FOR IMMEDIATE RELEASE
Orthomolecular Medicine News Service, October 4, 2021

Update on the beneficial effects of vitamin D for cancer, cardiovascular disease, type 2 diabetes and COVID-19

by William B. Grant, PhD

OMNS (Oct. 4, 2021) The scientific evidence that vitamin D reduces risk of many types of conditions and diseases and improves disease outcomes is moderately strong. [1] However, the allopathic/Western medical system in charge of medical policy considers vitamin D to be inexpensive competition and has done everything possible to cast doubt on vitamin D and block its approval for use by physicians for preventing or treating disease. How they use the Disinformation Playbook was spelled out in 2018. [2] One way this Playbook is used is to demand verification of vitamin D's effects through randomized controlled trials (RCTs). Unfortunately, over 95% of vitamin D RCTs were based on guidelines for pharmaceutical drugs. They were based on vitamin D dose, and often included participants with relatively high serum 25-hydroxyvitamin D [25(OH)D] concentrations given relatively low vitamin D doses. Thus, these RCTs started from misguided assumptions and often incorrectly showed vitamin D supplements to be ineffective. However, the guidelines for RCTs for nutrients have been clearly outlined. They suggest starting with an understanding of the relationship between 25(OH)D levels and health to guide selection of participants and vitamin D doses, then using achieved 25(OH)D concentrations in the analysis [3,4]. A beneficial effect can only be expected when a participant deficient in an essential nutrient such as vitamin D is given a relatively large supplemental dose adequate to relieve the deficiency -- but in those RCTs that was not enforced. Thus, without successful RCTs, Western Medicine can easily deny that vitamin D has many benefits.

To set the stage for examining more recent results regarding vitamin D and health outcomes, we obtained mortality rates in Australia, China, the UK, and the USA in 2016 from the World Health Organization. [5] As can be seen in Table 1, for the countries selected, cardiovascular disease and cancer are the leading causes of death, followed by Alzheimer's disease, with modest contributions from other diseases. These statistics would therefore appear to highlight the importance of recent evidence from clinical studies regarding the benefits of higher 25-hydroxyvitamin D [25(OH)D] concentrations for some of these diseases and outcomes.

Table 1. Selected mortality rates (deaths/100,000/yr) in 2016 (males + females) (5)

Disease	Australia	China	UK	USA
All causes	336	617	390	493
Cardiovascular disease	81	263	91	134
Ischaemic heart disease	44	114	48	79
Stroke	19	117	22	23
Malignant neoplasms	106	135	122	114
Breast cancer (females)	16	6	19	18
Alzheimer's disease	23	35	38	32
Diabetes mellitus	9.6	9.5	4.2	15
Lower respiratory tract	7	12	19	11
Falls	5	7	4	6
Preterm birth complications	1.4	2.9	2.8	3.3

Cardiovascular disease

It has been known for decades that serum 25-hydroxyvitamin D [25(OH)D] concentrations are inversely correlated with risk of cardiovascular disease (CVD). [6] A recent RCT testing the effect of vitamin D and omega-3 fatty acids (VITAL) on cardiovascular disease and cancer found no benefit for CVD. [7,8]

However a recent meta-analysis of CVD risk with respect to serum 25(OH)D levels showed a significant result. [9] A total of 79 studies (46,713 CVD cases in 1 397 831 participants) were included in the meta-analysis, of which 61 studies examined the risk of CVD incidence events, and 18 studies examined risk of recurrent CVD events. The risk of CVD incidence and recurrent CVD was significantly higher in the lowest than the highest category of circulating 25(OH)D. Fatal CVD incidence events had a linear inverse relationship up to about 25 ng/ml, while non-fatal incidence events had a linear inverse relationship up to 65 ng/ml.

An analysis of 20,000 US Veteran Health Administration patients followed from 1999 to 2018 with baseline 25(OH)D <50 nmol/L (20 ng/ml), with some supplementing with vitamin D to increase their serum level of 25(OH)D, found that those who achieved a level of >75 nmol/L (30 ng/ml) had about a 30% reduced risk of myocardial infarction compared to those who did not. [10] In addition, the all-cause mortality rate was 40% lower for those who achieved a serum 25(OH)D level >50 nmol/L (20 ng/ml) than for those who did not. Thus, the null finding in the VITAL study could be due to enrolling participants with a high level of serum 25(OH)D.

