Vitamin D supplementation and bone turnover in advanced heart failure: the EVITA trial.

Low vitamin D status is common in patients with heart failure and may influence bone health. A daily vitamin D dose of 4000 IU (moderately high dose) for 3 years had however no effect on parameters of bone metabolism, even in patients with very low vitamin D status. INTRODUCTION: Low vitamin D status is common in patients with heart failure (HF) and has been related to disturbed bone turnover. The present study investigated the effect of a daily vitamin D3 dose of 4000 IU on bone turnover markers (BTMs) in patients with advanced HF and 25-hydroxyvitamin D (25OHD) concentrations < 75 nmol/L. METHODS: In this pre-specified secondary analysis of a randomized controlled trial, we assessed in 158 male HF patients (vitamin D group: n = 80; placebo group: n = 78) between-group differences in calciotropic hormones (25OHD, 1,25-dihydroxyvitamin D [1,25(OH)2D], intact parathyroid hormone [iPTH]), and BTMs (cross-linked C-telopeptide of type I collagen, bone-specific alkaline phosphatase, undercarboxylated osteocalcin). Comparisons were performed at the end of a 3-year vitamin D supplementation period with adjustments for baseline values. RESULTS: Compared with placebo, vitamin D increased 25OHD on average by 54.3 nmol/L. At study termination, 25OHD and 1,25(OH)2D were significantly higher (P < 0.001 and P = 0.007, respectively), whereas iPTH tended to be lower in the vitamin D group than in the placebo group (P = 0.083). BTMs were initially within their reference ranges and did not differ significantly between groups at study termination, neither in the entire study cohort nor when data analysis was restricted to the subgroup of patients with initial 25OHD concentrations < 30 nmol/L (n = 54) or to patients with initial hyperparathyroidism (n = 65) (all P values > 0.05). CONCLUSIONS: A daily vitamin D3 dose of 4000 IU did not influence BTMs. Data indicate that vitamin D supplementation will not lower bone turnover in male patients with heart failure.

Independent associations of vitamin D metabolites with anemia in patients referred to coronary angiography: the LURIC study.

PURPOSE: Anemia and vitamin D deficiency are both frequent in adult patients. Whether low vitamin D metabolite levels are an independent risk factor for different subtypes of anemia remains to be studied in detail. METHODS: In 3299 patients referred for coronary angiography, we investigated the association of 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D [1,25(OH)2D] with anemia [hemoglobin (Hb) <12.5 g/dl] of specific subtypes. RESULTS: Compared with patients with 25OHD levels in the adequate range (50-125 nmol/l), patients with deficient 25OHD concentrations (<30 nmol/l; 33.6 % of patients) had 0.6 g/dl lower Hb levels. Hb values were 1.3 g/dl lower in patients with 1,25(OH)2D levels <40 pmol/l (5.4 % of patients), compared with patients in the highest 1,25(OH)2D category (>70 pmol/l). Of the participants, 16.7 % met the criteria for anemia. In multivariate-adjusted regression analyses, the odds ratios for anemia in the lowest 25OHD and 1,25(OH)2D categories were 1.52 (95 % CI 1.15-2.02) and 3.59 (95 % CI 2.33-5.52), compared with patients with 25OHD levels in the adequate range and patients with 1,25(OH)2D levels >70 pmol/l. The probability of anemia was highest in patients with combined 25OHD and 1,25(OH)2D deficiency [multivariable-adjusted odds ratio 5.11 (95 % CI 2.66-9.81)]. Patients with anemia of chronic kidney disease had the highest prevalence of 25OHD deficiency and 1,25(OH)2D concentrations of <40 pmol/l. CONCLUSIONS: Low 25OHD and 1,25(OH)2D concentrations are independently associated with anemia. Patients with poor kidney function are most affected. Interventional trials are warranted to prove whether administration of plain or activated vitamin D can prevent anemia.

Randomized supplementation of 4000 IU vitamin D3 daily vs placebo on the prevalence of anemia in advanced heart failure: the EVITA trial.

