Effect of intermittent vitamin D3 on vascular function and symptoms in chronic fatigue syndrome--a randomised controlled trial.

BACKGROUND AND AIMS: Low 25-hydroxyvitamin D levels are common in patients with chronic fatigue syndrome; such patients also manifest impaired vascular health. We tested whether high-dose intermittent oral vitamin D therapy improved markers of vascular health and fatigue in patients with chronic fatigue syndrome. METHODS AND RESULTS: Parallel-group, double-blind, randomised placebo-controlled trial. Patients with chronic fatigue syndrome according to the Fukuda (1994) and Canadian (2003) criteria were randomised to receive 100,000 units oral vitamin D3 or matching placebo every 2 months for 6 months. The primary outcome was arterial stiffness measured using carotid-femoral pulse wave velocity at 6 months. Secondary outcomes included flow-mediated dilatation of the brachial artery, blood pressure, cholesterol, insulin resistance, markers of inflammation and oxidative stress, and the Piper Fatigue scale. As many as 50 participants were randomised; mean age 49 (SD 13) years, mean baseline pulse wave velocity 7.8 m/s (SD 2.3), mean baseline office blood pressure 128/78 (18/12) mmHg and mean baseline 25-hydroxyvitamin D level 46 (18) nmol/L. 25-hydroxyvitamin D levels increased by 22 nmol/L at 6 months in the treatment group relative to placebo. There was no effect of treatment on pulse wave velocity at 6 months (adjusted treatment effect 0.0 m/s; 95% CI -0.6 to 0.6; p = 0.93). No improvement was seen in other vascular and metabolic outcomes, or in the Piper Fatigue scale at 6 months (adjusted treatment effect 0.2 points; 95% CI -0.8 to 1.2; p = 0.73). CONCLUSION: High-dose oral vitamin D3 did not improve markers of vascular health or fatigue in patients with chronic fatigue syndrome. TRIAL REGISTRATION: www.controlled-trials.com, ISRCTN59927814.

Vitamin D and the cardiovascular system.

Vitamin D, a secosteroid hormone, affects multiple biological pathways via both genomic and nongenomic signalling. Several pathways have potential benefit to cardiovascular health, including effects on parathyroid hormone, the renin-angiotensin-aldosterone system, vascular endothelial growth factor and cytokine production, as well as direct effects on endothelial cell function and myocyte calcium influx. Observational data supports a link between low vitamin D metabolite levels and cardiovascular health. Cross-sectional data shows associations between low 25-hydroxyvitamin D levels and stroke, myocardial infarction, diabetes mellitus, hypertension, and heart failure. Longitudinal data also suggests a relationship with incident hypertension and new cardiovascular events. However, these associations are potentially confounded by reverse causality and by the effects that other cardiovascular risk factors have on vitamin D metabolite levels. Intervention studies to date suggest a modest antihypertensive effect of vitamin D, no effect on serum lipids, a small positive effect on insulin resistance and fasting glucose, and equivocal actions on arterial stiffness and endothelial function. Analysis of cardiovascular event data collected from osteoporosis trials does not currently show a clear signal for reduced cardiovascular events with vitamin D supplementation, but results may be confounded by the coadministration of calcium, and by the secondary nature of the analyses. Despite mechanistic and observational data that suggest a protective role for vitamin D in cardiovascular disease, intervention studies to date are less promising. Large trials using cardiovascular events as a primary outcome are needed before vitamin D can be recommended as a therapy for cardiovascular disease.

Effect of vitamin D supplementation on glycaemic control and insulin resistance: a systematic review and meta-analysis.

