Obesity, Vitamin D Deficiency
Conditions
Keywords
Obesity, Vitamin D Deficiency, Vascular Function, Insulin resistance, metabolic syndrome
Brief summary
In this study, we will test the central hypothesis that enhancement of vitamin D status in obese and overweight children will improve their vascular health and their cardiovascular disease (CVD) and metabolic syndrome risk profile.
Detailed description
Our primary objective is to determine, in obese and overweight children aged 10 to 18 years with vitamin D deficiency (defined as serum 25-hydroxyvitamin D \<20 ng/mL), the efficacy of enhanced vitamin D3 supplementation in improving vascular endothelial function, arterial stiffness, insulin sensitivity, and metabolic syndrome risk status; and to assess whether these effects are dose-dependent. As a secondary objective, we will examine the vitamin D supplementation-induced effect on adipokines and inflammatory markers relevant to CVD risk. In a double-masked, controlled trial, we will randomize 252 eligible children to receive either 600 IU (conventional supplementation), or 1000 IU or 2000 IU (enhanced supplementation) of vitamin D3 daily for 6 months. In terms of reporting of results, the following pre-specified outcomes are included in the primary manuscript (PubMed PMID:31950134 -- see Reference section for citation details) 1. Waist Circumference 2. Serum High Density Lipoprotein (HDL) Cholesterol 3. Serum Triglycerides 4. Inflammatory markers (Plasma TNF-alpha, high-sensitivity C-reactive protein, and IL-6) 5. Adiopkines (Plasma Leptin and Adiponectin) Plasma nitric oxide metabolites were not measured.
Interventions
DIETARY_SUPPLEMENTVitamin D3
Tablet form
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Office of Dietary Supplements (ODS)
University of Pittsburgh
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
10 Years to 18 Years
Healthy volunteers
Yes
Inclusion criteria
* Eligible subjects will be 10 to 18 years of age; * obese or overweight (BMI ≥85th %tile); * otherwise healthy, and * have a serum 25(OH)D concentration \<20 ng/mL Children taking multivitamins should be able to hold off their multivitamins during the course of the study.
Exclusion criteria
Children will be excluded if they * (a) have hepatic or renal disease, metabolic rickets, malabsorptive disorders, primary hyperparathyroidism, hyperthyroidism, or other chronic disorders that could affect vitamin D metabolism; * (b) are receiving treatment with anticonvulsants, systemic glucocorticoids, pharmacologic doses of vitamin D (≥1000 IU of vitamin D2 or D3 daily), antihypertensives, vasoactive drugs, antilipidemics, metformin, antipsychotics, or other oral insulin regulators; * (c) have cholelithiasis or urolithiasis; * (d) have type 1 or type 2 diabetes; or * (e) have a condition or underlying abnormality that could compromise the safety of the subject. Post-menarchial girls with a positive pregnancy test at randomization, or subjects found during the screening phase to have hypercalcemia (serum calcium \>10.8 mg/dL) or significant fasting hyperglycemia (fasting blood glucose ≥ 125 mg/dL) will also be excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Flow-mediated Dilation (FMD) Percentage | 6 months | Brachial artery flow-mediated dilation percentage is a measure of endothelial function. FMD percentage calculation is based on baseline brachial artery diameter(brachialADbase) and change in brachial artery diameter (brachialADchange) during post-occlusive reactive hyperemia. FMD% was determined using the formula (brachialADchange/brachialADbase) x 100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pulse-wave Velocity (PWV) | 6 months | PWV is a measure of arterial stiffness. Higher values of PWV indicate greater degree of arterial stiffness. |