BACKGROUND: Low 25-hydroxyvitamin D (25OHD) levels (< 75 nmol/l) are inversely associated with anemia prevalence. Since anemia and low 25OHD levels are common in patients with heart failure (HF), we aimed to investigate whether vitamin D supplementation can reduce anemia prevalence in advanced HF. METHODS: EVITA (Effect of Vitamin D on Mortality in Heart Failure) is a randomized, placebo-controlled clinical trial in patients with initial 25OHD levels < 75 nmol/l. Participants received either 4000 IU vitamin D3 daily or a matching placebo for 36 months. A total of 172 patients (vitamin D group: n = 85; placebo group: n = 87) were investigated in this pre-specified secondary data analysis. Hemoglobin (Hb) and other hematological parameters were measured at baseline and study termination. Assessment of between-group differences in anemia prevalence and Hb concentrations was performed at study termination, while adjusting for baseline differences. RESULTS: In the vitamin D and placebo group, baseline proportions of patients with anemia (Hb < 12.0 g/dL in females and < 13.0 g/dL in males) were 17.2% and 10.6%, respectively (P = 0.19). At study termination, the proportion of patients with anemia in the vitamin D and placebo groups was 32.2% and 31.8%, respectively (P > 0.99). There was no between-group difference in change in the Hb concentrations (- 0.04 g/dL [95%CI:-0.53 to 0.45 g/dL]; P = 0.87). Results regarding anemia risk and Hb concentrations were similar in the subgroup of patients with chronic kidney disease (vitamin D group: n = 26; placebo group: n = 23). Moreover, results did not differ substantially when data analysis was restricted to patients with deficient baseline 25OHD levels. CONCLUSIONS: A daily vitamin D supplement of 4000 IU did not reduce anemia prevalence in patients with advanced HF. Data challenge the clinical relevance of vitamin D supplementation to increase Hb levels. TRIAL REGISTRATION: The study was registered at EudraCT (No. 2010-020793-42) and clinicaltrials.gov ( NCT01326650 ).

Effects of vitamin D supplementation on glycated haemoglobin and fasting glucose levels in hypertensive patients: a randomized controlled trial.

AIM: To investigate the efficacy of vitamin D supplementation on glycaemic control. METHODS: The Styrian Vitamin D Hypertension Trial was a single-centre, double-blind, placebo-controlled study conducted between 2011 and 2014 at the Medical University of Graz, Austria. We enrolled 200 people with arterial hypertension and 25-hydroxyvitamin D [25(OH)D] concentrations <30 ng/mL. Study participants were randomized to receive either 2800 IU of vitamin D or placebo per day for 8 weeks. The present study was a post hoc analysis that incorporated an analysis of covariance (ancova) approach, while adjusting for baseline differences. RESULTS: A total of 185 participants [mean ± standard deviation age, 60.1 ± 11.3 years; 47% women; mean 25(OH)D 21.2 ± 5.6 ng/mL, mean glycated haemoglobin (HbA1c) 44.8 ± 11.8 mmol/mol and mean body mass index 30.4 ± 5.4 kg/m(2) ] completed the trial. ancova showed a mean treatment effect [95% confidence interval (CI)] on HbA1c of -3.52 (-6.7 to -0.34) mmol/mol (p = .045). There was no difference in fasting glucose -4.7 mg/dL (95% CI -16.3 to 6.9; p = .426). CONCLUSIONS: Vitamin D supplementation in obese hypertensive patients with low 25(OH)D reduces HbA1c levels. This finding warrants further investigation into potential vitamin D effects on glucose homeostasis.

Vitamin D metabolites and fibroblast growth factor-23 in patients with left ventricular assist device implants: association with stroke and mortality risk.