AIMS: To systematically review the evidence for the effect of vitamin D supplementation on glycaemia, insulin resistance, progression to diabetes and complications of diabetes. METHODS: Systematic review and meta-analysis. We searched databases including MEDLINE, EMBASE and the Cochrane Library for randomized controlled trials comparing vitamin D or analogues with placebo. We extracted data on fasting glucose, glycaemic control, insulin resistance, insulin/C-peptide levels, micro- and macrovascular outcomes and progression from non-diabetes to diabetes. Studies were assessed independently by two reviewers according to a pre-specified protocol. RESULTS: Fifteen trials were included in the systematic review. Trial reporting was of moderate, variable quality. Combining all studies, no significant improvement was seen in fasting glucose, HbA(1c) or insulin resistance in those treated with vitamin D compared with placebo. For patients with diabetes or impaired glucose tolerance, meta-analysis showed a small effect on fasting glucose (-0.32 mmol/l, 95%CI -0.57 to -0.07) and a small improvement in insulin resistance (standard mean difference -0.25, 95%CI -0.48 to -0.03). No effect was seen on glycated haemoglobin in patients with diabetes and no differences were seen for any outcome in patients with normal fasting glucose. Insufficient data were available to draw conclusions regarding micro- or macrovascular events; two trials failed to show a reduction in new cases of diabetes in patients treated with vitamin D. CONCLUSIONS: There is currently insufficient evidence of beneficial effect to recommend vitamin D supplementation as a means of improving glycaemia or insulin resistance in patients with diabetes, normal fasting glucose or impaired glucose tolerance.

The effect of vitamin D replacement on markers of vascular health in stroke patients - a randomised controlled trial.

BACKGROUND AND AIMS: Low vitamin D levels are associated with increased incidence of future cardiovascular events and are common in stroke patients. We tested whether vitamin D supplementation could reduce blood pressure and improve markers of vascular health in patients who had previously suffered a stroke. METHODS AND RESULTS: Randomised, placebo-controlled, double-blind trial. Community-dwelling patients with a history of stroke and baseline 25-hydroxyvitamin D levels <75 nmol/L received 100,000 units of oral vitamin D2 or placebo at baseline. Office and 24 h blood pressure, endothelial function measured by flow-mediated dilatation of the brachial artery, cholesterol, oxidised low density lipoprotein, B-type natriuretic peptide and heart rate turbulence were measured at baseline, 8 weeks and 16 weeks. 58 patients were randomised. Mean age was 67 years, mean baseline blood pressure 128/72 mmHg, mean baseline 25-hydroxyvitamin D level was 38 nmol/L. Serum 25-hydroxyvitamin D levels were higher in the intervention group at 8 weeks compared to placebo (54 vs 42 nmol/L, P = 0.002) and remained higher at 16 weeks. Office systolic and diastolic blood pressure showed no significant change between groups at 8 weeks (systolic 126.1 vs 131.3 mmHg; adjusted P = 0.97); (diastolic 73.1 vs 74.9 mmHg, adjusted P = 0.15). Flow mediated dilatation was significantly higher in the intervention group at 8 weeks (6.9% vs 3.7%, adjusted P = 0.007) but was not significantly different at 16 weeks. CONCLUSIONS: High dose oral vitamin D supplementation did not improve blood pressure but produced short-term improvement in endothelial function in stroke patients with well-controlled baseline blood pressure. CLINICAL TRIALS REGISTRATION: ISRCTN28737567.

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.

The assessment of sarcopenia and the frailty phenotype in the outpatient care of older people: implementation and typical values obtained from the Newcastle SarcScreen project.

PURPOSE: Sarcopenia and the frailty phenotype both indicate older adults at risk of adverse health outcomes and yet are not widely assessed in practice. We developed the Newcastle SarcScreen to enable assessment of these two ageing syndromes during clinical care. In the setting of our Older People's Medicine Day Unit, our aims were to describe the implementation of the SarcScreen and to examine the typical values obtained. METHODS: The SarcScreen comprised height, weight, questions (three on the Fried frailty phenotype and five on the SARC-F questionnaire), grip strength and gait speed. We analysed data from 552 patients completing the SarcScreen. We expressed grip strength as Z-scores (number of standard deviations above the mean expected for a patient's age and sex). RESULTS: It was possible to implement the SarcScreen. In 552 patients (65.9% females) with mean age 80.1 (7.7) years, grip strength was feasible in 98.2% and gait speed in 82.1%. Gait speed was typically not assessed due to mobility impairment. Most patients had weak grip strength (present in 83.8%), slow gait speed (88.8%) and the frailty phenotype (66.2%). We found a high prevalence of probable sarcopenia and the frailty phenotype across all age groups studied. This was reflected by low grip strength Z-scores, especially at younger ages: those aged 60-69 had grip strength 2.7 standard deviations (95% CI 2.5-2.9) below that expected. CONCLUSION: It is possible to implement an assessment of sarcopenia and the frailty phenotype as part of the routine outpatient care of older people.

