Should vitamin D supplements be recommended to prevent chronic diseases?BMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h321 (Published 29 January 2015) Cite this as: BMJ 2015;350:h321
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The current article provides a comprehensive overview of the existing knowledge and finding of the available evidence between vitamin D and the risk of cardiovascular diseases, cancer, type 2 diabetes and general mortality. The authors have also pointed out several issues in the existing literature, one of which is the lack of robust evidence between vitamin D and chronic diseases. They have gathered information post 2012 about newer evidence and found to be lacking even after searching large clinical trial databases. In their opinion, study having a large sample size of 1000 or more in the clinical trials could provide adequate information. This presumption should be based on the current available knowledge on the findings of clinical trials or based on the observational studies. The findings in the risk reduction, reduction in incidence or mortality from all chronic causes may be referred for the calculation.
Considering the Cochrane review article they have quoted (1), the reduction of 0.4% mortality over 4.4 years from 11.4% to 11.0% with vitamin D supplementation, at 80% power, the sample size calculation comes to 99456, which seems to be very large. The evidence that is obtained from studies with smaller sample size than this figure may not give accurate evidence statistically. Thus, we need to have larger sample size studies, which may be multicentric, covering different ethnic groups (both white and black skin).
1. Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, et al. Vitamin D supplementation for prevention of mortality in adults.Cochrane Database Syst Rev2014;1:CD007470.
Competing interests: No competing interests
I found the article by Meyer et al interesting. There is a major issue which needs to be addressed.
The National Institute for Health and Care Excellence organisation in UK has published Public Health 56 guidelines with eleven recommendations in November 2014 to increase Vitamin-D supplement use to prevent vitamin-D deficiency among at risk groups including people with darker skin, for example, people of South-Asian family origin.
These recommendations are targeted for the whole health system e.g. Department of Health; Public Health England and supplement manufacturers. The Public Health Advisory Committee UK (PHAC) recommends certain research questions should be addressed including: How effective and cost effective are interventions to increase vitamin-D access, uptake, adherence or status among identified at risk groups? Does effectiveness vary by age, gender, ethnicity, socioeconomic or other specific population characteristics? How to promote vitamin-D supplements among at risk groups, improve the local population's awareness and attitude towards vitamin-D supplements and uptake of vitamin-D supplements.
PHAC has also identified a number of gaps in the evidence related to the programmes. There was a lack of good quality interventions aiming to increase Vitamin-D supplement use among at risk groups in England and on whether the following affect the effectiveness of interventions to increase vitamin-D supplement use among at risk groups: religion, place of residence, occupation, education, socioeconomic position or a sense of community.
The recommendations are applicable to all at risk groups but there is a particular need for research in people over 65, people with darker skin and people living in institutions. The implementation has been successful as many South-Asians (grandparents originating from India, Pakistan, Bangladesh) (people with darker skin) are on vitamin-D supplements in England and they comply with vitamins more than the other medications. There is a low threshold for checking 25 (OH) D vitamin concentrations in South-Asians and indications are multiple (aches and pains, diabetes, hypertension etc.).
All the recommendations, research requirements, gaps in research are centred on vitamin-D supplements.
This is the case even though the US Preventive Services Task Force states vitamin-D supplements show no overall effect on cardiovascular disease, cancer, or mortality (www.ncbi.nlm.nih.gov/books/NBK43437) and that current evidence is insufficient to assess the balance of benefits and harms of screening for vitamin-D deficiency in asymptomatic adults 1.
Research resources are finite in these times of austerity and there are cost implications with vitamin-D supplementation at population level, as vitamin-D deficiencies are up to 70% in some population groups [although these figures might not be true as they are based on study assays of total serum 25 (OH) D (D3 cholecalciferol + D2 ergocalciferol)]. True deficiency ought to be defined as low concentrations of biological active 1,25-VitD3. Getting adequate vitamin-D from outdoor Ultraviolet B (UVB) exposure ought to be a population-health goal. Measures to increase biological activity of 1,25-VitD3 derived from UVB exposure through outdoor physical activity may well have the potential to stimulate both the increased biosynthesis and the bioavailability of cholecalciferol. Moreover, there is no issue of hypervitaminosis with UVB derived vitamin-D 2. Optimum doses of vitamin-D supplementation are not established and high doses induce ectopic vascular calcification. Vitamin-D is used to induce arterioscelerosis in mice experiments 3. However, research trials with vitamin-D supplements continue to be funded because it is fashionable 1. Therefore by prescribing vitamin-D supplements with or without calcium the health fraternity might be causing more harm than benefit to populations especially South-Asians.
