Anastassios G. Pittas

Systematic Review: Vitamin D and Cardiometabolic Outcomes

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.

Vitamin D and type 2 diabetes: a systematic review

Background/Objectives:Vitamin D may modify the risk of type 2 diabetes mellitus. The aim of this review was to examine the association between vitamin D status and incident type 2 diabetes, and the effect of vitamin D supplementation on glycemic outcomes.Methods:We performed a systematic review of English-language studies using MEDLINE through February 2011. Longitudinal cohort studies reporting associations between vitamin D status and incident type 2 diabetes, and randomized controlled trials (RCTs) of vitamin D supplementation, were included. Study characteristics and results were extracted, and study quality was assessed.Results:A total of 8 observational cohort studies and 11 RCTs were included. In meta-analyses of observational studies, vitamin D intake >500 international units (IU)/day decreased the risk of type 2 diabetes by 13% compared with vitamin D intake <200 IU/day. Individuals with the highest vitamin D status (>25 ng/ml) had a 43% lower risk of developing type 2 diabetes (95% confidence interval 24, 57%) compared with those in the lowest group (<14 ng/ml). In post hoc analyses from eight trials among participants with normal glucose tolerance at baseline and in three small underpowered (n=32–62) trials of patients with established type 2 diabetes, there was no effect of vitamin D supplementation on glycemic outcomes. In two trials among patients with baseline glucose intolerance, vitamin D supplementation improved insulin resistance.Conclusions:Vitamin D may play a role in type 2 diabetes; however, to better define the role of vitamin D in the development and progression of type 2 diabetes, high-quality observational studies and RCTs that measure blood 25-hydroxyvitamin D concentration and clinically relevant glycemic outcomes are needed.

Association between serum osteocalcin and markers of metabolic phenotype.

CONTEXT Osteocalcin has been reported to contribute to the regulation of glucose tolerance and insulin secretion and sensitivity in experimental animals. OBJECTIVE Our objective was to examine the association between serum osteocalcin concentration and markers of dysmetabolic phenotype using data from a completed clinical trial in adults age 65 and older [n = 380, mean age 71 yr, body mass index (BMI) 26.9 kg/m(2), 5% with diabetes]. RESEARCH DESIGN AND METHODS In cross-sectional analyses (baseline data), we estimated the associations of serum osteocalcin and urine N-telopeptide with markers of metabolic phenotype including fasting plasma glucose (FPG) (primary outcome), fasting insulin, insulin sensitivity estimated by homeostasis model assessment for insulin resistance, plasma high-sensitivity C-reactive protein, IL-6, and measures of adiposity (BMI and body fat) (secondary outcomes) after multivariate adjustment for potential confounders. In prospective analysis (placebo arm), we estimated the associations of osteocalcin and N-telopeptide with change in the primary outcome, FPG, over a 3-yr period. RESULTS In cross-sectional analyses, serum osteocalcin concentration was inversely associated with FPG (P = 0.01), fasting insulin (P = 0.006), homeostasis model assessment for insulin resistance (P = 0.002), high-sensitivity C-reactive protein (P = 0.01), IL-6 (P = 0.02), BMI (P < 0.001), and body fat (P < 0.001). When participants were divided into tertiles by serum osteocalcin, mean FPG was 97.1 vs. 104.8 mg/dl in the highest vs. lowest osteocalcin tertile, respectively (P < 0.01). In prospective analyses, exposure to higher osteocalcin levels during follow-up was associated with a significantly lower rise in FPG at 3 yr. Urine N-telopeptide was not associated with any marker of metabolic phenotype. CONCLUSIONS Serum osteocalcin concentration was inversely associated with blood markers of dysmetabolic phenotype and measures of adiposity. Our findings should be considered hypothesis generating, and they need to be replicated in human studies designed to test the hypothesis that osteocalcin affects metabolism.

Effects of vitamin D and calcium supplementation on pancreatic β cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial

BACKGROUND A suboptimal vitamin D and calcium status has been associated with higher risk of type 2 diabetes in observational studies, but evidence from trials is lacking. OBJECTIVE We determined whether vitamin D supplementation, with or without calcium, improved glucose homeostasis in adults at high risk of diabetes. DESIGN Ninety-two adults were randomly assigned in a 2-by-2 factorial-design, double-masked, placebo-controlled trial to receive either cholecalciferol (2000 IU once daily) or calcium carbonate (400 mg twice daily) for 16 wk. The primary outcome was the change in pancreatic β cell function as measured by the disposition index after an intravenous-glucose-tolerance test. Other outcomes were acute insulin response, insulin sensitivity, and measures of glycemia. RESULTS Participants had a mean age of 57 y, a body mass index (BMI; in kg/m(2)) of 32, and glycated hemoglobin (Hb A(1c)) of 5.9%. There was no significant vitamin D × calcium interaction on any outcomes. The disposition index increased in the vitamin D group and decreased in the no-vitamin D group (adjusted mean change ± SE: 300 ± 130 compared with -126 ± 127, respectively; P = 0.011), which was explained by an improvement in insulin secretion (62 ± 39 compared with -36 ± 37 mU · L(-1) · min, respectively; P = 0.046). Hb A(1c) increased less, but nonsignificantly, in the vitamin D group than in the no-vitamin D group (0.06 ± 0.03% compared with 0.14 ± 0.03%, respectively; P = 0.081). There was no significant difference in any outcomes with calcium compared with no calcium. CONCLUSION In adults at risk of type 2 diabetes, short-term supplementation with cholecalciferol improved β cell function and had a marginal effect on attenuating the rise in Hb A(1c). This trial was registered at clinicaltrials.gov as NCT00436475.

