Elsevier

The Lancet

Volume 371, Issue 9607, 12–18 January 2008, Pages 117-125
The Lancet

Articles
Efficacy of cholesterol-lowering therapy in 18 686 people with diabetes in 14 randomised trials of statins: a meta-analysis

https://doi.org/10.1016/S0140-6736(08)60104-XGet rights and content

Summary

Background

Although statin therapy reduces the risk of occlusive vascular events in people with diabetes mellitus, there is uncertainty about the effects on particular outcomes and whether such effects depend on the type of diabetes, lipid profile, or other factors. We undertook a prospective meta-analysis to help resolve these uncertainties.

Methods

We analysed data from 18 686 individuals with diabetes (1466 with type 1 and 17 220 with type 2) in the context of a further 71 370 without diabetes in 14 randomised trials of statin therapy. Weighted estimates were obtained of effects on clinical outcomes per 1·0 mmol/L reduction in LDL cholesterol.

Findings

During a mean follow-up of 4·3 years, there were 3247 major vascular events in people with diabetes. There was a 9% proportional reduction in all-cause mortality per mmol/L reduction in LDL cholesterol in participants with diabetes (rate ratio [RR] 0·91, 99% CI 0·82–1·01; p=0·02), which was similar to the 13% reduction in those without diabetes (0·87, 0·82–0·92; p<0·0001). This finding reflected a significant reduction in vascular mortality (0·87, 0·76–1·00; p=0·008) and no effect on non-vascular mortality (0·97, 0·82–1·16; p=0·7) in participants with diabetes. There was a significant 21% proportional reduction in major vascular events per mmol/L reduction in LDL cholesterol in people with diabetes (0·79, 0·72–0·86; p<0·0001), which was similar to the effect observed in those without diabetes (0·79, 0·76–0·82; p<0·0001). In diabetic participants there were reductions in myocardial infarction or coronary death (0·78, 0·69–0·87; p<0·0001), coronary revascularisation (0·75, 0·64–0·88; p<0·0001), and stroke (0·79, 0·67–0·93; p=0·0002). Among people with diabetes the proportional effects of statin therapy were similar irrespective of whether there was a prior history of vascular disease and irrespective of other baseline characteristics. After 5 years, 42 (95% CI 30–55) fewer people with diabetes had major vascular events per 1000 allocated statin therapy.

Interpretation

Statin therapy should be considered for all diabetic individuals who are at sufficiently high risk of vascular events.

Introduction

At least 170 million people worldwide are estimated to have diabetes mellitus, and this number is predicted to more than double by 2030.1 The rapid rise in prevalence is mainly attributable to an increased incidence of type 2 diabetes. Since both types of diabetes are associated with a substantially increased risk of atherosclerotic vascular disease,2, 3, 4 identification of treatments for the prevention of major occlusive vascular events is a public-health priority.

Both types of diabetes are associated with dyslipidaemia, but the pattern of abnormality differs between them. In type 2 diabetes, triglyceride concentrations are high but HDL cholesterol concentrations tend to be low, whereas in type 1 diabetes triglyceride concentrations are generally lower than those in type 2 diabetes, and HDL cholesterol levels are average or even high.5 In both diseases, the concentration of LDL cholesterol in the blood is generally similar to the population average, although this apparently benign pattern can mask an increase in atherogenic small dense LDL particles.6 Observational studies in different populations have shown that a positive log-linear relation exists between blood LDL cholesterol and the risk of coronary heart disease, with this association continuing well below the range of typical cholesterol levels in developed countries.4, 7, 8 For example, in around 360 000 men who were screened for the Multiple Risk Factor Intervention Trial (MRFIT),4 every 1 mmol/L lower blood total cholesterol was associated with about a 50% lower risk of death from coronary heart disease, irrespective of blood cholesterol at baseline. In the 5000 men who had reported a history of diabetes at the baseline assessment for MRFIT, the relation between blood cholesterol and risk of coronary mortality was of similar magnitude, but the absolute risk of coronary mortality was three to five times higher than it was in those without diabetes.9

We have previously reported the results of a collaborative meta-analysis of 14 randomised trials of statin therapy (the Cholesterol Treatment Trialists' [CTT] Collaboration).10 Our results showed that lowering LDL cholesterol by 1 mmol/L reduces the risk of major vascular events (defined as the composite outcome of myocardial infarction or coronary death, stroke, or coronary revascularisation) by about a fifth in a wide range of high-risk participants, largely irrespective of baseline lipid profile or other presenting characteristics, including diabetes. However, there are still some uncertainties about the effects of statins in people with diabetes. For example, there is little information about the separate effects on major coronary events (ie, myocardial infarction or death from coronary heart disease), on stroke, and on the need for coronary revascularisation. Moreover, whether the benefits of statin therapy are worthwhile in people with diabetes who do not have any history of occlusive vascular disease is unknown. To resolve these uncertainties, we undertook prespecified analyses in the 18 686 participants with diabetes in the 14 statin trials contributing to the CTT meta-analysis.

Section snippets

Study design

Randomised trials were eligible for inclusion if: (i) the main effect of at least one of the trial interventions was to modify lipid levels; (ii) the trial was unconfounded with respect to this intervention (ie, no other differences in modification of risk factors between the relevant treatment groups were intended); and (iii) the trial aimed to recruit 1000 or more participants with treatment duration lasting at least 2 years. The principal planned analyses, as prespecified in the published

Results

Individual participant data were available from 14 trials of statin therapy (table 1).15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 Overall, diabetes was reported in 18 686 participants at trial entry, most of whom had type 2 diabetes; the remaining 71 370 participants were not known to have diabetes (table 1). Table 2 shows the characteristics of participants with and without diabetes, with subdivision by type of diabetes. Compared to participants without diabetes, the mean

Discussion

The main report of the Cholesterol Treatment Trialists' (CTT) Collaboration showed that statin therapy safely reduces the 5-year incidence of major coronary events, coronary revascularisation, and stroke by about a fifth per mmol/L reduction in LDL cholesterol, largely irrespective of initial lipid profile or other baseline characteristics.10 Larger reductions in LDL cholesterol were associated with greater proportional reductions in major vascular events, which meant that the expected absolute

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