0

The full content of Annals is available to subscribers

Subscribe/Learn More  >
Reviews |

Systematic Review: Vitamin D and Cardiometabolic Outcomes

Anastassios G. Pittas, MD, MS; Mei Chung, MPH; Thomas Trikalinos, MD; Joanna Mitri, MD; Michael Brendel, BA; Kamal Patel, MPH; Alice H. Lichtenstein, DSc; Joseph Lau, MD; and Ethan M. Balk, MD, MPH
[+] Article and Author Information

From Tufts Evidence-based Practice Center, Tufts Medical Center and Friedman School of Nutrition Science and Policy, and Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts.


Disclaimer: The opinions expressed are those of the authors and do not reflect the official position of AHRQ, the National Institutes of Health, the U.S. Department of Health and Human Services, the Public Health Agency of Canada, or Health Canada.

Acknowledgment: The authors thank Stanley Ip, MD; Jounghee Lee, PhD; Gowri Raman, MD; Athina Tatsioni, MD, PhD; and Teruhiko Terasawa, MD, for their work on the Tufts Evidence-based Practice Center evidence report on vitamin D and calcium, although they were not primarily responsible for cardiometabolic outcomes and did not participate in the writing of this manuscript.

Grant Support: By AHRQ (contract HHSA 290-2007-10055-I), National Institutes of Health (research grants R01DK76092 and R01DK79003 from the National Institute of Diabetes and Digestive and Kidney Disease and the Office of Dietary Supplements and grant R21DK78867 from the National Institute of Diabetes and Digestive and Kidney Disease), U.S. Department of Health and Human Services, and the Public Health Agency of Canada.

Potential Conflicts of Interest: Dr. Pittas: Grants received (institution): National Institute for Diabetes and Digestive and Kidney Disorders. Ms. Chung: Grants received (institution): AHRQ. Dr. Trikalinos: Grants received (institution): AHRQ. Support for travel to meetings for the study or otherwise: Institute of medicine. Mr. Brendel: Grants received (institution): AHRQ. Dr. Patel: Grants received (institution): AHRQ. National Institute for Diabetes and Digestive and Kidney Disorders, Office of Dietary Supplements, Public Health Agency of Canada. Dr. Lau: Grants received (institution): AHRQ. Grants/grants pending (institution): AHRQ. Payment for writing or reviewing the manuscript: AHRQ. Dr. Balk: Grants received: AHRQ. Grants received (institution): AHRQ. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M09-2011.

Requests for Single Reprints: Ethan M. Balk, MD, MPH, Tufts Evidence-based Practice Center, Tufts Medical Center, Box 63, 800 Washington Street, Boston, MA 02111; e-mail, ebalk@tuftsmedicalcenter.org.

Current Author Addresses: Drs. Pittas and Mitri: Tufts Medical Center, 800 Washington Street, Box 268, Boston, MA 02111.

Drs. Trikalinos, Lau, and Balk; Ms. Chung; Mr. Brendel; and Mr. Patel: Tufts Medical Center, 800 Washington Street, Box 63, Boston, MA 02111.

Dr. Lichtenstein: Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, Boston, MA 02111.

Author Contributions: Conception and design: A.G. Pittas, M. Chung, J. Mitri, A.H. Lichtenstein, J. Lau, E.M. Balk.

Analysis and interpretation of the data: A.G. Pittas, M. Chung, T. Trikalinos, J. Mitri, A.H. Lichtenstein, E.M. Balk.

Drafting of the article: A.G. Pittas, J. Mitri, E.M. Balk.

Critical revision of the article for important intellectual content: A.G. Pittas, M. Chung, T. Trikalinos, J. Mitri, A.H. Lichtenstein, J. Lau, E.M. Balk.

Final approval of the article: A.G. Pittas, M. Chung, T. Trikalinos, A.H. Lichtenstein, J. Lau, E.M. Balk.

Statistical expertise: M. Chung, T. Trikalinos, E.M. Balk.

Obtaining of funding: A.G. Pittas, J. Lau, E.M. Balk.

Administrative, technical, or logistic support: K. Patel, J. Lau.

Collection and assembly of data: A.G. Pittas, M. Chung, J. Mitri, M. Brendel, K. Patel, E.M. Balk.


Ann Intern Med. 2010;152(5):307-314. doi:10.7326/0003-4819-152-5-201003020-00009
Text Size: A A A

Background: Vitamin D may modify risk for cardiometabolic outcomes (type 2 diabetes, hypertension, or cardiovascular disease).

Purpose: To examine the association between vitamin D status, including the effect of vitamin D supplementation, and cardiometabolic outcomes in generally healthy adults.

Data Sources: English-language studies in MEDLINE (inception to 4 November 2009) and the Cochrane Central Register of Controlled Trials (fourth quarter of 2009).

Study Selection: 11 reviewers screened citations to identify longitudinal cohort studies that reported associations between vitamin D status and cardiometabolic outcomes, including randomized trials of vitamin D supplementation.

