Cardiovascular Disease, Hypertension, Insulin Resistance, Type 2 Diabetes Mellitus, Vitamin D Deficiency
Conditions
Keywords
Vitamin D, Insulin Resistance, Type 2 Diabetes Mellitus, Cardiovascular Disease
Brief summary
In recent years, vitamin D has been shown not only to be important for bone and calcium metabolism but also for homeostasis of critical tissues involved in vascular disease in patients with diabetes. Epidemiological studies indicated the high prevalence of vitamin D deficiency among Type 2 DM patients and suggest an increased risk of cardiovascular disease and hypertension with low vitamin D levels. The objective of this proposal is to evaluate the effects of vitamin D replacement on blood pressure control and vascular disease in vitamin D deficient hypertensive patients with diabetes
Detailed description
This is a double blinded, placebo controlled trial. Patients who meet the inclusion criteria will be randomized to placebo or 25(OH)D3, 4,000 IU/d orally for 16 weeks. Enrolled patients will be tested for 24h-blood pressure, brachial arterial blood flow, vascular inflammatory markers and macrophage inflammatory response to modified-lipoproteins at baseline, middle and at the end of the study.
Interventions
DRUGVitamin D3
Cholecalciferol 4000 units orally daily Calcium carbonate 500 mg orally twice daily
DRUGPlacebo
Placebo pill orally daily Calcium carbonate 500 mg twice daily
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
American Diabetes Association
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
25 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes * 25 (OH) vitamin D levels \< 25 ng/ml * Age 25 to 80 years * Not on insulin for diabetes treatment * HbA1c 5.5% -9.5% * Mild/moderately increased blood pressure (systolic 120-160, diastolic 80-100) off BP medications
Exclusion criteria
* Pregnancy * Patients with systolic \>160 or diastolic \>100 mmHg * High urine calcium or history of recurrent kidney stones * Cardiovascular disease * Stage 3 or worse chronic kidney disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 0, 2, and 4 months | 24-hour blood pressure collected by ambulatory automated arm cuff, central mean arterial blood pressure (MAP) collected by non-invasive arterial tonometry and pulse wave analysis/pulse wave velocity, office blood pressure collected by manual aneroid sphygmomanometry. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Macrophage Cholesterol Metabolism | 0 and 4 months | Macrophage uptake of labeled oxidized low density lipoprotein, assessed by the ratio of post-treatment cholesterol uptake to baseline uptake. |
| Serum Calcium | 0, 2, and 4 Month | Serum calcium assessed by photometric assessment after calcium reaction with NM-BAPTA, then with EDTA |
| HbA1C | 0, 2, and 4 month | HbA1c percentage assessed by turbidimetric inhibition immunoassay for hemolyzed whole blood |
| Brachial Artery Reactivity Testing | 0, 2, and 4 months | Brachial artery response to hyperemia assessed by measuring brachial artery diameter every 30 seconds for 180 seconds after a 5-minute occlusion with arm cuff above systolic blood pressure, with response defined as maximal percentage increase above baseline. |
| hsCRP | 0, 2, and 4 Month | High sensitivity C-reactive protein assessed by particle-enhanced immunoturbidimetric assay |
| Fasting Glucose | 0, 2, and 4 Month | Serum fasting glucose assessed by hexokinase method |
| Urine Calcium to Creatinine Ratio. | 0, 2 and 4 Months | Urine calcium to creatinine ratio assessed by spectrophotometry |
| Vitamin D | 0, 2, and 4 Month | 25(OH) Vitamin D assess by liquid chromatography with tandem mass spectrometry |
Countries
United States
Participant flow
Recruitment details
Potential participants will contact the principal investigator or research team through recruitment materials including emails to Washington University/Barnes Jewish/Children's staff, flyers, referrals through other physicians or the recruitment enhancement core, the Veterans Affairs Medical Center and Grace Hill Family Medical Center.
Pre-assignment details
The third arm signed consent and are enrolled in the study but only for a single blood draw. They were not randomized and did not receive any intervention. No data was collected for any pre-specified primary or secondary outcomes from these participants.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients in the control group will receive placebo pills (instead of vitamin D) and calcium carbonate 500 mg twice daily.
Placebo: Placebo pill orally daily Calcium carbonate 500 mg twice daily | 44 |
| Vitamin D Patients in the vitamin D group will receive cholecalciferol 4000 units daily and calcium carbonate 500 mg twice daily.
