Safety and Tolerability of Vitamin D Supplementation in the Vitamin D and Type 2 Diabetes (D2d) Study – A Randomized Trial in Persons With Prediabetes

Abstract Objectives The routine use of vitamin D supplements has increased substantially in the United States. However, the safety and tolerability of long-term use of high-dose vitamin D are unknown. We assessed the safety and tolerability of vitamin D3 at a dose of 4000 IU daily in the vitamin D and type 2 diabetes (D2d) trial. Methods Persons with overweight/obesity and prediabetes without a recent history of nephrolithiasis, hypercalcemia, hypercalciuria, or other conditions potentially associated with vitamin D use, were randomized to either daily 4000 IU of vitamin D3 or placebo. Participants were allowed to take vitamin D up to 1000 IU/day and calcium up to 600 mg/day, in addition to study medication. Incident adverse events (AE), defined as any untoward or unfavorable medical occurrence, were ascertained in both groups at in-person visits and interim phone or email encounters four times a year. Serious AEs (SAE) were defined as those AEs that resulted in death, new or prolonged hospitalization, persistent or significant disability, or congenital anomaly or birth defect, or were life threatening or represented another significant hazard. Results A total of 8,304 AEs occurred during three years of follow-up. AEs were less frequent in the vitamin D group compared to placebo [4039 (116.1 events per 100 person-years) vs. 4265 (123.8 events per 100 person-years) (Incidence Rate Ratio [IRR] = 0.94; 95% Confidence Interval (CI) 0.90, 0.98)]. The overall frequency of protocol-specified AEs of interest was low, including nephrolithiasis, hypercalcemia, hypercalciuria, and low estimated glomerular filtration rate (eGFR) with no significant between-group differences. There were also no significant differences between the vitamin D and placebo groups in SAEs (IRR = 0.95; 95% CI 0.81, 1.13). Conclusions Vitamin D3 supplementation at 4,000 IU per day was safe and well-tolerated and did not increase risk of AEs or SAEs, including those typically associated with vitamin D excess such as hypercalciuria or nephrolithiasis. Funding Sources National Institute of Diabetes and Digestive and Kidney Diseases, Office of Dietary Supplements of the National Institutes of Health, the American Diabetes Association.

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Vitamin D Supplementation and Cognition in People with Type 2 Diabetes: A Randomized Control Trial

Journal of Diabetes Research ◽

10.1155/2019/5696391 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Mary A. Byrn ◽

William Adams ◽

Sue Penckofer ◽

Mary Ann Emanuele

Keyword(s):

Type 2 Diabetes ◽

Vitamin D ◽

Cognitive Function ◽

Randomized Control Trial ◽

Low Dose ◽

Vitamin D Supplementation ◽

High Dose ◽

Significant Finding ◽

Randomized Control

Aim. Type 2 diabetes increases the risk of cognitive decline which adversely impacts self-management of the disease. Evidence also supports a relationship between low serum 25(OH)D levels and poor cognition. The purpose of this trial was to assess vitamin D supplementation on cognitive executive functioning in persons living with type 2 diabetes. Methods. This was a double-blinded RCT where participants were randomized to receive either weekly vitamin D3 supplementation (50,000 IUs) or a matching comparator (5,000 IUs) for three months. The primary outcome was a battery of neuropsychological tests. Serum 25(OH)D was measured by liquid chromatography/tandem mass spectrometry. Repeated assessments of cognitive measures were collected over 12 weeks using alternative testing forms to minimize practice effects. Results. Thirty participants were randomized to either the low-dose allocation (n=15) or the high-dose allocation (n=15). Most participants were female (83%) and identified as Black (57%). For all cognition measures, there was no statistically significant finding between participants who received high-dose vitamin D supplementation and those who received low-dose supplementation. However, when assessing cognitive function in both groups over time, minimal improvement on the Symbol-Digits, the Stroop Interference Test, and the Trail Making Test Part B was observed. Conclusions. To our knowledge, this is the first randomized control trial to examine the effects of vitamin D supplementation on cognitive function in people with type 2 diabetes. However, no significant differences in cognitive outcomes between participants who received high-dose therapy and those who received low dose were found.

