Vitamin K Supplementation to Improve Vascular Stiffness in CKD: The K4Kidneys Randomized Controlled Trial.

BACKGROUND: Vascular calcification, a risk factor for cardiovascular disease, is common among patients with CKD and is an independent contributor to increased vascular stiffness and vascular risk in this patient group. Vitamin K is a cofactor for proteins involved in prevention of vascular calcification. Whether or not vitamin K supplementation could improve arterial stiffness in patients with CKD is unknown. METHODS: To determine if vitamin K supplementation might improve arterial stiffness in patients in CKD, we conducted a parallel-group, double-blind, randomized trial in participants aged 18 or older with CKD stage 3b or 4 (eGFR 15-45 ml/min per 1.73 m2). We randomly assigned participants to receive 400 µg oral vitamin K2 or matching placebo once daily for a year. The primary outcome was the adjusted between-group difference in carotid-femoral pulse wave velocity at 12 months. Secondary outcomes included augmentation index, abdominal aortic calcification, BP, physical function, and blood markers of mineral metabolism and vascular health. We also updated a recently published meta-analysis of trials to include the findings of this study. RESULTS: We included 159 randomized participants in the modified intention-to-treat analysis, with 80 allocated to receive vitamin K and 79 to receive placebo. Mean age was 66 years, 62 (39%) were female, and 87 (55%) had CKD stage 4. We found no differences in pulse wave velocity at 12 months, augmentation index at 12 months, BP, B-type natriuretic peptide, or physical function. The updated meta-analysis showed no effect of vitamin K supplementation on vascular stiffness or vascular calcification measures. CONCLUSIONS: Vitamin K2 supplementation did not improve vascular stiffness or other measures of vascular health in this trial involving individuals with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Vitamin K therapy to improve vascular health in patients with chronic kidney disease, ISRCTN21444964 (www.isrctn.com).

Acceptability and feasibility of magnetic femoral nerve stimulation in older, functionally impaired patients.

OBJECTIVE: Magnetic femoral nerve stimulation to test muscle function has been largely unexplored in older people. We assessed acceptability, feasibility, along with reproducibility and correlation with other physical function measures. RESULTS: Study 1 recruited older people with sarcopenia. Stimulation was performed at baseline and 2 weeks along with six minute walk (6MW), maximum voluntary quadriceps contraction, short physical performance battery and grip strength. Acceptability was measured using visual analog scales. Study 2 used baseline data from a trial of older people. We correlated stimulation results with 6MW, maximal voluntary contraction and muscle mass. Maximum quadriceps twitch tension was measured in both studies, evoked using biphasic magnetic stimulation of the femoral nerve. In study 1 (n = 12), magnetic stimulation was well tolerated with mean discomfort rating of 9% (range 0-40%) on a visual analog scale. Reproducibility was poor (intraclass correlation coefficient 0.06; p = 0.44). Study 2 (n = 64) showed only weak to moderate correlations for maximum quadriceps twitch tension with other measures of physical function (6 minute walk test r = 0.24, p = 0.06; maximal voluntary contraction r = 0.26; p = 0.04). We conclude that magnetic femoral nerve stimulation is acceptable and feasible but poorly reproducible in older, functionally impaired people.

Effect of Vitamin D Supplementation on Markers of Vascular Function: A Systematic Review and Individual Participant Meta-Analysis.

BACKGROUND: Low 25-hydroxyvitamin D levels are associated with an increased risk of cardiovascular events, but the effect of vitamin D supplementation on markers of vascular function associated with major adverse cardiovascular events is unclear. METHODS AND RESULTS: We conducted a systematic review and individual participant meta-analysis to examine the effect of vitamin D supplementation on flow-mediated dilatation of the brachial artery, pulse wave velocity, augmentation index, central blood pressure, microvascular function, and reactive hyperemia index. MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and http://www.ClinicalTrials.gov were searched until the end of 2016 without language restrictions. Placebo-controlled randomized trials of at least 4 weeks duration were included. Individual participant data were sought from investigators on included trials. Trial-level meta-analysis was performed using random-effects models; individual participant meta-analyses used a 2-stage analytic strategy, examining effects in prespecified subgroups. 31 trials (2751 participants) were included; 29 trials (2641 participants) contributed data to trial-level meta-analysis, and 24 trials (2051 participants) contributed to individual-participant analyses. Vitamin D3 daily dose equivalents ranged from 900 to 5000 IU; duration was 4 weeks to 12 months. Trial-level meta-analysis showed no significant effect of supplementation on macrovascular measures (flow-mediated dilatation, 0.37% [95% confidence interval, -0.23 to 0.97]; carotid-femoral pulse wave velocity, 0.00 m/s [95% confidence interval, -0.36 to 0.37]); similar results were obtained from individual participant data. Microvascular function showed a modest improvement in trial-level data only. No consistent benefit was observed in subgroup analyses or between different vitamin D analogues. CONCLUSIONS: Vitamin D supplementation had no significant effect on most markers of vascular function in this analysis.

