Vitamin D Levels and the Risk of Mortality in the General Population

Abstract & Commentary

By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationship to this field of study.

Synopsis: Correlating the findings in the 13,331 adults 20 years or older in the Third National Health and Nutrition Examination Survey (NHANES III) revealed that vitamin D deficiency is a risk factor for developing cardiovascular disease and is associated with increased all-cause mortality.

Source: Melamed ML, et al. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 2008;168:1629-1637.

Vitamin D deficiency has been noted to occur in one-third to one-half of otherwise healthy middle-aged to elderly adults in the United States and even worldwide.1-4 Clinical studies have suggested that low 25-hydroxyvitamin D (25(0H)D) levels may affect the renin-angiotensin system,5 the inflammatory system,6 the endothelium,7 the frequency of myocardial infarction,8 hypertension,9 congestive heart failure,10 diabetes mellitus,10-12 and cardiovascular risk.13,14 In addition, 25(OH)D has been demonstrated to have antiproliferative activity, which may influence cancer risk.15,16

Low 25(OH)D levels in hemodialysis patients have been associated with increased all-cause mortality,17 and finally, treatment of patients with vitamin D supplementation has been associated with lower all-cause mortality compared to individuals randomized to placebo therapy.18

Because no published studies have evaluated the relationship between 25(OH)D and mortality risk in the general population, Melamed and his colleagues reviewed the association of low 25(OH)D levels with all-cause, cancer, and cardiovascular disease (CVD) mortality in 13,331 nationally representative adults 20 years or older from the Third National Health and Nutrition Examination Survey (NHANES III) linked mortality files.19 The vitamin D levels of the participants were collected from 1988 to 1994 and they were then passively followed for mortality through the year 2000. In multivariate models, subjects in the lowest quartile compared to those in the highest quartile were found to have a 26% increase in all-cause mortality in the general population, independent of baseline demographics, traditional and nontraditional CVD risk factors, and measures of a healthy lifestyle.

Commentary

The Melamed study19 yielded a number of interesting observations. The association of low 25(OH)D levels with mortality was strongest in those without CVD, without hypertension, and without diabetes mellitus, suggesting that low vitamin D levels are not simply markers of poor general health. In fact, the data seem to suggest that 25(OH)D deficiency may play an important role in all-cause mortality even before CVD is established, that is, even among those individuals without pre-existing diabetes mellitus, hypertension, and CVD. It must be clearly recognized that the Melamed study was only an observational study and, therefore, causality cannot be inferred even after adjusting for all known traditional CVD risk factors and nontraditional risk factors including markers of a healthy lifestyle. The specific causes of mortality that accounted for the elevated all-cause mortality risk associated with 25(OH)D deficiency could not be accurately determined; therefore, further studies are needed to confirm these findings and establish the mechanisms underlying these observations. If the conclusions outlined above are confirmed, randomized clinical trials will be needed to determine whether vitamin D supplementation at higher doses could have any potential benefit in reducing future mortality risk in those individuals with 25(OH)D deficiency.

Although the results of the Melamed observational study are similar to findings of many other studies8,14,20 suggesting that vitamin D deficiency is a risk factor for developing cardiovascular disease and is associated with increased all-cause mortality, further clinical and experimental studies are needed to validate these findings and to determine whether correction of vitamin D deficiency could contribute to the prevention of CVD and decrease all-cause mortality risk. In conclusion, although the value of vitamin D supplementation is clinically unproven at this time, it still might be prudent to consider recommending administration of at least 800 IU daily for all adults and especially for those whose lifestyle and/or illnesses prevents them from being outdoors for adequate periods of time.

References

1. Hollick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 2006;81: 353-373.

2. Malabanan A, et al. Redefining vitamin D insufficiency. Lancet 1998;351:805-806.

3. Chapuy MC, et al. Prevalence of vitamin D insufficiency in an adult normal population. Osteoporosis Int 1997;7: 439-443.

4. Nesby-O'Dell S, et al. Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: Third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr 2002; 76:187-192.

5. Li YC, et al. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 2002;110:229-238.

6. Mathiew C, Adorini L. The coming of age of 1,25-dihydroxyvitamin D(3) analogs as immunomodulatory agents. Trends Mol Med 2002;8:174-179.

7. Merke J, et al. Identification and regulation of 1,25-dihydroxyvitamin D3 receptor activity and biosynthesis of 1,25 dihydroxyvitamin D3. Studies in cultured bovine aortic endothelial cells and human dermal capillaries. J Clin Invest 1989;83:1903-1915.

8. Scragg R, et al. Myocardial infarction is inversely associated with plasma 25-hydroxyvitamin D3 levels: A community-based study. Int J Epidemiol 1990;19:559-563.

9. Forman JP, et al. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension. Hypertension 2007;49: 1063-1069.

10. Zittermann A, et al. Low vitamin D status: A contributing factor in the pathogenesis of congestive heart failure? J Am Coll Cardiol 2003;41:105-112.

11. Pittas AG, et al. Vitamin D and calcium intake in relation to type 2 diabetes in women. Diabetes Care 2006;29:650-656.

12. Chonchol M, Scragg R. 25-hydroxyvitamin D, insulin resistance, and kidney function in the Third National Health and Nutrition Examination Survey. Kidney Int 2007;71:134-139.

13. Levin A, Li YC. Vitamin D and its analogues: Do they protect against cardiovascular disease in patients with kidney disease? Kidney Int 2005;68:1973-1981.

14. Cigolini M, et al. Serum 25-hydroxyvitamin D3 concentrations and prevalence of cardiovascular disease among type 2 diabetic patients. Diabetes Care 2006;29:722-724.

15. Giovannucci E, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 2006;98:451-459.

16. Banerjee P, Chatterjee M. Antiproliferative role of vitamin D and its analogs—a brief overview. Mol Cell Biochem 2003;253:247-254.

17. Wolf M, et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int 2007;72:1004-1013.

18. Thomas MK, et al. Hypovitaminosis D in medical inpatients. N Engl J Med 1998;338:777-783.

19. Melamed ML, et al. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 2008;168:1629-1637.

20. Poole KE, et al. Reduced vitamin D in acute stroke. Stroke 2006;37:243-245.