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Vitamin D3 supplementation improves serum SFRP5 and Wnt5a levels in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trial

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000509 ◽

2018 ◽

Vol 88 (1-2) ◽

pp. 73-79 ◽

Cited By ~ 2

Author(s):

Farzaneh Rezagholizadeh ◽

Seyed Ali Keshavarz ◽

Mahmoud Djalali ◽

Esmaeel Yussefi Rad ◽

Shahab Alizadeh ◽

...

Keyword(s):

Type 2 Diabetes ◽

Vitamin D ◽

Vitamin D3 ◽

Integration Site ◽

Fasting Blood Glucose ◽

Controlled Clinical Trial ◽

Double Blind ◽

Tnf Α ◽

Vitamin D3 Supplementation

Abstract. Objective: To explore the effect of vitamin D3 on novel serum adipokines, secreted frizzled-related protein 5 (SFRP5) and Wingless-Type MMTV Integration Site Family Member 5a (Wnt5a) levels in Type 2 Diabetes Mellitus (T2DM) patients. Methods: Forty patients (16 women and 24 men) with type 2 diabetes participated in this double-blind, randomized, placebo-controlled clinical trial study. Participants were randomly assigned to receive 4000 IU vitamin D3 (n = 20) or placebo (n = 20) daily for 2 months. Anthropometric indices, fasting blood glucose (FBS), hemoglobin A1c (HbA1c), insulin, serum tumor necrosis factor (TNF)-α, Wnt5a, SFRP5, physical activity, lipid profile, dietary intake, and serum calcidiol were assessed at the baseline and after 8 weeks. Results: In the group receiving Vitamin D, a significant increase in Calicidiol (15.03 ± 10.44 vs. 27.33 ± 11.2 ng/dl; P = < 0.001), SFRP5 (3.6 ± 0.46 vs. 3.98 ± 0.59 ng/ml; P = 0.01), and Wnt5a (0.33 ± 0.129 vs. 0.29 ± 0.047; P = 0.03) was observed. After two months supplementation, there were significant between-group differences in Calicidiol (27.33 ± 11.2 vs. 17.9 ± 12.95 ng/dl; P = 0.01), TNF-α (89.22 ± 34.28 vs. 164.93 ± 120.45 ng/ml; P = 0.006), Wnt5a (0.29 ± 0.047 vs. 0.33 ± 0.09; P = 0.04), and HbA1c (6.6 ± 0.96 % vs. 7.64 ± 1.15 %; p = 0.002). Moreover, the net changes (end – baseline) of Calicidiol (P = < 0.001), SFRP5 (P = 0.04), Wnt5a (P = 0.005), TNF-α (P = 0.01), insulin (P = 0.03), and QUICKI (P = 0.01) was significant between the groups. There were no significant effects on FBS and homeostasis model of assessment-estimated insulin resistance (HOMA-IR). Conclusion: 8 weeks of vitamin D3 supplementation for patients with type 2 diabetes may increase serum anti-inflammatory adipokine SFRP5 but decrease serum pro-inflammatory Wnt5a and TNF-α.

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Vitamina D e rachitismo carenziale

Medico e Bambino ◽

10.53126/meb39426 ◽

2020 ◽

Vol 39 (7) ◽

pp. 426-429

Author(s):

Anna Agrusti ◽

Sarah Contorno ◽

Irene Bruno ◽

Giulia Gortani ◽

Egidio Barbi

Keyword(s):

