et al.22 analysed whether individuals with MCI benefitted from treatment with vitamin or mineral supplements. They identified eight RCTs that examined B vitamins (vitamin B6, vitamin B12, and folic acid combined or folic acid alone), vitamin E, and vitamin E combined with vitamin C, as well as a study of one essential mineral (chromium). Levels of vitamin supplementation exceeded RDA levels and varied across studies. For the RCTs of B vitamins, none reported incidence of dementia, and there was little to no effect of the supplements (taken for 6 to 24 months) on episodic memory, executive function, speed of processing, or quality of life. However, one study indicated a slower rate of brain atrophy over two years. In the RCT of vitamin E, there was no effect regarding progression from MCI to Alzheimer's dementia during the three‐year study, and no effect on overall cognitive function, episodic memory, speed of processing, clinical global impression, functional performance, adverse events, or mortality. The quality of the design was low for both the single trial of combined vitamins E and C and the single trial of chromium. The trials were small in the case of chromium (n = 26) and had only a single cognitive outcome of interest, so the supplements' effects could not be confirmed. In summary, evidence is lacking for the benefits of these supplements for MCI.22 Although interest in vitamins, minerals, and overall dietary guidance for preventing cognitive decline and Alzheimer’s disease is high, evidence‐based recommendations cannot yet be made from the available science.20,21,22
Eye disorders – age‐related macular degeneration and age‐related cataracts
Age‐related macular degeneration (AMD) is a leading cause of vision loss. Risk factors for AMD include genetic predisposition, high oxidative stress, smoking, and poor diet.23 Dietary factors such as antioxidants, minerals, and vitamins, as well as lutein and zeaxanthin, are of particular interest for eye health.23 Lutein and zeaxanthin are carotenoids that cannot be synthesized in the body or converted to vitamin A and are in the macular pigment; however, they currently are not considered essential micronutrients. There is evidence from cohort studies for a role of diet in preventing and slowing the progression of AMD. Much of the interest in and knowledge to date regarding micronutrients comes from the two Age‐Related Eye Disease Studies (AREDS and AREDS2) as summarized in Cochrane Reviews.24,25 Additional RCTs are helping to identify the specific nutrient(s) and other bioactive compounds in the diet that are most likely to prevent or slow the progression of AMD.24,25
Prevention of AMD
A Cochrane Review of supplementation studies in participants without AMD considered five RCTs investigating vitamin C, vitamin E, beta‐carotene, and MVM supplements (Centrum Silver®).24 The authors concluded that neither vitamin E (four studies) nor beta‐carotene (two studies) nor vitamin C (one study) prevented AMD. However, the study of MVM showed an increased risk of any AMD. Other adverse effects were not consistently reported, but one of the studies of vitamin E supplements showed an excess of haemorrhagic strokes, and there is evidence from other large studies that supplements of beta‐carotene increase the risk of lung cancer in those who smoke or who have been exposed to asbestos.
Slowing the progression of AMD
There has been considerable study of the potential for micronutrient supplements to slow the progression of established AMD at both early and later stages. A recent Cochrane Review identified 19 RCTs that included studies of MVM supplements, zinc, vitamin E, and lutein and zeaxanthin.25 The MVM supplements in these trials typically contained antioxidant nutrients such as vitamin C, vitamin E, beta‐carotene, lutein and zeaxanthin, and zinc and copper. Nine studies examined MVMs in those with early and moderate AMD, with the result that various AMD‐related outcomes were delayed in the MVM‐treated groups. Six studies examined lutein (with or without zeaxanthin), and there was little to no effect on progression to late AMD and vision loss. Among the five studies that examined zinc, there was evidence that zinc and other antioxidant nutrients (MVM) slow the progression to late AMD and vision loss. The one study that examined vitamin E (without other nutrients) showed no benefit in delaying vision loss. Adverse events were not consistently assessed across these studies. At present, the findings from AREDS and AREDS2 provide much of the evidence for current practices regarding the use of nutrient supplements to delay the progression of AMD.24,25 As understanding about nutrients and eye disease evolved, the original AREDS formula was modified based on the results of AREDS2 to replace beta‐carotene with lutein and zeaxanthin and to lower the zinc content. The AREDS2 MVM formulation is available commercially.26
Prevention and slowing of age‐related cataract (ARC) development
Cataracts also increase in prevalence with age; other risk factors include ultraviolet radiation, smoking, alcohol, and type 2 diabetes. There has been interest in whether antioxidant nutrients might prevent or slow the progression of age‐related cataracts (ARC).27,28 However, the absence of proof of efficacy led to recommendations in a 2012 Cochrane Review that no further studies be conducted for the effect of beta‐carotene, vitamin C, or vitamin E on ARC.27 Since then, findings from cohort studies with dietary nutrient intake continue to indicate an association of several vitamins and carotenoids with reduced risk of ARC (12 cohort studies).28 In contrast, eight RCTs of supplements of vitamin E and beta‐carotene did not show a reduction of risk for ARC.28 Likewise, in AREDS2, supplementation with lutein and zeaxanthin did not decrease the prevalence of cataract surgery.29
Cancer and cardiovascular diseases – selenium
Selenium has been identified as a nutrient of concern in community‐dwelling older adults.8 According to a Cochrane Review, because of the use of selenium in enriched foods, supplements, and fertilizers in some countries, there could be an increased perception that selenium reduces the risk of cardiovascular disease and other chronic diseases.30 However, the results of studies to date are equivocal. Based on the results of 12 RCTs that provided selenium supplements to adults considered primarily healthy and well‐nourished, it was concluded that selenium supplements did not influence all‐cause mortality, CVD mortality, non‐fatal CVD events, or all CVD events (fatal and non‐fatal). In agreement with other studies, adverse events associated with selenium supplementation included alopecia and dermatitis.
Cai et al.31 examined relationships of selenium and cancer from RCT, cohort, or case‐control studies that included selenium as baseline exposure and outcomes as cancer events (incidence and mortality). Sixty‐nine studies were identified that were assessed through meta‐analysis, meta‐regression, and dose‐response analyses. Overall, high serum/plasma or toenail selenium had some efficacy for cancer prevention, such that higher selenium exposure decreased the risk of breast cancer, lung cancer, oesophagal cancer, gastric cancer, and prostate cancer but not colorectal cancer, bladder cancer, or skin cancer.31 In contrast to this finding, Vincenti et al.32 conducted meta‐analyses of RCT and cohort studies of selenium in a Cochrane Review and found that the higher quality RCTs showed no benefit for selenium supplements in reducing the risk of cancer. Unexpectedly, some RCTs suggested that selenium supplementation may increase the risks of high‐grade prostate cancer and type 2 diabetes.32
Based on the contradictory nature of the evidence, supplementation with selenium to reduce the risk of cancer or cardiovascular diseases does not appear warranted at this time. In the next section, comprehensive meta‐analyses of several vitamins and minerals, alone or in combination, are reviewed for their health benefits and risks regarding cardiovascular disease and cancer.
Cancer and cardiovascular diseases – multiple vitamins and minerals
Cancer and cardiovascular diseases are leading causes of mortality worldwide, and there is interest in whether micronutrients provide primary or secondary prevention against these diseases. The USPSTF has many recommendations on preventing cardiovascular disease and cancer, including smoking cessation; screening for lipid disorders, hypertension, diabetes, and cancer; obesity screening and counselling; and aspirin use.15