Serum 25(OH)D Concentration, Vitamin D Supplementation, and Risk of Cardiovascular Disease and Mortality in Patients with Type 2 Diabetes or Prediabetes: a Systematic Review and Dose-Response Meta-Analysis.

BACKGROUND: Evidence is uncertain about the association between serum 25-hydroxyvitamin D (25(OH)D) concentration and health outcomes in people with type 2 diabetes. OBJECTIVES: We aimed to assess the association between vitamin D status and all-cause mortality and cardiovascular disease in people with type 2 diabetes. METHODS: We did a systematic search in PubMed, Scopus, CENTRAL, and Web of Science until May 2022. We selected 1) cohort studies investigating the association between serum 25(OH)D concentration and mortality or cardiovascular disease in people with type 2 diabetes or prediabetes and 2) randomized trials of vitamin D supplementation in these patients. We used random-effects pairwise meta-analyses to calculate summary relative risks (RRs) and 95% confidence intervals (CI). RESULTS: 21 cohort studies and 6 randomized trials were included. Compared with sufficient vitamin D status (≥50 nmol/L), the RR of all-cause mortality was 1.36 (95% CI: 1.23, 1.49; n = 11 studies, GRADE = moderate) for vitamin D insufficiency (25 to <50 nmol/L), and 1.58 (1.33, 1.83; n = 16, GRADE = moderate) for deficiency (<25 nmol/L). Similar findings were observed for cardiovascular mortality and morbidity but not for cancer mortality. The certainty of evidence ranged from very low to moderate. Dose-response meta-analyses indicated nonlinear associations, with the lowest risk at 25(OH)D ∼60 nmol/L for all-cause and cardiovascular mortality. Supplementation with vitamin D did not reduce the risk of all-cause mortality (RR: 0.96, 95% CI: 0.79, 1.16; risk difference per 1000 patients: 3 fewer, 95% CI: 16 fewer, 12 more; n = 6 trials with 7316 participants; GRADE = low) or the risk of cardiovascular mortality and morbidity (very low- to low-certainty evidence). CONCLUSIONS: Vitamin D deficiency and insufficiency are associated with a higher risk of all-cause and cardiovascular mortality in patients with type 2 diabetes or prediabetes. Vitamin D deficiency should be corrected in patients with type 2 diabetes to reach normal serum 25(OH)D concentrations, preferably 60 nmol/L. SYSTEMATIC REVIEW REGISTRATION: This systemic review was registered at PROSPERO as CRD42022326429 (=https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=326429).

Prediction of Vitamin D Deficiency in Older Adults: The Role of Machine Learning Models.

CONTEXT: Conventional prediction models for vitamin D deficiency have limited accuracy. BACKGROUND: Using cross-sectional data, we developed models based on machine learning (ML) and compared their performance with those based on a conventional approach. METHODS: Participants were 5106 community-resident adults (50-84 years; 58% male). In the randomly sampled training set (65%), we constructed 5 ML models: lasso regression, elastic net regression, random forest, gradient boosted decision tree, and dense neural network. The reference model was a logistic regression model. Outcomes were deseasonalized serum 25-hydroxyvitamin D (25(OH)D) <50 nmol/L (yes/no) and <25 nmol/L (yes/no). In the test set (the remaining 35%), we evaluated predictive performance of each model, including area under the receiver operating characteristic curve (AUC) and net benefit (decision curves). RESULTS: Overall, 1270 (25%) and 91 (2%) had 25(OH)D <50 and <25 nmol/L, respectively. Compared with the reference model, the ML models predicted 25(OH)D <50 nmol/L with similar accuracy. However, for prediction of 25(OH)D <25 nmol/L, all ML models had higher AUC point estimates than the reference model by up to 0.14. AUC was highest for elastic net regression (0.93; 95% CI 0.90-0.96), compared with 0.81 (95% CI 0.71-0.91) for the reference model. In the decision curve analysis, ML models mostly achieved a greater net benefit across a range of thresholds. CONCLUSION: Compared with conventional models, ML models predicted 25(OH)D <50 nmol/L with similar accuracy but they predicted 25(OH)D <25 nmol/L with greater accuracy. The latter finding suggests a role for ML models in participant selection for vitamin D supplement trials.

Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials.

BACKGROUND: A 2017 meta-analysis of data from 25 randomised controlled trials (RCTs) of vitamin D supplementation for the prevention of acute respiratory infections (ARIs) revealed a protective effect of this intervention. We aimed to examine the link between vitamin D supplementation and prevention of ARIs in an updated meta-analysis. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov registry for studies listed from database inception to May 1, 2020. Double-blind RCTs of vitamin D3, vitamin D2, or 25-hydroxyvitamin D (25[OH]D) supplementation for any duration, with a placebo or low-dose vitamin D control, were eligible if they had been approved by a research ethics committee, and if ARI incidence was collected prospectively and prespecified as an efficacy outcome. Studies reporting results of long-term follow-up of primary RCTs were excluded. Aggregated study-level data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. Using the proportion of participants in each trial who had one or more ARIs, we did a random-effects meta-analysis to obtain pooled odds ratios (ORs) and 95% CIs to estimate the effect of vitamin D supplementation on the risk of having one or more ARIs (primary outcome) compared with placebo. Subgroup analyses were done to estimate whether the effects of vitamin D supplementation on the risk of ARI varied according to baseline 25(OH)D concentration (<25 nmol/L vs 25·0-49·9 nmol/L vs 50·0-74·9 nmol/L vs >75·0 nmol/L), vitamin D dose (daily equivalent of <400 international units [IU] vs 400-1000 IU vs 1001-2000 IU vs >2000 IU), dosing frequency (daily vs weekly vs once per month to once every 3 months), trial duration (≤12 months vs >12 months), age at enrolment (<1·00 years vs 1·00-15·99 years vs 16·00-64·99 years vs ≥65·00 years), and presence versus absence of airway disease (ie, asthma only, COPD only, or unrestricted). Risk of bias was assessed with the Cochrane Collaboration Risk of Bias Tool. The study was registered with PROSPERO, CRD42020190633. FINDINGS: We identified 1528 articles, of which 46 RCTs (75 541 participants) were eligible. Data for the primary outcome were obtained for 48 488 (98·1%) of 49 419 participants (aged 0-95 years) in 43 studies. A significantly lower proportion of participants in the vitamin D supplementation group had one or more ARIs (14 332 [61·3%] of 23 364 participants) than in the placebo group (14 217 [62·3%] of 22 802 participants), with an OR of 0·92 (95% CI 0·86-0·99; 37 studies; I2=35·6%, pheterogeneity=0·018). No significant effect of vitamin D supplementation on the risk of having one or more ARIs was observed for any of the subgroups defined by baseline 25(OH)D concentration. However, protective effects of supplementation were observed in trials in which vitamin D was given in a daily dosing regimen (OR 0·78 [95% CI 0·65-0·94]; 19 studies; I2=53·5%, pheterogeneity=0·003), at daily dose equivalents of 400-1000 IU (0·70 [0·55-0·89]; ten studies; I2=31·2%, pheterogeneity=0·16), for a duration of 12 months or less (0·82 [0·72-0·93]; 29 studies; I2=38·1%, pheterogeneity=0·021), and to participants aged 1·00-15·99 years at enrolment (0·71 [0·57-0·90]; 15 studies; I2=46·0%, pheterogeneity=0·027). No significant interaction between allocation to the vitamin D supplementation group versus the placebo group and dose, dose frequency, study duration, or age was observed. In addition, no significant difference in the proportion of participants who had at least one serious adverse event in the vitamin supplementation group compared with the placebo group was observed (0·97 [0·86-1·07]; 36 studies; I2=0·0%, pheterogeneity=0·99). Risk of bias within individual studies was assessed as being low for all but three trials. INTERPRETATION: Despite evidence of significant heterogeneity across trials, vitamin D supplementation was safe and overall reduced the risk of ARI compared with placebo, although the risk reduction was small. Protection was associated with administration of daily doses of 400-1000 IU for up to 12 months, and age at enrolment of 1·00-15·99 years. The relevance of these findings to COVID-19 is not known and requires further investigation. FUNDING: None.

