Systematic review: Vitamin D and cardiometabolic outcomes

Abstract

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.

Figure 1

Association between vitamin D status and incident hypertension (Figure 1A) and cardiovascular disease (Figure 1B) in longitudinal observational cohorts. 25(OH)D, 25-hydroxyvitamin D; FOS, Framingham Follow-up Study; HPFS, Health Professionals Follow-up Study; LURIC, Ludwigshafen Risk and Cardiovascular Health; MFHS, Mini-Finland Health Survey; NHANES III, Third National Health and Nutrition Examination Survey; NHS, Nurses Health Study; NHS-2, Nurses Health Study-2. To convert 25(OH)D concentration from nmol/L to ng/mL divide by 2.459. Relative risks (and 95% confidence intervals) of each quantile of 25(OH)D concentration compared to the highest concentration quantile for studies with incident hypertension (1A) and cardiovascular events (1B) outcomes. In figure 1A, the diamond represents the meta-analysis summary relative risk and 95% confidence interval for the lowest quantiles (black circles) compared to the highest quantiles (on the reference line); Relative risk=1.76; 95% CI 1.27, 2.44; I²=0%. Figure 1B does not include data from Marniemi et al. (32) because the quantiles were not defined. Solid lines in Figure 1B indicate that trends were statistically significant; dashed lines that trends were not statistically significant. * Estimate from reported data; no confidence interval data available. † To make studies graphically comparable, data were converted to provide estimates of relative risks if the lowest quintile were the reference group. The original study (Kilkkinen et al. (30)) used the highest quintile as the reference group.

Figure 1

Association between vitamin D status and incident hypertension (Figure 1A) and cardiovascular disease (Figure 1B) in longitudinal observational cohorts. 25(OH)D, 25-hydroxyvitamin D; FOS, Framingham Follow-up Study; HPFS, Health Professionals Follow-up Study; LURIC, Ludwigshafen Risk and Cardiovascular Health; MFHS, Mini-Finland Health Survey; NHANES III, Third National Health and Nutrition Examination Survey; NHS, Nurses Health Study; NHS-2, Nurses Health Study-2. To convert 25(OH)D concentration from nmol/L to ng/mL divide by 2.459. Relative risks (and 95% confidence intervals) of each quantile of 25(OH)D concentration compared to the highest concentration quantile for studies with incident hypertension (1A) and cardiovascular events (1B) outcomes. In figure 1A, the diamond represents the meta-analysis summary relative risk and 95% confidence interval for the lowest quantiles (black circles) compared to the highest quantiles (on the reference line); Relative risk=1.76; 95% CI 1.27, 2.44; I²=0%. Figure 1B does not include data from Marniemi et al. (32) because the quantiles were not defined. Solid lines in Figure 1B indicate that trends were statistically significant; dashed lines that trends were not statistically significant. * Estimate from reported data; no confidence interval data available. † To make studies graphically comparable, data were converted to provide estimates of relative risks if the lowest quintile were the reference group. The original study (Kilkkinen et al. (30)) used the highest quintile as the reference group.

Figure 2

Meta-analyses of the effect of vitamin D supplementation on net change in systolic (2A) and diastolic (2B) blood pressure. WHI, Women’s Health Initiative trial. Weighted mean difference and 95% confidence intervals in change in systolic (Figure 2A) and diastolic (Figure 2B) blood pressure for vitamin D supplementation versus placebo. The studies are arranged along the vertical axis according to the baseline blood pressure. The circle sizes are proportional to the study size. The black diamond represents the primary meta-analyses. Grey diamonds represent sensitivity and subgroup analyses. Dashed lines indicate studies for which standard errors were not reported; see footnotes. * (Krause (39)) An estimate for the 95% confidence interval was derived from the reported full ranges of changes in blood pressure. † (Margolis (WHI) (38)) The 95% confidence interval is within the circle. ‡ (Schleithoff (34)) An estimate for the 95% confidence interval was derived from the reported interquartile ranges of changes in blood pressure.

Figure 2

Meta-analyses of the effect of vitamin D supplementation on net change in systolic (2A) and diastolic (2B) blood pressure. WHI, Women’s Health Initiative trial. Weighted mean difference and 95% confidence intervals in change in systolic (Figure 2A) and diastolic (Figure 2B) blood pressure for vitamin D supplementation versus placebo. The studies are arranged along the vertical axis according to the baseline blood pressure. The circle sizes are proportional to the study size. The black diamond represents the primary meta-analyses. Grey diamonds represent sensitivity and subgroup analyses. Dashed lines indicate studies for which standard errors were not reported; see footnotes. * (Krause (39)) An estimate for the 95% confidence interval was derived from the reported full ranges of changes in blood pressure. † (Margolis (WHI) (38)) The 95% confidence interval is within the circle. ‡ (Schleithoff (34)) An estimate for the 95% confidence interval was derived from the reported interquartile ranges of changes in blood pressure.