Moira Strand Hutchinson

Tracking of Serum 25-Hydroxyvitamin D Levels During 14 Years in a Population-based Study and During 12 Months in an Intervention Study

Low serum 25-hydroxyvitamin D (25(OH)D) levels are associated with risk factors for cardiovascular disease, and they also appear to predict later development of type 2 diabetes, cancer, and an increased mortality rate. These predictions are all based on a single 25(OH)D measurement, but so far there are no known reports on tracking of serum 25(OH)D levels. In the present Norwegian study, serum 25(OH)D levels were measured 1) in 2,668 subjects in the 1994 and 2008 Tromsø surveys and 2) every third month for 1 year in 94 subjects randomly assigned to placebo in a vitamin D intervention study. There was a marked seasonal variation in 25(OH)D, and, depending on the method of adjusting for season, the correlation coefficient between serum 25(OH)D measurements from 1994 and 2008 ranged from 0.42 to 0.52. In the 1-year intervention study, the correlation between baseline and 12-month values was 0.80. Apart from the effect of season, changes in weight, intake of vitamin D, and physical activity were related to change in serum 25(OH)D levels. Tracking of serum 25(OH)D appears similar to that for blood pressure and serum lipids, and it provides some support for the use of a single 25(OH)D measurement to predict future health outcomes.

Low serum 25-hydroxyvitamin D levels are associated with increased all-cause mortality risk in a general population: the Tromsø study.

OBJECTIVE Ecologic and observational studies have suggested an association between serum 25-hydroxyvitamin D (25(OH)D) levels and cardiovascular disease (CVD) risk factors, CVD mortality, and cancer mortality. Based on this, low serum 25(OH)D levels should be associated with higher all-cause mortality in a general population. This hypothesis was tested in the present study. DESIGN The Tromsø study is a longitudinal population-based multipurpose study initiated in 1974 with focus on lifestyle-related diseases. Our data are based on the fourth Tromsø study carried out in 1994-1995. METHODS Information about death and cause of death was registered by obtaining information from the National Directory of Residents and the Death Cause Registry. Serum 25(OH)D was measured in 7161 participants in the fourth Tromsø study. Results are presented for smokers (n=2410) and non-smokers (n=4751) separately as our immunoassay seems to overestimate 25(OH)D levels for smokers. RESULTS During a mean 11.7 years of follow-up, 1359 (19.0%) participants died. In multivariate regression models, there was a significantly increased risk of all-cause mortality (hazard ratio (HR) 1.32, confidence interval (CI) 1.07-1.62) among non-smoking participants in the lowest 25(OH)D quartile when compared with participants in the highest quartile. Equivalent results for smokers were not significant (HR 1.06, CI 0.83-1.35). CONCLUSIONS Low serum 25(OH)D levels were associated with increased all-cause mortality for non-smokers, but the results did not reach statistical significance for smokers. However, low 25(OH)D levels are known to be associated with impaired general health, and randomized controlled studies are needed to address the question of causality.

High serum 25-hydroxyvitamin D concentrations are associated with a favorable serum lipid profile

Background/Objectives:Low serum 25-hydroxyvitamin D (25(OH)D) concentrations are related to increased mortality. One possible explanation could be an association between serum 25(OH)D and serum lipids.Subjects/Methods:The study was performed at the University of Tromsø, Northern Norway. In total, 8018 nonsmoking and 2087 smoking subjects were included in a cross-sectional study performed in 2008, and 1762 nonsmoking and 397 smoking subjects in a longitudinal study from 1994/1995 to 2008. Nonfasting serum 25(OH)D, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), LDL-C/HDL-C ratio and triacylglycerol (TAG) were measured.Results:After adjustment for gender, age, sample month and body mass index in the cross-sectional study, there was a significant increase in serum TC, HDL-C and LDL-C, and a significant decrease in serum LDL-C/HDL-C ratio and TAG across increasing serum 25(OH)D quartiles. For serum HDL-C and TAG in nonsmokers the differences between the means for the highest and lowest serum 25(OH)D quartiles were 6.0 and 18.5%, respectively. In the longitudinal study, an increase in serum 25(OH)D was associated with a significant decrease in serum TAG.Conclusions:There is a cross-sectional association between serum 25(OH)D and serum lipids, and a longitudinal association over 14 years between serum 25(OH)D and TAG, which may contribute to explain the relation between low serum 25(OH)D concentrations and mortality.

