CHICAGO – Evidence continues to build that vitamin E, an antioxidant supplement that became discredited and discarded for preventing cardiovascular disease events through the accumulated results from several large, negative trials, may actually have a substantial benefit for a select subgroup of patients with diabetes.
The key appears to be targeting vitamin E to patients with diabetes who also have a haptoglobin 2-2 genotype, which means they lack a robust antioxidant effect from this blood protein. Roughly a third of people in Western populations carry this genotype. Everyone else has a 1-1 or 2-1 genotype, both of which produce haptoglobin with adequate antioxidant activity.
The latest results to back up this paradigm came from a post hoc analysis of the 1,027 women with diabetes enrolled in the Women’s Health Study (WHS). In this analysis, women with diabetes and the haptoglobin 2-2 genotype who received an every-other-day supplement of 600 IU of vitamin E had a 15% reduced rate of cardiovascular disease events during an average 10 years of follow-up compared with similar women randomized to placebo, Dr. Shany Blum said at the annual scientific sessions of the American Heart Association. In contrast, post hoc analysis of WHS women with diabetes and the 2-1 genotype who received vitamin E showed a 20%-25% increased rate of cardiovascular disease events during follow-up compared with similar women who received placebo.
The stroke rate in women with the 2-1 haptoglobin genotype totaled 5.7% in those who received vitamin E and 1.2% in the placebo arm, a 4.5-fold increased rate of stroke after adjustment, said Dr. Blum, a researcher at the Technion-Israel Institute of Technology in Haifa, Israel.
These findings follow similar observations about the interaction of vitamin E and the haptoglobin genotype in both women and men with diabetes in a post hoc analysis of data from the Heart Outcomes Prevention Evaluation (HOPE) study (New Engl. J. Med. 2000;342:154-60), and from a prospective test of vitamin E compared with placebo in 1,434 patients with diabetes and the haptoglobin 2-2 genotype in the Israel Cardiovascular Events Reduction With Vitamin E (ICARE) study (Arterioscler. Thromb. Vasc. Biol. 2008;28:341-7).
Both studies used a daily supplement with 400 IU of vitamin E. The Haifa researchers published a meta-analysis of the results from HOPE and ICARE in patients with diabetes analyzed by their haptoglobin genotype last May (Pharmacogenomics 2010;11:675-84).
"We have now addressed, in three independent studies, the ability to target specifically haptoglobin 2-2 individuals with antioxidant treatment, particularly vitamin E," said Dr. Andrew P. Levy, professor of anatomy and cell biology at the Technion-Israel Institute and the lead investigator of these analyses and the ICARE study.
"We’ve now shown in the HOPE study, ICARE, and WHS that patients with the 2-2 genotype [and diabetes] benefited from receiving vitamin E. In HOPE, they had about a 30% reduction in cardiovascular events [compared with patients who received placebo], in ICARE about a 45% reduction in cardiovascular events, and in the WHS about a 15% reduction in cardiovascular events," Dr. Levy said in an interview. The HOPE and WHS studies "had previously both shown no overall benefit from vitamin E" compared with placebo when the analysis included all participants, regardless of their diabetes status and haptoglobin genotype status. "But when we specifically targeted people with 2-2, they benefited from vitamin E treatment."
New Analyses Endorse Role for Vitamin E
The analyses done by Dr. Levy and his associates are fascinating, intriguing, and suggestive. The cardiology community discarded vitamin E as a beneficial supplement based on the results of several large clinical trials. But the Haifa group went back, phenotyped the study participants using stored blood specimens, and found that vitamin E produced a benefit that was hiding in plain sight.
Based on the evidence the group has reported so far, I think it is unlikely that the committee currently writing the Adult Treatment Panel IV for the National Heart, Lung, and Blood Institute will include an official recommendation on targeting a vitamin E supplement to patients with diabetes who carry the haptoglobin 2-2 genotype. But the evidence is now compelling enough for individual physicians to present the case to patients with diabetes and ask if they would like to have their haptoglobin genotype checked and go on vitamin E if they have the 2-2 profile. The 400-IU/day dose of vitamin E that Dr. Levy and his associates tested in their ICARE study is cheap and innocuous, with an adverse effect profile that is very nearly zero but which could produce a significant benefit.
Testing for the haptoglobin profile need only be done once, and can be done as either a genotype test, or as a phenotype test based on the haptoglobin forms in a patient’s blood. Testing is critical because patients who carry a haptoglobin genotype that is not 2-2 appear to be harmed by vitamin E treatment. Vitamin E cannot simply be given to everyone with diabetes.
Unfortunately, vitamin E is so cheap that no drug company will be motivated to fund the large, prospective study needed to confirm the benefits that Dr. Levy’s analyses and study results have suggested. Companies that offer haptoglobin testing stand to gain the most financially from large-scale adoption of this approach, but those companies are generally too small to have the resources to fund a large trial. That leaves it to a public health agency, such as the National Institutes of Health, but the NIH is currently so strapped for funds that it is also unlikely to sponsor this study.
Dr. Eliot A. Brinton is director of the metabolism section in the division of cardiovascular genetics at the University of Utah in Salt Lake City. He said that he has served as a consultant to, or a speaker for, Abbott, Amarin, AstraZeneca, Atherotech, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Kaneka, Kowa, Kronos Longevity Research Institute, Merck, and Takeda. He has received research grants from Abbott, the Aurora Foundation, and GlaxoSmithKline. He has been an expert witness for the law firm Reilly Pozner.
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