Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium

Gaksch, Martin; Jorde, Rolf; Grimnes, Guri; Joakimsen, Ragnar Martin; Schirmer, Henrik; Wilsgaard, Tom; Mathiesen, Ellisiv B.; Njølstad, Inger; Løchen, Maja‐Lisa; März, Winfried; Kleber, Marcus E.; Tomaschitz, Andreas; Grübler, Martin; Eiríksdóttir, Guðný; Gudmundsson, Elias F.; Harris, Tamara B.; Cotch, Mary Frances; Aspelund, Thor; Gudnason, Vilmundur; Rutters, Femke; Beulens, Joline W.J.; Riet, Esther van't; Nijpels, Giel; Dekker, Joost; Grove‐Laugesen, Diana; Rejnmark, Lars; Busch, Markus; Mensink, Gert; Scheidt‐Nave, Christa; Thamm, Michael; Swart, Karin M. A.; Brouwer, Ingeborg A.; Lips, Paul; Schoor, Natasja M. van; Sempos, Christopher T.; Durazo‐Arvizu, Ramón; Škrabáková, Zuzana; Dowling, Kirsten G.; Cashman, Kevin D.; Kiely, Máiréad; Pilz, Stefan

doi:10.1371/journal.pone.0170791

Cited by 246 publications

(215 citation statements)

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“…18 Results were expressed as means with standard deviations or as median with interquartile range. In our analyses, we performed comparisons between the first tertile and the upper tertiles because previous studies indicate that detrimental effects of vitamin D become only apparent at severely depressed 25(OH)D levels.…”

Section: Resultsmentioning

confidence: 99%

“…In our analyses, we performed comparisons between the first tertile and the upper tertiles because previous studies indicate that detrimental effects of vitamin D become only apparent at severely depressed 25(OH)D levels. 18 Results were expressed as means with standard deviations or as median with interquartile range. Categorical variables were given as percentage or number of observations.…”

Section: Resultsmentioning

confidence: 99%

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Vitamin D deficiency in patients with diastolic dysfunction or heart failure with preserved ejection fraction

et al. 2019

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Aims Vitamin D deficiency is prevalent in heart failure (HF), but its relevance in early stages of heart failure with preserved ejection fraction (HFpEF) is unknown. We tested the association of 25‐hydroxyvitamin D [25(OH)D] serum levels with mortality, hospitalizations, cardiovascular risk factors, and echocardiographic parameters in patients with asymptomatic diastolic dysfunction (DD) or newly diagnosed HFpEF. Methods and results We measured 25(OH)D serum levels in outpatients with risk factors for DD or history of HF derived from the DIAST‐CHF study. Participants were comprehensively phenotyped including physical examination, echocardiography, and 6 min walk test and were followed up to 5 years. Quality of life was evaluated by the Short Form 36 (SF‐36) questionnaire. We included 787 patients with available 25(OH)D levels. Median 25(OH)D levels were 13.1 ng/mL, mean E/e′ medial was 13.2, and mean left ventricular ejection fraction was 59.1%. Only 9% ( n = 73) showed a left ventricular ejection fraction <50%. Fifteen per cent ( n = 119) of the recruited participants had symptomatic HFpEF. At baseline, participants with 25(OH)D levels in the lowest tertile (≤10.9 ng/L; n = 263) were older, more often symptomatic (oedema and fatigue, all P ≤ 0.002) and had worse cardiac [higher N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) and left atrial volume index, both P ≤ 0.023], renal (lower glomerular filtration rate, P = 0.012), metabolic (higher uric acid levels, P < 0.001), and functional (reduced exercise capacity, 6 min walk distance, and SF‐36 physical functioning score, all P < 0.001) parameters. Increased NT‐proBNP, uric acid, and left atrial volume index and decreased SF‐36 physical functioning scores were independently associated with lower 25(OH)D levels. There was a higher risk for lower 25(OH)D levels in association with HF, DD, and atrial fibrillation (all P ≤ 0.004), which remained significant after adjusting for age. Lower 25(OH)D levels (per 10 ng/mL decrease) tended to be associated with higher 5 year mortality, P = 0.05, hazard ratio (HR) 1.55 [1.00; 2.42]. Furthermore, lower 25(OH)D levels (per 10 ng/mL decrease) were related to an increased rate of cardiovascular hospitalizations, P = 0.023, HR = 1.74 [1.08; 2.80], and remained significant after adjusting for age, P = 0.046, HR = 1.63 [1.01; 2.64], baseline NT‐proBNP, P = 0.048, HR = 1.62 [1.01; 2.61], and other selected baseline characteristics and co‐morbidities, P = 0.043, HR = 3.60 [1.04; 12.43]. Conclusions Lower 25(OH)D levels were associated with reduced functional capac...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Vitamin D deficiency in patients with diastolic dysfunction or heart failure with preserved ejection fraction