Leucine and ACE inhibitors as therapies for sarcopenia (LACE trial): study protocol for a randomised controlled trial.

BACKGROUND: Sarcopenia (the age-related loss of muscle mass and function) is a major contributor to loss of mobility, falls, loss of independence, morbidity and mortality in older people. Although resistance training is effective in preventing and reversing sarcopenia, many older people are sedentary and either cannot or do not want to exercise. This trial examines the efficacy of supplementation with the amino acid leucine and/or angiotensin converting enzyme inhibition to potentially improve muscle mass and function in people with sarcopenia. Promising preliminary data exist from small studies for both interventions, but neither has yet been tested in adequately powered randomised trials in patients with sarcopenia. METHODS: Leucine and ACE inhibitors in sarcopenia (LACE) is a multicentre, masked, placebo-controlled, 2 × 2 factorial randomised trial evaluating the efficacy of leucine and perindopril (angiotensin converting enzyme inhibitor (ACEi)) in patients with sarcopenia. The trial will recruit 440 patients from primary and secondary care services across the UK. Male and female patients aged 70 years and over with sarcopenia as defined by the European Working Group on Sarcopenia (based on low total skeletal muscle mass on bioimpedance analysis and either low gait speed or low handgrip strength) will be eligible for participation. Participants will be excluded if they have a contraindication to, or are already taking, an ACEi, angiotensin receptor blocker or leucine. The primary clinical outcome for the trial is the between-group difference in the Short Physical Performance Battery score at all points between baseline and 12 months. Secondary outcomes include appendicular muscle mass measured using dual-energy X-ray absorptiometry, muscle strength, activities of daily living, quality of life, activity using pedometer step counts and falls. Participants, clinical teams, outcomes assessors and trial analysts are masked to treatment allocation. A panel of biomarkers including microRNAs, neurohormones, genetic polymorphisms and markers of inflammation relevant to muscle pathophysiology will be measured to explore predictors of response and further elucidate mechanisms underlying sarcopenia. Participants will receive a total of 12 months of either perindopril or placebo and either leucine or placebo. DISCUSSION: The results will provide the first robust test of the overall clinical and cost-effectiveness of these novel therapies for older patients with sarcopenia. TRIAL REGISTRATION: ISRCTN, ISRCTN90094835 . Registered on 18 February 2015.

Effect of Vitamin D Supplementation on Blood Pressure: A Systematic Review and Meta-analysis Incorporating Individual Patient Data.

IMPORTANCE: Low levels of vitamin D are associated with elevated blood pressure (BP) and future cardiovascular events. Whether vitamin D supplementation reduces BP and which patient characteristics predict a response remain unclear. OBJECTIVE: To systematically review whether supplementation with vitamin D or its analogues reduce BP. DATA SOURCES: We searched MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and http://www.ClinicalTrials.com augmented by a hand search of references from the included articles and previous reviews. Google was searched for gray literature (ie, material not published in recognized scientific journals). No language restrictions were applied. The search period spanned January 1, 1966, through March 31, 2014. STUDY SELECTION: We included randomized placebo-controlled clinical trials that used vitamin D supplementation for a minimum of 4 weeks for any indication and reported BP data. Studies were included if they used active or inactive forms of vitamin D or vitamin D analogues. Cointerventions were permitted if identical in all treatment arms. DATA EXTRACTION AND SYNTHESIS: We extracted data on baseline demographics, 25-hydroxyvitamin D levels, systolic and diastolic BP (SBP and DBP), and change in BP from baseline to the final follow-up. Individual patient data on age, sex, medication use, diabetes mellitus, baseline and follow-up BP, and 25-hydroxyvitamin D levels were requested from the authors of the included studies. For trial-level data, between-group differences in BP change were combined in a random-effects model. For individual patient data, between-group differences in BP at the final follow up, adjusted for baseline BP, were calculated before combining in a random-effects model. MAIN OUTCOMES AND MEASURES: Difference in SBP and DBP measured in an office setting. RESULTS: We included 46 trials (4541 participants) in the trial-level meta-analysis. Individual patient data were obtained for 27 trials (3092 participants). At the trial level, no effect of vitamin D supplementation was seen on SBP (effect size, 0.0 [95% CI, -0.8 to 0.8] mm Hg; P=.97; I2=21%) or DBP (effect size, -0.1 [95% CI, -0.6 to 0.5] mm Hg; P=.84; I2=20%). Similar results were found analyzing individual patient data for SBP (effect size, -0.5 [95% CI, -1.3 to 0.4] mm Hg; P=.27; I2=0%) and DBP (effect size, 0.2 [95% CI, -0.3 to 0.7] mm Hg; P=.38; I2=0%). Subgroup analysis did not reveal any baseline factor predictive of a better response to therapy. CONCLUSIONS AND RELEVANCE: Vitamin D supplementation is ineffective as an agent for lowering BP and thus should not be used as an antihypertensive agent.

