Supplements, mortality and disease incidence - nothing has changed

In this post I would like to highlight the following review because a few people from our nutrition department were involved in it and I've been looking forward to their final analysis for some time. Sorry, if I'm rambling too much but whenever I am too perfectionist then no blogging gets done at all!

Schwingshackl, Lukas, et al. "Dietary Supplements and Risk of Cause-Specific Death, Cardiovascular Disease, and Cancer: A Systematic Review and Meta-Analysis of Primary Prevention Trials." Advances in Nutrition: An International Review Journal 8.1 (2017): 27-39.

Our aim was to assess the efficacy of dietary supplements in the primary prevention of cause-specific death, cardiovascular disease (CVD), and cancer by using meta-analytical approaches. Electronic and hand searches were performed until August 2016. Inclusion criteria were as follows: 1) minimum intervention period of 12 mo; 2) primary prevention trials; 3) mean age ≥18 y; 4) interventions included vitamins, fatty acids, minerals, supplements containing combinations of vitamins and minerals, protein, fiber, prebiotics, and probiotics; and 5) primary outcome of all-cause mortality and secondary outcomes of mortality or incidence from CVD or cancer.
Pooled effects across studies were estimated by using random-effects meta-analysis. Overall, 49 trials (69 reports) including 287,304 participants met the inclusion criteria. Thirty-two trials were judged as low risk-, 15 trials as moderate risk-, and 2 trials as high risk-of-bias studies. 
Supplements containing vitamin E (RR: 0.88; 95% CI: 0.80, 0.96) significantly reduced cardiovascular mortality risk, whereas supplements with folic acid reduced the risk of CVD (RR: 0.81; 95% CI: 0.70, 0.94). Vitamins D, C, and K; selenium; zinc; magnesium; and eicosapentaenoic acid showed no significant risk reduction for any of the outcomes. On the contrary, vitamin A was linked to an increased cancer risk (RR: 1.16; 95% CI: 1.00, 1.35). Supplements with β-carotene showed no significant effect; however, in the subgroup with β-carotene given singly, an increased risk of all-cause mortality by 6% (RR: 1.06; 95% CI: 1.02, 1.10) was observed.
Taken together, we found insufficient evidence to support the use of dietary supplements in the primary prevention of cause-specific death, incidence of CVD, and incidence of cancer. The application of some supplements generated small beneficial effects; however, the heterogeneous types and doses of supplements limit the generalizability to the overall population.

Should you supplement?

Vitamin E: CVD mortality down, all-cause tends to be up. Consistent with prior studies. Not a value proposition. Verdict: Stay conservative. Vitamin E sufficiency seems beneficial. Get it from diet.

Folic acid: CVD incidence down. Sort of consistent with prior studies. Verdict:  Stay conservative. Folic acid sufficiency seems beneficial. Get it from diet.

Selenium: All-cause trends down. Given failure of high dose SELECT trial, it is likely that mere Se sufficiency is optimal and successful studies were performed in populations with marginal Se status. 
Verdict:  Stay conservative. If you are at risk for deficiency, take a very low dose supplement!

Vit D: All cause mortality trends down, this is consistent with other studies showing 0-10% improved all-cause mortality. Awaiting large studies, but most sun-avoiding people would be safe to try supplementing in the range of 700-1000 IU.

Vitamin A, beta-carotene: Vit A associated with cancer incidence, beta-carotene not consistently so. Verdict: Get it from diet, don't overdo it.

Magnesium, EPA, vitamin K: Too few datapoints

Calcium: evidence of reduced cancer incidence, but small dataset, probably colorectal cancer effect. 
 Verdict: Stay conservative. Ca sufficiency seems beneficial. If you are at risk for deficiency, take a very low dose supplement!

As you can see from the abstract, all the risk ratios are quite modest and as we will see below there are other problems as well.