PURPOSE: Stroke and mortality risk in patients with left ventricular assist device (LVAD) implants continue to be high. Whether nonclassical cardiovascular risk markers such as vitamin D metabolites and fibroblast growth factor (FGF)-23 contribute to this risk remains to be studied, and this was the objective of our work. METHODS: In 154 LVAD patients (91 HeartWare and 63 HeartMate II implants), we measured circulating 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D3 (1,25[OH]2D3), parathyroid hormone (PTH) and FGF-23 shortly before LVAD implantation and investigated their association with stroke and mortality risk during 1-year follow-up. RESULTS: Of the study cohort, 34.4 and 92.2%, respectively, had deficient 25OHD (<25 nmol/l) and 1,25(OH)2D3 (<41 pmol/l) values, whereas 42.6 and 98.7%, respectively, had elevated PTH levels (>6.7 pmol/l) and FGF-23 values above the reference range (100 RU/ml). One-year freedom from stroke was 80.9 %, and 1-year survival was 64.3%. The multivariable-adjusted hazard ratio of stroke was 2.44 (95% CI: 1.09-5.45; P = 0.03) for the subgroup of 25OHD levels <25 nmol/l (reference group: 25OHD levels ≥25 nmol/l). The multivariable-adjusted hazard ratio of 1-year mortality was 2.78 (95% CI: 1.52-5.09; P = 0.001) for patients with 25OHD levels <25 nmol/l compared with patients with 25OHD levels ≥25 nmol/l. PTH, FGF-23 and 1,25(OH)2D3 were not associated with stroke or mortality risk. CONCLUSIONS: In LVAD patients, deficient 25OHD levels are independently associated with high stroke and mortality risk. If confirmed in randomized controlled trials, preoperative correction of deficient vitamin D status could be a promising measure to reduce stroke and mortality risk in LVAD patients.

Evolving biomarkers improve prediction of long-term mortality in patients with stable coronary artery disease: the BIO-VILCAD score.

OBJECTIVE: Algorithms to predict the future long-term risk of patients with stable coronary artery disease (CAD) are rare. The VIenna and Ludwigshafen CAD (VILCAD) risk score was one of the first scores specifically tailored for this clinically important patient population. The aim of this study was to refine risk prediction in stable CAD creating a new prediction model encompassing various pathophysiological pathways. Therefore, we assessed the predictive power of 135 novel biomarkers for long-term mortality in patients with stable CAD. DESIGN, SETTING AND SUBJECTS: We included 1275 patients with stable CAD from the LUdwigshafen RIsk and Cardiovascular health study with a median follow-up of 9.8 years to investigate whether the predictive power of the VILCAD score could be improved by the addition of novel biomarkers. Additional biomarkers were selected in a bootstrapping procedure based on Cox regression to determine the most informative predictors of mortality. RESULTS: The final multivariable model encompassed nine clinical and biochemical markers: age, sex, left ventricular ejection fraction (LVEF), heart rate, N-terminal pro-brain natriuretic peptide, cystatin C, renin, 25OH-vitamin D3 and haemoglobin A1c. The extended VILCAD biomarker score achieved a significantly improved C-statistic (0.78 vs. 0.73; P = 0.035) and net reclassification index (14.9%; P < 0.001) compared to the original VILCAD score. Omitting LVEF, which might not be readily measureable in clinical practice, slightly reduced the accuracy of the new BIO-VILCAD score but still significantly improved risk classification (net reclassification improvement 12.5%; P < 0.001). CONCLUSION: The VILCAD biomarker score based on routine parameters complemented by novel biomarkers outperforms previous risk algorithms and allows more accurate classification of patients with stable CAD, enabling physicians to choose more personalized treatment regimens for their patients.

Association of bone turnover markers with mortality in women referred to coronary angiography: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

UNLABELLED: We examined the association of fatal events with beta-crosslaps (ß-CTX) and osteocalcin (OC) concentrations in women. We observed an independent association of ß-CTX and OC concentrations with fatal events in women at high to intermediate cardiovascular risk. INTRODUCTION: There is some evidence suggesting an association of ß-CTX and OC with fatal events in men and frail elderly subjects. We aimed to examine the association of fatal events with ß-CTX and OC in women. METHODS: We measured ß-CTX and OC in 986 women aged 65 (58-72) years referred to coronary angiography. RESULTS: Compared to the first ß-CTX quartile, the crude hazard ratios (HRs) for all-cause and cardiovascular mortality in the highest ß-CTX quartile were 2.50 (1.65-3.81) and 3.28 (1.82-5.91), respectively. In multivariate adjusted models, HRs for all-cause and cardiovascular mortality in the highest ß-CTX quartile were 1.72 (1.09-2.70) and 2.31 (1.24-4.32), respectively. The lowest 25-hydroxyvitamin D [25(OH)D] quartile was significantly associated with increased risk of all-cause and cardiovascular mortality in multivariate adjusted models. In those models, the highest ß-CTX quartile was associated with an increased risk of all-cause and cardiovascular mortality. For OC concentrations, we found a reverse J-shaped association with noncardiovascular mortality. Using the first quartile as reference, crude and multivariate adjusted HRs for noncardiovascular mortality in the second and third OC quartile were 0.41 (0.19-0.90) [multivariate: 0.40 (0.18-0.88)] and 0.51 (0.25-1.06) [multivariate: 0.43 (0.20-0.94)], respectively. The lowest 25(OH)D quartile was associated with a trend towards increased risk of noncardiovascular mortality in multivariate analysis. In that analysis, OC quartile 2 and 3 were significantly associated with lower risk of noncardiovascular mortality. CONCLUSIONS: We observed an independent association of high ß-CTX with all-cause and cardiovascular mortality and a reverse J-shaped association of OC with noncardiovascular mortality.