Vitamin D ◽

Vitamin D Deficiency ◽

Vitamin D3 ◽

Vitamin D Supplementation ◽

High Dose ◽

The Sun ◽

Phosphorus Metabolism ◽

Calcium Phosphorus ◽

Vitamin D3 Supplementation ◽

First Year Of Life

Mouhamed, a 7-year-old boy of African origin, presented with progressive fatigue and difficulty in walking. He was never treated with vitamin D supplementation. The evaluation of his calcium-phosphorus metabolism revealed a myopathy related to severe rickets. Therefore, he was treated with high-dose vitamin D3 and myopathy and fatigue progressively resolved. Vitamin D plays a crucial role in the calcium-phosphorus metabolism, by acting on enterocytes, osteoclasts and renal tubule. Vitamin D deficiency is defined when the 25OHD value is less than 20 ng/ml. In order to guarantee the assumption of the minimum daily dose of vitamin D, it is recommended to start vitamin D3 supplementation in all newborns and infants in their first year of life, regardless of the feeding modality. Exposure to the sun is essential for the activation of vitamin D, so dark-skinned children and mothers or those little exposed to the sun should start vitamin D3 supplementation. Vitamin D3 should also be supplemented in children with cerebral palsy and in patients treated with anti-epileptic drugs. Other conditions at risk of vitamin D deficiency are inflammatory bowel disease, celiac disease, cystic fibrosis, obesity, liver failure, cholestasis and vegetarian or vegan diets. Classic signs of rickets are the rickety rosary, the widening of the wrist and the arching of the tibia. Severe hypocalcaemia secondary to vitamin D deficiency can occur with dilated cardiomyopathy or convulsions, especially in dark-skinned infants. Vitamin D deficiency should be considered in children with progressive myopathy or muscular weakness, especially in dark-skinned ones or in those poorly exposed to the sun for cultural or religious reasons.

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The effect of high-dose vitamin D supplementation on insulin resistance and arterial stiffness in patients with type 2 diabetes

The Korean Journal of Internal Medicine ◽

10.3904/kjim.2014.29.5.620 ◽

2014 ◽

Vol 29 (5) ◽

pp. 620 ◽

Cited By ~ 49

Author(s):

Ohk-Hyun Ryu ◽

Wankyo Chung ◽

Sungwha Lee ◽

Kyung-Soon Hong ◽

Moon-Gi Choi ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Vitamin D ◽

Arterial Stiffness ◽

Vitamin D Supplementation ◽

High Dose ◽

High Dose Vitamin

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No effect of vitamin D supplementation on metabolic parameters but on lipids in patients with type 2 diabetes and chronic kidney disease

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000642 ◽

2020 ◽

pp. 1-10

Author(s):

Jiwoon Kim ◽

Ji Sun Nam ◽

Heejung Kim ◽

Hye Sun Lee ◽

Jung Eun Lee

Keyword(s):

Type 2 Diabetes ◽

Chronic Kidney Disease ◽

Vitamin D ◽

Kidney Disease ◽

Vitamin D Supplementation ◽

Lipid Profiles ◽

Metabolic Parameters ◽

Injection Group ◽

Different Doses

Abstract. Background/Aims: Trials on the effects of cholecalciferol supplementation in type 2 diabetes with chronic kidney disease patients were underexplored. Therefore, the aim of this study was to investigate the effects of two different doses of vitamin D supplementation on serum 25-hydroxyvitamin D [25(OH)D] concentrations and metabolic parameters in vitamin D-deficient Korean diabetes patients with chronic kidney disease. Methods: 92 patients completed this study: the placebo group (A, n = 33), the oral cholecalciferol 1,000 IU/day group (B, n = 34), or the single 200,000 IU injection group (C, n = 25, equivalent to 2,000 IU/day). 52% of the patients had less than 60 mL/min/1.73m2 of glomerular filtration rates. Laboratory test and pulse wave velocity were performed before and after supplementation. Results: After 12 weeks, serum 25(OH)D concentrations of the patients who received vitamin D supplementation were significantly increased (A, -2.4 ± 1.2 ng/mL vs. B, 10.7 ± 1.2 ng/mL vs. C, 14.6 ± 1.7 ng/mL; p < 0.001). In addition, the lipid profiles in the vitamin D injection group (C) showed a significant decrease in triglyceride and a rise in HDL cholesterol. However, the other parameters showed no differences. Conclusions: Our data indicated that two different doses and routes of vitamin D administration significantly and safely increased serum 25(OH)D concentrations in vitamin D-deficient diabetes patients with comorbid chronic kidney disease. In the group that received the higher vitamin D dose, the lipid profiles showed significant improvement, but there were no beneficial effects on other metabolic parameters.