A community-based open-label vitamin D supplementation study enrolled 8155 participants, gave them 4000 IU vitamin D supplements, and counseled them on how to achieve 25(OH)D >100 nmol/L (40 ng/ml). [11] At baseline, 592 participants were hypertensive. After a year, 71% were no longer hypertensive and the group had lowered their mean systolic blood pressure by 14 -18 mmHg and diastolic blood pressure by 12 mmHg.

Thus there is now very good evidence that higher 25(OH)D levels can reduce risk of CVD.

Cancer

The role of vitamin D in reducing risk of cancer was proposed on the basis of an ecological study of colon cancer mortality rates with respect to geographical variations of annual solar radiation in the U.S. by the brothers Cedric and Frank Garland. [12] By 2013, many single-country ecological studies extended the number of cancers with incidence and/or mortality rates inversely correlated with solar UVB to about 20. [13] In addition, meta-analyses of observational studies of cancer incidence with respect to serum 25(OH)D level found strong inverse correlations for cancers of the breast [14] and colorectum. [15] An observational study involving participants from two vitamin D RCTs as well as community-based participants in an open-label vitamin D supplementation study with 25(OH)D measured every six months found breast cancer incidence rates were reduced by 80% for >150 nmol/L (60 ng/ml) vs. <50 nmol/L (20 ng/ml). [16]

The results of the VITaminD and OmegA-3 TriaL (VITAL) regarding risk of cancer and cardiovascular disease were reported in 2019 . [7,8] There were over 25,000 participants including over 5000 black participants, with half of them assigned to the vitamin D3-treatment arm and given 2000 IU/d vitamin D3. The mean 25(OH)D for those providing values was 31 ng/ml (78 nmol/L). While all-cancer and cardiovascular disease incidence were not significantly different from those in the placebo arm, all-cancer mortality rates were statistically significantly lower by 25%. In addition, cancer incidence rates were lower by 25% for black participants and significantly lower by 25% for those with a BMI <25 kg/m². Evidently the vitamin D dose, set in 2010, was too low.

Alzheimer's disease

There is modest evidence that vitamin D reduces risk of Alzheimer's disease. A prospective study found that there was a modest increase in risk as 25(OH)D levels decreased below 20 ng/ml. [17]

Diabetes mellitus

Observational studies have reported inverse correlations between serum 25(OH)D level an type 2 diabetes mellitus (T2DM). The first report was in 2006. [18] In 2013, a meta-analysis found an inverse correlation between serum 25(OH)D and risk of T2DM out to >50 ng/ml. [19]

The Vitamin D and Type 2 Diabetes (D2d) Study enrolled 2423 prediabetics and gave those in the treatment arm 4000 IU/d vitamin D3 to investigate whether it would reduce the risk of conversion to diabetes. While the risk for the entire cohort was not significantly different between treatment and control arms, a secondary analysis found that every 25 nmol/L increase in 25(OH)D between 50-70 nmol/L to >125 nmol/L in the treatment arm reduced risk of type 2 diabetes by 25%, T2DM risks falling by up to 70% in those achieving 25(OH)D ≥ 100 nmol/L (40 ng/ml). [20]

Pregnancy and birth outcomes

Vitamin D status during pregnancy is also very important. An open-label vitamin D supplementation study involving 1064 pregnant women in South Carolina gave the women free bottles of 5000 IU vitamin D3 and counseled them on how to achieve 25(OH)D >100 nmol/L (40 ng/ml). [21] Women with 25(OH)D ≥ 100 nmol/L had a 62% lower risk of preterm birth compared to those <50 nmol/L (20 ng/ml) (p<0.0001).

COVID-19

Chronic diseases such as cancer, cardiovascular disease, diabetes, and hypertension are associated with increased risk for COVID-19 mortality. [22] Thus, taking vitamin D supplements to reduce risk of these chronic diseases will help reduce the risk of severe COVID-19. In addition, achieving a serum 25(OH)D concentration of 55 ng/ml will reduce by 50% the risk of being SARS-CoV-2 seropositive. [23,24] This level of vitamin D, along with several other essential nutrients (vitamin C, vitamin K2, magnesium, zinc, and selenium) can greatly reduce the risk of viral infection for individuals who have deficiencies of these nutrients. [25-30] However, taking high-dose vitamin D supplements over an extended period can increase the amount of calcium absorbed from the gastrointestinal tract. Taking vitamin K2 supplements reduces the risk of vascular calcification as well as having a positive impact on osteoporosis and cardiovascular disease. [31] Nattokinase is a convenient source of vitamin K2.