Aldosterone to active Renin ratio as screening test for primary aldosteronism: reproducibility and influence of orthostasis and salt loading.

Measurement of the aldosterone to active renin ratio (AARR) is the recommended screening test for primary aldosteronism (PA), but several sampling conditions impact on the AARR. We aimed to evaluate the reproducibility and the influence of orthostasis and salt loading on the AARR. The Graz Endocrine Causes of Hypertension (GECOH) study is a diagnostic accuracy study among hypertensive patients at a tertiary care centre in Graz, Austria. With a median interval of 4 weeks we determined the AARR under standardized sampling conditions twice in the sitting position, after 1h in the supine position, and after a salt infusion test (SIT). We identified 9 patients with PA and 151 patients with essential hypertension (EH). The Pearson correlation coefficient between both AARR measurements in the sitting position was 0.79 (p<0.001). In EH, recumbency was associated with a significant decrease of aldosterone and, to a lesser extent, of renin, thus lowering the AARR as compared to the sitting position (p<0.001 for all). In PA, recumbency had only minor effects, but it increased the rate of false negative AARR. SIT suppressed the AARR and its components in EH, whereas in PA only renin was slightly decreased. AARR has a good intra-individual reproducibility and decreases during recumbency. These results suggest that a single AARR determination in the sitting position is a reliable screening tool for PA.

Determinants of circulating calcitriol in cardiovascular disease.

Circulating calcitriol may contribute to the risk of cardiovascular disease (CVD), but its regulation in patients with CVD is poorly characterized. We therefore aimed to assess determinants of circulating calcitriol in these patients. We analyzed 2183 independent samples from a large cohort of patients scheduled for coronary angiography and 1727 independent samples from different other cohorts from patients with a wide range of CVDs, including heart transplant candidates, to quantify the association of different parameters with circulating calcitriol. We performed univariable and multivariable linear regression analyses using the mathematical function that fitted best with circulating calcitriol. In the multivariable analysis of the large single cohort, nine parameters remained significant, explaining 30.0 % (32.4 % after exclusion of 22 potential outliers) of the variation in circulating calcitriol (r=0.548). Log-transformed 25-hydroxyvitamin D [25(OH)D] and log-transformed glomerular filtration rate were the strongest predictors, explaining 17.6 % and 6.6 %, respectively, of the variation in calcitriol. In the analysis of the combined other cohorts, including heart transplant candidates, the multivariable model explained a total of 42.6 % (46.1 % after exclusion of 21 potential outliers) of the variation in calcitriol (r=0.653) with log-transformed fibroblast growth factor-23 and log-transformed 25(OH)D explaining 29.0 % and 6.2 %, respectively. Circulating 25(OH)D was positively and FGF-23 inversely associated with circulating calcitriol. Although significant, PTH was only a weak predictor of calcitriol in both analyses (<2.5 %). In patients with CVD, FGF-23 and 25(OH)D are important independent determinants of circulating calcitriol. The relative importance of these two parameters may vary according to CVD severity. Future studies should focus on the clinical importance of regulating circulating calcitriol by different parameters.

Association of bone turnover markers with mortality in men referred to coronary angiography.

