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


In our study, 400 IU/day of RRR- -tocopheryl acetate administered for an average of 4.5 years to people with diabetes and at high risk for CV events had a neutral effect on CV outcomes, on microvascular complications, and on glycemic control.

The results on CV outcomes are very robust, with a large number of events and with consistent lack of benefit associated with vitamin E therapy on the composite primary outcome, on each component of the primary outcome, and on all secondary and additional CV outcomes for the entire diabetic study population and for all subgroups evaluated.

In spite of the strong biological rationale for a fundamental role of oxidative stress in atherosclerosis and the supportive epidemiological data, randomized clinical trials have overall, with few exceptions, failed to detect clear benefits of vitamin E supplementation on the progression of atherosclerotic lesions or on clinical events.[8,9,10,11,15,16] While vitamin E was shown to improve endothelial function in short-term studies,[4] there is no conclusive proof of long-term beneficial effects on human atherosclerosis,[15] and a recent trial in patients with coronary disease and low HDL cholesterol suggested that combined antioxidant vitamin therapy may even diminish the benefits attained on coronary disease progression with a statin and niacin.[16] Several previous large randomized trials have generally failed to demonstrate consistent CV benefits associated with vitamin E supplementation.[8,9,10,11,17] Few people with diabetes were enrolled in these trials and none reported data separately for people with diabetes. Furthermore, none of these trials reported information on nephropathy and on other microvascular outcomes. More recently, the Heart Protection Study enrolled over 5,900 high-risk people with diabetes and showed no CV benefits for combined therapy with vitamins E, C, and ß-carotene.[18]

An epidemiological report suggested that vitamin E may prevent the development of diabetes,[19] and a few small randomized trials showed improved glycemic control in people with diabetes receiving vitamin E supplements, while a number of other small randomized trials found no impact of vitamin E on glycemia.[20] We found no effect of vitamin E on HbA1c levels in patients with diabetes and no impact on the development of new diabetes in close to 6,000 individuals without diabetes at baseline.

Hyperglycemia-induced PKC activation has been proposed as an important pathway for the development of microvascular complications in diabetes.[7] High doses of vitamin E decreased PKC activation and prevented or reversed abnormalities in the retinal and renal vessels and in mesangial cells in some animal models, although the published results are inconsistent.[7,21,22] Small clinical studies have reported improved retinal blood flow, renal function, and nerve conduction in patients with diabetes receiving high-dose -tocopherol.[23,24] Our study, the largest to date to evaluate the effects of vitamin E on diabetic microvascular complications, showed neutral effects on renal function and on need for retinal laser therapy. While the lack of retinal photographs and/or retinal flow studies may be considered a limitation of the study and subtle early treatment effects on the retina may have been missed, urinary protein excretion and the development of diabetic nephropathy were carefully evaluated and the study had high power to detect clinically important benefits.

Several explanations have been proposed for the observed lack of benefit with vitamin E in recent large trials. Steinberg hypothesized that the effect of antioxidants in atherosclerosis is exerted primarily on early lesions and may be difficult to detect in middle-aged and elderly individuals with advanced disease, and that trials of longer duration than those designed to test pharmacological interventions may be required.[25] Experimental data suggest that vitamin E can become pro-oxidative and that combined antioxidant vitamins can reduce the HDL2-cholesterol subfraction.[16] Some investigators advocate the use of higher doses of vitamin E, similar to those used in experimental animal studies, in which vitamin E was effective in preventing PKC activation and in reducing endothelial cell toxicity and markers of inflammation.[4,7] Finally, it has been suggested that the average Western diet may provide adequate supplies of vitamin E in a large proportion of individuals and that it may be difficult to observe benefits in this population with the use of additional supplemental vitamin E intake.[26]

Based on current evidence, the widespread use of supplemental vitamin E cannot be endorsed as a means to reduce vascular complications in people with diabetes. Our efforts should be directed toward the aggressive management of hyperglycemia and of additional risk factors for atherosclerosis and for microvascular damage.


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