Does Vitamin D Supplementation Reduce the Risk of Cardiovascular Events?

By Karina Vivar, MS4

Faculty Peer Reviewed

Vitamin D deficiency is highly prevalent in the U.S. and worldwide, and the problem appears to be worsening.  By definition, vitamin D deficiency is a serum 25-hydroxyvitamin D (25-OH D) level of less than 20 ng/mL.  Vitamin D insufficiency is defined as a serum 25-OH D level from 20 to 30 ng/mL.  Unless there is a high risk for fracture and a clinical suspicion of deficiency, it is not routine to screen for vitamin D deficiency, due to laboratory variability and cost of testing.  Therefore, rather than screen patients for deficiency, the Institute of Medicine (IOM) recommends that adults 19 to 50 years old receive 200 IU of vitamin D per day, adults 51 to 70 receive 400 IU per day, and adults over 71 receive 600 IU per day, through diet or supplementation. Certain populations–the elderly, the chronically ill, those with dark skin, and those with limited sunlight exposure–require much higher daily doses of vitamin D, at least 800 to 1000 IU per day.  Even healthy, normal-weight patients may require 2000 IU per day to achieve a serum level of 25-OH D over 30 ng/mL, a daily intake significantly greater than that recommended by the IOM.[1]^,[2]

Interest in vitamin D has increased as epidemiological and clinical studies have revealed potential non-skeletal effects of vitamin D.  From depression to cancer, diabetes to multiple sclerosis, and cognition to chronic pain, these studies have drawn a correlation between vitamin D deficiency and disease, including cardiovascular disease.  Analyses of epidemiological studies such as the Third National Health and Nutrition Examination Survey (NHANES III) and longitudinal cohort studies like the Framingham Offspring Study have found a statistically significant inverse relationship between 25-OH D serum levels and coronary artery disease, as well as the cardiovascular risk factors obesity, hypertension, diabetes, hypertriglyceridemia, and hypercholesterolemia.[3]^,[4] Moreover, numerous studies have independently associated low 25-OH D levels with congestive heart failure, calcific aortic stenosis, increased body-mass index, and metabolic syndrome.^2,[5]

It is known that vitamin D receptors are present on vascular smooth muscle, endothelium, and cardiomyocytes.  However, the exact mechanism behind vitamin D’s cardioprotective effects has yet to be elucidated.  It is hypothesized that vitamin D downregulates the renin-angiotensin-aldosterone system to lower blood pressure, improves insulin secretion and sensitivity, improves vascular remodeling in response to injury and atherosclerosis, and decreases parathyroid hormone levels.  The studies investigating these hypotheses are still in preclinical phases, but these preliminary data have shown that the benefit of vitamin D supplementation may have biological plausibility.[6]

Knowing the observational correlations between low vitamin D levels and increased risk of cardiovascular disease, as well as the potential mechanisms behind this relationship, should clinicians recommend vitamin D supplementation in order to reduce the risk of cardiovascular events?

Only a handful of prospective observational studies and randomized control trials have examined the association between vitamin D supplementation and the risk for cardiovascular disease.  The most consistent evidence supporting vitamin D supplementation is for patients on hemodialysis.  Patients with end-stage renal disease commonly experience secondary hyperparathyroidism, as the kidneys are unable to convert 25-OH vitamin D to 1,25-dihydroxyvitamin D, the active form.  These patients are usually maintained on activated vitamin D.  Cardiovascular disease is the most common cause of mortality in this population.  In a study from 2005, the incidence of cardiovascular-related mortality was lower in hemodialysis patients who received activated injectable vitamin D: 7.6 deaths per 100 person-years, compared with 14.6 deaths per 100 person-years in those who did not receive vitamin D.[7] Other studies have demonstrated a similar effect with oral and injectable vitamin D.¹

Generalizability of these results to other populations has not yet been shown. A cohort study of 34,486 postmenopausal women in the U.S. found only a minimal reduction in cardiovascular-related mortality for those who took daily supplemental vitamin D compared to those who did not.[8] A randomized controlled trial from the U.K. examined the effects of a single 100,000 IU dose of vitamin D taken orally every four months for five years in men and women.  This study found a slightly lower incidence of cardiovascular-related mortality in the supplementation group compared to the placebo group, though this difference was not statistically significant.[9] The largest trial of vitamin D supplementation thus far has been the Women’s Health Initiative, in which two groups of generally healthy, postmenopausal women were given a combination of calcium and vitamin D or placebo.  Supplementation over a 7-year period had no effect on coronary risk.[10] However, the amount of vitamin D given per day (400 IU) was probably not adequate to attain a serum 25-OH D level above 30 ng/mL.  More likely, supplementation of at least 1000 IU is required to achieve this serum level.¹