Plasma 25-Hydroxyvitamin D Is Associated with Markers of the Insulin Resistant Phenotype in Nondiabetic Adults

We examined the cross-sectional association between plasma 25-hydroxyvitamin D [25(OH)D] and markers of the insulin resistant phenotype. Plasma 25(OH)D concentrations were measured in 808 nondiabetic participants of the Framingham Offspring Study. Outcome measures included fasting and 2-h post 75-g oral glucose tolerance test (OGTT) glucose and insulin; these were used to calculate the homeostatic model assessment-insulin resistance (HOMA-IR) and insulin sensitivity index (ISI(0,120)). We also measured plasma adiponectin, triacylglycerol, and HDL cholesterol concentrations as markers of the insulin-resistant phenotype. After adjusting for age, sex, BMI, waist circumference, and current smoking status, plasma 25(OH)D concentration was inversely associated with fasting plasma glucose and insulin concentrations, and HOMA-IR. Compared with the participants in the lowest tertile category of plasma 25(OH)D, those in the highest tertile category had a 1.6% lower concentration of fasting plasma glucose (P-trend = 0.007), 9.8% lower concentration of fasting plasma insulin (P-trend = 0.001), and 12.7% lower HOMA-IR score (P-trend < 0.001). After adjusting for age and sex, plasma 25(OH)D was positively associated with ISI(0,120), plasma adiponectin, and HDL cholesterol and inversely associated with plasma triacylglycerol, but these associations were no longer significant after further adjustment for BMI, waist circumference, and current smoking status. 25(OH)D and 2-h post-OGTT glucose were not associated. Among adults without diabetes, vitamin D status was inversely associated with surrogate fasting measures of insulin resistance. These results suggest that vitamin D status may be an important determinant for type 2 diabetes mellitus.

Blood 25-Hydroxy Vitamin D Levels and Incident Type 2 Diabetes: A meta-analysis of prospective studies

OBJECTIVE To quantitatively assess the strength and shape of the association between blood 25-hydroxy vitamin D [25(OH)D] levels and incident risk of type 2 diabetes. RESEARCH DESIGN AND METHODS A systematic search of the MEDLINE and Embase databases and a hand search of references from original reports were conducted up to 31 October 2012. Prospective observational studies that assessed the association between blood levels of 25(OH)D and risk of incident type 2 diabetes were included for meta-analysis. DerSimonian and Laird’s random-effects model was used. A quadratic spline regression analysis was used to examine the shape of the association with a generalized least-squares trend test performed for the dose-response relation. RESULTS A total of 21 prospective studies involving 76,220 participants and 4,996 incident type 2 diabetes cases were included for meta-analysis. Comparing the highest to the lowest category of 25(OH)D levels, the summary relative risk for type 2 diabetes was 0.62 (95% CI 0.54–0.70). A spline regression model showed that higher 25(OH)D levels were monotonically associated with a lower diabetes risk. This inverse association did not differ by sex, duration of follow-up, study sample size, diabetes diagnostic criteria, or 25(OH)D assay method. A linear trend analysis showed that each 10 nmol/L increment in 25(OH)D levels was associated with a 4% lower risk of type 2 diabetes (95% CI 3–6; P for linear trend < 0.0001). CONCLUSIONS Our meta-analysis showed an inverse and significant association between circulating 25(OH)D levels and risk of type 2 diabetes across a broad range of blood 25(OH)D levels in diverse populations.

Effect of Chromium Supplementation on Glucose Metabolism and Lipids

OBJECTIVE—A systematic review of the effect of chromium supplementation on glucose metabolism and lipid levels. RESEARCH DESIGN AND METHODS—A literature search was conducted in MEDLINE and the Commonwealth Agricultural Bureau. Eligible studies were English language randomized controlled trials of chromium supplement intake ≥3 weeks, with ≥10 participants receiving chromium. All trials with glucose metabolism outcomes and trials of individuals with diabetes or glucose intolerance for lipid outcomes were included. Meta-analyses were performed as appropriate. RESULTS—Forty-one studies met criteria, almost half of which were of poor quality. Among participants with type 2 diabetes, chromium supplementation improved glycosylated hemoglobin levels by −0.6% (95% CI −0.9 to −0.2) and fasting glucose by −1.0 mmol/l (−1.4 to −0.5) but not lipids. There was no benefit in individuals without diabetes. There were some indications of dose effect and differences among chromium formulations. Larger effects were more commonly observed in poor-quality studies. The evidence was limited by poor study quality, heterogeneity in methodology and results, and a lack of consensus on assessment of chromium status. CONCLUSIONS—No significant effect of chromium on lipid or glucose metabolism was found in people without diabetes. Chromium supplementation significantly improved glycemia among patients with diabetes. However, future studies that address the limitations in the current evidence are needed before definitive claims can be made about the effect of chromium supplementation.

