Supplements Are Safe... Right?

This little blurb is to remind us all that we cannot consider supplements benign. 

Back in the 70s and 80s they noticed that smokers who ate more fruit and vegetables tended to get lower incidences of lung cancer. Looking to improve health, the researches thought, let's find the chemical in vegetables driving this protective mechanism, isolate it, and see if we can reduce lung cancer incidence with a pill. They picked Beta Carotene (a pro vitamin that is converted into Vitamin A in the liver) and its down stream product Vitamin A as the likely chemical reducing the cancer risk.

NERD NOTE: Vitamins are defined as "any of a group of organic compounds which are essential for normal growth and nutrition and are required in small quantities in the diet because they cannot be synthesized by the body." Organic meaning made of carbon in this instance. Thus by definition it is the beta carotene that is in fact the vitamin. Vitamin A is a misnomer and is in fact not a vitamin because the body produces it from beta carotene in the liver... OK back to the topic at hand...

To test the theory of beta carotene and Vitamin A as the likely chemical they organized and ran a multicenter, randomized, double-blind, placebo-controlled primary prevention trial involving 18,314 smokers that were given either 1) 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) or 2) Placebo. They published the study in 1996. Honestly I think the abstract says it best so here you go:

"Abstract

Background. Lung cancer and cardiovascular disease are major causes of death in the United States. It has been proposed that carotenoids and retinoids are agents that may prevent these disorders. Methods. We conducted a multicenter, randomized, double-blind, placebo-controlled primary prevention trial — the Beta-Carotene and Retinol Efficacy Trial — involving a total of 18,314 smokers, former smokers, and workers exposed to asbestos. The effects of a combination of 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) in the form of retinyl palmitate per day on the primary end point, the incidence of lung cancer, were compared with those of placebo. Results. A total of 388 new cases of lung cancer were diagnosed during the 73,135 person-years of followup (mean length of follow-up, 4.0 years). The active-treatment group had a relative risk of lung cancer of 1.28 (95 percent confidence interval, 1.04 to 1.57; P0.02), as compared with the placebo group. There were no statistically significant differences in the risks of other types of cancer. In the active-treatment group, the relative risk of death from any cause was 1.17 (95 percent confidence interval, 1.03 to 1.33); of death from lung cancer, 1.46 (95 percent confidence interval, 1.07 to 2.00); and of death from cardiovascular disease, 1.26 (95 percent confidence interval, 0.99 to 1.61). On the basis of these findings, the randomized trial was stopped 21 months earlier than planned; follow-up will continue for another 5 years. Conclusions. After an average of four years of supplementation, the combination of beta carotene and vitamin A had no benefit and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos. (N Engl J Med 1996;334:1150-5.)

As you can see from the cover graphic, placed below as well, the treatment of 30 mg of beta carotene per day and 25,000 IU of vitamin A daily increased the incidence of lung cancer in these men. (In the graph, the higher the line goes on the Y-axis, the more men in that group developed lung cancer)

Furthermore, when looking as cardiovascular disease and all cause mortality, the picture follows a similar trend, with the treatment of 30 mg of beta carotene per day and 25,000 IU of vitamin A daily leading to an increase in both cardiovascular disease and all cause mortality. (In the graph, the higher the line goes on the Y-axis, the more men in that group had an ASCVD event or died)

In fact, for the men in the study, taking the treatment of 30 mg of beta carotene per day and 25,000 IU of vitamin A daily lead to:

- a 28% increased relative risk of lung cancer of HR 1.28 (95%CI 1.04 to 1.57; P0.02)

- an 18% increased likelihood of death in general. HR 1.18 (95%CI 1.02 to 1.37) 

- a 46% increased likelihood of death from lung cancer. HR 1.46 (95%CI 1.07 to 2.00)

-and while not statically significant, it trended toward a 26% increased likelihood of death from cardiovascular causes. HR 1.26 (95%CI 0.99 to 1.61)

Not great... not benign.

Should this example scare us from taking any supplements ever. No, definitely not.

Should this example show us that we need to be prudent, focused, and judicious in our use of supplements.. absolutely. 

Take home: supplements are not always benign, and their negative effect might not be seen for years down the line. Be judicious when you are taking them.

LINK TO PAPER

Omenn, G.S., Goodman, G.E., Thornquist, M.D., Balmes, J., Cullen, M.R., Glass, A., Keogh, J.P., Meyskens Jr, F.L., Valanis, B., Williams Jr, J.H. and Barnhart, S., 1996. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. New England journal of medicine, 334(18), pp.1150-1155.