UNLABELLED: We aimed to examine the association of fatal events with osteocalcin (OC) and beta-crosslaps (ß-CTX) levels in men. We observed a U-shaped association of OC and ß-CTX levels with fatal events in a large cohort of men at high cardiovascular risk. INTRODUCTION: Accumulating evidence suggests an association of low OC levels with metabolic disturbances. Whether OC levels are related to fatal events is, however, less clear. Further, high ß-CTX levels are linked to increased mortality. We aimed to examine the association of fatal events with both OC and ß-CTX in men. METHODS: We measured OC and ß-CTX in 2,271 men referred to coronary angiography (1997-2000). RESULTS: We observed a U-shaped association of OC and ß-CTX with fatal events. Crude hazard ratios (HRs) for all-cause and non-cardiovascular mortality in the highest OC quintile were 1.38 (1.04-1.83) and 1.47 (0.89-2.40), respectively, and 2.11 (1.61-2.75) and 2.06 (1.29-3.29) for men in the lowest compared to the third OC quintile. In multivariate-adjusted models, HRs for all-cause, and non-cardiovascular mortality in the lowest OC quintile were 1.63 (1.23-2.16) and 1.79 (1.10-2.92), respectively, compared to the third OC quintile, whereas the association of high OC with mortality lost its significance. Crude and multivariate-adjusted HRs for cardiovascular mortality in the lowest OC quintile compared to the third OC quintile were 2.08 (1.49-2.90) and 1.74 (1.24-2.46), respectively. Moreover, high as well as low ß-CTX levels were independently associated with all-cause (quintile 1 vs. quintile 3: HR 1.42 (1.05-1.92); quintile 5 vs. quintile 3: HR 1.79 (1.31-2.45)) and cardiovascular mortality (quintile 1 vs. quintile 3: HR 1.55 (1.05-2.28); quintile 5 vs. quintile 3: HR 1.85 (1.23-2.77)). CONCLUSIONS: We observed a U-shaped association of OC and ß-CTX with fatal events in a large cohort of men at high cardiovascular risk.

Associations of homoarginine with bone metabolism and density, muscle strength and mortality: cross-sectional and prospective data from 506 female nursing home patients.

UNLABELLED: In female nursing home patients, homoarginine was associated with lower bone turnover, higher bone density, lower mortality and, by trend, with muscle strength. INTRODUCTION: Homoarginine, a cationic amino acid, may be relevant for muscusloskeletal health because it inhibits alkaline phosphatases (AP) and is involved in nitric oxide and energy metabolism. We aimed to evaluate whether homoarginine serum concentrations are associated with bone density and metabolism, muscle strength, fractures and mortality. METHODS: We examined a cohort of female nursing home patients that underwent quantitative bone ultrasound (QUS) measurements and assessments of knee extensor strength. Measurements of serum homoarginine, C-terminal telopeptide cross-links (ß-CTxs) and osteocalcin were also performed at baseline. Thereafter, patients were followed-up with respect to fractures and mortality. RESULTS: Serum homoarginine concentrations were determined in 506 female study participants (mean age: 83.9 ± 6.0 years). Homoarginine was inversely correlated with ß-CTxs (r = -0.26; p < 0.001) and osteocalcin (r = -0.21; p < 0.001), and these associations remained significant in multiple regression analyses. Multivariate regression analyses showed that homoarginine is significantly associated with calcaneus stiffness (beta coefficient = 0.11; p = 0.020) and by trend with knee extensor strength (beta coefficient = 0.09; p = 0.065). During a mean follow-up time of 27 ± 8 months, we recorded 119 deaths (23.5%) and 63 fractures (12.5%). In multivariate analyses, homoarginine was associated with significantly reduced risk of mortality and the combined endpoint of fractures and mortality. CONCLUSIONS: Whether homoarginine metabolism is critically involved into the pathogenesis of musculoskeletal diseases and fatal events warrants further studies.

Vitamin D: do we get enough? A discussion between vitamin D experts in order to make a step towards the harmonisation of dietary reference intakes for vitamin D across Europe.

UNLABELLED: On September 29, 2011, acknowledged experts in the field of vitamin D, mainly European, were brought together in order to discuss the recent scientific advances in relation to vitamin D: the current requirements and associations with various health outcomes. In this article, the discussions resulting from the meeting are summarized. INTRODUCTION: Several groups at risk for developing vitamin D insufficiency have been identified. Accordingly, reviews indicate that a significant percentage of the population worldwide have serum 25-hydroxyvitamin D levels below 50 nmol/l. In addition to the role of vitamin D in bone health, recent studies suggest that it may play a pivotal role in other systems, e.g., the cardiovascular system, pancreas, muscle, immune system and brain. Most evidence, however, is obtained from observational studies and yet inconclusive. METHODS: To exchange and broaden knowledge on the requirements for vitamin D and its effect on various health outcomes, a workshop entitled "Vitamin D Expert Meeting: Do we get enough?", was organized. RESULTS: Despite low vitamin D levels worldwide, consensus on the definition of deficiency is not yet reached. In order to define cut-off points for vitamin D whilst taking into account extraskeletal health effects, randomized controlled trials in these fields are warranted. The experts do emphasize that there is evidence to suggest an important role for vitamin D in the maintenance of optimal bone health at all ages and that vitamin D supplementation, in most studies co-administered with calcium, reduces fracture risk in the senior population. CONCLUSION: To reach a serum 25-hydroxyvitamin D level of 50 nmol/l older adults aged ≥65 years are therefore recommended to meet a mean daily vitamin D intake of 20 µg (800 IU), which is best achieved with a supplement.

