Jump to content

Risky supplementation

Recommended Posts

This is an article from Al's papers citations, which caught my attention and probably needs to be pondered upon. It's yet another caution against the use of high doses of supplements, especially the antioxidants, in some ocular patologies related to oxidative damage.





Conclusions There is probable evidence for a protective effect of fruits and vegetables, vitamin C and E on CAT and AMD, however AMD risk increases with higher intakes of supplemental vitamin C. Higher intakes of dietary meat also increase the risk of CAT and AMD. Dietary intake of vitamin A and its derivatives appear protective against CAT, but not in supplemental form. Vitamin A in both diet and supplement form appears to be protective against AMD. Due to the low number of published studies, the evidence regarding the prevention of GLA through higher consumption of antioxidant supplements and/or vegetables and fruit is unclear, with more research warranted. A higher intake of fruit and vegetables is protective against AMD, but otherwise unclear. There is limited evidence that dietary iron and calcium are protective against GLA. Based on the literature to date, it would be safe to advise patients with a family history of oxidative stress related ocular disease to consume a diet high in particularly those rich in vitamin C and E. These is some evidence that high intakes of supplemental forms of antioxidants are damaging and we would recommend further investigation into appropriate dose, form and timing of antioxidant consumption. AUTHOR DISCLOSURES All authors declare no conflict of interest or funding sources.



Food components and ocular pathophysiology: a critical appraisal of the role of oxidative mechanisms.
Raman R, Vaghefi E, Braakhuis AJ.
Asia Pac J Clin Nutr. 2017;26(4):572-585. doi: 10.6133/apjcn.082016.01.
PMID: 28582804
Three of the major ocular diseases, namely cataracts, age-related macular degeneration and glaucoma are associated with oxidative damage. Disease risk and progression may be reduced through consumption of dietary components. To critically examine the literature on dietary and supplemental intakes of fruit and vegetables, meat, antioxidants (vitamins C, E and A), calcium, folate, iron, and their association with ocular disease.
Google Scholar and key references from texts and publications were searched using search terms (eye disease, antioxidants), (vision, nutrition), no date restriction, only articles in English were included.
We found probable evidence that dietary intake of fruits and vegetables, and vitamin C lowered incidence of cataracts and age-related macular degeneration. In high supplemental doses, vitamin C increases macular degeneration risk. Vitamin A from food was protective for cataracts and glaucoma, but not in supplemental form. Vitamin A was associated with lower incidence of macular degeneration. We also found probable evidence that higher intakes of meat increased the risk of cataracts and macular degeneration. Dietary calcium and iron appeared protective against glaucoma, but not in supplemental form.
While a nutrient rich diet high in fruit and vegetables, and associated antioxidants appeared to be protective, we would caution intake of supplementary antioxidants for those with ocular disease.


Link to comment
Share on other sites

McCoy, I took note of that as well and read the full text of the study.   The conclusions there seem far less alarming and  far less certain.  (Of course, this  wouldn't in any case undermine your general caution against the use of high dose supplements.)


In the summary we find the statement:


In high supplemental doses, vitamin C increases macular degeneration risk.


But in the full text we find  the less categorical statement:


Literature presented in Table 3 suggests that while the dietary data on vitamin C is unclear with a trend to decreasing disease risk, supplemental vitamin-C appears to increase AMD risk. [emphasis added]



In Table 3,  I found two studies related to a possible Vit C- supplement- caused increase in AMD risk.   I'm a little tired now, so I probably missed something.