Effect of vitamin D supplement on depression scores in people with low levels of serum 25-hydroxyvitamin D: nested case-control study and randomised clinical trial.

AIMS To compare depressive symptoms in participants with low and high serum 25-hydroxyvitamin D (25(OH)D) levels and to examine whether supplementation with vitamin D(3) would improve symptoms in those with low serum 25(OH)D levels. METHOD Participants with low 25(OH)D levels were randomised to either placebo or 40 000 IU vitamin D(3) per week for 6 months. Individuals with high serum 25(OH)D levels were used as nested controls. Depressive symptoms were evaluated with the Beck Depression Inventory, Hospital Anxiety and Depression Scale, Seasonal Pattern Assessment Scale and Montgomery-Åsberg Depression Rating Scale. The study was registered at ClinicalTrials.gov (NCT00960232). RESULTS Participants with low 25(OH)D levels (n = 230) at baseline were more depressed (P<0.05) than participants with high 25(OH)D levels (n = 114). In the intervention study no significant effect of high-dose vitamin D was found on depressive symptom scores when compared with placebo. CONCLUSIONS Low levels of serum 25(OH)D are associated with depressive symptoms, but no effect was found with vitamin D supplementation.

Serum 25-Hydroxyvitamin D Levels Are Strongly Related to Systolic Blood Pressure But Do Not Predict Future Hypertension

Vitamin D receptors have been detected in vascular smooth muscle cells, and 1,25-dihydroxyvitamin D inhibits the renin mRNA expression. Epidemiological studies show an inverse relation between serum 25-hydoxyvitamin D levels and blood pressure, and low serum 25-hydoxyvitamin D levels are reported to be predictors of future development of hypertension. This may indicate an important role for vitamin D in blood pressure regulation. In the present study, 25-hydoxyvitamin D was measured in sera collected in 1994 from 4125 subjects who did not use blood pressure medication, and thereafter measurement was repeated in 2008 for 2385 of these subjects. In sera from 1994 there was a significant decrease in age, body mass index, and systolic blood pressure and a significant increase in physical activity score across increasing 25-hydoxyvitamin D quartiles. After adjusting for sex, age, body mass index, and physical activity, the difference in systolic blood pressure between the lowest and highest serum 25-hydoxyvitamin D quartiles was 3.6 mm Hg. After adjustment for confounders, serum 25-hydoxyvitamin D from 1994 did not predict future hypertension or increase in blood pressure, nor was there any significant association between change in serum 25-hydoxyvitamin D from 1994 to 2008 and change in blood pressure. Our results do not support a causal role for vitamin D in blood pressure regulation, and large randomized clinical trials, preferably including subjects with hypertension and/or low serum 25-hydoxyvitamin D levels, are greatly needed to clarify whether vitamin D supplementation affects the blood pressure.

Effect of smoking on the serum levels of 25-hydroxyvitamin D depends on the assay employed