Vitamin D and Clinical Cancer Outcomes: A Review of Meta-Analyses.

The relationship between vitamin D status or supplementation and cancer outcomes has been examined in several meta-analyses. To address remaining knowledge gaps, we conducted a systematic overview and critical appraisal of pertinent meta-analyses. For meta-analyses of trials, we assessed their quality using AMSTAR-2 (A Measurement Tool to Assess Systematic Reviews), strength of associations using umbrella review methodology and credibility of evidence using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) criteria. Meta-analyses of observational studies reported inverse associations of 25OHD with risk of cancer incidence and cancer mortality and, particularly for colorectal cancer, fulfilled some of Bradford-Hill's causation criteria. In meta-analyses of trials, vitamin D supplementation did not affect cancer incidence. However, we found credible evidence that vitamin D supplementation reduced total cancer mortality risk, with five out of six meta-analyses reporting a relative risk (RR) reduction of up to 16%: RR, 0.84 (95% CI, 0.74-0.95). The strength of the association, however, was classified as weak. This was true among meta-analyses of high, moderate, and lower quality (AMSTAR-2-rated). Trials did not include large numbers of vitamin D-deficient participants; many tested relatively low doses and lacked sufficiently powered data on site-specific cancers. In conclusion, meta-analyses show that, although observational evidence indicates that low vitamin D status is associated with a higher risk of cancer outcomes, randomized trials show that vitamin D supplementation reduces total cancer mortality, but not cancer incidence. However, trials with larger proportions of vitamin D-insufficient participants and longer durations of follow-up, plus adequately powered data on site-specific common cancers, would provide further insight into the evidence base. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Is There Proof of Extraskeletal Benefits From Vitamin D Supplementation From Recent Mega Trials of Vitamin D?

Scientific interest in possible extraskeletal effects of vitamin D first appeared in the 1930s soon after the structure of vitamin D was characterized, and increased in the 1980s with the development of assays of 25-hydroxyvitamin D status as a marker of vitamin D status, which in observational epidemiological studies was shown to be inversely associated with many nonskeletal diseases. This resulted in the start of seven large randomized controlled trials (n > 2000 participants in each) of vitamin D supplementation giving higher doses than previously used. The intervention periods in these trials collectively started in 2009 and continued to 2020. They have recruited participants, mostly of both sexes and over the age of 50 years, from many countries and have given either daily or monthly doses of vitamin D. Collectively, the trials have a wide range of outcomes with the main focus on the prevention of cancer, cardiovascular disease, and fractures, besides many other outcomes. The findings of four trials have been published, and they have shown that vitamin D supplementation does not prevent hard-disease endpoints, such as cardiovascular disease, cancer, fractures, or falls, aside from a possible beneficial effect against cancer mortality. In contrast, beneficial effects were seen for intermediate outcomes such as BMD of spine and hips, arterial function, and lung function, especially in people with vitamin D deficiency. The finding of a benefit primarily in people with vitamin D deficiency, if confirmed by the other trials, would support a population approach to preventing vitamin D deficiency using fortification rather than the high-risk approach of screening for deficiency combined with supplementation. The findings on other outcomes from the three published trials, along with the findings from the four unpublished trials, are expected within the next 2 to 3 years to clarify the role of vitamin D supplementation in preventing nonskeletal disease. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of aggregate data from randomised controlled trials.