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Vitamin D Supplementation and Serum Levels of Magne-sium and Selenium in Type 2 Diabetes Mellitus Patients: Gender Dimorphic Changes

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000190 ◽

2014 ◽

Vol 84 (1-2) ◽

pp. 27-34 ◽

Cited By ~ 7

Author(s):

Nasser M. Al-Daghri ◽

Khalid M. Alkharfy ◽

Nasiruddin Khan ◽

Hanan A. Alfawaz ◽

Abdulrahman S. Al-Ajlan ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Vitamin D ◽

Type 2 Diabetes Mellitus ◽

Serum Levels ◽

Vitamin D Supplementation ◽

Serum Selenium ◽

Dependent Manner

The aim of our study was to evaluate the effects of vitamin D supplementation on circulating levels of magnesium and selenium in patients with type 2 diabetes mellitus (T2DM). A total of 126 adult Saudi patients (55 men and 71 women, mean age 53.6 ± 10.7 years) with controlled T2DM were randomly recruited for the study. All subjects were given vitamin D3 tablets (2000 IU/day) for six months. Follow-up mean concentrations of serum 25-hydroxyvitamin D [25-(OH) vitamin D] significantly increased in both men (34.1 ± 12.4 to 57.8 ± 17.0 nmol/L) and women (35.7 ± 13.5 to 60.1 ± 18.5 nmol/L, p < 0.001), while levels of parathyroid hormone (PTH) decreased significantly in both men (1.6 ± 0.17 to 0.96 ± 0.10 pmol/L, p = 0.003) and women (1.6 ± 0.17 to 1.0 ± 0.14 pmol/L, p = 0.02). In addition, there was a significant increase in serum levels of selenium and magnesium in men and women (p-values < 0.001 and 0.04, respectively) after follow-up. In women, a significant correlation was observed between delta change (variables at six months-variable at baseline) of serum magnesium versus high-density lipoprotein (HDL)-cholesterol (r = 0.36, p = 0.006) and fasting glucose (r = - 0.33, p = 0.01). In men, there was a significant correlation between serum selenium and triglycerides (r = 0.32, p = 0.04). Vitamin D supplementation improves serum concentrations of magnesium and selenium in a gender-dependent manner, which in turn could affect several cardiometabolic parameters such as glucose and lipids.

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Design and Main Results of STURDY: A Randomized Clinical Trial of Four Vitamin D3 Doses to Prevent Falls in Older Adults

Innovation in Aging ◽

10.1093/geroni/igaa057.2737 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 759-759

Author(s):

Lawrence Appel ◽

Jennifer Schrack ◽

Erin Michos ◽

Christine Mitchell ◽

Stephen Juraschek ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D3 ◽

Primary Outcome ◽

Vitamin D Supplementation ◽

Dose Finding ◽

High Dose ◽

Hazard Ratios ◽

Risk Of Falls ◽

Event Rates ◽

And Control

Abstract STURDY was a Bayesian, response-adaptive trial with dose-finding and confirmatory stages. Participants (n=688; ≥70years with serum 25(OH)D of 10-29ng/mL) were randomized to 200 (control), 1000, 2000, or 4000 IU/day of vitamin D3. The primary outcome was time to first fall or death over 2 years. During dose-finding, the best non-control dose was determined to be 1000IU/day based on higher primary outcome event rates in the 2000 and 4000IU/day doses than the 1000IU/day dose (posterior probability of being best dose=0.90; hazard ratios[HR] were 1.86 [95%CI: 1.16-2.97] and 1.68 [95%CI: 1.05-2.69], respectively). Participants were then switched from other non-control doses to 1000IU/day, and event rates did not differ between the pooled higher doses and control groups (HR=1.02, P=0.84). There was no heterogeneity by baseline 25(OHD). In conclusion, high-dose vitamin D supplementation ≥1000IU/day did not prevent falls. Whether vitamin D doses >2000IU/day increase the risk of falls is uncertain.

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