| Augmentation Index at Heart Rate of 75 Beats/Min (AIx-75) | 6 months | AIx-75 is a measure of arterial stiffness. AIx was measured through radial arterial tonometry using SphygmoCor. Radial pulse waveform are analyzed through an automatic software function to determine aortic pulse waveform and aortic or central systolic (cSBP) and diastolic blood pressure (cDBP), and these measurements are further analyzed automatically to calculate AIx. AIx is a composite measure of the magnitude of wave reflection and arterial stiffness in all conduit arteries which affect the timing of the wave reflection. AIx = P2-P1/cSBP-cDBP, where P1 is the height of the incident pressure wave form during systole, P2 is the height of the reflected wave added to the incident wave, cSBP is the aortic systolic BP, and cDBP is the aortic diastolic BP. AIx adjusted to heart rate of 75 beats/min (AIx-75) is a validated index of arterial stiffness, with higher values indicating higher degree of arterial stiffness. |
| Central Systolic Blood Pressure | 6 months | a measure of cardiometabolic health |
| Central Diastolic Blood Pressure | 6 months | a measure of cardiometabolic health |
| Systemic Diastolic Blood Pressure | 6 months | a measure of cardiometabolic health |
| Fasting Blood Glucose | 6 months | a measure of cardiometabolic health |
| 1/Fasting Insulin Ratio | 6 months | 1/fasting insulin ratio is a measure of insulin sensitivity. Increases in 1/fasting insulin ratio indicate improvements in insulin sensitivity. |
| Systemic Systolic Blood Pressure | 6 months | a measure of cardiometabolic health |
Other
| Measure | Time frame | Description |
|---|---|---|
| Body Mass Index (BMI) | 6 months | a surrogate measure of adiposity |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vitamin D3 2000 IU Vitamin D3 2000 IU tablet once daily by mouth for 6 months
Vitamin D3: Tablet form | 75 |
| Vitamin D3 1000 IU Vitamin D3 1000 IU tablet by mouth once daily for 6 months
Vitamin D3: Tablet form | 74 |
| Vitamin D3 600 IU Vitamin D3 600 IU tablet by mouth once daily for 6 months
Vitamin D3: Tablet form | 76 |
| Total | 225 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 16 | 23 | 22 |
| Overall Study | Withdrawal by Subject | 1 | 3 | 4 |
Baseline characteristics
| Characteristic | Vitamin D3 600 IU | Total | Vitamin D3 2000 IU | Vitamin D3 1000 IU |
|---|---|---|---|---|
| Age, Continuous | 13.5 years STANDARD_DEVIATION 2.3 | 13.6 years STANDARD_DEVIATION 2.3 | 13.9 years STANDARD_DEVIATION 2.4 | 13.5 years STANDARD_DEVIATION 2.2 |
| Body Mass Index | 30.7 kg/m^2 STANDARD_DEVIATION 6.9 | 30.3 kg/m^2 STANDARD_DEVIATION 6.3 | 30.3 kg/m^2 STANDARD_DEVIATION 5.8 | 30.0 kg/m^2 STANDARD_DEVIATION 6.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 10 Participants | 7 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 74 Participants | 215 Participants | 68 Participants | 73 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Obese (BMI > or = 95th percentile) | 53 Participants | 150 Participants | 47 Participants | 50 Participants |
| Race/Ethnicity, Customized American Indian | 2 Participants | 9 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 5 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Black | 71 Participants | 211 Participants | 70 Participants | 70 Participants |
| Race/Ethnicity, Customized Hawaiian | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 3 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 8 Participants | 31 Participants | 11 Participants | 12 Participants |
| Serum 25-hydroxyvitamin D (25[OH]D) | 14.3 ng/mL STANDARD_DEVIATION 4.3 | 14.3 ng/mL STANDARD_DEVIATION 3.7 | 14.2 ng/mL STANDARD_DEVIATION 3.5 | 14.4 ng/mL STANDARD_DEVIATION 3.4 |
| Serum parathyroid hormone (PTH) | 51.7 pg/mL STANDARD_DEVIATION 20.6 | 49.8 pg/mL STANDARD_DEVIATION 19.6 | 52.0 pg/mL STANDARD_DEVIATION 19.9 | 45.7 pg/mL STANDARD_DEVIATION 18 |
| Sex: Female, Male Female | 54 Participants | 147 Participants | 48 Participants | 45 Participants |
| Sex: Female, Male Male | 22 Participants | 78 Participants | 27 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 75 | 0 / 74 | 0 / 76 |
| other Total, other adverse events | 24 / 75 | 20 / 74 | 26 / 76 |
| serious Total, serious adverse events | 1 / 75 | 0 / 74 | 0 / 76 |
Outcome results
Primary
Flow-mediated Dilation (FMD) Percentage
Brachial artery flow-mediated dilation percentage is a measure of endothelial function. FMD percentage calculation is based on baseline brachial artery diameter(brachialADbase) and change in brachial artery diameter (brachialADchange) during post-occlusive reactive hyperemia. FMD% was determined using the formula (brachialADchange/brachialADbase) x 100.