Vitamin D3: Cholecalciferol 4000 units orally daily Calcium carbonate 500 mg orally twice daily | 50 |
| Non-intervention Blood Collection Patients received no intervention. This is a one-time blood collection only. | 31 |
| Total | 125 |
Baseline characteristics
| Characteristic | Vitamin D | Non-intervention Blood Collection | Total | Placebo |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 7 Participants | 16 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 44 Participants | 24 Participants | 109 Participants | 41 Participants |
| Age, Continuous | 56.1 years STANDARD_DEVIATION 9.3 | 53.8 years STANDARD_DEVIATION 13.2 | 54.3 years STANDARD_DEVIATION 1.7 | 52.9 years STANDARD_DEVIATION 8.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 23 Participants | 25 Participants | 76 Participants | 28 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 5 Participants | 47 Participants | 15 Participants |
| Region of Enrollment United States | 50 participants | 31 participants | 125 participants | 44 participants |
| Sex: Female, Male Female | 28 Participants | 24 Participants | 69 Participants | 17 Participants |
| Sex: Female, Male Male | 22 Participants | 7 Participants | 56 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 50 |
| other Total, other adverse events | 0 / 44 | 0 / 50 |
| serious Total, serious adverse events | 0 / 44 | 0 / 50 |
Outcome results
Primary
Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP)
24-hour blood pressure collected by ambulatory automated arm cuff, central mean arterial blood pressure (MAP) collected by non-invasive arterial tonometry and pulse wave analysis/pulse wave velocity, office blood pressure collected by manual aneroid sphygmomanometry.
Time frame: 0, 2, and 4 months
Population: Occasional patients had missing blood pressure data or dropped out of the study prior to completion.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 4 Month, Office SBP | 129.6 mm Hg | Standard Deviation 16.9 |
| Placebo | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 4 Month, Central MAP | 102.6 mm Hg | Standard Deviation 9.3 |
| Placebo | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 0 Month, Office DBP | 79.2 mm Hg | Standard Deviation 10.7 |
| Placebo | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 0 Month, Daytime MAP | 99.8 mm Hg | Standard Deviation 6.3 |
| Placebo | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 4 Month, Office DBP | 79.6 mm Hg | Standard Deviation 9.5 |
| Placebo | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 0 Month, Nighttime MAP | 89.4 mm Hg | Standard Deviation 8.2 |
| Placebo | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 2 Month, Office DBP | 79.2 mm Hg | Standard Deviation 10.5 |
| Placebo | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 2 Month, Daytime MAP | 97.6 mm Hg | Standard Deviation 10.7 |
| Placebo | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 0 Month, Central MAP | 103.9 mm Hg | Standard Deviation 9.3 |
| Placebo | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 2 Month, Nighttime MAP | 86.6 mm Hg | Standard Deviation 9.7 |
| Placebo | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 2 Month, Office SBP | 127.6 mm Hg | Standard Deviation 16.4 |
| Placebo | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 4 Month, Daytime MAP | 100.0 mm Hg | Standard Deviation 10.7 |
| Placebo | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 2 Month, Central MAP | 100.6 mm Hg | Standard Deviation 9 |
| Placebo | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 4 Month, Nighttime MAP | 89.1 mm Hg | Standard Deviation 12 |
| Placebo | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 0 Month, Office SBP | 126.6 mm Hg | Standard Deviation 14.3 |
| Vitamin D | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 4 Month, Nighttime MAP | 90.3 mm Hg | Standard Deviation 11 |
| Vitamin D | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 0 Month, Office SBP | 131.1 mm Hg | Standard Deviation 14.9 |
| Vitamin D | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 0 Month, Office DBP | 78.9 mm Hg | Standard Deviation 10.4 |
| Vitamin D | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 2 Month, Office SBP | 133.2 mm Hg | Standard Deviation 14.7 |
| Vitamin D | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 2 Month, Office DBP | 79.9 mm Hg | Standard Deviation 11.2 |
| Vitamin D | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 4 Month, Office SBP | 132.7 mm Hg | Standard Deviation 13 |
| Vitamin D | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 4 Month, Office DBP | 77.9 mm Hg | Standard Deviation 12 |
| Vitamin D | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 0 Month, Central MAP | 107.2 mm Hg | Standard Deviation 9.9 |
| Vitamin D | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 2 Month, Central MAP | 107.8 mm Hg | Standard Deviation 12 |
| Vitamin D | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 4 Month, Central MAP | 105.2 mm Hg | Standard Deviation 12.8 |
| Vitamin D | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 0 Month, Daytime MAP | 101.6 mm Hg | Standard Deviation 7.6 |
| Vitamin D | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 0 Month, Nighttime MAP | 92.2 mm Hg | Standard Deviation 9.8 |
| Vitamin D | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 2 Month, Daytime MAP | 101.7 mm Hg | Standard Deviation 9.8 |
| Vitamin D | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 2 Month, Nighttime MAP | 94.0 mm Hg | Standard Deviation 13.7 |
| Vitamin D | Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP) | 4 Month, Daytime MAP | 99.1 mm Hg | Standard Deviation 9.7 |
Secondary
Brachial Artery Reactivity Testing
Brachial artery response to hyperemia assessed by measuring brachial artery diameter every 30 seconds for 180 seconds after a 5-minute occlusion with arm cuff above systolic blood pressure, with response defined as maximal percentage increase above baseline.
