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September 2001; Volume 4; 100-103
By Robert J. Nardino, MD, FACP
Everywhere you turn there is another health-related product touting the alleged beneficial effects of antioxidants. Nevertheless, there may be some substance to the hype. One example is in the prevention and treatment of diabetic retinopathy. Continued insight into the origin of microvascular problems in diabetes mellitus and interest in the use of antioxidants in other retinal conditions, including age-related macular degeneration, have led to further investigation of the use of antioxidants, particularly vitamin E, in the treatment of this devastating complication of diabetes mellitus.
There are a variety of explanations for how and why microangiopathy occurs in patients with diabetes mellitus, although the exact mechanism has yet to be elucidated. Just as carcinogenesis and cellular apoptosis appear to be related, free radicals and oxidative processes are linked.
Italian investigators found increased levels of free radicals in the retina of diabetic patients, with a greater concentration in those with more severe retinopathy.1 A more recent U.S study confirmed increased levels of free radicals, as well as reduced levels of the important endogenous antioxidants, glutathione and superoxide dismutase, in 73 diabetic patients compared to controls.2 However, there was no association between the level and the severity of retinopathy.
Chinese investigators looked at blood viscosity and lipid peroxidation in 13 patients with type 2 diabetes and retinopathy.3 They found that giving 300 mg vitamin E tid reduced red blood cell deformability, attributable to decreased oxidative stress. There was no change in viscosity or red cell rigidity in this study.
Other evidence suggested that antioxidants could reverse endothelial dysfunction in humans. Vitamin C was shown to restore endothelium-dependent vasodilation in diabetic patients, further evidence that antioxidants play an important role in this regard.4 Vitamin E (1,000 IU/d) improved endothelial function as assessed by brachial artery ultrasound in 41 type 1 diabetics.5
Mechanism of Action
Free radicals are reactive oxygen species that are generated under normal physiological processes, as well as in pathological situations. A free radical is simply a molecule with one unpaired electron, which determines its highly reactive nature. Cellular free radicals are generated constantly, but the body has a defense. Antioxidants like glutathione, vitamin E, and vitamin C lend electrons to render free radicals neutral. Thus, vitamin E inhibits lipid peroxidation, which prevents damage to cell membranes and also prevents modification of low-density lipoprotein to a more atherogenic molecule. Vitamin C regenerates vitamin E; that is, it restores the donated electron to vitamin E.
An epidemiologic study looked at the intake of antioxidants and the incidence of retinopathy in 387 patients with type 2 diabetes.6 Dietary intake was assessed with a 24-hour recall interview, and supplements were assessed and confirmed by examining the labels of bottles brought in by the participants. Statistical analysis sought to associate intake of vitamin C, beta-carotene, and vitamin E (by quintiles) with the presence of retinopathy as classified by fundoscopic stereophotography. Overall, there was no beneficial effect. In fact, in patients not taking insulin, higher intake of vitamin E and beta-carotene was associated with more severe retinopathy.
There are limitations to the 24-hour recall method, however, which is specific only for that time period and does not account for the probable variation in dietary intake. Also, causation cannot be established. In fact, the negative association found between vitamin E and retinopathy could have resulted from supplementation in response to knowledge about incipient or progressing eye disease.
In 1999, investigators from Harvard Medical School and the Joslin Diabetes Center published the results of a randomized, controlled trial of vitamin E supplementation in patients with type 1 diabetes.7 The study’s objective was to determine if vitamin E had any effect on retinal blood flow. (See Table 1 for a comparison of diabetic retinopathy trials.)
|Table 1: Comparison of interventions for diabetic retinopathy|
|Intensive glycemic control||Reduced progression of retinopathy by 63%||Large RCT||15|
|Vitamin E supplementation||Improved retinal blood flow; no clinical endpoint||Small RCT||7|
|Aggressive blood pressure control||No effect on retinopathy||RCT||16|
|Aspirin||Improved retinal blood flow||Observational||17|
|Key: RCT = Randomized, controlled trial|
Investigators enrolled 36 patients who had minimal or no retinopathy and type 1 diabetes for less than 10 years. They also included nine nondiabetic control subjects. All were randomly assigned to receive vitamin E at a dose of 1,800 IU/d or placebo; after four months, they were crossed over to the other treatment for another four months. Retinal blood flow was determined with video flourescein angiography. At baseline, retinal blood flow was significantly reduced in diabetic patients compared to nondiabetics.