BACKGROUND: A 2017 meta-analysis of data from 25 randomised controlled trials of vitamin D supplementation for the prevention of acute respiratory infections revealed a protective effect of the intervention. Since then, 20 new RCTs have been completed. METHODS: Systematic review and meta-analysis of data from randomised controlled trials (RCTs) of vitamin D for ARI prevention using a random effects model. Pre-specified sub-group analyses were done to determine whether effects of vitamin D on risk of ARI varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration or dosing regimen. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and the ClinicalTrials.gov registry from inception to 1st May 2020. Double-blind RCTs of supplementation with vitamin D or calcidiol, of any duration, were eligible if they were approved by a Research Ethics Committee and if ARI incidence was collected prospectively and pre-specified as an efficacy outcome. Aggregate data, stratified by baseline 25(OH)D concentration, were obtained from study authors. The study was registered with PROSPERO (no. CRD42020190633). FINDINGS: We identified 45 eligible RCTs (total 73,384 participants). Data were obtained for 46,331 (98.0%) of 47,262 participants in 42 studies, aged 0 to 95 years. For the primary comparison of vitamin D supplementation vs. placebo, the intervention reduced risk of ARI overall (Odds Ratio [OR] 0.91, 95% CI 0.84 to 0.99; P for heterogeneity 0.01). No statistically significant effect of vitamin D was seen for any of the sub-groups defined by baseline 25(OH)D concentration. However, protective effects were seen for trials in which vitamin D was given using a daily dosing regimen (OR 0.75, 95% CI 0.61 to 0.93); at daily dose equivalents of 400-1000 IU (OR 0.70, 95% CI 0.55 to 0.89); and for a duration of ≤12 months (OR 0.82, 95% CI 0.72 to 0.93). No significant interaction was seen between allocation to vitamin D vs. placebo and dose frequency, dose size, or study duration. Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (OR 0.97, 95% CI 0.86 to 1.09). Risk of bias within individual studies was assessed as being low for all but three trials. A funnel plot showed left-sided asymmetry (P=0.008, Egger's test). INTERPRETATION: Vitamin D supplementation was safe and reduced risk of ARI, despite evidence of significant heterogeneity across trials. Protection was associated with administration of daily doses of 400-1000 IU vitamin D for up to 12 months. The relevance of these findings to COVID-19 is not known and requires investigation. FUNDING: None.

A prediction tool for vitamin D deficiency in New Zealand adults.

PURPOSE: This study aims to develop a model for predicting vitamin D deficiency in New Zealand adults using easily accessible clinical characteristics. METHODS: Data were derived from the Vitamin D Assessment (ViDA) study dataset. Included participants in the main analysis were aged 50-84 years and resided in Auckland, New Zealand. The dataset was split into a discovery dataset in which the prediction model was developed (n = 2036) and a validation dataset in which it was tested (n = 2037). The prediction model was developed using clinical characteristics in a logistic regression analysis with deseasonalised serum 25OHD (DS-25OHD) as the dependent variable. RESULTS: DS-25OHD < 40 nmol/L was found in 8.2% of European participants, 18.8% of Maori participants, 23.1% of Pacific participants and 52.2% of South Asian participants. Predictors for DS-25OHD < 40 nmol/L in the European sub-cohort included increasing age, female sex, higher body mass index, current smoking, no alcohol intake, lower self-reported general health status, lower physical activity hours, lower outdoor hours and no use of vitamin D-containing supplementation. The area under the curve in the discovery dataset was 0.73, and in the validation dataset was 0.71. Of those with a prediction score ≥ 10 (total risk score range 0-21.5), the sensitivity and specificity for predicting vitamin D deficiency was 0.90 and 0.41, respectively. CONCLUSION: Non-European ethnicity is an important risk factor for vitamin D deficiency. Our vitamin D deficiency prediction model performed well and demonstrates its potential as a tool that can be integrated into clinical practice for the prediction of vitamin D deficiency.