Time frame: 0, 2, and 4 months
Population: Some patients were unable to obtain adequate ultrasound images for BART analysis or did not show up for some visits
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Brachial Artery Reactivity Testing | 0 Month | 7.8 percentage of dilation | Standard Deviation 5.9 |
| Placebo | Brachial Artery Reactivity Testing | 2 Month | 8.5 percentage of dilation | Standard Deviation 6.6 |
| Placebo | Brachial Artery Reactivity Testing | 4 Month | 7.8 percentage of dilation | Standard Deviation 4.6 |
| Vitamin D | Brachial Artery Reactivity Testing | 0 Month | 8.6 percentage of dilation | Standard Deviation 5.6 |
| Vitamin D | Brachial Artery Reactivity Testing | 2 Month | 7.5 percentage of dilation | Standard Deviation 4.9 |
| Vitamin D | Brachial Artery Reactivity Testing | 4 Month | 7.8 percentage of dilation | Standard Deviation 7.7 |
Secondary
Fasting Glucose
Serum fasting glucose assessed by hexokinase method
Time frame: 0, 2, and 4 Month
Population: 1 placebo subject was unable to give samples at the 2 month visit, and 2 subjects were unable to give samples at the 4 month visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Fasting Glucose | 0 Month, Fasting Glucose | 126.7 mg/dL | Standard Deviation 34.5 |
| Placebo | Fasting Glucose | 2 Month, Fasting Glucose | 137.4 mg/dL | Standard Deviation 57.6 |
| Placebo | Fasting Glucose | 4 Month, Fasting Glucose | 138.4 mg/dL | Standard Deviation 55.2 |
| Vitamin D | Fasting Glucose | 0 Month, Fasting Glucose | 123.3 mg/dL | Standard Deviation 39.1 |
| Vitamin D | Fasting Glucose | 2 Month, Fasting Glucose | 124.9 mg/dL | Standard Deviation 51 |
| Vitamin D | Fasting Glucose | 4 Month, Fasting Glucose | 128.7 mg/dL | Standard Deviation 42.4 |
Secondary
HbA1C
HbA1c percentage assessed by turbidimetric inhibition immunoassay for hemolyzed whole blood
Time frame: 0, 2, and 4 month
Population: 1 placebo subject was unable to give samples at the 2 month visit, and 2 subjects were unable to give samples at the 4 month visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | HbA1C | HbA1c 0 month | 7.0 percentage | Standard Deviation 1.2 |
| Placebo | HbA1C | HbA1c 2 month | 7.4 percentage | Standard Deviation 1.8 |
| Placebo | HbA1C | HbA1c 4 month | 7.4 percentage | Standard Deviation 1.9 |
| Vitamin D | HbA1C | HbA1c 0 month | 7.0 percentage | Standard Deviation 1.2 |
| Vitamin D | HbA1C | HbA1c 2 month | 6.9 percentage | Standard Deviation 1.2 |
| Vitamin D | HbA1C | HbA1c 4 month | 7.0 percentage | Standard Deviation 1.1 |
Secondary
hsCRP
High sensitivity C-reactive protein assessed by particle-enhanced immunoturbidimetric assay
Time frame: 0, 2, and 4 Month
Population: Several subjects were unable to give a sample at various time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | hsCRP | 0 Month, hsCRP | 3.7 mg/L | Standard Deviation 3 |
| Placebo | hsCRP | 2 Month, hsCRP | 3.6 mg/L | Standard Deviation 2.9 |
| Placebo | hsCRP | 4 Month, hsCRP | 4.2 mg/L | Standard Deviation 4 |
| Vitamin D | hsCRP | 0 Month, hsCRP | 6.0 mg/L | Standard Deviation 7 |
| Vitamin D | hsCRP | 2 Month, hsCRP | 5.9 mg/L | Standard Deviation 6.6 |
| Vitamin D | hsCRP | 4 Month, hsCRP | 6.7 mg/L | Standard Deviation 8.5 |
Secondary
Macrophage Cholesterol Metabolism
Macrophage uptake of labeled oxidized low density lipoprotein, assessed by the ratio of post-treatment cholesterol uptake to baseline uptake.