After treatment with vitamin E, retinal blood flow improved in the diabetic subjects to the point that it was comparable to that of the nondiabetic participants. In addition, the hyperfiltration associated with early diabetic renal disease also normalized. This is a short-term study, looking at a physiologic response rather than a clinical endpoint, but nevertheless the results are encouraging. Also of note is the dose used, which is higher than the doses seen in the studies of vitamin E and macrovascular disease (400-800 IU/d).
Vitamin E has been linked to bleeding complications when used in the treatment of retinopathy of prematuri-ty.8 A link with venous thromboembolism was reported in a case series.9 Many of the patients had concurrent risk factors. An earlier body of literature proposed vitamin E as a possible preventive therapy for thromboembolic disease, potentially confounding these data.
There is some conflicting information about the interaction of vitamin E and warfarin. There are case reports of elevated prothrombin times and bleeding episodes in patients stabilized on warfarin who subsequently started vitamin E. On the other hand, a study of 21 patients on
warfarin given 800 IU of vitamin E showed no effect on the international normalizing ratio (INR).10 However, the study only lasted one month. There is speculation that vitamin E may interfere with the synthesis of vita- min K-dependent clotting factors. It is recommended that the prothrombin time/INR be closely monitored after initiation or discontinuation of vitamin E therapy.
The weight-loss agent orlistat (Xenical) is reported to block the absorption of vitamin E by up to 60%. The manufacturer recommends spacing the dose of orlistat from vitamin E by at least two hours.
Population-based studies have demonstrated a possible protective effect of vitamin E against age-related macular degeneration.11 Several large prospective randomized trials are now in progress to examine further the benefits of vitamin E in the prevention of macular degeneration and cataracts.
Patients with documented coronary artery disease who supplemented with vitamin E (400-800 IU) had a decreased incidence of non-fatal cardiac events in the Cambridge Heart Antioxidant Study.12
Vitamin E can be found in vegetable oils, margarine, nuts, seeds, avocados, and safflower oil. The recommended dietary intake of vitamin E is 30 IU/d. Dietary fat restriction can limit the consumption of vitamin E.
Vitamin E can be obtained as a supplement in natural (d-alpha-tocopherol) or synthetic (dl-alpha-tocopherol) form. It appears that the natural form is superior in terms of absorption and retention in the body, although there is ongoing debate as to the degree to which bioavailability differs.13 Most supplements contain the synthetic form, but increasingly, natural supplements are available, although they are more expensive. (See Table 2 for a price comparison.) Further complicating the issue are data from a population-based study which indicated that women with greater dietary intake of vitamin E had fewer cardiac events, whereas those who supplemented did not (although the study was not designed to test the hypothesis that supplementation prevents cardiac events).14
|Table 2: Price comparison of vitamin E supplements|
|Nature Made||800 IU||Natural||60||$14.99|
|Source: On-line mail-order companies.|
The single randomized trial of vitamin E and diabetic retinopathy was a short-term study, and it used the surrogate endpoint of retinal blood flow rather than the progression of retinopathy. Mounting information about the origin of microvascular disease and the effect of vitamin E on these oxidative reactions provide theoretical support for its use. Questions remain, however. Does vitamin E provide benefit in addition to that of tight control? Since vitamin E has been associated with a risk of hemorrhage, what is the risk of retinal hemorrhage and clinical worsening in the presence of proliferative retinopathy? Can vitamin E prevent the "early worsening" seen in some patients who begin intensive glycemic control (about 13% of intensively treated people in the Diabetes Control and Complications Trial15). Only further prospective controlled trials can provide answers.
The evidence for vitamin E use for the prevention or treatment of diabetic retinopathy is preliminary. A single randomized trial shows it to be safe for short-term use. Patients who are taking warfarin should use caution and their INR should be monitored closely.
Dr. Nardino is Program Director of the Internal Medicine Residency at the Hospital of Saint Raphael in New Haven, CT, and Assistant Clinical Professor of Medicine, Yale University School of Medicine.
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3. Chung TW, et al. Reducing lipid peroxidation stress of erythrocyte membrane by alpha-tocopherol nicotinate plays an important role in improving blood rheological properties in type 2 diabetic patients with retinopathy. Diabet Med 1998;15:380-385.
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15. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986.
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17. Feke GT, et al. Retinal blood flow increases following short-term aspirin usage in type I diabetics with no or minimal retinopathy. Ophthalmic Res 1996;28: 108-116.