Conclusion

There is now reasonably strong evidence that serum 25(OH)D levels in the range 40-80 ng/ml can significantly reduce the risk of the diseases associated with the greatest mortality rates in developed countries. To achieve these levels could take 5000 to 10,000 IU/d vitamin D3, which is safe not only by the Institute of Medicine, [32] but also based on many patient years of treatment with 5,000 to 50,000 IU/d vitamin D3 in a hospital in Ohio. [33]

References

1. Pludowski P, Holick MF, Grant WB, et al. (2018) Vitamin D supplementation guidelines. J Steroid Biochem Mol Biol. 175:125-35. https://pubmed.ncbi.nlm.nih.gov/28216084

2. Grant WB. (2018) Vitamin D acceptance delayed by Big Pharma following the Disinformation Playbook: Orthomolecular Medicine News Service. http://www.orthomolecular.org/resources/omns/v14n22.shtml.

3. Heaney RP. (2014) Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 72:48-54. https://pubmed.ncbi.nlm.nih.gov/24330136

4. Grant WB, Boucher BJ, Bhattoa HP, Lahore H. (2018) Why vitamin D clinical trials should be based on 25-hydroxyvitamin D concentrations. J Steroid Biochem Mol Biol. 177:266-9. https://pubmed.ncbi.nlm.nih.gov/28842142

5. WHO. (2018) Global Health Estimates 2016: Deaths by Cause, Age, Sex, by Country and by Region, 2000-2016. Geneva: World Health Organization. https://www.who.int/healthinfo/global_burden_disease/GHE2016_Deaths_WBInc_2000_2016.xls

6. Scragg R, Jackson R, Holdaway IM, Lim T, Beaglehole R. (1990) Myocardial infarction is inversely associated with plasma 25-hydroxyvitamin D3 levels: a community-based study. Int J Epidemiol. 19:559-63. https://pubmed.ncbi.nlm.nih.gov/2262248

7. Manson JE, Cook NH, Lee IM, et al. (2019) Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N Engl J Med. 380:23-32. https://pubmed.ncbi.nlm.nih.gov/30415637

8. Manson JE, Cook NR, Lee IM, et al. (2019) Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 380:33-44. https://pubmed.ncbi.nlm.nih.gov/30415629

9. Jani R, Mhaskar K, Tsiampalis T, et al. (2021) Circulating 25-hydroxy-vitamin D and the risk of cardiovascular diseases. Systematic review and meta-analysis of prospective cohort studies. Nutrition, Metabolism, Cardiovascular Diseases. 2021. Journal pre-proof. https://www.nmcd-journal.com/article/S0939-4753(21)00443-9/pdf

10. Acharya P, Dalia T, Ranka S, et al. (2021) The Effects of Vitamin D Supplementation and 25-Hydroxyvitamin D Levels on the Risk of Myocardial Infarction and Mortality. J Endocr Soc. 5:bvab124. https://pubmed.ncbi.nlm.nih.gov/34396023

11. Mirhosseini N, Vatanparast H, Kimball SM. (2017) The Association between Serum 25(OH)D Status and Blood Pressure in Participants of a Community-Based Program Taking Vitamin D Supplements. Nutrients. 9:1244. https://pubmed.ncbi.nlm.nih.gov/29135923

12. Garland CF, Garland FC. (1980) Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol. 9:227-231. https://pubmed.ncbi.nlm.nih.gov/7440046

13. Moukayed M, Grant WB. (2013) Molecular link between vitamin D and cancer prevention. Nutrients. 5:3993-4021. https://pubmed.ncbi.nlm.nih.gov/24084056

14. Song D, Deng Y, Liu K, et al. (2019) Vitamin D intake, blood vitamin D levels, and the risk of breast cancer: a dose-response meta-analysis of observational studies. Aging (Albany NY). 11:12708-12732. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949087

15. McCullough ML, Zoltick ES, Weinstein SJ, et al. (2019) Circulating Vitamin D and Colorectal Cancer Risk: An International Pooling Project of 17 Cohorts. J Natl Cancer Inst. 111:158-169. https://pubmed.ncbi.nlm.nih.gov/29912394

16. McDonnell SL, Baggerly CA, French CB, et al. (2018) Breast cancer risk markedly lower with serum 25-hydroxyvitamin D concentrations >/=60 vs <20 ng/ml (150 vs 50 nmol/L): Pooled analysis of two randomized trials and a prospective cohort. PLoS One. 13(6):e0199265. https://pubmed.ncbi.nlm.nih.gov/29906273

17. Littlejohns TJ, Henley WE, Lang IA, et al.(2014) Vitamin D and the risk of dementia and Alzheimer disease. Neurology. 83:920-928. https://pubmed.ncbi.nlm.nih.gov/25098535