Some recommend intentional sun exposure in addition to calcium and vitamin D to elevate vitamin D levels.  Greater than 90% of serum vitamin D is produced cutaneously when ultraviolet (UV) B radiation photoisomerizes 7-dehydrocholesterol to precholecalciferol, which in turn is isomerized by heat to cholecalciferol (vitamin D3).[11] Researchers have demonstrated that an exposure of 1 minimal erythema dose (MED) to the whole body results in the cutaneous synthesis of an equivalent of 10,000 to 25,000 IU of oral vitamin D.  Extrapolating from these data, proponents of “safe sun” maintain that exposing one quarter of the body—arms, face, and hands—to 0.25 MED of sunlight will produce vitamin D3 equivalent to 1000 IU taken by mouth.[12] Several factors influence cutaneous vitamin D production and no recommendation can be made regarding the amount of sunlight exposure required to match oral vitamin D supplementation.  Variables include skin pigmentation, latitude, time of day, altitude, ozone concentration, pollution, cloud cover, and sunscreen use.¹¹ Since UV light exposure is a known cause of skin cancer, the American Academy of Dermatology and the International Agency for Research on Cancer do not advocate intentional, unprotected sun exposure for vitamin D supplementation.  Oral vitamin D supplements are a safer mode of elevating serum vitamin D levels.¹²

In summary, there is evidence suggesting that vitamin D supplementation contributes to decreasing cardiovascular risk.  While more research must be performed to determine guidelines, it has been demonstrated that low levels of vitamin D are associated with increased cardiovascular disease and that adequate vitamin D supplementation can reduce mortality due to cardiovascular disease.  Supplementation to achieve these protective effects most likely requires higher doses than currently recommended.¹ Thus, if a patient is at increased risk of cardiovascular events and has risks of vitamin D deficiency, oral supplementation of at least 1000 IU of vitamin D per day may be beneficial.  For many patients, vitamin D supplementation is already indicated for prevention of osteoporosis.  In light of the above studies, increasing an  existing dose of vitamin D to at least 1000 IU per day may also help improve cardiovascular health.

Karina Vivar is a 4th year medical student at NYU School of Medicine

Peer reviewed by Eugenia Gianos, MD, Attending Physician, Dept. of Medicine (Cardiology), NYU Langone Medical Center

Image courtesy of Wikimedia Commons.

References:

1.  Wang L, Manson JE, Song Y, Sesso HD.  Vitamin D and calcium supplementation in prevention of cardiovascular events.  Ann Intern Med.  2010;152(5):315-323.  http://www.annals.org/content/152/5/315.abstract

2.  Stechschulte SA, Kirsner RS, Federman DG.  Vitamin D: bone and beyond, rationale and recommendations for supplementation.  Am J Med.  2009;122(9):793-802.

3.  Martins D, Wolf M, Pan D, et al. Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey.  Arch Intern Med. 2007;167(11):1159-1165.  http://archinte.ama-assn.org/cgi/content/full/167/11/1159

4.  Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease.  Circulation.  2008;117(4):503-511.

5.  Adams JS, Hewison M.  Update in vitamin D.  J Clin Endocrinol Metab.  2010;95(2):471-478.  http://jcem.endojournals.org/cgi/content/full/95/2/471

6.  Judd SE, Tangpricha V.  Vitamin D deficiency and risk for cardiovascular disease.  Am J Med Sci. 2009;338(1):40-44.  http://journals.lww.com/amjmedsci/Abstract/2009/07000/Vitamin_D_Deficiency_and_Risk_for_Cardiovascular.17.aspx

7.  Teng M, Wolf M, Lowrie E, et al.  Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol. 2005;16(4):1115-1125.  http://jasn.asnjournals.org/cgi/content/full/16/4/1115

8.  Bostick RM, Kushi LH, Wu Y, Meyer KA, Sellers TA, Folsom AR. Relation of calcium, vitamin D, and dairy food intake to ischemic heart disease mortality among postmenopausal women. Am J Epidemiol. 1999;149(2):151-161.  http://www.ncbi.nlm.nih.gov/pubmed/9921960

9.  Trivedi DP, Doll R, Khaw KT.  Effect of four monthly oral vitamin D₃ supplementation on fractures and mortality in men and women living in the community: randomized double blind controlled trial. BMJ. 2003;326(7387):326-332.

10.  Hsia J, Heiss G, Ren H, et al.  Calcium/vitamin D supplementation and cardiovascular events.  Circulation. 2007;115(7):846-854.  http://circ.ahajournals.org/cgi/content/short/115/7/846

11.   Diehl JW, Chiu MW.  Effects of ambient sunlight and photoprotection on vitamin D status.  Dermatol Ther. 2010;23(1):48-60.  http://www.ncbi.nlm.nih.gov/pubmed/20136908

12.  Terushkin V, Bender A, Psaty EL, Engelsen O, Wang SQ, Halpern AC.  Estimated equivalency of vitamin D production from natural sun exposure versus oral vitamin D supplementation across seasons at two US latitudes.  J Am Acad Dermatol. 2010;62(6):929.   http://www.ncbi.nlm.nih.gov/pubmed/20363523

Share: Twitter | Facebook | Email