Time frame: 0 and 4 months
Population: This analysis was only performed in a subset of patients.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Macrophage Cholesterol Metabolism | 1.01 unitless (ratio) | Standard Deviation 0.24 |
| Vitamin D | Macrophage Cholesterol Metabolism | 0.47 unitless (ratio) | Standard Deviation 0.072 |
Secondary
Serum Calcium
Serum calcium assessed by photometric assessment after calcium reaction with NM-BAPTA, then with EDTA
Time frame: 0, 2, and 4 Month
Population: 1 placebo subject was unable to give samples at the 2 month visit, and 2 subjects were unable to give samples at the 4 month visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Serum Calcium | 0 Month, serum ca | 9.1 mg/dL | Standard Deviation 0.5 |
| Placebo | Serum Calcium | 2 Month, serum ca | 9.2 mg/dL | Standard Deviation 0.4 |
| Placebo | Serum Calcium | 4 Month, serum ca | 9.1 mg/dL | Standard Deviation 0.4 |
| Vitamin D | Serum Calcium | 0 Month, serum ca | 9.1 mg/dL | Standard Deviation 0.4 |
| Vitamin D | Serum Calcium | 2 Month, serum ca | 9.1 mg/dL | Standard Deviation 0.4 |
| Vitamin D | Serum Calcium | 4 Month, serum ca | 9.3 mg/dL | Standard Deviation 0.3 |
Secondary
Urine Calcium to Creatinine Ratio.
Urine calcium to creatinine ratio assessed by spectrophotometry
Time frame: 0, 2 and 4 Months
Population: 1 placebo subject was unable to give samples at the 2 month visit, and 2 subjects were unable to give samples at the 4 month visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Urine Calcium to Creatinine Ratio. | 0 Month, ca to creatinine ratio | 69.8 mg/gm | Standard Deviation 49.8 |
| Placebo | Urine Calcium to Creatinine Ratio. | 2 Month, ca to creatinine ratio | 102.3 mg/gm | Standard Deviation 80.1 |
| Placebo | Urine Calcium to Creatinine Ratio. | 4 Month, ca to creatinine ratio | 89.9 mg/gm | Standard Deviation 80.9 |
| Vitamin D | Urine Calcium to Creatinine Ratio. | 0 Month, ca to creatinine ratio | 88.1 mg/gm | Standard Deviation 94.8 |
| Vitamin D | Urine Calcium to Creatinine Ratio. | 2 Month, ca to creatinine ratio | 114.1 mg/gm | Standard Deviation 62.5 |
| Vitamin D | Urine Calcium to Creatinine Ratio. | 4 Month, ca to creatinine ratio | 134.5 mg/gm | Standard Deviation 106.5 |
Secondary
Vitamin D
25(OH) Vitamin D assess by liquid chromatography with tandem mass spectrometry
Time frame: 0, 2, and 4 Month
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Vitamin D | 4 Month, Vitamin D | 44.5 pg/mL | Standard Deviation 18.2 |
| Placebo | Vitamin D | 0 Month, Vitamin D | 46.1 pg/mL | Standard Deviation 15.9 |
| Placebo | Vitamin D | 2 Month, Vitamin D | 37.7 pg/mL | Standard Deviation 16 |
| Vitamin D | Vitamin D | 4 Month, Vitamin D | 42.7 pg/mL | Standard Deviation 17.1 |
| Vitamin D | Vitamin D | 0 Month, Vitamin D | 40.1 pg/mL | Standard Deviation 11.9 |
| Vitamin D | Vitamin D | 2 Month, Vitamin D | 40.7 pg/mL | Standard Deviation 11.3 |