Effect of vitamin D supplementation on orthostatic hypotension: data from the vitamin D in isolated systolic hypertension randomized controlled trial.

OBJECTIVE: Orthostatic hypotension commonly accompanies supine hypertension, and is associated with low 25-hydroxyvitamin D levels. We tested whether high-dose intermittent oral vitamin D therapy could ameliorate orthostatic hypotension in older patients with isolated systolic hypertension. METHODS: We conducted a subgroup analysis of data from a parallel-group, double-blind, randomized, placebo-controlled trial. Patients aged over 70 years with supine office SBP above 140 mmHg and DBP below 90 mmHg received 100 000 units oral vitamin D3 or matching placebo every 3 months for 1 year. Office supine and standing blood pressure were measured at baseline, and 3, 6, 9 and 12 months, along with arterial stiffness and flow-mediated dilatation of the brachial artery. RESULTS: Of 159 patients randomized to the main trial, 75 patients with orthostatic hypotension at baseline were included in this analysis. The mean age was 78 (SD 5) years, baseline blood pressure was 162/76 mmHg and the mean baseline orthostatic fall in blood pressure on standing was 32/5 mmHg. After adjustment for baseline age, 25-hydroxyvitamin D, SBP and orthostatic fall, the fall in SBP was less in the vitamin D group at 3 months [treatment effect 6 mmHg, 95% confidence interval (CI) 0 to 12], but repeated-measures analysis showed no significant treatment effect (3 mmHg for systolic fall, 95% CI -1 to 8; 1 mmHg for diastolic fall, 95% CI -1 to 3). CONCLUSION: Twelve months of intermittent, high-dose oral vitamin D3 did not significantly improve orthostatic hypotension in older patients with isolated systolic hypertension.

Vitamin D therapy to reduce blood pressure and left ventricular hypertrophy in resistant hypertension: randomized, controlled trial.

Low 25-hydroxyvitamin D levels are associated with higher prevalent blood pressure. We tested whether high-dose intermittent oral vitamin D therapy could reduce blood pressure and left ventricular mass in patients with hypertension resistant to conventional treatment. We conducted a parallel-group, double-blind, randomized placebo-controlled trial. Patients with supine office blood pressure >140/90 mm Hg on ≥3 antihypertensive agents received 100 000 U oral vitamin D3 or matching placebo every 2 months. Office and 24-hour ambulatory blood pressure, glucose, and cholesterol were measured at baseline, 2, 4, and 6 months; left ventricular mass index was measured by cardiac MRI on a subgroup at baseline and 6 months. The primary outcome was mean 24-hour ambulatory blood pressure at 6 months. A total of 68 participants were randomized, 34 in each group. Mean age was 63 (SD 11) years, mean baseline office blood pressure was 154/84 (13/10) mm Hg, and mean baseline 25-hydroxyvitamin D level was 42 (16) nmol/L. Treatment with vitamin D did not reduce 24-hour ambulatory blood pressure (adjusted treatment effects: systolic, +3 mm Hg; 95% confidence interval, -4 to +11; P=0.33; diastolic, -2 mm Hg; 95% confidence interval, -6 to +2; P=0.29); similar results were seen for office blood pressure. Left ventricular mass index was measured in a subgroup (n=25); no reduction was seen with vitamin D treatment (adjusted treatment effect, +4 g/m(2); 95% confidence interval, 0 to +7; P=0.04). There was no significant change in cholesterol or glucose levels. Thus, 6 months of intermittent, high-dose oral vitamin D3 did not reduce blood pressure or left ventricular mass in patients with resistant hypertension.