Time frame: 6 months
Population: Intention to treat with all available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin D3 2000 IU | Flow-mediated Dilation (FMD) Percentage | 7.61 percentage of baseline dilation | Standard Deviation 5.15 |
| Vitamin D3 1000 IU | Flow-mediated Dilation (FMD) Percentage | 8.27 percentage of baseline dilation | Standard Deviation 5.92 |
| Vitamin D3 600 IU | Flow-mediated Dilation (FMD) Percentage | 7.31 percentage of baseline dilation | Standard Deviation 5.14 |
p-value: 0.88Mixed Models Analysis
Secondary
1/Fasting Insulin Ratio
1/fasting insulin ratio is a measure of insulin sensitivity. Increases in 1/fasting insulin ratio indicate improvements in insulin sensitivity.
Time frame: 6 months
Population: intention to treat with all available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin D3 2000 IU | 1/Fasting Insulin Ratio | 0.08 ratio | Standard Deviation 0.06 |
| Vitamin D3 1000 IU | 1/Fasting Insulin Ratio | 0.06 ratio | Standard Deviation 0.04 |
| Vitamin D3 600 IU | 1/Fasting Insulin Ratio | 0.06 ratio | Standard Deviation 0.04 |
p-value: 0.12Mixed Models Analysis
Secondary
Augmentation Index at Heart Rate of 75 Beats/Min (AIx-75)
AIx-75 is a measure of arterial stiffness. AIx was measured through radial arterial tonometry using SphygmoCor. Radial pulse waveform are analyzed through an automatic software function to determine aortic pulse waveform and aortic or central systolic (cSBP) and diastolic blood pressure (cDBP), and these measurements are further analyzed automatically to calculate AIx. AIx is a composite measure of the magnitude of wave reflection and arterial stiffness in all conduit arteries which affect the timing of the wave reflection. AIx = P2-P1/cSBP-cDBP, where P1 is the height of the incident pressure wave form during systole, P2 is the height of the reflected wave added to the incident wave, cSBP is the aortic systolic BP, and cDBP is the aortic diastolic BP. AIx adjusted to heart rate of 75 beats/min (AIx-75) is a validated index of arterial stiffness, with higher values indicating higher degree of arterial stiffness.