I want to explain the author's conclusions based on the example of calcium. Why are the authors so skeptical? "Taken together, we found insufficient evidence to support the use of dietary supplements in the primary prevention of cause-specific death, incidence of CVD, and incidence of cancer. The application of some supplements generated small beneficial effects; however, the heterogeneous types and doses of supplements limit the generalizability to the overall population."
It is perhaps hard to understand for a lay person at first glance why we don't want to take lots of Ca for cancer. The finding is significant, great, no? No. In fact, the calcium data is based on 2 studies and some 30+30 cases of cancer. Most studies are performed with non-cancer primary endpoints leading to potential bias, if people in the low Ca group went more often to the doctor because of fractures and then their cancer was discovered, for example. Most Ca studies are fracture studies, so they cannot be generalized to the young population at large.
Furthermore, with calcium there is the theoretical risk of promoting vascular calcification, but I speculate (based on preliminary reading) that this only applies to high doses of calcium that are taken in one go. It seems phosphate is much more important for calcification because it is less tightly regulated than Ca. In this analysis there was no CVD risk after pooling n~7 calcium studies (similar to 
PMID: 25042841). I don't recall many large calcium studies for primary prevention and perhaps it is time to revive this concept? Calcium hasn't been on my radar for a long time, I must admit. A quick glance through PUBMED: "calcium randomized primary (trial OR study) (cancer OR mortality)" confirms that I probably recall correctly. Very few primary prevention studies and mixed data on Ca vs. adenoma recurrence.

Although of limited power, calcium supplementation was associated with a decreased risk of cancer incidence compared with control groups in the present meta-analysis. Nevertheless, these results should be interpreted with caution, because only a very low number of cancer cases were included in the meta-analysis (30 cancer cases in the intervention groups compared with 23 in the control groups). A meta-analysis of prospective observational studies showed that calcium supplements and nondairy products fortified with calcium significantly reduced the risk of colorectal cancer by 8% (108). In contrast, a meta-analysis of cohort studies showed that a 400-g/d increase in dietary calcium was positively associated with prostate cancer...

Interestingly, the two calcium studies included were:
The moderately large Lappe study (n~1000), which is quite famous...
Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007;85:1586–91.

...and this tiny one (n~200-300)
Chailurkit LO, Saetung S, Thakkinstian A, Ongphiphadhanakul B, Rajatanavin R. Discrepant influence of vitamin D status on parathyroid hormone and bone mass after two years of calcium supplementation. Horumon To Rinsho 2010;73:167–72.

But the much, much larger WHI (n~30 000) was excluded from this meta-analysis because it used 1000 mg Ca + 400 IU Vitamin D and it failed to show any effect on cancer. I almost forgot this problem, and so the calcium hypothesis seems quite dead in the water: RCTs are mixed, small effect sizes, etc...

Comment on folate: 
Previous meta-analyses showed that vitamin B supplements (one-carbon metabolites) lowered the risk of stroke, but not CVD, myocardial infarction, coronary heart disease, cardiovascular death, or all-cause mortality (10). It was shown that folic acid supplementation had no significant effect on cardiovascular events, overall cancer, or mortality in high-risk patients (104). Compared with previous meta-analyses, we found new evidence for a beneficial effect of folic acid in the primary prevention of CVD. Supplementation with folic resulted in a 19% decrease in CVD risk compared with a placebo or control group. Our observations are largely based on a recently published Chinese multicenter trial in 20,702 hypertensive adults, which showed a 19% decreased risk of CVD (50). In addition, observational studies in the past have observed a link between low folate intake and risk of CVD (105, 106).
As we can see again, a single large study can have a big impact on the analysis.  So is it time to revive the dreary saga of homocysteine lowering? Perhaps choosing at risk populations? (I get the feeling this was already tried and I am just forgetting.) Or should we just promote a healthy diet as a simple, "natural", proven source of folate?

The story goes like that....
Preliminary data is supportive and then comes along a large trial to refute the hypothesis. Beneficial dietary carotenoids -> CARET; selenium data (as in this analysis) -> SELECT; calcium data (as in this analysis) -> WHI; beneficial dietary folate -> lots of mixed trials; beneficial dietary Vitamin E -> lots of mixed trials.
So how can we be hopeful about vitamin D? Because the jury is out, for vitamin D we only have preliminary data and it hasn't reached the phase when supplement hypotheses are sunk by controlled trials. Note: The large WHI study used a very low dose of vitamin D and most people discount it siding with the vitamin D "optimists". Magnesium and vitamin K are also in the early optimist stage. Finally, I want to somewhat revise my neutral stance on zinc from my prior post. In this study zinc supplementation had a small non-significant benefit on cancer mortality, which is not influencing my opinion. However, due to purely mechanistic considerations I want to upgrade zinc from "boring" to worth studying (c.f. Cd, metallothionein).