Multivitamins and mortality

# Overview
Use of multivitamin supplements in the US has increased tremendously in past decade. According to the data from National Center for Health Statistics, over 50% of adults in the United States consume dietary supplements, with approximately 35% of adults taking multivitamin supplements. Annual multivitamin and dietary supplements sales total to $ 20 billion. Studies on multivitamin supplements have shown conflicting evidence on their effect on mortality, with majority of studies showing a reduction in mortality and a few demonstrating an increase.

# Mode of Action
- Free radical formation in the cell is a result of normal energy metabolism leading to oxidant stress. It may also occur as a consequence of exposure to environmental agents like cigarette smoking.
- Oxidative damage to cell disrupts the normal structure and function of DNA and lipids (causing lipid peroxidation) giving rise to cancer and atherosclerosis.
- Vitamins, being anti-oxidants, prevent this damage caused by free radicals by antagonizing its effect, thereby preventing cancers and atherosclerosis.

# Landmark Studies

## Iowa Women's Health Study 
- This was an observational study that assessed the long term effects of multivitamin supplements on all-cause mortality. It included 38,772 women with a mean age of 61.6 years at baseline.
- The study found increase in risk of total mortality in women on dietary and vitamin supplements, with highest increase in mortality seen in women on iron supplements. Calcium supplement intake was associated with a decrease in mortality.
- Limitations of the study include:
Confounding factors: Smoking status, alcohol intake, BMI and lipid levels were not excluded to minimize bias.
The study heavily relied on questionnaire
Compliance of the women taking multivitamin and mineral supplements was not considered
Although the multivitamin and dietary mineral intake patterns in these women were observed, the serum levels of vitamins and minerals were not studied to correlate the occurrence of death with intake of the supplements.
- Confounding factors: Smoking status, alcohol intake, BMI and lipid levels were not excluded to minimize bias.
- The study heavily relied on questionnaire
- Compliance of the women taking multivitamin and mineral supplements was not considered
- Although the multivitamin and dietary mineral intake patterns in these women were observed, the serum levels of vitamins and minerals were not studied to correlate the occurrence of death with intake of the supplements.
In contradiction to the above findings, another recent prospective longitudinal cohort study that assessed the long term effects of calcium on cardiovascular mortality demonstrated an increase in death rates from all causes and cardiovascular diseases in those on calcium supplements.

## Physician's Health Study II (Prevention of Cancer)
- This was a large scale randomized, double-blinded, placebo-controlled trial done on 14,641 US male physicians aged 50 years or older with 1312 men having a history of cancer.
- All the subjects were then randomly assigned to receive either multivitamins or placebo and followed-up for a median of 11.2 years. The primary end points included total cancer, with other site specific cancers as secondary end points.
- Compared to placebo, the incidence of total cancer in men on multivitamin supplements in this study showed a modest but statistically significant reduction.

## Physician's Health Study II (Cardiovascular mortality)
- The above study population of 14,641 US male physicians were studied for effects of long term multivitamin supplements use on cardiovascular mortality. They were randomly assigned to multivitamins and placebo group, and followed up for a period of 11.2 years
- The study demonstrated no significant effects of daily multivitamin on cardiovascular events, including total MI and total stroke. Also, there was no significant difference seen in total cardiovascular mortality in the two groups.

## Physician's Health Study II (Effects of Vitamin E and Vitamin C on Cardiovascular Mortality)
- This study also analyzed the above data to assess the effects of vitamin E and vitamin C supplements on cardiovascular mortality.
- At the end of the follow-up period of 11.2 years, it was found that neither vitamin E nor vitamin C reduced the risk of major cardiovascular events.

## Cancer Prevention Study - II 
- Another large prospective study done by CDC and National center for environmental health, included 1,063,023 men and women to determine the effects of multivitamins supplements on incidence of cardiovascular disease, cerebrovascular disease and cancer.
- They compared the mortality in these healthy subjects by dividing the cohort into 4 subgroups:
Multivitamin group: Those consuming multivitamins including vitamin B12, B6, folic acid, etc.
Vitamin A, C and E group
Combination of multivitamin and vitamin A, C and E group
Non-vitamin users
- Multivitamin group: Those consuming multivitamins including vitamin B12, B6, folic acid, etc.
- Vitamin A, C and E group
- Combination of multivitamin and vitamin A, C and E group
- Non-vitamin users
- The incidence of cardiovascular and cerebrovascular deaths was the same in multivitamin group and non-users, whereas it was 15% lower in those on combination of multivitamin and vitamin A, C and E.
- The multivitamin and the combination group had minimal effects on overall cancer mortality. However, mortality from all cancers increased in male smokers in these groups and decreased in male non-smokers who belonged to the combination group. No such associations were seen in females.
- The risk of ischemic heart disease and stroke mortality was lower in those on combination of vitamins than multivitamins alone and non-users. The risk of cancer was increased in multivitamin users who smoked than those who did not.

# Other Studies
- A cohort study performed in Washington, assessed the long term effects of vitamin supplements on cardiovascular mortality using data collected from 77,719 residents of the Washington State aged 50 to 76 years by filling a questionnaire. The study demonstrated a small decrease in risk of cardiovascular mortality with vitamin E use and no effect with the use of vitamin C.
- A similar prospective cohort study done by Muntwyler et al. on 83,639 healthy US male physicians, showed no significant effects of vitamin C and vitamin E intake on increase in cardiovascular mortality.
- A meta-analysis report from randomized controlled trials also showed no significant effects of multivitamin and multimineral intake on cardiovascular mortality.