Time frame: 6 months
Population: intention to treat with all available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin D3 2000 IU | Augmentation Index at Heart Rate of 75 Beats/Min (AIx-75) | 3.75 ratio | Standard Deviation 8.44 |
| Vitamin D3 1000 IU | Augmentation Index at Heart Rate of 75 Beats/Min (AIx-75) | 2.22 ratio | Standard Deviation 10.97 |
| Vitamin D3 600 IU | Augmentation Index at Heart Rate of 75 Beats/Min (AIx-75) | 1.74 ratio | Standard Deviation 10.29 |
p-value: 0.61Mixed Models Analysis
Secondary
Central Diastolic Blood Pressure
a measure of cardiometabolic health
Time frame: 6 months
Population: intention to treat with all available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin D3 2000 IU | Central Diastolic Blood Pressure | 68.69 mmHg | Standard Deviation 5.87 |
| Vitamin D3 1000 IU | Central Diastolic Blood Pressure | 65.33 mmHg | Standard Deviation 8.27 |
| Vitamin D3 600 IU | Central Diastolic Blood Pressure | 68.57 mmHg | Standard Deviation 6.58 |
p-value: 0.0117Mixed Models Analysis
Secondary
Central Systolic Blood Pressure
a measure of cardiometabolic health
Time frame: 6 months
Population: intention to treat with all available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin D3 2000 IU | Central Systolic Blood Pressure | 98.45 mmHg | Standard Deviation 7.2 |
| Vitamin D3 1000 IU | Central Systolic Blood Pressure | 96.05 mmHg | Standard Deviation 8.19 |
| Vitamin D3 600 IU | Central Systolic Blood Pressure | 98.50 mmHg | Standard Deviation 7.84 |
p-value: 0.24Mixed Models Analysis
Secondary
Fasting Blood Glucose
a measure of cardiometabolic health
Time frame: 6 months
Population: intention to treat with all available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin D3 2000 IU | Fasting Blood Glucose | 88.41 mg/dL | Standard Deviation 6.33 |
| Vitamin D3 1000 IU | Fasting Blood Glucose | 88.48 mg/dL | Standard Deviation 7.05 |
| Vitamin D3 600 IU | Fasting Blood Glucose | 90.44 mg/dL | Standard Deviation 6.04 |
p-value: 0.0945Mixed Models Analysis
Secondary
Pulse-wave Velocity (PWV)
PWV is a measure of arterial stiffness. Higher values of PWV indicate greater degree of arterial stiffness.
Time frame: 6 months
Population: intention to tread with all available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin D3 2000 IU | Pulse-wave Velocity (PWV) | 4.85 meters/second | Standard Deviation 0.76 |
| Vitamin D3 1000 IU | Pulse-wave Velocity (PWV) | 4.85 meters/second | Standard Deviation 0.63 |
| Vitamin D3 600 IU | Pulse-wave Velocity (PWV) | 4.88 meters/second | Standard Deviation 0.75 |
p-value: 0.85Mixed Models Analysis
Secondary
Systemic Diastolic Blood Pressure
a measure of cardiometabolic health
Time frame: 6 months
Population: intention to treat with all available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin D3 2000 IU | Systemic Diastolic Blood Pressure | 67.57 mmHg | Standard Deviation 5.81 |
| Vitamin D3 1000 IU | Systemic Diastolic Blood Pressure | 64.73 mmHg | Standard Deviation 8.44 |
| Vitamin D3 600 IU | Systemic Diastolic Blood Pressure | 67.30 mmHg | Standard Deviation 6.53 |
p-value: 0.0256Mixed Models Analysis
Secondary
Systemic Systolic Blood Pressure
a measure of cardiometabolic health
Time frame: 6 months
Population: intention to treat with all available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin D3 2000 IU | Systemic Systolic Blood Pressure | 114.71 mmHg | Standard Deviation 8.45 |
| Vitamin D3 1000 IU | Systemic Systolic Blood Pressure | 114.88 mmHg | Standard Deviation 11.76 |
| Vitamin D3 600 IU | Systemic Systolic Blood Pressure | 115.70 mmHg | Standard Deviation 9.55 |
p-value: 0.53Mixed Models Analysis
Other Pre-specified
Body Mass Index (BMI)
a surrogate measure of adiposity
Time frame: 6 months
Population: intention to treat with all available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vitamin D3 2000 IU | Body Mass Index (BMI) | 30.82 kg/m^2 | Standard Deviation 6.12 |
| Vitamin D3 1000 IU | Body Mass Index (BMI) | 30.99 kg/m^2 | Standard Deviation 6.41 |
| Vitamin D3 600 IU | Body Mass Index (BMI) | 30.62 kg/m^2 | Standard Deviation 6.78 |
p-value: 0.0094Mixed Models Analysis