Allopurinol reduces left ventricular mass in patients with type 2 diabetes and left ventricular hypertrophy.

OBJECTIVES: This study sought to ascertain whether high-dose allopurinol causes regression of left ventricular mass (LVM) in patients with type 2 diabetes mellitus (T2DM). BACKGROUND: Left ventricular hypertrophy (LVH) is common in T2DM and contributes to patients' high cardiovascular (CV) event rate. Oxidative stress (OS) has been implicated in LVH development, and allopurinol has been previously shown to reduce vascular OS. We therefore investigated whether allopurinol causes regression of LVH in patients with T2DM. METHODS: We conducted a randomized, double-blind, placebo-controlled study of 66 optimally-treated T2DM patients with echocardiographic evidence of LVH. Allopurinol, 600 mg/day, or placebo was given over the study period of 9 months. The primary outcome was reduction in LVM as calculated by cardiac magnetic resonance imaging at baseline and at 9 months' follow-up. Secondary endpoints were change in flow-mediated dilation and augmentation index. RESULTS: Allopurinol significantly reduced absolute LVM (-2.65 ± 5.91 g vs. placebo group +1.21 ± 5.10 g [p = 0.012]) and LVM indexed to body surface area (-1.32 ± 2.84 g/m(2) vs. placebo group +0.65 ± 3.07 g/m(2) [p = 0.017]). No significant changes were seen in either flow-mediated dilation or augmentation index. CONCLUSIONS: Allopurinol causes regression of LVM in patients with T2DM and LVH. Regression of LVH has been shown previously to improve CV mortality and morbidity. Therefore, allopurinol therapy may become useful to reduce CV events in T2DM patients with LVH. (Allopurinol in Patients with Diabetes and LVH; UKCRN 8766).

Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial.

IMPORTANCE: Observational data link low 25-hydroxyvitamin D levels to both prevalent blood pressure and incident hypertension. No clinical trial has yet examined the effect of vitamin D supplementation in isolated systolic hypertension, the most common pattern of hypertension in older people. OBJECTIVE: To test whether high-dose, intermittent cholecalciferol supplementation lowers blood pressure in older patients with isolated systolic hypertension. DESIGN: Parallel group, double-blind, placebo-controlled randomized trial. SETTING: Primary care clinics and hospital clinics. PARTICIPANTS: Patients 70 years and older with isolated systolic hypertension (supine systolic blood pressure >140 mm Hg and supine diastolic blood pressure <90 mm Hg) and baseline 25-hydroxyvitamin D levels less than 30 ng/mL were randomized into the trial from June 1, 2009, through May 31, 2011. INTERVENTIONS: A total of 100,000 U of oral cholecalciferol or matching placebo every 3 months for 1 year. MAIN OUTCOMES AND MEASURES: Difference in office blood pressure, 24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, insulin resistance, and b-type natriuretic peptide level during 12 months. RESULTS: A total of 159 participants were randomized (mean age, 77 years). Mean baseline office systolic blood pressure was 163/78 mm Hg. Mean baseline 25-hydroxyvitamin D level was 18 ng/mL. 25-Hydroxyvitamin D levels increased in the treatment group compared with the placebo group (+8 ng/mL at 1 year, P < .001). No significant treatment effect was seen for mean (95% CI) office blood pressure (−1 [−6 to 4]/−2 [−4 to 1] mm Hg at 3 months and 1 [−2 to 4]/0 [−2 to 2] mm Hg overall treatment effect). No significant treatment effect was evident for any of the secondary outcomes (24-hour blood pressure, arterial stiffness, endothelial function, cholesterol level, glucose level, and walking distance). There was no excess of adverse events in the treatment group, and the total number of falls was nonsignificantly lower in the group receiving vitamin D (36 vs 46, P = .24). CONCLUSIONS AND RELEVANCE: Vitamin D supplementation did not improve blood pressure or markers of vascular health in older patients with isolated systolic hypertension. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN92186858.

Effects of vitamin D supplementation on markers of vascular function after myocardial infarction--a randomised controlled trial.