Study #1


Dietary antioxidant intake and incidence of early age-related maculopathy




To investigate associations between dietary intake, including modest supplement intake, of antioxidant vitamins and zinc at baseline and the 5-year incidence of early age-related maculopathy (ARM). Population-based cohort study. From 1992 through 1994, 3654 persons aged 49 years or more (82% of those eligible) living in two postcode areas west of Sydney, Australia, were examined for the Blue Mountains Eye Study baseline. Five years later, 2335 persons (75% of known survivors) were reexamined. A 145-item Food Frequency Questionnaire (FFQ) was used to assess nutrient intakes. Of the 2335 people who attended a follow-up visit, 1989 (85%) had completed a FFQ at baseline. The nutrients examined in this study included: alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein and zeaxanthin, lycopene, retinol, vitamin A, vitamin C, and zinc. Early ARM was assessed by masked grading of stereo retinal photographs. Definitions for incidence closely followed those used in the Beaver Dam Eye Study. Early ARM developed in 192 persons (8.7% 5-year incidence) who did not have either late or early ARM at baseline. Of these, 159 persons completed the FFQ at baseline. After adjusting for age, gender, family history of ARM, and smoking status at baseline, no associations, or any trends suggesting possible association, were found between baseline intake of the nutrients examined, apart from vitamin C, and the 5-year incidence of early ARM. Compared with the lowest quintile, increasing baseline intakes of vitamin C, from diet and supplements, was associated with an increased risk of incident early ARM (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.0-3.0; and OR, 2.3; 95% CI, 1.3-4.0 for the fourth and fifth quintiles, respectively). Our cohort study of an older population could not find evidence of protection associated with usual dietary antioxidant or zinc intakes (including use of supplements) on the 5-year incidence of early ARM.

[emphasis added]


 I notice right off the bat that the possible increased risk of early ARM is in relation to increased intakes of vitamin C from diet as well as supplements.     Perhaps you can dig up the full text and look into it further,  but I'm reluctant to draw alarmist conclusions from what I see there.


Study #2:


Prospective cohort study of antioxidant vitamin supplement use and the risk of age-related maculopathy. Am J Epidemiol. 1999 Mar 1;149(5):476-84. PMID:10067908




In a prospective cohort study, the authors examined whether self-selection for antioxidant vitamin supplement use affects the incidence of age-related maculopathy. The study population consisted of 21,120 US male physician participants in the Physicians' Health Study I who did not have a diagnosis of age-related maculopathy at baseline (1982). During an average of 12.5 person-years of follow-up, a total of 279 incident cases of age-related maculopathy with vision loss to 20/30 or worse were confirmed by medical record review. In multivariate analysis, as compared with nonusers of supplements, persons who used vitamin E supplements had a possible but nonsignificant 13% reduced risk of age-related maculopathy (relative risk = 0.87, 95 percent confidence interval (CI) 0.53-1.43), while users of multivitamins had a possible but nonsignificant 10% reduced risk (relative risk = 0.90, 95% CI 0.68-1.19). Users of vitamin C supplements had a relative risk of 1.03 (95% CI 0.71-1.50). These observational data suggest that among persons who self-select for supplemental use of antioxidant vitamin C or E or multivitamins, large reductions in the risk of age-related maculopathy are unlikely. Randomized trial data are accumulating to enable reliable detection of the existence of more plausible small-to-moderate benefits of these agents alone and in combination on age-related maculopathy. [emphasis added]


You can get the full text here:



Compared with nonusers of supplements, users of vitamins C and/or E had a relative risk for age-related maculopathy of only 0.95 (95 percent confidence interval (CI) 0.53-1.71) according to analyses that adjusted for age and treatment assignment (table 3, analysis A). Users of multivitamins plus vitamins C and/or E had a relative risk of 1.06 (95 percent CI 0.71-1.58). Those who used multivitamins only had a nonsignificant 13 percent reduced risk of age-related maculopathy (relative risk (RR) = 0.87, 95 percent CI 0.63-1.21) after adjustment for age and treatment assignment. Controlling for other potential risk factors further reduced the relative risk for users of multivitamins only, but the reduction remained statistically nonsignificant (RR = 0.82, 95 percent CI 0.59-1.15).