18. Pittas AG, Dawson-Hughes B, Li T, et al. (2006) Vitamin D and calcium intake in relation to type 2 diabetes in women. Diabetes Care. 29:650-656. https://pubmed.ncbi.nlm.nih.gov/16505521

19. Song Y, Wang L, Pittas AG, et al. (2013) Blood 25-hydroxy vitamin D levels and incident type 2 diabetes: a meta-analysis of prospective studies. Diabetes Care. 36:1422-1428. https://pubmed.ncbi.nlm.nih.gov/23613602

20. Dawson-Hughes B, Staten MA, Knowler WC, et al. (2020) Intratrial exposure to vitamin D and new-onset diabetes among adults with prediabetes: A secondary analysis from the Vitamin D and Type 2 Diabetes (D2d) Study. Diabetes Care. 43:2916-2922. https://pubmed.ncbi.nlm.nih.gov/33020052

21. McDonnell SL, Baggerly KA, Baggerly CA, et al. (2017) Maternal 25(OH)D concentrations >/=40 ng/mL associated with 60% lower preterm birth risk among general obstetrical patients at an urban medical center. PLoS One. 12(7):e0180483. https://pubmed.ncbi.nlm.nih.gov/28738090

22. Ssentongo P, Ssentongo AE, Heilbrunn ES, et al.(2020) Association of cardiovascular disease and 10 other pre-existing comorbidities with COVID-19 mortality: A systematic review and meta-analysis. PLoS One. 15(8):e0238215. https://pubmed.ncbi.nlm.nih.gov/32845926

23. Kaufman HW, Niles JK, Kroll MH, Bi C, Holick MF. (2020) SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels. PLoS One. 15(9):e0239252. https://pubmed.ncbi.nlm.nih.gov/32941512

24. Charoenngam N, Shirvani A, Holick MF. (2021) Vitamin D and Its Potential Benefit for the COVID-19 Pandemic. Endocr Pract. 27:484-493. https://pubmed.ncbi.nlm.nih.gov/33744444

25. Ghelani D, Alesi S, Mousa A. (2021) Vitamin D and COVID-19: An Overview of Recent Evidence. Int J Mol Sci. 22:10559. https://doi.org/10.3390/ijms221910559

26. Gonzalez MJ, Olalde J, Rodriguez JR, et al. (2018) Metabolic Correction and Physiologic Modulation as the Unifying Theory of the Healthy State: The Orthomolecular, Systemic and Functional Approach to Physiologic Optimization. J Orthomol Med. 33(1). https://isom.ca/article/metabolic-correction-physiologic-modulation-unifying-theory-healthy-state

27. Cámara M, Sánchez-Mata MC, Fernández-Ruiz V, et al. (2021) A Review of the Role of Micronutrients and Bioactive Compounds on Immune System Supporting to Fight against the COVID-19 Disease. Foods. 10:1088. https://pubmed.ncbi.nlm.nih.gov/34068930

28. Berger MM, Herter-Aeberli I, Zimmermann ME, et al. (2021) Strengthening the immunity of the Swiss population with micronutrients: A narrative review and call for action. Clin Nutr ESPEN. 43:39-48. https://pubmed.ncbi.nlm.nih.gov/34024545

29. Smith RG (2021) Vitamins and minerals for lowering risk of disease: Adding to the evidence. Orthomolecular Medicine News Service. http://orthomolecular.org/resources/3omns/v17n10.shtml

30. Schuetz P, Gregoriano C, Keller U (2021) Supplementation of the population during the COVID-19 pandemic with vitamins and micronutrients - how much evidence is needed? Swiss Med Wkly. 151:w20522. https://pubmed.ncbi.nlm.nih.gov/34010429

31. Khalil Z, Alam B, Akbari AR, Sharma H. (2021) The Medical Benefits of Vitamin K2 on Calcium-Related Disorders. Nutrients. 13:691. https://pubmed.ncbi.nlm.nih.gov/33670005

32. Ross AC, Manson JE, Abrams SA, et al. (2011) The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 96:53-58. https://pubmed.ncbi.nlm.nih.gov/21118827

33. McCullough PJ, Lehrer DS, Amend J. (2019) Daily oral dosing of vitamin D3 using 5000 TO 50,000 international units a day in long-term hospitalized patients: Insights from a seven year experience. J Steroid Biochem Mol Biol. 189:228-39. https://pubmed.ncbi.nlm.nih.gov/30611908

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