Data Extraction: 5 independent reviewers extracted data about study conduct, participant characteristics, outcomes, and quality. Differences were resolved by consensus.

Data Synthesis: 13 observational studies (14 cohorts) and 18 trials were eligible. Three of 6 analyses (from 4 different cohorts) reported a lower incident diabetes risk in the highest versus the lowest vitamin D status groups. Eight trials found no effect of vitamin D supplementation on glycemia or incident diabetes. In meta-analysis of 3 cohorts, lower 25-hydroxyvitamin D concentration was associated with incident hypertension (relative risk, 1.8 [95% CI, 1.3 to 2.4]). In meta-analyses of 10 trials, supplementation nonsignificantly reduced systolic blood pressure (weighted mean difference, −1.9 mm Hg [CI, −4.2 to 0.4 mm Hg]) and did not affect diastolic blood pressure (weighted mean difference, −0.1 mm Hg [CI, −0.7 to 0.5 mm Hg]). Lower 25-hydroxyvitamin D concentration was associated with incident cardiovascular disease in 5 of 7 analyses (6 cohorts). Four trials found no effect of supplementation on cardiovascular outcomes.

Limitations: Studies included primarily white participants. Observational studies were heterogeneous. Several trials reported post hoc analyses.

Conclusion: The association between vitamin D status and cardiometabolic outcomes is uncertain. Trials showed no clinically significant effect of vitamin D supplementation at the dosages given.

Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Disease, the National Institutes of Health Office of Dietary Supplements, U.S. Food and Drug Administration, Agency for Healthcare Research and Quality, and Public Health Agency of Canada.

Figures

Grahic Jump Location
Appendix Figure.
Literature search and selection.

* We screened 16 733 citations for a wide array of clinical outcomes. The 5739 citations refer to those specifically from the cardiovascular outcomes search, but we also screened potentially relevant citations from searches for other outcomes for cardiovascular outcomes.

† We retrieved 584 full-text articles for review for a wide array of clinical outcomes. The 106 articles refer to those specifically marked as having a cardiovascular outcome, but we also screened potentially relevant citations from searches for other outcomes for cardiovascular outcomes.

Grahic Jump Location
Grahic Jump Location
Figure 1.
Association between vitamin D status and incident hypertension or cardiovascular disease in longitudinal observational cohorts.

Relative risks (and 95% CIs) for each 25(OH)D concentration quartile compared with the highest concentration quartile. 25(OH)D = 25-hydroxyvitamin D; HPFS = Health Professionals Follow-up Study; NHS = Nurses' Health Study; NHS-2 = Nurses' Health Study 2. Top. Association between vitamin D status and incident hypertension. The diamond represents the meta-analysis summary relative risk and 95% CI for the lowest quantiles (black circles) versus the highest quantiles (on the reference line); relative risk, 1.76 (CI, 1.27 to 2.44); I= 0%. Bottom. Association between vitamin D status and cardiovascular disease. Data from Marniemi and colleagues (34) were not included because the quantiles were not defined.

* Estimate from reported data; no CI data were available.

† To make studies graphically comparable, we converted data to provide estimates of relative risks if the lowest quintile was the reference group. The original study (40) used the highest quintile as the reference group.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Meta-analyses of the effect of vitamin D supplementation on net change in blood pressure.

Weighted mean difference and 95% CIs for change in blood pressure from vitamin D supplementation versus placebo. Studies are arranged according to baseline blood pressure. The circle sizes are proportional to the study size. The black diamond represents the primary meta-analyses, and the other diamonds represent sensitivity and subgroup analyses. Dashed lines indicate studies for which SEs were not reported. Top. Changes in systolic blood pressure. Bottom. Changes in diastolic blood pressure.

* We estimated the 95% CI from the reported full range of changes in blood pressure.

† The 95% CI is in the circle.

‡ We estimated the 95% CI from the reported interquartile ranges of changes in blood pressure.

Grahic Jump Location

Tables

References

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

Submit a Comment
Vitamin D as Emerging Risk Factor for CVD?
Posted on March 18, 2010
Francisco Ramirez Lafita MD, FACP
ANAV Dept of Health. L'Hospitalet de l'Infant 43890, Spain
Conflict of Interest: None Declared

Papers by Pittas, Wang and Guallar (1,2, 3) bring up a hot topic on emerging risk factors for cardiovascular disease (CVD). Beside the traditional risk factors for CVD, studies have found consistent relationships between markers of inflammation and risk of future cardiovascular events. In fact, C-reactive protein (CRP) has been proposed as an emerging risk factor for CVD as have been inflammatory diseases (RA, SLE, Vasculitis) In the last years, a growing number of reports describe that vitamin D holds anti-inflammatory properties as vitamin D was found to inhibit pro-inflammatory cytokines.

