Wang N, Fulcher J, Abeysuriya N, et al. 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. Lancet Diabetes Endocrinol. 2020 Jan;8(1):36-49. doi: 10.1016/S2213-8587(19)30388-2. (Systematic review)

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.


Discipline Area Score
Family Medicine (FM)/General Practice (GP) 7 / 7
General Internal Medicine-Primary Care(US) 7 / 7
Internal Medicine 6 / 7
Cardiology 6 / 7
Nephrology 6 / 7
Endocrine 5 / 7
Neurology 5 / 7
Comments from MORE raters

Family Medicine (FM)/General Practice (GP) rater

Extremely well conducted systematic review and meta-analysis with key implications, among other things, for the primary prevention of atherosclerotic disease. To become even more relevant, this study should be followed by another one evaluating the evidence on the side effects of LDL-lowering drugs –statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors. My only methodologically concern with this article is that the analyses use only one single outcome-variable, namely risk of major vascular events (a composite of cardiovascular mortality, myocardial infarction, ischemic stroke and coronary revascularization) and does not replicate the analyses for each of the components of the variable.

General Internal Medicine-Primary Care(US) rater

This a very positive study. Interestingly, as opposed to the Jupiter trial, there was no mention of increased incidence of diabetes. In Jupiter there was a decrease in adverse events in spite of the increase risk of Type 2 diabetes. Long-term consequences of extreme lipid lowering remain to be seen.

General Internal Medicine-Primary Care(US) rater

This is another study showing what we initially believed, ie, the lower the better rather than the start the statin based on risk and then don't follow lab.

Internal Medicine rater

This is an important meta-analysis, providing evidence for cholesterol lowering treatment across a wide range of patient groups.

Nephrology rater

As a nephrologist, I would be more interested to learn what is the effect of cholesterol-lowering drugs in advanced and in end-stage kidney disease. Is the effect similar to that seen in mild or moderate chronic kidney disease? We still do not know who should routinely use statins and other lipid-lowering drugs in advanced CKD and in dialysis patients. Unfortunately such patients are underrepresented in clinical trials and therefore in systemic reviews. The current review has the same limitation.
Comments from EvidenceAlerts subscribers

Dr. Hisham Aldabbagh (3/2/2020 6:54 AM)

Thanks for your systematic literature review. Your grand efforts are appreciated; however, what about the new emerging information concerning the total risk impact of the cholesterol involvement process in cardiovascular morbidity since this risk impact was reduced or minimized compared with all previous established attitudes and information.

Dr. Rajeev Gupta (3/1/2020 2:26 PM)

The study reconfirms the available data of a 0.5% reduction in the risk for MACE with 1 mEq/L lowering of LDL-C, with statins/ezetamibe/PCSK-9I. Importantly and interestingly, the issue of benefit, if any, in patients with ESRD is still not addressed. Perhaps participant-level meta-analysis of these patients added big charm to the study.