The fatty liver index is associated with increased mortality in subjects referred to coronary angiography.

BACKGROUND AND AIMS: Fatty liver index (FLI), a surrogate parameter for nonalcoholic fatty liver disease, is an emerging risk factor for cardiovascular diseases and mortality. We aimed to evaluate whether FLI is associated with all-cause, cardiovascular, and non-cardiovascular mortality as well as fatal cancer in a cohort of subjects routinely referred to coronary angiography. METHODS AND RESULTS: FLI was calculated using BMI (body mass index), waist circumference (WC), triglycerides (TG) and gamma-glutamyl transferase (GGT) in 3270 subjects who were referred to coronary angiography (1997-2000). The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes, cardiovascular causes, non-cardiovascular causes, and fatal cancer. After a median follow-up time of 7.7 years, 740 subjects (22.6%) had died. There were 437 deaths due to cardiovascular disease and 303 deaths due to non-cardiovascular disease. Age-, sex-, and BMI-adjusted HRs (with 95% confidence intervals) for all-cause, cardiovascular, and non-cardiovascular mortality in the highest compared to the lowest FLI quartile were 2.56 (1.90-3.43; p < 0.001), 2.17 (1.47-3.22; p < 0.001), and 3.49 (2.16-5.66; p < 0.001), respectively. In age-, sex-, and BMI-adjusted analyzes, we found no significant association of FLI with fatal cancer. Multivariate adjusted HRs for all-cause, cardiovascular, non-cardiovascular mortality, and fatal cancer in the highest compared to the lowest FLI quartile were 2.17 (1.58-2.99; p < 0.001), 1.64 (1.07-2.51; p = 0.023), 3.72 (2.22-6.24; p < 0.001), and 2.33 (1.01-5.41; p = 0.048) respectively. CONCLUSION: In subjects referred to coronary angiography, high FLI levels are independently associated with increased all-cause, cardiovascular, and non-cardiovascular mortality as well as fatal cancer.

Future directions in vitamin D and cardiovascular research.

AIMS: Evidence is accumulating that vitamin D status may influence the risk of cardiovascular disease (CVD). Final confirmation for a causal relationship between vitamin D and CVD is however still lacking. The present viewpoint article outlines several future research directions to close this gap. DATA SYNTHESIS: Future directions include the need of performing large randomised controlled supplementation trials with vitamin D in specific risk groups. In addition, large register sets of data on vitamin D supplementation can be used, provided that adequate statistical methods such as propensity score modelled analysis are applied. To better understand vitamin D-mediated effects on CVD risk, the routine measurement of circulating levels of the hormonal vitamin D form, 1,25-dihydroxyvitamin D, is also necessary, in addition to the determination of its precursor 25-hydroxyvitamin D. Further, genetic association studies may help in clarifying the contribution of vitamin D to the development of CVD. Finally, the interrelationship of vitamin D with physical activity should be considered when studying CVD risk. CONCLUSIONS: Overall, it can be expected that the next 10-15 years will provide an increased clarity concerning the role of vitamin D in CVD.

Vitamin D status, incident diabetes and prospective changes in glucose metabolism in older subjects: the Hoorn study.