For exudative macular degeneration (data not shown), users of vitamins C and/or E only had a significantly elevated risk for disease (RR = 2.60, 95 percent CI 1.17-5.78) compared with nonusers of supplements according to analyses adjusted for age and treatment assignment. However, there were only seven cases of exudative macular degeneration in this supplement group. Relative risks for users of multivitamins only (RR = 1.18, 95 percent CI 0.63-2.22) and for users of multivitamins plus vitamins C and/or E (RR = 1.06, 95 percent CI 0.45-2.50) were slightly above 1.00. Results were essentially unchanged after controlling for other possible risk factors for agerelated maculopathy.


When we analyzed supplement use by comparing users of specific supplements (with or without other supplements) with nonusers of supplements in separate regression models, we noted no significant increase or decrease in risk for either age-related maculopathy or exudative macular degeneration. At baseline, 9.8 percent of physicians reported use of vitamin C supplements, 5.1 percent reported vitamin E supplementation, and 19.5 percent reported multivitamin use. Compared with nonusers of supplements, users of vitamin C supplements had a relative risk of 1.03 (95 percent Cl 0.71-1.50) for age-related maculopathy after adjustment for age, treatment assignment, and other possible risk factors (table 3, analysis B). Persons taking vitamin E supplements had a nonsignificant 13 percent reduced risk of age-related maculopathy (RR = 0.87, 95 percent Cl 0.53-1.43) and users of multivitamins had a nonsignificant 10 percent reduced risk of disease (RR = 0.90, 95 percent Cl 0.68-1.19) in models controlling for other possible risk factors for age-related maculopathy. There were no statistically significant trends of decreased risk with increasing duration of supplemental use (<5 years, 5-10 years, >10 years) of vitamin C, vitamin E, or multivitamins (data not shown).


For exudative macular degeneration, there was a modest but statistically nonsignificant increased risk of disease for users of vitamin C supplements (RR =1.41, 95 percent Cl 0.70-2.83) after adjustment for other possible risk factors for age-related maculopathy. Relative risks for users of vitamin E (RR = 1.10, 95 percent Cl 0.43-2.80) and users of multivitamins (RR = 1.07, 95 percent Cl 0.61-1.88) were near the null value of 1.0.   [emphasis added]


Again,  I don't see all that much there that is alarming in term of supplementation.  (How much vitamin C were these physicians taking?)


Perhaps with your formidable  research/analytical skills you can do a better job than I  did  at finding the solid evidence that justifies the conclusion, "in high supplemental doses, vitamin C increases macular degeneration risk", if such evidence exists. 


Link to comment
Share on other sites

Sibiriak, thanks for the 'your formidable  research/analytical skills' but I'm really a newbee in this nutritional arena, although I've been dealing with statistics and data analysis in other areas.


It's strange but, to tell you the truth, I had your same impression by reading the full text and especially the tables. Then the final conclusions seem a little milder than the abstract. I believe a more thorough reading is needed to understand the source of the authors' words of caution.

Link to comment
Share on other sites

High doses of vitamin C, E, or A are in any case certainly suspect,  not to mention excessive calcium, iron and other nutrients.


In relation to eye health,  there seems to be more focus these days on lutein and zeaxanthin,  and supplementation with those nutrients has it controversies as well.

Link to comment
Share on other sites

  • 3 months later...

From Al Pater:  Another case where natural intake vs supplementation of a nutrient may have divergent effects.




Toenail selenium levels and prevalence of dyslipidaemia among Korean adults.

Jang J, Morris JS, Park K.
Br J Nutr. 2017 Sep;118(6):473-480. doi: 10.1017/S0007114517002343.
PMID: 28980892


