Ben Schöttker

Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States

Objective To investigate the association between serum 25-hydroxyvitamin D concentrations (25(OH)D) and mortality in a large consortium of cohort studies paying particular attention to potential age, sex, season, and country differences. Design Meta-analysis of individual participant data of eight prospective cohort studies from Europe and the US. Setting General population. Participants 26 018 men and women aged 50-79 years Main outcome measures All-cause, cardiovascular, and cancer mortality. Results 25(OH)D concentrations varied strongly by season (higher in summer), country (higher in US and northern Europe) and sex (higher in men), but no consistent trend with age was observed. During follow-up, 6695 study participants died, among whom 2624 died of cardiovascular diseases and 2227 died of cancer. For each cohort and analysis, 25(OH)D quintiles were defined with cohort and subgroup specific cut-off values. Comparing bottom versus top quintiles resulted in a pooled risk ratio of 1.57 (95% CI 1.36 to 1.81) for all-cause mortality. Risk ratios for cardiovascular mortality were similar in magnitude to that for all-cause mortality in subjects both with and without a history of cardiovascular disease at baseline. With respect to cancer mortality, an association was only observed among subjects with a history of cancer (risk ratio, 1.70 (1.00 to 2.88)). Analyses using all quintiles suggest curvilinear, inverse, dose-response curves for the aforementioned relationships. No strong age, sex, season, or country specific differences were detected. Heterogeneity was low in most meta-analyses. Conclusions Despite levels of 25(OH)D strongly varying with country, sex, and season, the association between 25(OH)D level and all-cause and cause-specific mortality was remarkably consistent. Results from a long term randomised controlled trial addressing longevity are being awaited before vitamin D supplementation can be recommended in most individuals with low 25(OH)D levels.

Strong associations of 25-hydroxyvitamin D concentrations with all-cause, cardiovascular, cancer, and respiratory disease mortality in a large cohort study

BACKGROUND Serum 25-hydroxyvitamin D [25(OH)D] concentration has been linked to mortality in several studies, but appropriate cutoffs to define risk categories are under debate. OBJECTIVE We aimed to conduct a repeated-measurements analysis on the association of serum 25(OH)D concentrations with all-cause and cause-specific mortality, with particular attention given to the shape of dose-response relations. DESIGN Concentrations of 25(OH)D were measured in n = 9578 baseline and n = 5469 5-y follow-up participants of the ESTHER study, which is a German population-based cohort aged 50-74 y at baseline. Deaths were recorded during 9.5 y of follow-up (median). Restricted cubic splines were used to assess dose-response relations, and Cox regression with time-dependent variables was used to estimate hazard ratios. RESULTS During follow-up, 1083 study participants died; of those, 350 individuals died of cardiovascular diseases, 433 individuals died of cancer, and 55 individuals died of respiratory diseases. The overall mortality [HR (95% CI)] of subjects with vitamin D deficiency [25(OH)D concentrations <30 nmol/L] or vitamin D insufficiency [25(OH)D concentrations from 30 to 50 nmol/L) was significantly increased [1.71 (1.43, 2.03) and 1.17 (1.02, 1.35), respectively] compared with that of subjects with sufficient 25(OH)D concentrations (>50 nmol/L)]. Vitamin D deficiency was also associated with increased cardiovascular mortality [1.39 (95% CI: 1.02, 1.89)], cancer mortality [1.42 (95% CI: 1.08, 1.88)] and respiratory disease mortality [2.50 (95% CI: 1.12, 5.56)]. The association of 25(OH)D concentrations with all-cause mortality proved to be a nonlinear inverse association with risk that started to increase at 25(OH)D concentrations <75 nmol/L. CONCLUSIONS In this large cohort study, serum 25(OH)D concentrations were inversely associated with all-cause and cause-specific mortality. In particular, vitamin D deficiency [25(OH)D concentration <30 nmol/L] was strongly associated with mortality from all causes, cardiovascular diseases, cancer, and respiratory diseases.

Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data

Background The utility of estimated glomerular filtration rate (eGFR) and albuminuria for cardiovascular prediction is controversial. Methods We meta-analyzed individual-level data from 24 cohorts (with a median follow-up time longer than 4 years, varying from 4.2 to 19.0 years) in the Chronic Kidney Disease Prognosis Consortium (637,315 participants without a history of cardiovascular disease) and assessed C-statistic difference and reclassification improvement for cardiovascular mortality and fatal and non-fatal cases of coronary heart disease, stroke, and heart failure in 5-year timeframe, contrasting prediction models consisting of traditional risk factors with and without creatinine-based eGFR and/or albuminuria (either albumin-to-creatinine ratio [ACR] or semi-quantitative dipstick proteinuria). Findings The addition of eGFR and ACR significantly improved the discrimination of cardiovascular outcomes beyond traditional risk factors in general populations, but the improvement was greater with ACR than with eGFR and more evident for cardiovascular mortality (c-statistic difference 0.0139 [95%CI 0.0105–0.0174] and 0.0065 [0.0042–0.0088], respectively) and heart failure (0.0196 [0.0108–0.0284] and 0.0109 [0.0059–0.0159]) than for coronary disease (0.0048 [0.0029–0.0067] and 0.0036 [0.0019–0.0054]) and stroke (0.0105 [0.0058–0.0151] and 0.0036 [0.0004–0.0069]). Dipstick proteinuria demonstrated smaller improvement than ACR. The discrimination improvement with kidney measures was especially evident in individuals with diabetes or hypertension but remained significant with ACR for cardiovascular mortality and heart failure in those without either of these conditions. In participants with chronic kidney disease (CKD), the combination of eGFR and ACR for risk discrimination outperformed most single traditional predictors; the c-statistic for cardiovascular mortality declined by 0.023 [0.016–0.030] vs. <0.007 when omitting eGFR and ACR vs. any single modifiable traditional predictors, respectively. Interpretation Creatinine-based eGFR and albuminuria should be taken into account for cardiovascular prediction, especially when they are already assessed for clinical purpose and/or cardiovascular mortality and heart failure are the outcomes of interest (e.g., the European guidelines on cardiovascular prevention). ACR may have particularly broad implications for cardiovascular prediction. In CKD populations, the simultaneous assessment of eGFR and ACR will facilitate improved cardiovascular risk classification, supporting current CKD guidelines. Funding US National Kidney Foundation and NIDDKBACKGROUND The usefulness of estimated glomerular filtration rate (eGFR) and albuminuria for prediction of cardiovascular outcomes is controversial. We aimed to assess the addition of creatinine-based eGFR and albuminuria to traditional risk factors for prediction of cardiovascular risk with a meta-analytic approach. METHODS We meta-analysed individual-level data for 637 315 individuals without a history of cardiovascular disease from 24 cohorts (median follow-up 4·2-19·0 years) included in the Chronic Kidney Disease Prognosis Consortium. We assessed C statistic difference and reclassification improvement for cardiovascular mortality and fatal and non-fatal cases of coronary heart disease, stroke, and heart failure in a 5 year timeframe, contrasting prediction models for traditional risk factors with and without creatinine-based eGFR, albuminuria (either albumin-to-creatinine ratio [ACR] or semi-quantitative dipstick proteinuria), or both. FINDINGS The addition of eGFR and ACR significantly improved the discrimination of cardiovascular outcomes beyond traditional risk factors in general populations, but the improvement was greater with ACR than with eGFR, and more evident for cardiovascular mortality (C statistic difference 0·0139 [95% CI 0·0105-0·0174] for ACR and 0·0065 [0·0042-0·0088] for eGFR) and heart failure (0·0196 [0·0108-0·0284] and 0·0109 [0·0059-0·0159]) than for coronary disease (0·0048 [0·0029-0·0067] and 0·0036 [0·0019-0·0054]) and stroke (0·0105 [0·0058-0·0151] and 0·0036 [0·0004-0·0069]). Dipstick proteinuria showed smaller improvement than ACR. The discrimination improvement with eGFR or ACR was especially evident in individuals with diabetes or hypertension, but remained significant with ACR for cardiovascular mortality and heart failure in those without either of these disorders. In individuals with chronic kidney disease, the combination of eGFR and ACR for risk discrimination outperformed most single traditional predictors; the C statistic for cardiovascular mortality fell by 0·0227 (0·0158-0·0296) after omission of eGFR and ACR compared with less than 0·007 for any single modifiable traditional predictor. INTERPRETATION Creatinine-based eGFR and albuminuria should be taken into account for cardiovascular prediction, especially when these measures are already assessed for clinical purpose or if cardiovascular mortality and heart failure are outcomes of interest. ACR could have particularly broad implications for cardiovascular prediction. In populations with chronic kidney disease, the simultaneous assessment of eGFR and ACR could facilitate improved classification of cardiovascular risk, supporting current guidelines for chronic kidney disease. Our results lend some support to also incorporating eGFR and ACR into assessments of cardiovascular risk in the general population. FUNDING US National Kidney Foundation, National Institute of Diabetes and Digestive and Kidney Diseases.