Increasing data suggest an inverse relationship between vitamin D deficiency and the prevalence of cardiovascular disease and classical risk factors as hypertension, diabetes, dyslipemia and the metabolic syndrome (4). The current review by Pittas et al on different longitudinal observational studies found that lower vitamin D status was associated with increased risk for CVD, but vitamin D supplements did not prevent diabetes, hypertension nor heart attack and stroke incidence. The potential protective role of vitamin D in the heart and the mechanism of action in this organ, are poorly understood (5). Results are controversial and a role for confounding factors as age, diet, etc, cannot be excluded as potential contributors for cardiovascular risk. As Pittas and at point out at their discussion, vitamin D is an excellent marker of good health and its presence in dairy products and fish might modify cardiovascular risk. .

Cross-sectional studies reflecting a hypothetical relationship between 25OHD levels and the presence of traditional (Framingham) cardiovascular risk factors as hypertension, cholesterol levels, diabetes, or the metabolic syndrome, should be interesting to perform.

References

1. Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K, et al. Systematic review: Vitamin D and cardiometabolic outcomes. Ann Intern Med. 2010;152:307-314.

2. Wang L, Manson JE, Song Y, Sesso HD. Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med. 2010;152:315-323.

3. Guallar E, Miller ER III, Ordovas JM, Stranges S. Vitamin D supplementation in the age of lost innocence. Ann Intern Med. 2010;152:327 - 329.

4. Baz-Hecht M, Goldfine AB.The impact of vitamin D deficiency on diabetes and cardiovascular risk. Curr Opin Endocrinol Diabetes Obes. 2010; 17: 113 -119

5. Lee W, Kang PM. Vitamin D deficiency and cardiovascular disease: Is there a role for vitamin D therapy in heart failure? Curr Opin Investig Drugs. 2010; 11: 309-314

Conflict of Interest:

None declared

Effect of calcitriol on cardiometabolic outcomes
Posted on March 22, 2010
Adarsh J. Sai
Creighton University School of Medicine Omaha NE
Conflict of Interest: None Declared
Pittas (1) and Wang et al. (2) concluded from their reviews that the effect of vitamin D supplementation on cardiovascular and diabetic outcomes is inconsistent. However, none of these reviews included any studies using calcitriol, the active metabolite of vitamin D. We thought it might be useful to present data from a completed study (STOP IT) (3). It was a randomized double blind controlled trial lasting 3 years of 489 Caucasian postmenopausal women (age 65-78 years). There were four treatment arms- conjugated equine estrogens 0.625mg/dl plus medroxyprogesterone acetate 2.5mg/d (HT), calcitriol 0.25mcg twice daily, HT plus calcitriol and placebo. The primary outcome was bone mineral density. The results compare data from baseline to end of study at 3 years. We excluded all subjects on hypertension and diabetes medications because they came fasting for all tests and thus included 393 women for fasting serum glucose (FSG) and 309 for blood pressure (BP) analysis. We found no significant effect of any intervention on BP. On calcitriol, the mean increase in systolic BP was 3.31 mm Hg (95 % CL -2.3 to 9) and for diastolic BP was 2.8 mm Hg (-1.02 to 6.5) versus placebo. On HT there was a significant decrease in FSG by 5.41 mg/dl versus placebo (p=0.003). On calcitriol FSG was higher by 0.8 mg/dl (p= 0.82) versus placebo. There was no effect of calcitriol on incident diabetes (Odds Ratio (OR) 1.005, 95 % CI 0.39 to 2.58) or hypertension (OR 2.24, 95% CI 0.2 to 25.1). We looked at glucose subgroups; in those with impaired FSG at baseline (101-125 mg/dl); on calcitriol there was a non-significant increase in FSG of 10.9 mg/dl, versus placebo (p = 0.72), and on HT, FSG decreased 16 mg/dl (p = 0.09) versus placebo. In the group with normal FSG at baseline (<101 mg/dl), calcitriol resulted in non significant decrease in FSG of 0.87 mg/dl versus placebo (p = 0.57) and on HT, FSG reduced by 3.6 mg/dl versus placebo (p= 0.03) Thus, calcitriol treatment had no effect on FSG whereas HT reduced FSG level in both groups. Our data agrees with Pittas (1) in that even calcitriol, the active metabolite of Vitamin D had no effect on either BP or FSG. The effect of HT on fasting serum glucose deserves attention and further research should be carried out to elucidate the role of HT in blood sugar control and diabetes.

References

1. Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K, et al. Systematic review: Vitamin D and cardiometabolic outcomes Ann Intern Med. 2010 Mar 2;152(5):307-14.

2. Wang L, Manson JE, Song Y, Sesso HD. Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events Ann Intern Med. 2010 Mar 2;152(5):315-23.

3. Gallagher JC, Fowler SE, Detter JR, Sherman SS. Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss J Clin Endocrinol Metab. 2001 Aug;86(8):3618-28.

Conflict of Interest:

Pfizer Consultant

Submit a Comment

Summary for Patients

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.

Toolkit

Buy Now

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Advertisement
Related Articles
Related Point of Care
Topic Collections
PubMed Articles
Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.
(Required)
(Required)