Summary

Vitamin E supplementation appears to be able to halve the frequency of cardiovascular events (cardiac death, heart attack, and stroke) in type 2 diabetics carrying a particular type of gene (the haptoglobin 2-2), who are at increased risk.

Introduction

Some recent studies have shown no benefits from vitamin E supplements in preventing cardiovascular events such as heart attack, angina, or stroke. Similar disappointing results have been reported for other antioxidants, such as beta-carotene. However, the studies did not look for possible benefits of these antioxidants in subgroups of patients that are exposed to excess oxidative stress.

This has been rectified by an Israeli study reported at the recent American Heart Association meeting, and now published online in Arteriosclerosis, Thrombosis, and Vascular Biology. The researchers studied type 2 diabetic patients who possessed a genetic makeup bearing a gene pair likely to offer inferior antioxidant protection; the effects of vitamin E supplementation on mortality in such patients was determined.

The genotype in question, haptoglobulin (Hp), has two common types of alleles denoted 1 and 2. The Hp 2 allele protein is less effetive in combating oxidative stress. The genotype distribution among western societies is 16% Hp 1-1, 36% Hp 2-2, and 48% Hp 2-1. In type 2 diabetics, those with Hp 2-2 have two to five times the incidence of cardiovascular events compared with those with the other allele combinations.

What was done

A total of 1,434 type 2 diabetic patients over 55 with the Hp 2-2 genotype were enrolled in this study; they could not have uncontrolled high blood pressure, or a recent heart attack or stroke. They were randomly allocated to take either vitamin E (d-alpha-tocopherol) 400 IU daily or a matching placebo pill.

The primary outcome measured was a combination of cardiovascular deaths, nonfatal heart attacks, and stroke. Secondary endpoints were overall mortality, congestive heart failure, and coronary bypass or stenting procedures. The duration of the study was 18 months.

The analyses reported here are confined to those patients who actually took their supplementation (vitamin E or placebo pills) for the duration of the study.

What was found

The average age of the participants was 69, and the duration of their diabetes roughly 11 years. The average HbA1c was 7.35%; over a third of the participants were taking aspirin and over half were taking a statin. Metformin was the antidiabetic agent of choice - it was taken by 58% of the subjects.

Among the 505 patients who took vitamin E there were 16 (2.2%) who had one or other of the critical cardiovascular events, compared with 33 (4.7%) of the 479 patients taking the placebo pills. This difference - more than a halving of events in the vitamin E group - was statistically significant i.e. it could not have occurred by chance alone.

The greatest effect was found in the frequency of nonfatal heart attacks, which occurred in 1% of vitamin E patients and 2.4% of placebo patients.

Although it was not part of the original analysis plan, the researchers compared the risks of cardiovascular events among those of the whole collective of diabetics who were genotyped: 1,248 Hp 2-1, 285 Hp 1-1, 726 Hp 2-2 allocated to vitamin E, and 708 Hp 2-2 allocated to placebo. The frequency of events was the same for the Hp 2-1 and Hp 1-1, and their values were compared with the two main study groups. The Hazard Ratio for the 726 Hp 2-2 patients was 1.1, and for the placebo Hp 2-2 group it was 2.3. This means that the risk of having a cardiovascular event for the subjects taking vitamin E was almost identical to that for patients with no, or only one, Hp 2 allele.

Conclusions

This study shows that there are benefits from vitamin E supplementation for a distinct population of patients, type 2 diabetics with the Hp 2-2 genotype. Such a genotype is encountered in 40% of individuals over 55 with diabetes, or approximately 2% to 3% of the general population.

This finding will raise interest in the relevant genotyping of individuals. A commercial genetic test for Hp 2-2 is in development. One of the authors of this study has a patent for a specific antibody to Hp 2-2, and Alteon Inc. is developing a testing kit. It seems likely that haptoglobin genotyping will become part of the evaluation of cardiovascular risk in diabetics in the near future, and vitamin E supplements will have been 'rehabilitated' as a useful measure in certain individuals.