Title: Potential weaknesses of vitamin E trials
Key words: free radical, cancer, cardiovascular disease, CVD, ageing, oxidative modification, low density lipoprotein, LDL, atherogenesis, antioxidants, vitamin E, supplements, supplementation, atherosclerosis, flavonoids, haemodialysis, synthetic vitamin E, isoprostane, excretion, pro-oxidant, atherosclerotic plaque, genotypes, combination, combination therapy,
Date: Sept 2006
Author: Morgan, G
Potential weaknesses of vitamin E trials
Free radical damage has been linked to cancer, cardiovascular disease and the ageing process (Halliwell 1999). Of these, cardiovascular disease (CVD) has been the most extensively studied as it offers a convenient model for longitudinal and intervention studies. Models such as Steinberg’s ‘oxidative modification’ hypothesis (Steinberg 1989, Diaz 1997) have helped support in vitro and in vivo evidence that oxidative damage to low density lipoproteins is central to atherogenesis and can be prevented by adequate levels of antioxidants.
Vitamin E has been shown to be the most powerful of the investigated antioxidants and an inverse relationship between plasma vitamin E levels and cardiovascular disease has been confirmed in cross-cultural surveys (Gey 1991). In spite of much observational and laboratory work indicating a protective role of antioxidants in atherosclerosis, large trials throughout the world have failed to show a similar consistently beneficial effect of vitamin E supplementation. Given the design of these trials how are we to interpret this so-called ‘antioxidant paradox’ (Halliwell 2000)? The following points need to be made:
1. Confounding factors render it unclear whether, in populations with elevated plasma vitamin E levels, reduced CVD causally reflects intakes of this particular antioxidant, other antioxidants such as the flavonoids, or other non-antioxidant or non-dietary factors.
2. Established atherosclerosis was present in all the trials so the selection of diseases, markers and clinical endpoints is critical in elucidating the efficacy or otherwise of supplementation. One trial included haemodialysis patients (SPACE 2000). Can general conclusions be derived from such a model? With four of the trials (GISSI 1999, HOPE 2000, CHAOS 1996, SPACE 2000), the yearly infarction rates were 2.5%, 3.8%, 5.1% and 12.3% respectively. Given such figures, were the Italians involved in the GISSI trial, for example, following a lifetime exposure to the Mediterranean diet and with their better pre-morbid condition compared to the UK participants in the CHAOS trial, less amenable to the benefits of supplementation? The negative results of the GISSI trial argue in favour of this point (Brown 1999).
3. Some trials, eg the GISSI, used lower doses of the less bioavailable synthetic vitamin E. Other trials, such as the CHAOS and SPACE trials, used up to 800 i.u. per day. Do negative results reflect a failure to reach certain threshold values?
4. Isoprostane excretion is considered the best index of lipid peroxidation and antioxidant activity. None of the trials monitored isoprostane excretion, so it is not clear that the trials measured what they purported to measure.
5. Were some beneficial antioxidant effects of vitamin E masked by pro-oxidant effects? Pro-oxidant effects might lead to instability of the atherosclerotic plaque with rupture of the cap and an increased infarction rate (Diaz 1997, Folk 1992). The results of the GISSI trial may be interpreted in this fashion as there was an initial – if not significant – rise in the infarction rate followed after some 200 days by a lowering of the rate, perhaps resulting from beneficial antioxidant effects.
6. The genotypes of the cohorts were not considered. With the GISSI trial, for example, would a high incidence of the apoE 3/4 genotype have impacted on any response to a Mediterranean diet and vitamin E supplementation? Other genotypic expression such as eNOS might also need to be considered (Hingorani 1999).
The multi-factorial aetiology of CHD and the design of intervention trials where the above factors were not factored into the analysis of the data, has led to a great debate over the value of such trials. Multivariate analyses have done little more than highlight the issues (Hooper 2001). Models looking at the evolution of atheromatous lesions over time in primate and human groups in terms such as intima-media thickness (Verlangieri 1992, Salonen 2000), would seem to offer an opportunity to monitor the effects of vitamin E and, though criticised (Kritharides 2001), offer a way forward. The effects of the higher doses of vitamin E and the possible potentiating effects of other antioxidants in combination needs also to be looked at in further trials.
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