Intensive LDL cholesterol-lowering treatment beyond current recommendations for the prevention of major vascular events: a systematic review and meta-analysis of randomised trials including 327 037 participants

Summary

Background

The benefits of LDL cholesterol-lowering treatment for the prevention of atherosclerotic cardiovascular disease are well established. However, the extent to which these effects differ by baseline LDL cholesterol, atherosclerotic cardiovascular disease risk, and the presence of comorbidities remains uncertain.

Methods

We did a systematic literature search (MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, from inception up to June 15, 2019) for randomised controlled trials of statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors with at least 1000 patient-years of follow-up. Random-effects meta-analysis and meta-regressions were done to assess for risk of major vascular events (a composite of cardiovascular mortality, non-fatal myocardial infarction, non-fatal ischaemic stroke, or coronary revascularisation) per 1 mmol/L (38·7 mg/dL) reduction in LDL cholesterol concentrations.

Findings

327 037 patients from 52 studies were included in the meta-analysis. Each 1 mmol/L reduction in LDL cholesterol was associated with a 19% relative risk (RR) reduction for major vascular events (RR 0·81 [95% CI 0·78–0·84]; p<0·0001). Similar reductions (per 1 mmol/L reduction in LDL cholesterol) were found in trials with participants with LDL cholesterol 2·60 mmol/L or lower, 2·61–3·40 mmol/L, 3·41–4·10 mmol/L, and more than 4·1 mmol/L (p=0·232 for interaction); and in a subgroup of patients who all had a baseline LDL cholesterol less than 2·07 mmol/L (80 mg/dL; RR 0·83 [95% CI 0·75–0·92]; p=0·001). We found greater RR reductions in patients at lower 10-year atherosclerotic cardiovascular disease risk (change in RR per 10% lower 10-year atherosclerotic cardiovascular disease 0·97 [95% CI 0·95–0·98]; p<0·0001) and in patients at younger age across a mean age of 50–75 years (change in RR per 10 years younger age 0·92 [0·83–0·97]; p=0·015). We found no difference in RR reduction for participants with or without diabetes (p=0·878 for interaction) and chronic kidney disease (p=0·934 for interaction).

Interpretation

For each 1 mmol/L LDL cholesterol lowering, the risk reduction of major vascular events is independent of the starting LDL cholesterol or the presence of diabetes or chronic kidney disease. Patients at lower cardiovascular risk and younger age might have a similar relative reduction in risk with LDL-cholesterol lowering therapies and future studies should investigate the potential benefits of earlier intervention.

Funding

None.

Introduction

LDL cholesterol is a well-established risk factor for the development of atherosclerotic cardiovascular disease. Studies from the Cholesterol Treatment Trialists' (CTT) Collaboration have shown that statin therapy can reduce the risk of major vascular events across a wide range of populations,¹ including men and women,² people at low risk of vascular disease,³ and older people.⁴ However, uncertainty remains regarding the optimal approach towards lowering LDL cholesterol, particularly in the context of the new LDL cholesterol-lowering therapies, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, as shown by differences in the guidelines of the major cardiovascular societies.5, 6, 7, 8, 9, 10 Which patients should be treated with lipid-lowering therapies, and what specific LDL cholesterol targets or percentage reductions should be set as treatment goals, remains unclear.

The focus in primary prevention has shifted to using LDL cholesterol thresholds and risk estimators of cardiovascular disease to guide the initiation of therapy. The American College of Cardiology/American Heart Association (ACC/AHA) and Canadian Cardiovascular Society (CCS) guidelines recommend a target LDL cholesterol concentration of either less than 1·8 mmol/L or a reduction of more than 50% in LDL cholesterol from baseline in high-risk patients.7, 9 The European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) released new guidelines in 2019 with the most aggressive target of less than 1·4 mmol/L and a reduction of more than 50% in LDL cholesterol.⁵ The relative merits of using LDL cholesterol thresholds in isolation, setting values for the proportion of LDL cholesterol lowering to be pursued, and assigning specific targets for therapy are uncertain. We aimed to help address these uncertainties by doing a systematic review and meta-analysis of all the available evidence from major randomised trials for established therapies for lowering LDL cholesterol (statins, ezetimibe, and PCSK9 inhibitors) to address four key questions. First, does reducing LDL cholesterol reduce the risk of cardiovascular events independent of the baseline LDL cholesterol concentration? Second, do patients with diabetes or chronic kidney disease have an increased benefit from LDL cholesterol-lowering therapies? Third, does baseline risk of atherosclerotic cardiovascular disease or cardiovascular death influence the risk reduction that is associated with reducing LDL cholesterol? Fourth, what are the safety profiles of therapies for reducing LDL cholesterol, and do specific drug class effects need to be considered?

Research in context

Evidence before this study

Statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce the risk of atherosclerotic cardiovascular disease. However, the extent to which the effects of these treatment differ by starting LDL cholesterol concentration, atherosclerotic cardiovascular disease risk, and the presence of comorbidities remains uncertain.

Added value of this study

We found that risk reduction of major vascular events is proportional to the degree of LDL cholesterol reduction, irrespective of the baseline LDL cholesterol concentration, and persists in patients with baseline LDL cholesterol less than 2·07 mmol/L. We found no difference in relative risk reduction for patients with chronic kidney disease or diabetes. We found a trend for greater relative risk reduction among patients at lower cardiovascular risk and younger age, although these findings are hypothesis generating only. Across all classes of LDL cholesterol-lowering drugs, the only evidence of adverse drug reactions was a greater incidence of increased aminotransferases and creatine kinase with statins and increased injection-site reactions with PCSK9 inhibitors.

Implications of all the available evidence

Risk reduction is independent of baseline LDL cholesterol concentration for each 1 mmol/L reduction in LDL cholesterol, which suggests that screening concentration alone should not be used as an indication for or against treatment. No threshold seems to exist below which LDL cholesterol-lowering therapy does not further reduce risk of major vascular events. Guidelines should focus on the absolute LDL cholesterol reduction rather than percentage reduction. Patients at lower cardiovascular risk and younger age might have a similar relative reduction in risk with LDL cholesterol-lowering therapies and future studies should investigate the role of earlier intervention.