Extent of Low-density Lipoprotein Cholesterol Reduction and All-cause and Cardiovascular Mortality Benefit: A Systematic Review and Meta-analysis

Lipid-modifying agents steadily lower low-density lipoprotein cholesterol (LDL-C) levels with the aim of reducing mortality. A systematic review and meta-analysis were conducted to determine whether all-cause or cardiovascular (CV) mortality effect size for lipid-lowering therapy varied according to the magnitude of LDL-C reduction. Electronic databases were searched, including PubMed and ClinicalTrials.gov , from inception to December 31, 2019. Eligible studies included randomized controlled trials that compared lipid-modifying agents (statins, ezetimibe, and PCSK-9 inhibitors) versus placebo, standard or usual care or intensive versus less-intensive LDL-C-lowering therapy in adults, with or without known history of CV disease with a follow-up of at least 52 weeks. All-cause and CV mortality as primary end points, myocardial infarction, stroke, and non-CV death as secondary end points. Absolute risk differences [ARD (ARDs) expressed as incident events per 1000 person-years], number needed to treat (NNT), and rate ratios (RR) were assessed. Sixty randomized controlled trials totaling 323,950 participants were included. Compared with placebo, usual care or less-intensive therapy, active or more potent lipid-lowering therapy reduced the risk of all-cause death [ARD -1.33 (-1.89 to -0.76); NNT 754 (529-1309); RR 0.92 (0.89-0.96)]. Intensive LDL-C percent lowering was not associated with further reductions in all-cause mortality [ARD -0.27 (-1.24 to 0.71); RR 1.00 (0.94-1.06)]. Intensive LDL-C percent lowering did not further reduce CV mortality [ARD -0.28 (-0.83 to 0.38); RR 1.02 (0.94-1.09)]. Our findings indicate that risk reduction varies across subgroups and that overall NNTs are high. Identifying patient subgroups who benefit the most from LDL-C levels reduction is clinically relevant and necessary.