The effect of different doses of vitamin D(3) on markers of vascular health in patients with type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: Low 25-hydroxyvitamin D levels predict future cardiovascular events and are common in patients with type 2 diabetes. We compared the effect of 100,000 and 200,000 IU doses of vitamin D(3) on endothelial function, blood pressure and markers of glycaemic control in patients with type 2 diabetes. METHODS: This was a randomised, parallel group, placebo-controlled trial. Patients with type 2 diabetes and baseline 25-hydroxyvitamin D levels <100 nmol/l were enrolled from community and hospital-based diabetes clinics. Participants were assessed in a university department of clinical pharmacology and received a single oral dose of placebo or vitamin D(3) (100,000 IU or 200,000 IU) at baseline, randomly allocated via numbered bottles prepared offsite; participants and investigators were both blinded to treatment allocation. Endothelial function, office blood pressure, B-type natriuretic peptide, insulin resistance and glycosylated haemoglobin were measured at baseline, and at 8 and 16 weeks. RESULTS: We randomised 61 participants to the three groups (placebo 22, 100,000 IU vitamin D(3) 19, 200,000 IU vitamin D(3) 20). There was no significant difference in the primary outcome of endothelial function at 8 weeks (placebo 5.2%, n = 22; 100,000 IU 4.3%, n = 19; 200,000 IU 4.9%, n = 17) or at 16 weeks. Insulin resistance and glycosylated haemoglobin did not improve with either dose of vitamin D(3). On covariate analysis, systolic blood pressure was significantly lower in both treatment arms than in the placebo group at 8 weeks (placebo 146.4 mmHg, 100,000 IU 141.4 mmHg [p = 0.04 vs placebo], 200,000 IU 136.8 mmHg [p = 0.03 vs placebo]). B-type natriuretic peptide levels were significantly lower in the 200,000 IU group by 16 weeks (placebo 34 pg/ml, 200,000 IU 21 pg/ml, p = 0.02). No significant excess of adverse effects was noted in the treatment arms. CONCLUSIONS/INTERPRETATION: High-dose vitamin D(3) improved systolic blood pressure and B-type natriuretic peptide levels, but not endothelial function, insulin resistance or glycosylated haemoglobin in patients with type 2 diabetes.

Association between the Use of Angiotensin-Blocking Medications with Hip Fracture and Death in Older People.

It is unclear if angiotensin blocking drugs (angiotensin converting enzyme inhibitors and angiotensin receptor blockers) reduce or increase the risk of falls and fractures. We retrospectively analysed routinely-collected, linked health and social care data for patients aged 65 and over from Tayside, Scotland, including hospital discharge diagnoses, biochemistry, deaths, care package provision and community prescribing. We conducted unadjusted and adjusted Cox regression analyses for time to hip fracture and time to death, for any exposure to angiotensin blocking drugs and for time-dependent exposure to angiotensin blocking drugs. We analysed data on 16782 patients. Angiotensin blocking drug use was associated with an exposure-dependent lower risk of hip fracture (hazard ratio 0.988 [95%CI 0.982-0.994] per year of exposure; p<0.001) and death (hazard ratio 0.986 [95%CI 0.983-0.989] per year of exposure; p<0.001). These findings call into question the appropriateness of stopping angiotensin blocking drugs for older people at risk of falls.

Vitamin D improves endothelial function in patients with Type 2 diabetes mellitus and low vitamin D levels.

AIMS: To test whether a single large dose of vitamin D2 can improve endothelial function in patients with Type 2 diabetes mellitus and low serum 25-hydroxyvitamin D levels. METHODS: Double-blind, parallel group, placebo-controlled randomized trial. A single dose of 100,000 IU vitamin D2 or placebo was administered to patients with Type 2 diabetes over the winter, when levels of circulating 25-hydroxyvitamin D were likely to be lowest. Patients were enrolled if their baseline 25-hydroxyvitamin D level was < 50 nmol/l. Endothelial function and blood pressure were measured and fasting blood samples were taken at baseline and 8 weeks after administration of vitamin D. RESULTS: Forty-nine per cent of subjects screened had 25-hydroxyvitamin D levels < 50 nmol/l. Thirty-four subjects completed the study, with a mean age of 64 years and a baseline 25-hydroxyvitamin D level of 38.3 nmol/l. Vitamin D supplementation increased 25-hydroxyvitamin D levels by 15.3 nmol/l relative to placebo and significantly improved flow mediated vasodilatation (FMD) of the brachial artery by 2.3%. The improvement in FMD remained significant after adjusting for changes in blood pressure. Vitamin D supplementation significantly decreased systolic blood pressure by 14 mmHg compared with placebo; this did not correlate with change in FMD. CONCLUSIONS: Vitamin D insufficiency is common in patients with Type 2 diabetes during winter in Scotland. A single large dose of oral vitamin D2 improves endothelial function in patients with Type 2 diabetes and vitamin D insufficiency.

