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

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.

Figure 1

Effects on any major vascular event in each study In the left panel, unweighted rate ratios (RRs) for each trial of the comparison of first event rates between randomly allocated treatment groups are plotted along with 99% CIs. Trials are ordered according to the absolute reduction in LDL cholesterol (LDL-C) at 1 year within each type of trial comparison (more vs less statin and statin vs control). In the right panel, rate ratios are weighted per 1·0 mmol/L LDL cholesterol difference at 1 year. Subtotals and totals with 95% CIs are shown by open diamonds.

Figure 2

Effects on each type of major vascular event In the left panel, unweighted rate ratios (RRs) are plotted for each comparison of first event rates between randomly allocated treatment groups. In the right panel, RRs are weighted per 1·0 mmol/L LDL cholesterol (LDL-C) difference at 1 year. RRs are shown with horizontal lines denoting 99% CIs or with open diamonds denoting 95% CIs. MI=myocardial infarction. CHD=coronary heart disease. CABG=coronary artery bypass graft. PTCA=percutaneous transluminal coronary angioplasty.

Figure 3

Effects on major vascular events per 1·0 mmol/L reduction in LDL cholesterol, by baseline prognostic factors Rate ratios (RRs) are plotted for each comparison of first event rates between treatment groups, and are weighted per 1·0 mmol/L LDL cholesterol (LDL-C) difference at 1 year. Missing data are not plotted. RRs are shown with horizontal lines denoting 99% CIs or with open diamonds showing 95% CIs. CHD=coronary heart disease. GFR=glomerular filtration rate.

Figure 4

Effects on major vascular events per 1·0 mmol/L reduction in LDL cholesterol, by baseline LDL cholesterol concentration on the less intensive or control regimen Rate ratios (RRs) are plotted for each comparison of first event rates between treatment groups, and are weighted per 1·0 mmol/L LDL cholesterol (LDL-C) difference at 1 year. Analyses were done with trial-specific and subgroup-specific LDL weights for each baseline LDL cholesterol category. Missing data are not plotted. RRs are shown with horizontal lines denoting 99% CIs or with open diamonds showing 95% CIs.

Figure 5

Effects on cause-specific mortality per 1·0 mmol/L reduction in LDL cholesterol Rate ratios (RRs) are plotted for each comparison of first event rates between treatment groups and are weighted per 1·0 mmol/L LDL cholesterol (LDL-C) difference at 1 year. RRs are shown with horizontal lines denoting 99% CIs or with open diamonds showing 95% CIs. CHD=coronary heart disease.

Figure 6

Effects on site-specific cancer incidence per 1·0 mmol/L reduction in LDL cholesterol Rate ratios (RRs) are plotted for each comparison of first event rates between treatment groups and are weighted per 1·0 mmol/L LDL cholesterol (LDL-C) difference at 1 year. RRs are shown with horizontal lines denoting 99% CIs or with open diamonds showing 95% CIs. Analyses are of first cancers, subdivided by site: gastrointestinal (International Classification of Disease codes version 9 140–159); genitourinary (179–189); respiratory (160–163,165); female breast (174); haematological (200–208); melanoma (172); other/unknown site (other cancers with codes 140–172, 174–209, plus deaths with codes 173, 210–239).