What factors modify the effect of monthly bolus dose vitamin D supplementation on 25-hydroxyvitamin D concentrations?

The increasing use of vitamin D supplements has stimulated interest in identifying factors that may modify the effect of supplementation on circulating 25-hydroxyvitamin D (25(OH)D) concentrations. Such information is of potential interest to researchers, clinicians and patients when deciding on bolus dose of vitamin D supplementation. We carried out a large randomized controlled trial of 5110 adults aged 50-84 years, of European/Other (84%), Polynesian (11%) and Asian (5%) ethnicity, to whom we gave a standard dose of vitamin D3 supplements (200,000 IU initially, then 100,000 IU monthly) which was taken with high adherence. All participants provided a baseline blood sample, and follow-up blood samples were collected at 6 months and annually for 3 years in a random sample of 441 participants, and also at 2 years in 413 participants enrolled in a bone density sub-study. Serum 25(OH)D was measured by LC/MSMS. Mixed model analyses were carried out on all 854 participants providing follow-up blood samples in multivariable models that included age, sex, ethnicity, body mass index (kg/m2), tobacco smoking, alcohol intake, physical activity, sun exposure, season, medical prescription of high-dose vitamin D3 (Cal.D.Forte tablets), asthma/COPD and the study treatment (vitamin D or placebo). The adjusted mean difference in 25(OH)D in the follow-up points between vitamin D supplementation and placebo groups was inversely related (all p for interaction <0.05) to baseline 25(OH)D, BMI, and hours of sun exposure, and higher in females, elders, and those with high frequency of alcohol, medical prescription of vitamin D, and asthma/COPD. The mean difference was not significantly related to ethnicity (p = 0.12), tobacco (p = 0.34), and vigorous activity (p = 0.33). In summary, these data show that vitamin D status, BMI, sun exposure hours, sex and asthma/COPD modify the 25(OH)D response to vitamin D supplementation. By contrast, ethnicity, tobacco smoking, and vigorous activity do not.

Association between serum 25-hydroxyvitamin D levels and self-reported chronic pain in older adults: A cross-sectional analysis from the ViDA study.

Chronic pain is a major contributor to the global burden of disability. Prior studies on the association between serum 25-hydroxyvitamin D (25(OH)D) levels and chronic pain have yielded mixed results. The Vitamin D Assessment study, a large randomized controlled trial from New Zealand, offered the opportunity to examine this association in data collected at baseline in all participants, and among those with arthritis or depression. A total of 5110 participants aged 50-84 years were recruited from community general practices. Chronic pain (lasting ≥6 months) and other baseline characteristics were collected at baseline interview. Serum 25(OH)D concentration was measured by liquid chromatography-tandem mass spectrometry. Associations between 25(OH)D levels and chronic pain were explored using multivariable log-binomial regression to estimate relative risks (RRs). Out of 5049 participants with complete data, 871 (17%) reported having this clinical outcome, and 1254 (25%) had a 25(OH)D concentration <50 nmol/L. There was no significant association between 25(OH)D and chronic pain, with vitamin D status categorized in four groups: <25.0, 25.0-49.9, 50.0-74.9, and ≥75.0 nmol/L (the highest group as reference). The unadjusted RRs were 1.09, 1.10, and 1.08, respectively (Ptrend = 0.24). Adjustment for demographics, lifestyle, BMI, medical history, prescription of analgesics and vitamin D supplements did not change this finding. Similar non-significant results were observed in participants with arthritis (n = 1732) or depression (n = 528). In this multi-ethnic, community-selected sample of older adults in New Zealand, serum 25(OH)D levels were not associated with chronic pain. These results do not support a role for low vitamin D status in the prevalence of chronic pain in older adults.

Effect of Monthly, High-Dose, Long-Term Vitamin D on Lung Function: A Randomized Controlled Trial.