The role of research training during higher medical education in the promotion of academic medicine in the UK.

OBJECTIVES: To examine the research activities and perceived barriers to research among higher specialist trainees in geriatric medicine and to show how trainees active in research might have a role in assisting their peers in getting started in research. DESIGN: Cross-sectional questionnaire survey on research activities, attitudes to doing research and perceived difficulties in doing research. SETTING AND PARTICIPANTS: Trainee members of the British Geriatrics Society (BGS) in the UK. RESULTS: A total of 122 responses (30% response rate) were received after a single mailing and a follow-up questionnaire to trainees attending the BGS national conference. Although 64% (67/104) of respondents would like to undertake a period of research, many perceived barriers preventing them from planning, funding and executing a research project. Among those who had not undertaken research, the majority (70%, 42/60) indicated that they have no clear idea of a topic to research, 64% (39/61) did not know how to develop an idea and 62% (38/61) indicated that they did not know how to get funding. Trainees motivated to do research were faced with particular difficulties with regards to funding and selection of a project topic. CONCLUSIONS: One useful method would be systematically to provide basic information to trainees on how to enter into the early stages of research. This would help to overcome some of the unnecessary uncertainty that many trainees keen to do research seem to have.

Effect of Vitamin K on Vascular Health and Physical Function in Older People with Vascular Disease--A Randomised Controlled Trial.

BACKGROUND AND AIMS: Vitamin K insufficiency is common and linked to an increased risk of cardiovascular disease and osteoporotic fractures. The aim of this study was to examine whether daily supplementation with oral vitamin K could improve vascular health and physical function in older people with established vascular disease. METHODS AND RESULTS: A double blind, randomised, placebo-controlled trial. Participants aged ≤ 70 years with a history of vascular disease were randomised to receive 6 months of daily oral 100mcg vitamin K2 (MK7 subtype) or matching placebo with outcomes measured at 0, 3 and 6 months. The primary outcome was between-group difference in endothelial function assessed using flow-mediated dilatation of the brachial artery at 6 months. Secondary outcomes included carotid-radial pulse wave velocity, augmentation index, blood pressure, carotid intima-media thickness, C-reactive protein, B-type natriuretic peptide, cholesterol and desphospho-uncarboxylated matrix Gla protein levels. Handgrip strength and the Short Physical Performance Battery assessed physical function, while postural sway was measured using a 3-dimensional force platform. RESULTS: 80 participants were randomised, mean age 77 (SD 5) years; 44/80 were male. Vitamin K levels rose in the intervention arm compared to placebo (+48 pg/ml vs -6 pg/ml, p=0.03) at 6 months. Desphospho-uncarboxylated Matrix Gla protein levels fell in the intervention group compared to placebo at 6 months (-130 [SD 117] pmol/L vs +13 [SD 180] pmol/L, p<0.001). No change was seen in endothelial function (between group difference -0.3% [95%CI -1.3 to 0.8], p=0.62). A modest, non-significant improvement in pulse wave velocity was seen in the vitamin K group (-0.8m/s [95%CI -1.8 to 0.3], p=0.15) while all other vascular and physical function outcomes unchanged. CONCLUSIONS: Six months of vitamin K2 supplementation did not improve markers of vascular health or physical function in older patients with vascular disease.

Hypothetical economic analysis of screening for left ventricular hypertrophy in high-risk normotensive populations.

