More Intensive LDL-C Lowering Reduces Major Vascular Events Beyond Current Recommendations: Systematic Review and Meta-Analysis

Abstract

Aims: To determine the relationship between more intensive low-density lipoprotein (LDL-C) lowering therapy and relative risk of major vascular events (MVEs) across different LDL-C levels. Methods: Randomised trials of statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors that reported rates of MVEs were included. Random-effects and network meta-analyses evaluated associations between baseline LDL-C, achieved LDL-C, degree of LDL-C lowering and 10-year risk of cardiovascular (CVD) death with the relative risk (RR) of MVEs. Results: Fifty studies, totalling 316,605 patients with mean follow-up 3.6 ± 1.6 years were included. Although more intensive LDL-C lowering was associated with greater reductions in MVEs in patients with higher baseline LDL-C (p < 0.001), there was benefit in further lowering LDL-C amongst subgroups of patients with all baseline LDL-C <2.07 mmol/l (RR, 0.89; 95% CI, 0.82–0.96). In a network meta-analysis, patients with achieved LDL-C <1.50 mmol/l were most likely free from MVEs (surface under the cumulative ranking curve, 0.98), followed by 1.50–1.79, 1.80–2.59, 2.60–3.39, 3.40–4.09 and ≥4.10 mmol/l respectively. In meta-regression of primary prevention trials, LDL-C lowering therapy provided greater RR reductions in MVEs in populations with lower 10-year risk of CVD death (p = 0.030). Patients aged >75 years who received intensive LDL-C lowering therapy had significantly less MVEs. There was significantly more adverse drug reactions in the intensive LDL-C lowering arm (RR, 1.18; 95% CI, 1.10–1.27), but no significant difference in serious adverse effects. Conclusions: This meta-analysis provides new evidence that further lowering LDL-C is associated with greater reductions in MVEs beyond current recommendations.