BACKGROUND: Low vitamin D levels are common, and are associated with a higher incidence of future vascular events. We tested whether vitamin D supplementation could improve endothelial function and other markers of vascular function in patients with a history of myocardial infarction. METHODS: Parallel group, placebo-controlled, double-blind randomised trial. Patients with a history of myocardial infarction were randomised to receive 100,000 units of oral vitamin D3 or placebo at baseline, 2 months and 4 months. Outcomes were measured at baseline, 2 and 6 months. Reactive hyperaemia index on fingertip plethysmography was the primary outcome. Secondary outcome measures included blood pressure, cholesterol, C-reactive protein, von Willebrand factor, tumour necrosis factor alpha, E-selectin, B-type natriuretic peptide, thrombomodulin and 25-hydroxyvitamin D levels. RESULTS: 75 patients were randomised, mean age 66 years. 74/75 (99%) completed 6 month follow-up. 25 hydroxyvitamin D levels increased in the intervention group relative to placebo (+13 vs +1 nmol/L, p=0.04). There was no between-group difference in change in reactive hyperaemia index between baseline and 6 months (-0.18 vs -0.07, p=0.40). Of the secondary outcomes, only C-reactive protein showed a significant decline in the intervention arm relative to placebo at 6 months (-1.3 vs 2.0mg/L, p=0.03). Systolic blood pressure (+1.4 vs +2.3 mmHg, p=0.79), diastolic blood pressure (+2.0 vs +0.8 mmHg, p=0.54) and total cholesterol (+0.26 vs +0.24 mmol/L, p=0.88) showed no between-group difference at 6 months. CONCLUSIONS: Supplementation with vitamin D did not improve markers of vascular function in patients with a history of myocardial infarction.

Mechanistic insights into the therapeutic use of high-dose allopurinol in angina pectoris.

OBJECTIVES: The aim of this study was to evaluate the effect of high-dose allopurinol on vascular oxidative stress (OS) and endothelial function in subjects with stable coronary artery disease (CAD). BACKGROUND: Allopurinol, a xanthine oxidase inhibitor, prolongs the time to chest pain during exercise in angina. We sought to ascertain whether allopurinol also improves endothelial dysfunction in optimally treated CAD patients, because such an effect might be of value to reduce future cardiovascular mortality. The mechanism of the anti-ischemic effect of allopurinol could be related to its reducing xanthine oxidase-induced OS, and our second aim was to see whether allopurinol really does reduce vascular tissue OS in CAD patients. METHODS: A randomized, double-blind, placebo-controlled, crossover study was conducted in 80 patients with CAD, comparing allopurinol (600 mg/day) with placebo. Endothelial function was assessed by forearm venous occlusion plethysmography, flow-mediated dilation, and pulse wave analysis. Vascular OS was assessed by intra-arterial co-infusion of vitamin C and acetylcholine. RESULTS: Compared with placebo, allopurinol significantly improved endothelium-dependent vasodilation, by both forearm venous occlusion plethysmography (93 ± 67% vs. 145 ± 106%, p = 0.006) and flow-mediated dilation (4.2 ± 1.8% vs. 5.4 ± 1.7%, p < 0.001). Vascular oxidative stress was completely abolished by allopurinol. Central augmentation index improved significantly with allopurinol (2.6 ± 7.0%, p < 0.001) but not with placebo. CONCLUSIONS: Our study demonstrates that, in optimally treated CAD patients, high-dose allopurinol profoundly reduces vascular tissue OS and improves 3 different measures of vascular/endothelial dysfunction. The former effect on OS might underpin the anti-ischemic effect of allopurinol in CAD. Both effects (on OS and endothelial dysfunction) increase the likelihood that high-dose allopurinol might reduce future cardiovascular mortality in CAD, over and above existing optimum therapy. (Exploring the therapeutic potential of xanthine oxidase inhibitor allopurinol in angina; ISRCTN15253766).

Impact of allopurinol use on urate concentration and cardiovascular outcome.