Smoking and All-Cause Mortality in Older People: Systematic Review and Meta-analysis

BACKGROUND Smoking is an established risk factor of premature death. However, most pertinent studies primarily relied on middle-aged adults. We performed a systematic review and meta-analysis of the empirical evidence on the association of smoking with all-cause mortality in people 60 years and older. METHODS A systematic literature search was conducted in multiple databases including MEDLINE, EMBASE, and ISI Web of Knowledge and complemented by cross-referencing to identify cohort studies published before July 2011. Core items of identified studies were independently extracted by 2 reviewers, and results were summarized by standard methods of meta-analysis. RESULTS We identified 17 studies from 7 countries. Current smoking was associated with increased all-cause mortality in all studies. Relative mortality (RM) compared with never smokers ranged from 1.2 to 3.4 across studies and was 1.83 (95% CI, 1.65-2.03) in the meta-analysis. A decrease of RM of current smokers with increasing age was observed, but mortality remained increased up to the highest ages. Furthermore, a dose-response relationship of the amount of smoked cigarettes and premature death was observed. Former smokers likewise had an increased mortality (meta-analysis: RM, 1.34; 95% CI, 1.28-1.40), but excess mortality compared with never smokers clearly decreased with duration of cessation. Benefits of smoking cessation were evident in all age groups, including subjects 80 years and older. CONCLUSIONS Smoking remains a strong risk factor for premature mortality also at older age. Smoking cessation is beneficial at any age.

Impact of smoking and smoking cessation on cardiovascular events and mortality among older adults: meta-analysis of individual participant data from prospective cohort studies of the CHANCES consortium

Objective To investigate the impact of smoking and smoking cessation on cardiovascular mortality, acute coronary events, and stroke events in people aged 60 and older, and to calculate and report risk advancement periods for cardiovascular mortality in addition to traditional epidemiological relative risk measures. Design Individual participant meta-analysis using data from 25 cohorts participating in the CHANCES consortium. Data were harmonised, analysed separately employing Cox proportional hazard regression models, and combined by meta-analysis. Results Overall, 503?905 participants aged 60 and older were included in this study, of whom 37?952 died from cardiovascular disease. Random effects meta-analysis of the association of smoking status with cardiovascular mortality yielded a summary hazard ratio of 2.07 (95% CI 1.82 to 2.36) for current smokers and 1.37 (1.25 to 1.49) for former smokers compared with never smokers. Corresponding summary estimates for risk advancement periods were 5.50 years (4.25 to 6.75) for current smokers and 2.16 years (1.38 to 2.39) for former smokers. The excess risk in smokers increased with cigarette consumption in a dose-response manner, and decreased continuously with time since smoking cessation in former smokers. Relative risk estimates for acute coronary events and for stroke events were somewhat lower than for cardiovascular mortality, but patterns were similar. Conclusions Our study corroborates and expands evidence from previous studies in showing that smoking is a strong independent risk factor of cardiovascular events and mortality even at older age, advancing cardiovascular mortality by more than five years, and demonstrating that smoking cessation in these age groups is still beneficial in reducing the excess risk.