Vitamin D: Beyond bone

In recent years, vitamin D has been received increased attention due to the resurgence of vitamin D deficiency and rickets in developed countries and the identification of extraskeletal effects of vitamin D, suggesting unexpected benefits of vitamin D in health and disease, beyond bone health. The possibility of extraskeletal effects of vitamin D was first noted with the discovery of the vitamin D receptor (VDR) in tissues and cells that are not involved in maintaining mineral homeostasis and bone health, including skin, placenta, pancreas, breast, prostate and colon cancer cells, and activated T cells. However, the biological significance of the expression of the VDR in different tissues is not fully understood, and the role of vitamin D in extraskeletal health has been a matter of debate. This report summarizes recent research on the roles for vitamin D in cancer, immunity and autoimmune diseases, cardiovascular and respiratory health, pregnancy, obesity, erythropoiesis, diabetes, muscle function, and aging.

Effect of Vitamin D3 Supplementation on Improving Glucose Homeostasis and Preventing Diabetes: A Systematic Review and Meta-Analysis

CONTEXT Observational studies report consistent associations between low vitamin D concentration and increased glycemia and risk of type 2 diabetes, but results of randomized controlled trials (RCTs) are mixed. OBJECTIVE The objective of the study was to systematically review RCTs that report on the effects of vitamin D supplementation on glucose homeostasis or diabetes prevention. DATA SOURCES Sources of data for the study were MEDLINE, EMBASE, SCOPUS, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment, and Science Citation Index from inception to June 2013. STUDY SELECTION Study selection was trials that compared vitamin D3 supplementation with placebo or a non-vitamin D supplement in adults with normal glucose tolerance, prediabetes, or type 2 diabetes. DATA EXTRACTION AND SYNTHESIS Two reviewers collected data and assessed trial quality using the Cochrane Risk of Bias tool. Random-effects models were used to estimate mean differences (MDs) and odds ratios. The main outcomes of interest were homeostasis model assessment of insulin resistance, homeostasis model assessment of β-cell function, hemoglobin A1c levels, fasting blood glucose, incident diabetes, and adverse events. DATA SYNTHESIS Thirty-five trials (43 407 patients) with variable risk of bias were included. Vitamin D had no significant effects on insulin resistance [homeostasis model assessment of insulin resistance: MD -0.04; 95% confidence interval (CI) -0.30 to 0.22, I-squared statistic (I(2)) = 45%], insulin secretion (homeostasis model of β-cell function: MD 1.64; 95% CI -25.94 to 29.22, I(2) = 40%), or hemoglobin A1c (MD -0.05%; 95% CI -0.12 to 0.03, I(2) = 55%) compared with controls. Four RCTs reported on the progression to new diabetes and found no effect of vitamin D (odds ratio 1.02; 95% CI 0.94 to 1.10, I(2) = 0%). Adverse events were rare, and there was no evidence of publication bias. CONCLUSIONS Evidence from available trials shows no effect of vitamin D3 supplementation on glucose homeostasis or diabetes prevention. Definitive conclusions may be limited in the context of the moderate degree of heterogeneity, variable risk of bias, and short-term follow-up duration of the available evidence to date.

Vitamin D and Diabetes

On the basis of evidence from animal and human studies, vitamin D has emerged as a potential risk modifier for type 1 and type 2 diabetes (type 1 diabetes and type 2 diabetes). Vitamin D is thought to have both direct (through activation of the vitamin D receptor) and indirect (via regulation of calcium homeostasis) effects on various mechanisms related to the pathophysiology of both types of diabetes, including pancreatic beta-cell dysfunction, impaired insulin action and systemic inflammation. Observational case-control studies have shown that vitamin D supplementation in pregnancy or early childhood is associated with reduced risk of incident type 1 diabetes. There are no trials on the effect of vitamin D (ergocalciferol or cholecalciferol) on type 1 diabetes. An association between vitamin D insufficiency and incident type 2 diabetes has been reported in longitudinal observational studies, but the association is not consistent. Results from small underpowered trials and post-hoc analyses of data from larger trials designed for bone-specific outcomes show no effect of vitamin D supplementation on glycemia in healthy adults but vitamin D may retard the progression to diabetes in adults with glucose intolerance. Because vitamin D is an excellent marker of general health status, the positive results reported in some observational studies might reflect unmeasured and unaccounted confounding. Therefore, the hypothesis that vitamin D may modify diabetes risk needs to be confirmed in trials specifically designed for that purpose.