Vitamin E in humans: an explanation of clinical trial failure.
OBJECTIVE
To describe the potential benefits and hazards of vitamin E supplementation and present a rational basis for understanding the conflicting results among randomized clinical trials, epidemiologic investigations, and animal studies on the use of vitamin E to prevent atherosclerosis.


METHODS
We conducted a retrospective review of the pertinent literature found in PubMed from 1981 through August 2005. The published data are analyzed and summarized.


RESULTS
The possible factors implicated for failure of vitamin E therapy include the following: (1) the inclusion of patients without biochemical evidence of increased oxidative stress, (2) the relatively short duration of treatment, (3) the use of suboptimal dosages of vitamin E, (4) the suppression of gamma-tocopherol by alpha-tocopherol, (5) the use of vitamin E supplementation without the concurrent use of vitamin C, (6) the lack of inclusion of biochemical markers of oxidative stress and markers of vascular response, (7) the inappropriate administration of vitamins relative to meal ingestion, and (8) the poor patient compliance and the lack of monitoring of vitamin E levels.


CONCLUSIONS
Large, randomized clinical trials have not yet substantiated a beneficial effect of use of vitamin E to reduce atherosclerotic risk in humans, despite demonstration of antioxidant effects in vitro and in animals. Only in subsets of patients at high risk for atherosclerosis has a beneficial effect been suggested. Before additional large, randomized clinical trials of vitamin E are performed, the specific biologic and surrogate marker effects of vitamin E in each target population must be defined more carefully. This approach will save resources, minimize untoward side effects, and identify the patients who will benefit the most.
Robinson
Irina
I
Department of Internal Medicine, Division of Endocrinology and Metabolism, University of New Mexico, Albuquerque, New Mexico 87131-0001, USA.
de Serna
Daniela Gonzalez
DG
Gutierrez
Absalon
A
Schade
David S
DS
D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D050197:Atherosclerosis / Q000188:drug therapy / Q000209:etiology; D001777:Blood Coagulation / Q000187:drug effects; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005982:Glutathione Transferase / Q000378:metabolism; D006333:Heart Failure / Q000453:epidemiology / Q000209:etiology; D006801:Humans; D008954:Models, Biological; D018384:Oxidative Stress / Q000502:physiology; D018570:Risk Assessment; D017211:Treatment Failure; D014810:Vitamin E / Q000009:adverse effects / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use*; D014812:Vitamin K / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D014812:Vitamin K; D014810:Vitamin E; D005982:Glutathione Transferase; D001205:Ascorbic Acid