Elsevier

The Lancet

Volume 364, Issue 9435, 21–27 August 2004, Pages 685-696
The Lancet

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Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial

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Summary

Background

Type 2 diabetes is associated with a substantially increased risk of cardiovascular disease, but the role of lipid-lowering therapy with statins for the primary prevention of cardiovascular disease in diabetes is inadequately defined. We aimed to assess the effectiveness of atorvastatin 10 mg daily for primary prevention of major cardiovascular events in patients with type 2 diabetes without high concentrations of LDL-cholesterol.

Methods

2838 patients aged 40–75 years in 132 centres in the UK and Ireland were randomised to placebo (n=1410) or atorvastatin 10 mg daily (n=1428). Study entrants had no documented previous history of cardiovascular disease, an LDL-cholesterol concentration of 4·14 mmol/L or lower, a fasting triglyceride amount of 6·78 mmol/L or less, and at least one of the following: retinopathy, albuminuria, current smoking, or hypertension. The primary endpoint was time to first occurrence of the following: acute coronary heart disease events, coronary revascularisation, or stroke. Analysis was by intention to treat.

Findings

The trial was terminated 2 years earlier than expected because the prespecified early stopping rule for efficacy had been met. Median duration of follow-up was 3·9 years (IQR 3·0–4·7). 127 patients allocated placebo (2·46 per 100 person-years at risk) and 83 allocated atorvastatin (1·54 per 100 person-years at risk) had at least one major cardiovascular event (rate reduction 37% [95% CI –52 to –17], p=0·001). Treatment would be expected to prevent at least 37 major vascular events per 1000 such people treated for 4 years. Assessed separately, acute coronary heart disease events were reduced by 36% (–55 to –9), coronary revascularisations by 31% (–59 to 16), and rate of stroke by 48% (–69 to –11). Atorvastatin reduced the death rate by 27% (–48 to 1, p=0·059). No excess of adverse events was noted in the atorvastatin group.

Interpretation

Atorvastatin 10 mg daily is safe and efficacious in reducing the risk of first cardiovascular disease events, including stroke, in patients with type 2 diabetes without high LDL-cholesterol. No justification is available for having a particular threshold level of LDL-cholesterol as the sole arbiter of which patients with type 2 diabetes should receive statins. The debate about whether all people with this disorder warrant statin treatment should now focus on whether any patients are at sufficiently low risk for this treatment to be withheld.

Introduction

Type 2 diabetes is associated with a two to fourfold increased risk of both coronary heart disease and stroke.1, 2, 3 Case-fatality rates for myocardial infarction and stroke are also raised,4, 5, 6 emphasising the need for primary prevention. Findings of observational studies1 suggest that lipid lowering should have an important place in the primary prevention of cardiovascular disease in people with diabetes. Although LDL-cholesterol is not usually greatly increased in such individuals, it is as least as strong a predictor of coronary heart disease risk as in the general population.1 In the UK Prospective Diabetes Study,7, 8 a 1·57-fold increased risk of coronary heart disease was reported for every 1 mmol/L increment in LDL-cholesterol. LDL-cholesterol also predicts stroke risk in patients with type 2 diabetes.9

Trials that included participants with diabetes and coronary heart disease have shown that cholesterol lowering with statins substantially reduces risk of subsequent cardiovascular events.10, 11, 12, 13 The benefit of lipid lowering for primary prevention of cardiovascular disease is based on evidence showing a significant 33% reduction of this disorder in 2912 patients with diabetes but no previous occlusive vascular disease in the Heart Protection Study (HPS)14 and a non-significant 16% reduction in coronary heart disease in 2532 hypertensive patients with diabetes without previous occurrence of coronary heart disease in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA).15

Current prescription rates for lipid lowering in patients with diabetes remain low, even in those with existing cardiovascular disease.16, 17 Researchers on the international AUDIT study18 reported that most diabetes specialists were not convinced of the need for lipid lowering down to current guideline targets for primary prevention of cardiovascular disease in type 2 diabetes. Furthermore, these guidelines are not consistent with respect to which patients with diabetes warrant lipid-lowering therapy.19, 20, 21 Thus, further evidence from clinical trials is needed to show the benefits of statin treatment for primary prevention of cardiovascular disease in type 2 diabetes more convincingly and to quantify the benefit more precisely.

The aim of the Collaborative Atorvastatin Diabetes Study (CARDS) was to assess the effectiveness of 10 mg of atorvastatin daily versus placebo in the primary prevention of cardiovascular disease in patients with type 2 diabetes. The trial was stopped 2 years earlier than planned because of significant benefit at the second interim analysis.

Section snippets

Patients and methods

The CARDS protocol has been described in detail elsewhere.22 The study was undertaken in accordance with the Declaration of Helsinki and the Guidelines on Good Clinical Practice. Every centre obtained local research ethics committee approval after approval from the multicentre research ethics committee. All patients gave fully informed written consent.

Results

Of 4053 individuals initially screened, 3249 (80%) entered the baseline phase (figure 1). Failure to meet the randomisation criteria was the most typical reason for not entering this phase (n=647; 81%); of the remaining patients, most simply no longer wanted, or were able, to take part. Of those entering the baseline phase, 2838 were randomised and took at least one dose of study drug. Three patients were randomised but took no drug because we realised they did not meet the entry criteria

Discussion

The results of CARDS show that atorvastatin 10 mg daily leads to a substantial reduction (37%) in major cardiovascular events in patients with type 2 diabetes with no history of cardiovascular disease and without high LDL-cholesterol concentrations; this drug also reduced the risk of stroke (48%). The treatment effect did not vary by pretreatment cholesterol amount. On-treatment LDL-cholesterol concentrations were substantially lower than current target amounts in most treatment guidelines, and

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