Multiple studies have elucidated the antioxidant properties of Se, which are now well known among the nutrition and biomedical science communities. Recently, considerable interest has been focused on the possible association between Se exposure and risk of metabolic disease, such as lipid dysregulation; however, there is limited epidemiological data on this topic. The present study aimed to investigate associations between toenail Se levels and dyslipidaemia or individual lipid levels, and to examine the effect of dietary supplement use on these associations. We analysed baseline data from a cohort in the Yeungnam area, including 232 men and 269 women. Information on demographic, dietary and lifestyle characteristics was obtained through a self-reported questionnaire. Se levels in toenail specimens were measured using neutron activation analysis. Fasting blood lipid levels were measured during medical examinations. After adjusting for multiple confounding variables, we observed no association between toenail Se levels and dyslipidaemia or individual lipid profiles. However, the association was modified by dietary supplement use. Among the supplement users, higher toenail Se levels were associated with a higher prevalence of lipid dysregulation, whereas non-users exhibited a lower prevalence of lipid dysregulation. Associations between toenail Se levels, lipid levels and dyslipidaemia may be influenced by taking dietary supplements. Future large-scale, prospective cohort studies should be conducted to further evaluate the association between Se levels in the body and metabolic health effects in light of increasing rates of dietary supplement use.

Link to comment
Share on other sites

The above discussion reminds me of  very simple, pragmatistic outlook in Valter Longo book on longevity. Since, he writes, it is not clear from literature whether supplements are beneficial or detrimental, it is suggested according to him to take'em a couple of times a week.


As far as I've noticed the users of this forum tend to take supplements when needed, i.e. when cronometer underlines a possible negative departure from the RDA. 


That's what I'm doing, also following the suggestion to take zinc supplements to bing cadmium.


What's clear is that some micronutrients in supplemental form might be risky, like A, E, B9...


Vit C and Selenium we have seen from the above articles. 

Link to comment
Share on other sites

when cronometer underlines a possible negative departure from the RDA.


There are so many variables  when it comes to the bioavailability of various nutrients-- variation between individuals, variation due to food matrix, food combinations etc.--that it would  seem advisable to get tested for key nutrient levels.  Of course,  that suggestion has many complications as well:  What kind of test (plasma, hair, toenails)?  How often? How reliable are the tests?

Link to comment
Share on other sites

When you have so many conflicting studies, I think one can reach some meta conclusions, from a purely analytical point of view. The conclusion is: the effects of supplementation are non-significant either way. Consider the following - there are an overwhelming number of studies that show the consumption of tobacco products (in whatever form: smoking, chewing etc.) is detrimental to health. There are virtually no studies that show benefits of smoking (some possible parkinson's related excepted). What does that tell me? It tells me that the effect of smoking is LARGE and CONSISTENT. I can reach a firm conclusion about tobacco products and health. But if I see a million studies say "A" and another million say "not-A", then my conclusion is that the effect, such as there may be is SMALL and INCONSISTENT. Because if it was large and clear cut, you'd have the same overwhelming result as with smoking.


Bottom line, when you have decades of research and thousands of studies with tens of millions of subjects and you are still getting entirely conflicting and fuzzy results, the meta conclusion is: the effect is SMALL. Otherwise you'd have the tobacco effect. So my conclusion is - tobacco clearly bad, supplements not much effect either way.


The important caveat here is that we are talking about people without frank deficiencies of vitamins and minerals, because there, the studies ARE unequivocal - if you have scurvy, supplementing with vit. C is DEFINITELY helpful. But note - those studies are clear-cut. There is no "conflicting studies" some of which show that C is helpful for scurvy and some that it is not. It's like with tobacco - LARGE and CONSISTENT effect. But that is not what happens when you start supplementing in people who have not been clinically diagnosed with frank deficiencies. So for ordinary people, it's as stated - the effects of supplementation are SMALL either way.

Link to comment
Share on other sites

TomBAvoider:  The conclusion is: the effects of supplementation are non-significant either way. Consider the following - there are an overwhelming number of studies that show the consumption of tobacco products



That comparison doesn't work for me because "supplementation" is an extremely broad category, while "tobacco products" is a much narrower one (although still not precise).


I have zero interest in knowing whether the "effects of supplementation" are significant or not.  I'm only interested in knowing the effects of very tightly defined substances under tightly defined conditions.

Link to comment
Share on other sites


This topic is now archived and is closed to further replies.

  • Create New...