Serum 25-hydroxyvitamin D levels and overall mortality. A systematic review and meta-analysis of prospective cohort studies

OBJECTIVE To provide a systematic review and meta-analysis of prospective, population-based cohort studies on the association of serum 25-hydroxyvitamin D (25(OH)D) and all-cause mortality. METHODS Relevant studies were identified by systematically searching Medline, EMBASE and ISI Web of Knowledge. Reported hazard ratios (HRs) for 25(OH)D categories were recalculated employing comprehensive trend estimation from summarized dose-response data and pooled in a random effects model meta-analysis. RESULTS Overall, 12 original studies were included in the review and meta-analysis comprising 32,142 mainly elderly study participants with measured 25(OH)D of whom 6921 died during follow-up. An inverse association between 25(OH)D levels and all-cause mortality was found in all but two studies that was statistically significant in several of the individual studies. In meta-analysis, 25(OH)D levels were significantly inversely associated with all-cause mortality with a pooled HR of 0.92 (95% confidence interval: 0.89-0.95) for a 20 nmol/l increase in 25(OH)D levels. CONCLUSION In this meta-analysis of prospective, population-based cohort studies, a 20 nmol/l increase in 25(OH)D levels was associated with an 8% lower mortality in the general elderly population. This agrees with results from meta-analyses on randomized controlled trials that found a decrease in mortality with vitamin D3 supplementation of a comparable magnitude.

Serum 25-hydroxyvitamin D levels and survival in colorectal and breast cancer patients: Systematic review and meta-analysis of prospective cohort studies

AIM To estimate the association between serum 25-hydroxyvitamin D (25(OH)D) levels and survival among colorectal and breast cancer patients. METHODS We performed a comprehensive literature search of prospective cohort studies assessing the association of serum 25(OH)D levels with survival in colorectal and breast cancer patients. Study characteristics and results were extracted and dose-response relationships were graphically displayed in a standardised manner. Meta-analyses using random effects models were performed to estimate pooled hazard ratios. RESULTS The systematic search yielded five studies including 2330 colorectal cancer patients and five studies including 4413 breast cancer patients all of which compared mortality across two to five categories of 25(OH)D levels. Among colorectal cancer patients, pooled hazard ratios (95% confidence intervals) comparing highest with lowest categories were 0.71 (0.55-0.91) and 0.65 (0.49-0.86) for overall and disease-specific mortality, respectively. For breast cancer patients, the corresponding pooled estimates were 0.62 (0.49-0.78) and 0.58 (0.38-0.84), respectively. No significant evidence of heterogeneity between studies was observed. CONCLUSION Higher 25(OH)D levels (>75nmol/L) were associated with significantly reduced mortality in patients with colorectal and breast cancer. Randomised controlled trials are needed to evaluate whether vitamin D supplementation can improve survival in colorectal and breast cancer patients with low vitamin D status (25(OH)D<50nmol/L) at diagnosis and before treatment.

High-density lipoprotein cholesterol, coronary artery disease, and cardiovascular mortality

AIMS High-density lipoprotein (HDL) cholesterol is a strong predictor of cardiovascular mortality. This work aimed to investigate whether the presence of coronary artery disease (CAD) impacts on its predictive value. METHODS AND RESULTS We studied 3141 participants (2191 males, 950 females) of the LUdwigshafen RIsk and Cardiovascular health (LURIC) study. They had a mean ± standard deviation age of 62.6 ± 10.6 years, body mass index of 27.5 ± 4.1 kg/m², and HDL cholesterol of 38.9 ± 10.8 mg/dL. The cohort consisted of 699 people without CAD, 1515 patients with stable CAD, and 927 patients with unstable CAD. The participants were prospectively followed for cardiovascular mortality over a median (inter-quartile range) period of 9.9 (8.7-10.7) years. A total of 590 participants died from cardiovascular diseases. High-density lipoprotein cholesterol by tertiles was inversely related to cardiovascular mortality in the entire cohort (P = 0.009). There was significant interaction between HDL cholesterol and CAD in predicting the outcome (P = 0.007). In stratified analyses, HDL cholesterol was strongly associated with cardiovascular mortality in people without CAD [3rd vs. 1st tertile: HR (95% CI) = 0.37 (0.18-0.74), P = 0.005], but not in patients with stable [3rd vs. 1st tertile: HR (95% CI) = 0.81 (0.61-1.09), P = 0.159] and unstable [3rd vs. 1st tertile: HR (95% CI) = 0.91 (0.59-1.41), P = 0.675] CAD. These results were replicated by analyses in 3413 participants of the AtheroGene cohort and 5738 participants of the ESTHER cohort, and by a meta-analysis comprising all three cohorts. CONCLUSION The inverse relationship of HDL cholesterol with cardiovascular mortality is weakened in patients with CAD. The usefulness of considering HDL cholesterol for cardiovascular risk stratification seems limited in such patients.