Although observational studies suggest positive vitamin D-lung function associations, randomized trials are inconsistent. We examined effects of vitamin D supplementation on lung function. We recruited 442 adults (50-84 years, 58% male) into a randomized, double-blinded, placebo-controlled trial. Participants received, for 1.1 years (median; range = 0.9-1.5 years), either (1) vitamin D3 200,000 IU, followed by monthly 100,000 IU doses (n = 226); or (2) placebo monthly (n = 216). At baseline and follow-up, spirometry yielded forced expiratory volume in 1 s (FEV1; primary outcome). Mean (standard deviation) 25-hydroxyvitamin D increased from 61 (24) nmol/L at baseline to 119 (45) nmol/L at follow-up in the vitamin D group, but was unchanged in the placebo group. There were no significant lung function improvements (vitamin D versus placebo) in the total sample, vitamin D-deficient participants or asthma/chronic obstructive pulmonary disease (COPD) participants. However, among ever-smokers (n = 217), the mean (95% confidence interval) FEV1 increase in the vitamin D versus placebo was 57 (4, 109) mL (p = 0.03). FEV1 increases were larger among vitamin D-deficient ever-smokers (n = 54): 122 (8, 236) mL (p = 0.04). FEV1 improvements were largest among ever-smokers with asthma/COPD (n = 60): 160 (53, 268) mL (p = 0.004). Thus, vitamin D supplementation did not improve lung function among everyone, but benefited ever-smokers, especially those with vitamin D deficiency or asthma/COPD.

Effect of Monthly, High-Dose, Long-Term Vitamin D Supplementation on Central Blood Pressure Parameters: A Randomized Controlled Trial Substudy.

BACKGROUND: The effects of monthly, high-dose, long-term (≥1-year) vitamin D supplementation on central blood pressure (BP) parameters are unknown. METHODS AND RESULTS: A total of 517 adults (58% male, aged 50-84 years) were recruited into a double-blinded, placebo-controlled trial substudy and randomized to receive, for 1.1 years (median; range: 0.9-1.5 years), either (1) vitamin D3 200 000 IU (initial dose) followed 1 month later by monthly 100 000-IU doses (n=256) or (2) placebo monthly (n=261). At baseline (n=517) and follow-up (n=380), suprasystolic oscillometry was undertaken, yielding aortic BP waveforms and hemodynamic parameters. Mean deseasonalized 25-hydroxyvitamin D increased from 66 nmol/L (SD: 24) at baseline to 122 nmol/L (SD: 42) at follow-up in the vitamin D group, with no change in the placebo group. Despite small, nonsignificant changes in hemodynamic parameters in the total sample (primary outcome), we observed consistently favorable changes among the 150 participants with vitamin D deficiency (<50 nmol/L) at baseline. In this subgroup, mean changes in the vitamin D group (n=71) versus placebo group (n=79) were -5.3 mm Hg (95% confidence interval [CI], -11.8 to 1.3) for brachial systolic BP (P=0.11), -2.8 mm Hg (95% CI, -6.2 to 0.7) for brachial diastolic BP (P=0.12), -7.5 mm Hg (95% CI, -14.4 to -0.6) for aortic systolic BP (P=0.03), -5.7 mm Hg (95% CI, -10.8 to -0.6) for augmentation index (P=0.03), -0.3 m/s (95% CI, -0.6 to -0.1) for pulse wave velocity (P=0.02), -8.6 mm Hg (95% CI, -15.4 to -1.9) for peak reservoir pressure (P=0.01), and -3.6 mm Hg (95% CI, -6.3 to -0.8) for backward pressure amplitude (P=0.01). CONCLUSIONS: Monthly, high-dose, 1-year vitamin D supplementation lowered central BP parameters among adults with vitamin D deficiency but not in the total sample. CLINICAL TRIAL REGISTRATION: URL: http://www.anzctr.org.au. Unique identifier: ACTRN12611000402943.