South-Asians are more likely to be viscerally obese, physically-inactive and insulin resistant. There is an increased risk of endothelial dysfunction leading to diabetes, ischaemic heart disease and ischaemic stroke when compared with Europeans. Cholesterol status is similar in both populations, but South-Asians tend to have increased serum concentrations of triglycerides and decreased concentrations of high density lipoprotein cholesterol than Europeans. Raised alanine aminotransferase as a marker of non-alcoholic fatty liver disease is common in apparently healthy British South-Asians and is significantly associated with an adverse metabolic and athero-thrombotic risk profile. The prevalence of hypertension and its association with cardiovascular diseases is not significantly greater in South-Asians than in Europeans 4. The prevalence of peripheral arterial disease, as measured by an ankle brachial index (ratio of ankle blood pressure and arm blood pressure) of less than 0.9, is lower, but the increase in ankle blood pressures (two on right and two on left leg) (probably as a marker of arterial wall stiffness or arterioscelerosis) and cardiovascular disease is much greater in South-Asian patients than in Europeans with a history of type 2 diabetes 5. There is no evidence that the diabetes and cardiovascular diseases status changes in South-Asians with vitamin-D supplementation or even with the fortification of foods with vitamin-D or differences in sun exposure in different continents 6. It is possible that although they exhibit low concentrations of 25 OH vitamin-D there is sequestrated vitamin-D in their increased visceral fat. Vitamin-D in ectopic fat is likely to not be available for conversion to bioavailable active vitamin-D and is causing arterial wall stiffening preferentially in the lower limbs of South-Asians.
Gaps in research on Vitamin-D ought to address the following:
1. Best way of assessing bioavailable active 1,25 dihydroxyvitamin-D3 or its metabolite e.g. 24-hydroxylase etc. to determine true vitamin-D status
2. Standardisation of vitamin-D binding proteins assays and formulae for calculation of free molecules
3. Mechanisms to increase bioavailable vitamin-D (figure1)
4. Whether biosynthesis is followed by bioavailability or does it happen in parallel.
5. To determine if there are differences in bioavailability of vitamin-D from supplements and UVB derived biosynthesized vitamin-D
6. Mechanisms to increase bioavailable vitamin-D in winter (?similar to mechanisms in hibernating arctic animals)
7. If increased outdoor activity increases bioavailable vitamin-D more than indoor activity
8. If indoor activity in summer increases bioavailable vitamin-D more than in winter
9. If outdoor activity reverses arterial stiffness through increased bioavailable vitamin-D and lowering of pulse wave velocity
10. If increased bioavailable vitamin-D reduces glycosylated haemoglobin and both ankle and brachial blood pressures particularly in South-Asians
Increasing biological-activity of sunshine (Ultraviolet-B (UVB) exposure) derived 1,25-VitD3 might be particularly relevant for more than a billion South-Asians worldwide 2.
(1) Kain Kirti. Some clinical trials are driven by fashion, not science. BMJ. In press.
(2) Kain K. Physical Activity, Ultraviolet B derived 1, 25-Vitamin D3 and Vascular Regeneration . Circulation. In press.
(3) Gaillard V, Casellas D, Seguin-Devaux C et al. Pioglitazone improves aortic wall elasticity in a rat model of elastocalcinotic arteriosclerosis. Hypertension 2005;46:372-379.
(4) Joshi P, Islam S, Pais P et al. Risk factors for early myocardial infarction in South Asians compared with individuals in other countries. JAMA 2007;297:286-294.
(5) Kain K, Brockway M, Ishfaq T et al. Ankle pressures in UK South Asians with diabetes mellitus: a case control study. Heart 2013;99:614-619.
(6) G R, Gupta A. Vitamin D deficiency in India: prevalence, causalities and interventions. Nutrients 2014;6:729-775.
Competing interests: No competing interests