Serum 25-Hydroxyvitamin D and Cancer Risk in Older Adults: Results from a Large German Prospective Cohort Study

Background: Several observational studies assessed the relationship between serum 25-hydroxyvitamin D [25(OH)D] concentrations and the risk of cancer but results were inconclusive. Methods: We measured 25(OH)D concentrations in a population-based cohort study of 9,949 men and women ages 50 to 74 years in Saarland, Germany. Comprehensively adjusted Cox regression models were applied to estimate HRs and 95% confidence intervals (CI) for the association between season-standardized 25(OH)D concentrations and total and site-specific cancer incidence. Results: Overall, during a median of 8 years of follow-up, 873 subjects developed cancer; the most common being prostate (171), breast (137), lung (136), and colorectal (136) cancer. Low season-standardized 25(OH)D (<30, 35, 40, or 36 nmol/L in winter, spring, summer, and autumn, respectively) was neither significantly associated with total cancer incidence (HR, 1.10; 95% CI, 0.93–1.30) nor with site-specific cancer incidence. However, a significantly increased overall cancer risk was observed for low 25(OH)D among men, nonobese subjects and subjects reporting low fish consumption and for high 25(OH)D in nonsmokers and nonobese subjects. Accordingly, restricted cubic splines to investigate dose–response relationships curves showed an inverse association of 25(OH)D levels and total cancer risk in men but not in women. Conclusions: 25(OH)D concentrations were significantly associated with overall cancer incidence in subgroups of this large cohort from Germany. No significant association was observed with site-specific cancers but this could be due to a limited statistical power for these endpoints. Impact: Further research should clarify whether and to what extent specific risk groups might profit from vitamin D supplementation. Cancer Epidemiol Biomarkers Prev; 22(5); 905–16. ©2013 AACR.

Circulating 25-hydroxyvitamin D serum concentration and total cancer incidence and mortality: A systematic review and meta-analysis

OBJECTIVE To conduct a systematic review and meta-analysis of longitudinal studies on the association of 25(OH)D with total cancer incidence and mortality. METHOD Relevant longitudinal observational studies were identified by systematically searching Ovid Medline, EMBASE, and ISI Web of Knowledge databases. Due to the heterogeneity across studies in categorizing 25(OH)D concentration, all results were recalculated for an increase of 25(OH)D by 50 nmol/L. RESULTS In meta-analyses with random effects models, the summary risk ratios and confidence intervals (RRs (95% CI)) for the association of an increase of 25(OH)D by 50 nmol/L with total cancer incidence (5 studies) and mortality (13 studies) were 0.89 (0.81, 0.97) and 0.83 (0.71, 0.96), respectively. In sex-specific analyses no significant association with total cancer incidence was observed among men or women. A clear inverse association with total cancer mortality was observed among women (0.76 (0.60, 0.98)) but not among men (0.92 (0.65, 1.32)). Large heterogeneity was observed for studies on total cancer mortality (P<0.01) but not for studies on cancer incidence (P=0.41). No publication bias was found. CONCLUSION The meta-analysis suggests a moderate inverse association of 25(OH)D concentration with total cancer incidence and mortality.