et al. 2019

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“…In addition to performing analyses in the total sample, we decided a priori to perform subgroup analyses among vitamin D–deficient persons. This is because nonlinear relationships between 25(OH)D concentration and health outcomes, including mortality and CVD, suggest that adverse effects associated with low vitamin D status are greatest in vitamin D–deficient persons, indicating that vitamin D supplementation could be more effective in such individuals. In further prespecified analyses, we examined 3‐way interactions among vitamin D deficiency (present or absent), treatment group, and time so as to test whether the effects of vitamin D were different in those with and without vitamin D deficiency and supplemented this with a subgroup analysis among people without vitamin D deficiency.…”

Section: Methodsmentioning

confidence: 99%

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

Sluyter

Camargo

Stewart

et al. 2017

JAHA

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BackgroundThe effects of monthly, high‐dose, long‐term (≥1‐year) vitamin D supplementation on central blood pressure (BP) parameters are unknown.Methods and ResultsA 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).ConclusionsMonthly, 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.

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“…A 2014 Cochrane meta-analysis showed a relevant and significant lower all-cause mortality of~7% and cancer mortality of~13% in patients who received vitamin D3 [69]. The results of a meta-analysis by using individual participant data conducted by Gaksch et al, analyzing almost 17,000 individuals, showed a strong association between low 25(OH)D and increased risk of all-cause mortality [70]. Using a Mendelian randomization with genetic variants in the vitamin D synthesis pathway, the analysis of Aspelund et al supports a causal relationship between vitamin D deficiency and increased all-cause mortality.…”

Section: Selected Target Organs Conditions and Endpointsmentioning

confidence: 99%

Vitamin D deficiency 2.0: an update on the current status worldwide

et al. 2020

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Vitamin D testing and the use of vitamin D supplements have increased substantially in recent years. Currently, the role of vitamin D supplementation, and the optimal vitamin D dose and status, is a subject of debate, because large interventional studies have been unable to show a clear benefit (in mostly vitamin D replete populations). This may be attributed to limitations in trial design, as most studies did not meet the basic requirements of a nutrient intervention study, including vitamin D-replete populations, too small sample sizes, and inconsistent intervention methods regarding dose and metabolites. Vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] < 50 nmol/L or 20 ng/ml) is associated with unfavorable skeletal outcomes, including fractures and bone loss. A 25(OH)D level of >50 nmol/L or 20 ng/ml is, therefore, the primary treatment goal, although some data suggest a benefit for a higher threshold. Severe vitamin D deficiency with a 25(OH)D concentration below <30 nmol/L (or 12 ng/ml) dramatically increases the risk of excess mortality, infections, and many other diseases, and should be avoided whenever possible. The data on a benefit for mortality and prevention of infections, at least in severely deficient individuals, appear convincing. Vitamin D is clearly not a panacea, and is most likely efficient only in deficiency. Given its rare side effects and its relatively wide safety margin, it may be an important, inexpensive, and safe adjuvant therapy for many diseases, but future large and well-designed studies should evaluate this further. A worldwide public health intervention that includes vitamin D supplementation in certain risk groups, and systematic vitamin D food fortification to avoid severe vitamin D deficiency, would appear to be important. In this narrative review, the current international literature on vitamin D deficiency, its relevance, and therapeutic options is discussed.

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Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium

Cited by 246 publications

References 37 publications

Vitamin D deficiency in patients with diastolic dysfunction or heart failure with preserved ejection fraction

Vitamin D deficiency in patients with diastolic dysfunction or heart failure with preserved ejection fraction

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

Vitamin D deficiency 2.0: an update on the current status worldwide

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