OBJECTIVE Because we found higher serum 25-hydroxyvitamin D (25(OH)D) levels among smokers than among non-smokers with analyses using an electrochemiluminescence immunoassay (ECLIA) from Roche, the purpose of the present study was to examine whether this difference between smokers and non-smokers was maintained using other serum 25(OH)D assays. DESIGN A cross-sectional population-based study on 6932 participants from the Tromsø study, 1994-1995, and one validation study comparing six different serum 25(OH)D assays in 53 non-smokers and 54 smokers were performed. METHODS The association between smoking, season and serum 25(OH)D as measured by ECLIA (Roche) was assessed in the population-based study using general linear models with multivariate adjustments. In the validation study, serum levels of 25(OH)D were analysed with liquid chromatography coupled with mass spectrometry assay from two different laboratories, RIA (DiaSorin), HPLC, RIA (IDS) and ECLIA (Roche). T-tests and linear mixed model analyses were performed to compare the serum 25(OH)D levels in smokers and non-smokers within and between the methods. RESULTS In the population-based study, the serum levels of 25(OH)D using the ECLIA method were 51.9, 53.2 and 72.0 nmol/l in never, former and current smokers (P<0.01). In the validation study, the serum concentration of 25(OH)D was 10.3 nmol/l higher in smokers than in non-smokers (P<0.01) using the ECLIA (Roche), while non-significantly lower serum levels of 25(OH)D were found in smokers using the other five methods. CONCLUSIONS These two studies indicate that the ECLIA (Roche) overestimates serum 25(OH)D levels in smokers by unknown mechanisms. If confirmed, this might have clinical consequences, and the issue needs further exploration.

The serum 25-hydroxyvitamin D response to vitamin D supplementation is related to genetic factors, BMI, and baseline levels

OBJECTIVE The serum 25-hydroxyvitamin D (25(OH)D) level is not only dependent on vitamin D intake and production in the skin but also dependent on genetic factors. Thus, in large genome-wide association studies, it has been shown that single nucleotide polymorphisms (SNPs) in the vitamin D binding protein (DBP), as well as in enzymes related to activation or degradation of vitamin D and its metabolites, are as important for the serum 25(OH)D level as the effect of season. How these SNPs affect the serum 25(OH)D response to vitamin D supplementation is uncertain. DESIGN AND METHODS Data were pooled from three randomized controlled trials where 40, 000 IU vitamin D/week was given for 6 months. Serum 25(OH)D was measured before and at the end of the intervention, and the subjects were genotyped for SNPs related to the serum 25(OH)D level. RESULTS Baseline 25(OH)D levels were significantly related to SNPs in the DBP and CYP2R1 genes. Those with SNPs associated with the lowest baseline 25(OH)D levels also had the smallest increase (delta) after supplementation. Those with the lowest baseline serum 25(OH)D (without regard to genotypes) had the highest increase (delta) after supplementation. Subjects with high BMI had lowest baseline 25(OH)D levels and also the smallest increase (delta) after supplementation. CONCLUSIONS The serum 25(OH)D response to supplementation depends on genes, baseline level, and BMI. However, whether this is clinically important or not depends on the therapeutic window of vitamin D, an issue that is still not settled.

No Effect of High-Dose Vitamin D Supplementation on Glycemic Status or Cardiovascular Risk Factors in Subjects With Prediabetes

OBJECTIVE In observational studies, low serum 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with insulin resistance and other risk factors for cardiovascular disease. RESEARCH DESIGN AND METHODS We present 1-year data from an ongoing 5-year trial in 511 individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) randomly assigned to 20,000 IU/week vitamin D3 or placebo. An oral glucose tolerance test was performed at baseline and after 1 year. RESULTS Mean baseline serum 25(OH)D was 59.9 nmol/L and 61.1 nmol/L in the vitamin D and placebo groups, respectively, and increased by 45.8 nmol/L and 3.4 nmol/L, respectively. With adjustment for baseline concentrations, no differences in measures of glucose metabolism, insulin secretion or sensitivity, blood pressure, or hs-CRP were found after 1 year. There was a slight, but significant decrease in total and LDL cholesterol in the vitamin D group compared with the placebo group, but as there was also a decrease in HDL cholesterol, the change in the total/HDL cholesterol ratio did not differ significantly. Only analyzing subjects with 25(OH)D <50 nmol/L did not change the results. CONCLUSIONS This study shows that vitamin D supplementation does not improve glycemic indices, blood pressure, or lipid status in subjects with IFG and/or IGT.