BACKGROUND AND AIMS: Vitamin D deficiency may contribute to impaired glucose metabolism and type 2 diabetes, especially in the elderly population. We aimed to evaluate whether baseline 25-hydroxyvitamin D (25[OH]D) levels are prospectively associated with deterioration of glucose metabolism and the incidence of diabetes. METHODS AND RESULTS: We examined a subsample from the population based Hoorn study among older men and women. Physical examinations were performed from 2000 to 2001 and included measurements of 25(OH)D. Glucose tolerance tests and HbA1c measurements were performed at baseline and at a follow-up between 2007 and 2009. We included 351 study participants (51% females; 67.9 ± 5.7 years). Baseline 25(OH)D levels were 56.7 ± 18.8 nmol/L and follow-up visits were performed after 7.5 ± 0.5 years. Among 280 study participants without diabetes at baseline we recorded 45 cases of incident diabetes. There was no significant association of 25(OH)D with the incidence of diabetes and with fasting and 2h postload glucose levels at follow-up. In analyses adjusted for age, sex, and baseline HbA1c there was, however, a significant association of 25(OH)D with follow-up HbA1c levels (beta coefficient=-0.085, p=0.085). This association was attenuated after further adjustments for BMI (beta coefficient=-0.079, p=0.064). CONCLUSIONS: In this study among the older population we observed no significant association of baseline 25(OH)D with glucose metabolism and incident diabetes. We found, however, a non-significant trend towards an inverse association of 25(OH)D with prospective changes in HbA1c that deserves further investigations.

Can vitamin D deficiency cause diabetes and cardiovascular diseases? Present evidence and future perspectives.

Several studies have shown that vitamin D may play a role in many biochemical mechanisms in addition to bone and calcium metabolism. Recently, vitamin D has sparked widespread interest because of its involvement in the homeostasis of the cardiovascular system. Hypovitaminosis D has been associated with obesity, related to trapping in adipose tissue due to its lipophilic structure. In addition, vitamin D deficiency is associated with increased risk of cardiovascular disease (CVD) and this may be due to the relationship between low vitamin D levels and obesity, diabetes mellitus, dyslipidaemia, endothelial dysfunction and hypertension. However, although vitamin D has been identified as a potentially important marker of CVD, the mechanisms through which it might modulate cardiovascular risk are not fully understood. Given this background, in this work we summarise clinical retrospective and prospective observational studies linking vitamin D levels with cardio-metabolic risk factors and vascular outcome. Moreover, we review various randomised controlled trials (RCTs) investigating the effects of vitamin D supplementation on surrogate markers of cardiovascular risk. Considering the high prevalence of hypovitaminosis D among patients with high cardiovascular risk, vitamin D replacement therapy in this population may be warranted; however, further RCTs are urgently needed to establish when to begin vitamin D therapy, as well as to determine the dose and route and duration of administration.

Effect of vitamin D supplementation on testosterone levels in men.

The male reproductive tract has been identified as a target tissue for vitamin D, and previous data suggest an association of 25-hydroxyvitamin D [25(OH)D] with testosterone levels in men. We therefore aimed to evaluate whether vitamin D supplementation influences testosterone levels in men. Healthy overweight men undergoing a weight reduction program who participated in a randomized controlled trial were analyzed for testosterone levels. The entire study included 200 nondiabetic subjects, of whom 165 participants (54 men) completed the trial. Participants received either 83 µg (3,332 IU) vitamin D daily for 1 year (n = 31) or placebo (n =2 3). Initial 25(OH)D concentrations were in the deficiency range (< 50 nmol/l) and testosterone values were at the lower end of the reference range (9.09-55.28 nmol/l for males aged 20-49 years) in both groups. Mean circulating 25(OH)D concentrations increased significantly by 53.5 nmol/l in the vitamin D group, but remained almost constant in the placebo group. Compared to baseline values, a significant increase in total testosterone levels (from 10.7 ± 3.9 nmol/l to 13.4 ± 4.7 nmol/l; p < 0.001), bioactive testosterone (from 5.21 ± 1.87 nmol/l to 6.25 ± 2.01 nmol/l; p = 0.001), and free testosterone levels (from 0.222 ± 0.080 nmol/l to 0.267 ± 0.087 nmol/l; p = 0.001) were observed in the vitamin D supplemented group. By contrast, there was no significant change in any testosterone measure in the placebo group. Our results suggest that vitamin D supplementation might increase testosterone levels. Further randomized controlled trials are warranted to confirm this hypothesis.

Association of vitamin D status with serum androgen levels in men.

