering in lower-risk individuals, supporting genetic studies, could strengthen the rationale for initiating LDL-C-lowering therapies at lower-risk levels. Objectives: To quantify i) how RRR for 3P-MACE per 1mmol/L LDL-C-lowering varies by baseline risk, ii) the absolute LDL-C reduction required to achieve 25 % RRR at varying risk thresholds. Methods: Systematic review and meta-analysis using EMBASE, MEDLINE, and CENTRAL searches for randomized, placebo-controlled lipid-lowering trials in populations with no or low (<20 %) prior atherosclerotic cardiovascular disease prevalence, reporting 3P-MACE (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke). Effect modification of placebo event rate on RRR/1mmol/L was assessed using mixed-effects meta-regression. A second meta-regression plotted the absolute LDL-C reduction associated with 25 % RRR across event-rates. Results: 17 trials (105,879 participants) reporting 6076 3P-MACE were included (12 statins only, 5 non-statins); mean age 63.0y, median follow-up 4.4y. LDL-C reduction ranged from 0.38-1.95 mmol/L and placebo event-rate ranged from 0.52 %/year-3.78 %/year. RRR per 1mmol/L LDL-C reduction attenuated from 36 % at 1 %/year event-rate to 13 % at 3 %/year ( Conclusion: Lower-risk primary prevention populations derive significantly greater relative benefits per 1mmol/L LDL-C lowering. Conversely, higher-risk populations derive less benefit per 1mmol/L LDL-C lowering and hence require greater absolute LDL-C reductions to achieve comparable relative treatment benefits. PROSPERO (CRD420251155320).