BACKGROUND: Left ventricular hypertrophy (LVH) measured by echocardiography is a powerful independent marker of increased cardiovascular risk. The prevalence of echocardiographic LVH in patients with high cardiovascular risk appears to be high, even in patients currently considered normotensive. AIM: To ascertain the likely costs of screening for and treating echocardiographic LVH in normotensive patients at high risk of cardiovascular events. DESIGN: Hypothetical economic analysis. METHODS: Cost analyses were based on known costs of echocardiography, costs of selected cardiovascular medications and prevalence of normotensive LVH in at-risk populations, combined with treatment effect data from studies of hypertensive patients with echocardiographic LVH. RESULTS: Screening costs per case for echocardiographic LVH are likely to be low, because of the high prevalence of the condition and the low unit cost of echocardiography. Treatment costs are likely to be comparable to those currently deemed acceptable in treating high-risk cardiovascular populations, e.g. the HOPE study population. DISCUSSION: The costs of screening for and treating LVH in normotensive patients at risk of cardiovascular events do not appear to be prohibitively high. Trials of screening and treatment for normotensive LVH seem therefore to be warranted.

Should we be giving enhanced vitamin D intakes to all?

It is widely established that vitamin D is critical for bone health. There is also an increasing body of evidence from observational studies that low levels of vitamin D are associated with a range of other disorders, including cancer and cardiovascular disease. People in temperate climates are often deficient in vitamin D, particularly in wintertime. The key question is whether there is sufficient evidence to justify supplementing vitamin D intakes for all. In this 'Controversy in Medicine', two international experts argue the case 'for' and 'against' universal vitamin D supplementation.

Development of a risk score to guide brain imaging in older patients admitted with falls and confusion.

OBJECTIVES: CT scanning of the brain is commonly performed in older people admitted to hospital with a fall, but the yield of positive findings is low. We used audit data to develop a risk-stratification score to guide more efficient use of CT scanning. METHODS: 12 potential predictors of positive CT findings were derived from a literature review. Case notes of consecutive patients presenting with falls and confusion who had undergone brain imaging were reviewed as part of an ongoing audit. Correlation of each factor with positive CT findings was undertaken and a final risk score was developed. Receiver-operating characteristic analysis was undertaken, an optimum cut-off identified, and positive and negative predictive values were calculated. RESULTS: 66 patients with a mean age of 74.8 years were included. 13 of the 66 (20%) brain imaging studies revealed a new pathology. Previous history of falls, atrial fibrillation, head or face trauma, focal neurological signs, warfarin use and a Glasgow coma score of <14 were significant univariate positive predictors. Antecedent dementia was included as a negative predictor. The final weighted score (range -1 to 8 points) gave an area under the curve of 0.83 (95% confidence interval 0.70 to 0.96, p<0.001). When using a cut-off of 3 points, sensitivity for significant new pathology on brain imaging was 83%, specificity was 89%, positive predictive value was 63% and negative predictive value was 96%. CONCLUSION: A simple weighted risk score may be able to guide the need for brain imaging in older people presenting to hospital with falls. The score requires validation in a larger, prospectively collected cohort.

Changes in serum magnesium and phosphate in older hospitalised patients--correlation with muscle strength and risk factors for refeeding syndrome.

OBJECTIVES: To evaluate changes in serum magnesium and phosphate over time in hospitalised older patients, examine whether such changes were associated with changes in muscle strength, and assess whether risk factors for refeeding syndrome were associated with falls in serum magnesium and phosphate. DESIGN AND SETTING: Community dwelling patients aged 70 and over, admitted to a specialist Medicine for the Elderly assessment unit were included in a prospective study. MEASUREMENTS: Weight, height, triceps skinfold thickness and mid arm circumference were recorded at baseline. Serum magnesium and phosphate was measured on admission, and at days 1, 2, 3, 5, 7, 10, 14, 21, 28 after admission, along with handgrip and quadriceps strength measured in the non-dominant limbs using a portable dynamometer. RESULTS: 43 patients were recruited with a mean age of 83.8 years (SD 7.5). 58% were female. Mean baseline serum magnesium and phosphate levels were 0.89 mmol/L and 1.07 mmol/L respectively. 10/43 patients had a fall in serum magnesium of at least 0.2 mmol/l from baseline and 20/43 had a similar fall in phosphate. No correlation was shown between these changes in electrolytes and muscle strength. Regression analyses did not show that risk factors for refeeding syndrome were associated with falls in electrolyte levels. CONCLUSION: Changes in serum magnesium and phosphate levels do not correlate with changes in muscle strength in older hospitalised patients. Risk factors for refeeding syndrome did not predict falls in serum phosphate or magnesium.