Cited by 6,550Lipoproteins and Cardiovascular HealthAcute Myocardial Infarction ResearchCancer, Lipids, and Metabolism

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Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials

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Abstract

Background Lowering of LDL cholesterol with standard statin regimens reduces the risk of occlusive vascular events in a wide range of individuals. We aimed to assess the safety and efficacy of more intensive lowering of LDL cholesterol with statin therapy.Methods We undertook meta-analyses of individual participant data from randomised trials involving at least 1000 participants and at least 2 years' treatment duration of more versus less intensive statin regimens (five trials; 39 612 individuals; median follow-up 5·1 years) and of statin versus control (21 trials; 129 526 individuals; median follow-up 4·8 years). For each type of trial, we calculated not only the average risk reduction, but also the average risk reduction per 1·0 mmol/L LDL cholesterol reduction at 1 year after randomisation.Findings In the trials of more versus less intensive statin therapy, the weighted mean further reduction in LDL cholesterol at 1 year was 0·51 mmol/L. Compared with less intensive regimens, more intensive regimens produced a highly significant 15% (95% CI 11-18; p<0·0001) further reduction in major vascular events, consisting of separately significant reductions in coronary death or non-fatal myocardial infarction of 13% (95% CI 7-19; p<0·0001), in coronary revascularisation of 19% (95% CI 15-24; p<0·0001), and in ischaemic stroke of 16% (95% CI 5-26; p=0·005). Per 1·0 mmol/L reduction in LDL cholesterol, these further reductions in risk were similar to the proportional reductions in the trials of statin versus control. When both types of trial were combined, similar proportional reductions in major vascular events per 1·0 mmol/L LDL cholesterol reduction were found in all types of patient studied (rate ratio [RR] 0·78, 95% CI 0·76-0·80; p<0·0001), including those with LDL cholesterol lower than 2 mmol/L on the less intensive or control regimen. Across all 26 trials, all-cause mortality was reduced by 10% per 1·0 mmol/L LDL reduction (RR 0·90, 95% CI 0·87-0·93; p<0·0001), largely reflecting significant reductions in deaths due to coronary heart disease (RR 0·80, 99% CI 0·74-0·87; p<0·0001) and other cardiac causes (RR 0·89, 99% CI 0·81-0·98; p=0·002), with no significant effect on deaths due to stroke (RR 0·96, 95% CI 0·84-1·09; p=0·5) or other vascular causes (RR 0·98, 99% CI 0·81-1·18; p=0·8). No significant effects were observed on deaths due to cancer or other non-vascular causes (RR 0·97, 95% CI 0·92-1·03; p=0·3) or on cancer incidence (RR 1·00, 95% CI 0·96-1·04; p=0·9), even at low LDL cholesterol concentrations.Interpretation Further reductions in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke, with each 1·0 mmol/L reduction reducing the annual rate of these major vascular events by just over a fifth. There was no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 2-3 mmol/L would reduce risk by about 40-50%.Funding UK Medical Research Council, British Heart Foundation, European Community Biomed Programme, Australian National Health and Medical Research Council, and National Heart Foundation.

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  1. 2000, Results of the low dose (20 mg) pravastatin GISSI Prevenzione trial in 4271 patients with recent myocardial infarction: do stopped trials contribute to overall knowledge?, Ital Heart J, 1, 810

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Metadata

Authors
Cholesterol Treatment Trialists' (CTT) Collaboration
Corresponding author
Cholesterol Treatment Trialists' (CTT) Collaboration
Venue
The Lancet
Publisher
Elsevier BV
Published
2010-11
Volume
376
Issue
9753
Pages
1670-1681
ISSN
  • 0099-5355 (ISSN-L)
  • 0140-6736
OpenAlex
W2164089346
Cited by
6,550
References
54
Citations by year
2026: 385 · 2025: 393 · 2024: 420 · 2023: 448 · 2022: 427 · 2021: 487 · 2020: 457 · 2019: 461 · 2018: 430 · 2017: 446 · 2016: 433 · 2015: 461 · 2014: 394 · 2013: 370 · 2012: 313
FWCI
49.94
Type
journal article
Language
en
Open access
Locations
  • The Lancet (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UEA Digital Repository (University of East Anglia) (submittedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
Funders
  • British Heart Foundation
  • University of Oxford
  • Medical Research Council
  • National Health and Medical Research Council
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
LDL cholesterol lowering, statin therapy, high-intensity statin therapy, major vascular events, coronary artery disease, myocardial infarction, ischemic stroke, coronary revascularization, all-cause mortality, cardiovascular risk reduction, drug safety, hypercholesterolemia, dyslipidemia
MeSH terms
Coronary Disease, Humans, Cholesterol, LDL, Myocardial Infarction, Randomized Controlled Trials as Topic, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Stroke

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