Elsevier

The Lancet

Volume 357, Issue 9260, 24 March 2001, Pages 905-910
The Lancet

Articles
Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study*

https://doi.org/10.1016/S0140-6736(00)04209-4Get rights and content

Summary

Background

Atherosclerosis is the most common complication of diabetes. Correction of hyperglycaemia helps to prevent microvascular complications but has little effect on macrovascular disease. Post-hoc analyses of diabetic subpopulations in lipid intervention trials suggest that correction of lipoprotein abnormalities will lead to a decrease in coronary-artery disease. The Diabetes Atherosclerosis Intervention Study (DAIS) was specifically designed to assess the effects of correcting lipoprotein abnormalities on coronary atherosclerosis in type 2 diabetes.

Methods

731 men and women with type 2 diabetes were screened by metabolic and angiographic criteria. 418 were randomly assigned micronised fenofibrate (200 mg/day) or placebo for at least 3 years. They were in good glycaemic control (mean haemoglobin A1c 7·5%), had mild lipoprotein abnormalities, typical of type 2 diabetes, and at least one visible coronary lesion. Half had no previous clinical coronary disease. Initial and final angiograms followed a standard protocol and were analysed by a computer-assisted quantitative approach. Missing data for the primary endpoints (minimum lumen diameter, mean segment diameter, and mean percentage stenosis) were imputed. Analyses were by intention to treat.

Findings

Total plasma cholesterol, HDL-cholesterol, LDL-cholesterol, and triglyceride concentrations all changed significantly more from baseline in the fenofibrate group (n=207) than in the placebo group (n=211). The fenofibrate group showed a significantly smaller increase in percentage diameter stenosis than the placebo group (mean 2·11 [SE 0·594] vs 3·65 [0·608]%, p=0·02), a significantly smaller decrease in minimum lumen diameter (−0·06 [0·016] vs −0·10 [0·016] mm, p=0·029), and a non-significantly smaller decrease in mean segment diameter (−0·06 [0·017] vs −0·08 [0·018] mm, p=0·171). The trial was not powered to examine clinical endpoints, but there were fewer in the fenofibrate group than the placebo group (38 vs 50).

Interpretation

DAIS suggests that treatment with fenofibrate reduces the angiographic progression of coronary-artery disease in type 2 diabetes. This effect is related, at least partly, to the correction of lipoprotein abnormalities, even those previously judged not to need treatment.

Introduction

Atherosclerosis is the most common complication of diabetes, particularly type 2 diabetes.1 Studies suggest that if hyperglycaemia is a risk factor for atherosclerosis in diabetes, its effect is weak.2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 By contrast, lipoprotein abnormalities do increase the risk of coronary-artery disease in diabetes.13, 14

The Diabetes Atherosclerosis Intervention Study (DAIS) was developed and conducted in collaboration with the WHO to find out whether correction of the dyslipoproteinaemias seen in type 2 diabetes would decrease the rate of angiographic progression of coronary-artery disease. In previous lipid intervention trials, only post-hoc subgroup analyses of people with diabetes have been presented.

The most common lipoprotein abnormality in diabetes is an increase in the triglyceride-rich lipoproteins and a decrease in HDL cholesterol.15 The DAIS planning committee therefore developed a double-blind randomised placebo-controlled protocol with micronized fenofibrate as the active study drug. So that the required population would be smaller and the study duration shorter, DAIS was designed as an angiographic study and was not powered to seek differences in clinical endpoints. The protocol, the baseline characteristics of the study population, the angiographic methods, and the biochemical laboratory methods have been described elsewhere.16, 17 This paper reports the first study results.

Section snippets

Patients

DAIS took place in 11 clinical centres in Canada, Finland, France, and Sweden. Eligible patients were men and women with type 2 diabetes aged 40–65 years, with or without previous coronary intervention. The lipid and diabetes eligibility characteristics were assessed during an 8-week dietary (American Heart Association/National Cholesterol Education Program step 1 diet) baseline period while the participant was off all lipid-lowering medications. The same diet was maintained throughout the

Results

731 patients were screened for inclusion, and 418 were found to meet the metabolic or cardiac entry criteria (figure 2). There were no differences between those who were and those who were not eligible for entry. Overall, the study participants had good glycaemic control and mild hypertriglyceridaemia (table 1). The placebo group had slightly higher HDL-cholesterol and fasting glucose concentrations than the fenofibrate group. Half of the participants had a clinical history of coronary disease.

Discussion

Coronary-artery disease is a very important cause of both death and disability in diabetes, so any possible preventive measures are vital. The UK Prospective Diabetes Study demonstrated the critical role of glycaemic control in preventing the microvascular complications of type 2 diabetes.10 That study also showed, however, that glycaemic control had little effect on macrovascular disease. Thus, the effects of correcting other coronary risk factors need to be examined. Lipoprotein abnormalities

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    *

    Study organisation given at the end of the paper

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