AIMS: To characterize patients with urate measurements by urate-lowering therapy (ULT) use and to study the impact of allopurinol treatment on cardiovascular and mortality outcomes. METHODS: A cohort study using a record-linkage database. The study included 7135 patients aged ≥60 years with urate measurements between 2000 and 2002 followed up until 2007. A Cox regression model was used. The association between urate levels, dispensed allopurinol and cardiovascular hospitalization and mortality was determined. RESULTS: Six thousand and forty-two patients were not taking ULT and 45.9% of those (2774 of 6042) had urate concentrations ≤6 mg dl(-1) . Among 1035 allopurinol users, 44.7% (45.6% for men and 43.3% for women) reached target urate concentration. There was no significant increased risk of cardiovascular events for allopurinol users when compared with non-ULT users [adjusted hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.95-1.26] and the non-ULT group with urate >6 mg dl(-1) (adjusted HR 1.07, 95% CI 0.89-1.28). Within the allopurinol use cohort, cardiovascular event rates were 74.0 (95% CI 61.9-86.1) per 1000 person years for the 100 mg group, 69.7 (49.6-89.8) for the 200 mg group and 47.6 (38.4-56.9) for the ≥300 mg group. Compared with low-dose (100 mg) users, high-dose (≥300 mg) users had significant reductions in the risk of cardiovascular events (adjusted HR 0.69, 95% CI 0.50-0.94) and mortality (adjusted HR 0.75, 95% CI 0.59-0.94). CONCLUSIONS: Less than 50% of patients taking allopurinol reached target urate concentration. Higher doses of allopurinol were associated with better control of urate and lower risks of both cardiovascular events and mortality.

The effects of vitamin D supplementation on physical function and quality of life in older patients with heart failure: a randomized controlled trial.

BACKGROUND: Low 25-hydroxyvitamin D levels, commonly found in older patients with heart failure, may contribute to the chronic inflammation and skeletal myopathy that lead to poor exercise tolerance. We tested whether vitamin D supplementation of patients with heart failure and vitamin D insufficiency can improve physical function and quality of life. METHODS AND RESULTS: In a randomized, parallel group, double-blind, placebo-controlled trial, patients with systolic heart failure aged >or=70 years with 25-hydroxyvitamin D levels <50 nmol/L (20 ng/mL) received 100,000 U of oral vitamin D2 or placebo at baseline and 10 weeks. Outcomes measured at baseline, 10 weeks, and 20 weeks were 6-minute walk distance, quality of life (Minnesota score), daily activity measured by accelerometry, Functional Limitations Profile, B-type natriuretic peptide, and tumor necrosis factor-alpha. Participants in the vitamin D group had an increase in their 25-hydroxyvitamin D levels compared with placebo at 10 weeks (22.9 versus 2.3 nmol/L [9.2 versus 0.9 ng/mL]; P<0.001) and maintained this increase at 20 weeks. The 6-minute walk did not improve in the treatment group relative to placebo. No significant benefit was seen on timed up and go testing, subjective measures of function, daily activity, or tumor necrosis factor. Quality of life worsened by a small, but significant amount in the treatment group relative to placebo. B-type natriuretic peptide decreased in the treatment group relative to placebo (-22 versus +78 pg/mL at 10 weeks; P=0.04). CONCLUSIONS: Vitamin D supplementation did not improve functional capacity or quality of life in older patients with heart failure with vitamin D insufficiency. Clinical Trial Registration- www.controlled-trials.com. Identifier: ISRCTN51372896.

Effect of vitamin D on blood pressure: a systematic review and meta-analysis.

OBJECTIVES: Vitamin D insufficiency has been linked to hypertension and cardiovascular events in observational studies. It is unclear whether vitamin D supplementation can reduce blood pressure, and, if so, by how much. METHODS: We performed a systematic review and meta-analysis to examine whether vitamin D reduces blood pressure. Databases including MEDLINE, EMBASE, the Cumulative Index to Nursing and Allied Health Literature and the Cochrane library were searched, supplemented by searches of grey literature, unpublished trials and references from included studies. Studies were assessed by two reviewers independently according to a prespecified protocol. Interventions included activated vitamin D, unactivated vitamin D2 and D3 and ultraviolet B radiation. RESULTS: Eleven randomized, controlled trials fulfilled the inclusion criteria. Studies were small and of variable methodological quality. Mean baseline blood pressure was more than 140/90 mmHg in eight studies. Meta-analysis of these eight studies showed a nonsignificant reduction in systolic blood pressure in the vitamin D group compared with placebo [-3.6 mmHg, 95% confidence interval (CI) -8.0 to 0.7]. A small, statistically significant reduction was seen in diastolic blood pressure (-3.1 mmHg, 95% CI -5.5 to -0.6). Subgroup analysis suggested that unactivated vitamin D produced a greater fall in systolic blood pressure than activated vitamin D (-6.2 mmHg, 95% CI -12.32 to -0.04, vs. +0.7 mmHg, 95% CI -4.8 to 6.2). No reduction in blood pressure was seen in studies examining patients who were normotensive at baseline. CONCLUSION: We found weak evidence to support a small effect of vitamin D on blood pressure in studies of hypertensive patients.