Vitamin D 20 000 IU per Week for Five Years Does Not Prevent Progression From Prediabetes to Diabetes

CONTEXT Vitamin D deficiency is associated with insulin resistance and risk of future diabetes. OBJECTIVE The objective of the study was to test whether supplementation with vitamin D to subjects with prediabetes will prevent progression to type 2 diabetes mellitus (T2DM). DESIGN This was a randomized controlled trial performed in 2008 through 2015. SETTING The study was conducted at the clinical research unit at a teaching hospital. PATIENTS Five hundred eleven subjects (mean age 62 y, 314 males) with prediabetes diagnosed with an oral glucose tolerance test as part of the Tromsø Study 2007–2008 were included. A total of 256 were randomized to vitamin D and 255 to placebo. Twenty-nine subjects in the vitamin D and 24 in the placebo group withdrew because of adverse events. INTERVENTIONS Interventions included vitamin D (cholecalciferol) 20 000 IU/wk vs placebo for 5 years. Annual oral glucose tolerance tests were performed. MAIN OUTCOME MEASURE Progression to T2DM was the main outcome measure. Secondary outcomes were change in glucose levels, insulin resistance, serum lipids, and blood pressure. RESULTS The mean baseline serum 25-hydroxyvitamin D level was 60 nmol/L (24 ng/mL). One hundred three in the vitamin D and 112 in the placebo group developed T2DM (hazard risk 0.90; 95% confidence interval 0.69–1.18, Cox regression, P = .45, intention to treat analysis). No consistent significant effects on the other outcomes were seen. Subgroup analyses in subjects with low baseline 25-hydroxyvitamin D yielded similar results. No serious side effects related to the intervention were recorded. CONCLUSIONS In subjects without vitamin D deficiency, vitamin D supplementation is unlikely to prevent progression from prediabetes to diabetes. Very large studies with inclusion of vitamin D-deficient subjects will probably be needed to show such a putative effect. This study tested if supplementation with vitamin D to subjects with prediabetes will prevent progression to type 2 diabetes (T2DM).

Effects of Vitamin D Binding Protein Phenotypes and Vitamin D Supplementation on Serum Total 25(OH)D and Directly Measured Free 25(OH)D

Objective To determine the relationship between serum total 25-hydroxyvitamin D (25(OH)D), directly measured free 25(OH)D and calculated free 25(OH)D with regard to vitamin D-binding protein (DBP) phenotypes, sex, BMI, age and season, and their interrelationship to vitamin D supplementation. Design, patients and interventions A randomized controlled trial with 20 000 IU of vitamin D3 per week or placebo for 12 months was designed. A total of 472 subjects, 236 in each of the intervention groups, were included in the analyses. Main outcome measures Baseline serum concentrations and increases in serum total 25(OH)D, directly measured free 25(OH)D, calculated free 25(OH)D and DBP. Results Serum total 25(OH)D and DBP concentrations were significantly lower in subjects with the phenotype Gc2/Gc2 compared to phenotypes with the Gc1S allele, and lower in males compared to females. When using directly measured free 25(OH)D, the differences related to DBP phenotypes and sexes were clearly diminished. All calculated free 25(OH)D concentrations were overestimated compared to the directly measured free 25(OH)D. Serum parathyroid hormone showed an inverse correlation with all vitamin D parameters analyzed. The increases after 12 months of vitamin D supplementation were not significantly different for any of the vitamin D parameters regardless of DBP phenotype, sex or age. Supplementation with vitamin D did not affect serum DBP. Conclusion Direct measurements of free 25(OH)D reduce the differences seen in total 25(OH)D between DBP phenotype groups and sexes, probably caused by differences in DBP concentrations. With conditions affecting serum DBP concentrations, direct measurements of free 25(OH)D should be considered.