Effects of Vitamin E on Cardiovascular and Microvascular Outcomes in High-Risk Patients With Diabetes

Eva Lonn, MD MSC, Salim Yusuf, MBBS, DPHIL, Byrcon Hoogwerf, MD, Janice Pogue, MSC, Qilong Yi, PHD, Bernard Zinman, MD, Jackie Bosch, MSC, Gilles Dagenais, MD, Johannes F.E. Mann, MD, Hertzel C. Gerstein, MD, MSC on behalf of the Heart Outcomes Prevention Evaluation (HOPE) Investigators


Diabetes Care. 2002;25(11) 

In This Article

Abstract and Introduction

Objectives: Experimental and observational studies suggest that vitamin E may reduce the risk of cardiovascular (CV) events and of microvascular complications in people with diabetes. However, data from randomized clinical trials are limited. Therefore, we evaluated the effects of vitamin E supplementation on major CV outcomes and on the development of nephropathy in people with diabetes.
Research Design and Methods: The Heart Outcomes Prevention Evaluation (HOPE) trial is a randomized clinical trial with a 2 x 2 factorial design, which evaluated the effects of vitamin E and of ramipril in patients at high risk for CV events. Patients were eligible for the study if they were 55 years or older and if they had CV disease or diabetes with at least one additional coronary risk factor. The study was designed to recruit a large number of people with diabetes, and the analyses of the effects of vitamin E in this group were preplanned. Patients were randomly allocated to daily treatment with 400 IU vitamin E and with 10 mg ramipril or their respective placebos and were followed for an average of 4.5 years. The primary study outcome was the composite of myocardial infarction, stroke, or CV death. Secondary outcomes included total mortality, hospitalizations for heart failure, hospitalizations for unstable angina, revascularizations, and overt nephropathy.
Results: There were 3,654 people with diabetes. Vitamin E had a neutral effect on the primary study outcome (relative risk = 1.03, 95% CI 0.88-1.21; P = 0.70), on each component of the composite primary outcome, and on all predefined secondary outcomes.
Conclusions: The daily administration of 400 IU vitamin E for an average of 4.5 years to middle-aged and elderly people with diabetes and CV disease and/or additional coronary risk factor(s) has no effect on CV outcomes or nephropathy.

Atherosclerotic cardiovascular (CV) diseases are a major source of morbidity and mortality in people with diabetes. Oxidative modification of LDL is an important step in the development and progression of atherosclerosis in experimental studies.[1] Diabetes is a condition associated with increased oxidative stress as a consequence of hyperglycemia. Therefore, the use of antioxidants in people with diabetes has been advocated.[2] Vitamin E is the most prevalent naturally occurring antioxidant and has been shown to retard atherosclerosis in animal models.[3] In addition to its antioxidant properties, vitamin E also reduces the cytotoxic effect of oxidized lipoproteins, smooth muscle cell proliferation, platelet adherence and aggregation, and inflammation, and it improves endothelial function.[3,4] Moreover, observational studies have suggested that supplemental vitamin E users have lower rates of coronary events.[5,6] Although most participants in these studies did not have diabetes, people with diabetes were not systematically excluded.

Vitamin E was also proposed for the prevention of microvascular complications of diabetes. Indeed, in animal models it decreases hyperglycemia-induced protein kinase C (PKC) activation and D-acetyl-glycerol (DAG) levels, which have been associated with abnormalities in the retinal, renal, and vascular tissues in diabetes.[7]

Despite these data, several large randomized clinical trials have failed to confirm benefits for vitamin E in CV prevention.[8,9,10,11] Such studies have enrolled few people with diabetes and, to date, there are no large published trials on the effects of vitamin E on either CV or microvascular outcomes in diabetes.

We recently published the results of the Heart Outcomes Prevention Evaluation (HOPE) trial, which found no CV benefits for vitamin E in individuals at high risk for CV events[12] In the current report, we describe the effects of vitamin E on CV events, on microvascular outcomes, and on glycemic control in the HOPE study participants with diabetes.


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