OBJECTIVE: Studies in rodents indicate a role of vitamin D in male reproduction, but the relationship between vitamin D and androgen levels in men is largely unexplored. We aimed to investigate the association of 25-hydroxyvitamin D [25(OH)D] levels with testosterone, free androgen index (FAI) and SHBG. Moreover, we examined whether androgen levels show a similar seasonal variation to 25(OH)D. DESIGN: In this cross-sectional study, 25(OH)D, testosterone and SHBG levels were assessed by immunoassay in 2299 men who were routinely referred for coronary angiography (1997-2000). MEASUREMENTS: Main outcome measures were associations of 25(OH)D levels with testosterone, SHBG and FAI. FAI was calculated as testosterone (nmol/l)/SHBG (nmol/l) x 100. RESULTS: Men with sufficient 25(OH)D levels (> or =30 microg/l) had significantly higher levels of testosterone and FAI and significantly lower levels of SHBG when compared to 25(OH)D insufficient (20-29.9 microg/l) and 25(OH)D-deficient (<20 microg/l) men (P < 0.05 for all). In linear regression analyses adjusted for possible confounders, we found significant associations of 25(OH)D levels with testosterone, FAI and SHBG levels (P < 0.05 for all). 25(OH)D, testosterone and FAI levels followed a similar seasonal pattern with a nadir in March (12.2 microg/l, 15.9 nmol/l and 40.8, respectively) and peak levels in August (23.4 microg/l, 18.7 nmol/l and 49.7, respectively) (P < 0.05 for all). CONCLUSION: Androgen levels and 25(OH)D levels are associated in men and reveal a concordant seasonal variation. Randomized controlled trials are warranted to evaluate the effect of vitamin D supplementation on androgen levels.

Sex steroids and mortality in men referred for coronary angiography.

OBJECTIVE: Accumulating evidence suggests that sex steroids are associated with various chronic diseases. We aimed at evaluating whether total testosterone (TT), free testosterone (FT) and sex hormone-binding globulin (SHBG) are associated with all-cause mortality and specific fatal events. DESIGN, SETTING AND PARTICIPANTS: We measured TT and SHBG levels in 2078 men who were routinely referred for coronary angiography (1997-2000). FT was calculated according to Vermeulen. MEASUREMENTS: The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes, from cardiovascular and non-cardiovascular causes and from cancer according to SHBG, FT and TT. RESULTS: Multivariable-adjusted HRs (with 95% confidence intervals) in the fourth compared to the first SHBG quartile for all-cause, non-cardiovascular and cancer mortality were 1·61 (1·16-2·23), 2·44 (1·39-4·28), and 2·86 (1·03-7·32), respectively. There was no significant association of SHBG levels with cardiovascular mortality. All-cause mortality was significantly reduced per 1 SD increase in FT in the multivariate-adjusted analyses [0·49 (0·30-0·81)]. We observed no significant associations of FT with cardiovascular and cancer mortality, and TT levels were not independently related to any fatal events. CONCLUSION: High levels of SHBG are associated with adverse health outcomes in a large cohort of older men referred for coronary angiography. Further studies are warranted to confirm our results and to elucidate the underlying mechanisms for our findings.

Aldosterone to renin ratio--a reliable screening tool for primary aldosteronism?

Primary aldosteronism (PA) is defined as inappropriately high and (relatively or absolutely) autonomous aldosterone secretion, which is not adequately suppressible by sodium loading. Recent evidence shows that the PA prevalence ranges from 3 to 32%. This high prevalence of PA is suggested to be the result of both more intense screening for PA and improvement of laboratory procedures. Inappropriate high aldosterone secretion is paralleled by severe target organ damage, underlining the importance for the identification of PA at an early stage. The aldosterone to renin ratio (ARR), which reflects aldosterone hypersecretion in regard to its principal trophin renin, is currently considered the most reliable tool for PA screening. Accumulating evidence, however, points to a considerable intra-individual variation of this ratio, emphasizing the importance of standardized screening procedures. In particular, laboratory methods, posture, antihypertensive medication, and dietary salt intake are significant effectors of ARR variation. Furthermore, differentiation between low-renin essential hypertension and PA is difficult and probably arbitrary. It is the purpose of the present review to issue the reliability of the ARR as a screening tool for PA. This review also provides an overview about the physiology of the renin-angiotensin-aldosterone system, highlights current laboratory methods for aldosterone and renin determination, and addresses potential influence factors on the ARR.