Vitamin D, Insulin Resistance, and Cardiovascular Disease

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT00736632
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), American Diabetes Association (Other)
• Enrollment: 125
• Location: 1
• Arms: 2
• Duration (Months): 152.4
• Patients Per Site Per Month: 0.8

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Vitamin D Deficiency; Insulin Resistance; Type 2 Diabetes Mellitus; Cardiovascular Disease; Hypertension	Drug: Vitamin D3; Drug: Placebo	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 125 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Vitamin D, Insulin Resistance, and Cardiovascular Disease
• Study Start Date: May 1, 2006
• Actual Primary Completion Date: Jan 13, 2019
• Actual Study Completion Date: Jan 13, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Patients in the control group will receive placebo pills (instead of vitamin D) and calcium carbonate 500 mg twice daily.	Drug: Placebo; Placebo pill orally daily Calcium carbonate 500 mg twice daily
Active Comparator: Vitamin D Patients in the vitamin D group will receive cholecalciferol 4000 units daily and calcium carbonate 500 mg twice daily.	Drug: Vitamin D3; Cholecalciferol 4000 units orally daily Calcium carbonate 500 mg orally twice daily; Other Names: Vitamin D

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. Serum Calcium [0, 2, and 4 Month]

   Serum calcium assessed by photometric assessment after calcium reaction with NM-BAPTA, then with EDTA

4. HbA1C [0, 2, and 4 month]

   HbA1c percentage assessed by turbidimetric inhibition immunoassay for hemolyzed whole blood

5. Vitamin D [0, 2, and 4 Month]

   25(OH) Vitamin D assess by liquid chromatography with tandem mass spectrometry

6. hsCRP [0, 2, and 4 Month]

   High sensitivity C-reactive protein assessed by particle-enhanced immunoturbidimetric assay

7. Fasting Glucose [0, 2, and 4 Month]

   Serum fasting glucose assessed by hexokinase method

8. Urine Calcium to Creatinine Ratio. [0, 2 and 4 Months]

   Urine calcium to creatinine ratio assessed by spectrophotometry

Eligibility Criteria

Criteria

• Ages Eligible for Study: 25 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington Universiy	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine
• National Heart, Lung, and Blood Institute (NHLBI)
• American Diabetes Association

Investigators

• Principal Investigator: Carlos Bernal-MIzrachi, M.D., Washington University School of Medicine

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 3, 2019

More Information

Additional Information:

• Washington University Endocrinology Department website

Publications

None provided.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT00736632
• Other Study ID Numbers: 201103002; R01HL094818
• First Posted: Aug 18, 2008
• Last Update Posted: Feb 10, 2020
• Last Verified: Jan 1, 2020

• Keywords provided by Washington University School of Medicine: Vitamin D; Insulin Resistance; Type 2 Diabetes Mellitus; Cardiovascular Disease
• Additional relevant MeSH terms: Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin Resistance; Vitamin D Deficiency; Vitamin D; Ergocalciferols; Cholecalciferol; Vitamins

Study Results

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 Detail	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.

Arm/Group Title	Placebo	Vitamin D	Non-Intervention Blood Collection
Arm/Group Description	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	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	Subjects without intervention will give a one-time blood sample for analysis of monocytes.
Period Title: Overall Study
STARTED	44	50	31
COMPLETED	44	50	31
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Placebo	Vitamin D	Non-intervention Blood Collection	Total
Arm/Group Description	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	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	Patients received no intervention. This is a one-time blood collection only.	Total of all reporting groups
Overall Participants	44	50	31	125
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	41 93.2%	44 88%	24 77.4%	109 87.2%
>=65 years	3 6.8%	6 12%	7 22.6%	16 12.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.9 (8.8)	56.1 (9.3)	53.8 (13.2)	54.3 (1.7)
Sex: Female, Male (Count of Participants)
Female	17 38.6%	28 56%	24 77.4%	69 55.2%
Male	27 61.4%	22 44%	7 22.6%	56 44.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	1 2.3%	0 0%	0 0%	1 0.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	28 63.6%	23 46%	25 80.6%	76 60.8%
White	15 34.1%	27 54%	5 16.1%	47 37.6%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	1 3.2%	1 0.8%
Region of Enrollment (participants) [Number]
United States	44 100%	50 100%	31 100%	125 100%

Outcome Measures

1. Primary Outcome

Title	Hypertension (24h Blood Pressure, Central Blood Pressure, and Office BP)
Description	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

Outcome Measure Data

Analysis Population Description

Occasional patients had missing blood pressure data or dropped out of the study prior to completion.

Arm/Group Title	Placebo	Vitamin D
Arm/Group Description	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	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
Measure Participants	44	50
0 Month, Office SBP	126.6 (14.3)	131.1 (14.9)
0 Month, Office DBP	79.2 (10.7)	78.9 (10.4)
2 Month, Office SBP	127.6 (16.4)	133.2 (14.7)
2 Month, Office DBP	79.2 (10.5)	79.9 (11.2)
4 Month, Office SBP	129.6 (16.9)	132.7 (13.0)
4 Month, Office DBP	79.6 (9.5)	77.9 (12.0)
0 Month, Central MAP	103.9 (9.3)	107.2 (9.9)
2 Month, Central MAP	100.6 (9.0)	107.8 (12.0)
4 Month, Central MAP	102.6 (9.3)	105.2 (12.8)
0 Month, Daytime MAP	99.8 (6.3)	101.6 (7.6)
0 Month, Nighttime MAP	89.4 (8.2)	92.2 (9.8)
2 Month, Daytime MAP	97.6 (10.7)	101.7 (9.8)
2 Month, Nighttime MAP	86.6 (9.7)	94.0 (13.7)
4 Month, Daytime MAP	100.0 (10.7)	99.1 (9.7)
4 Month, Nighttime MAP	89.1 (12.0)	90.3 (11.0)

2. Secondary Outcome

Title	Brachial Artery Reactivity Testing
Description	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

Outcome Measure Data

Analysis Population Description

Some patients were unable to obtain adequate ultrasound images for BART analysis or did not show up for some visits

Arm/Group Title	Placebo	Vitamin D
Arm/Group Description	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	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
Measure Participants	44	50
0 Month	7.8 (5.9)	8.6 (5.6)
2 Month	8.5 (6.6)	7.5 (4.9)
4 Month	7.8 (4.6)	7.8 (7.7)

3. Secondary Outcome

Title	Macrophage Cholesterol Metabolism
Description	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

Outcome Measure Data

Analysis Population Description

This analysis was only performed in a subset of patients.

Arm/Group Title	Placebo	Vitamin D
Arm/Group Description	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	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
Measure Participants	15	11
Mean (Standard Deviation) [unitless (ratio)]	1.01 (0.24)	0.47 (0.072)

4. Secondary Outcome

Title	Serum Calcium
Description	Serum calcium assessed by photometric assessment after calcium reaction with NM-BAPTA, then with EDTA
Time Frame	0, 2, and 4 Month

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Vitamin D
Arm/Group Description	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	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
Measure Participants	44	50
0 Month, serum ca	9.1 (0.5)	9.1 (0.4)
2 Month, serum ca	9.2 (0.4)	9.1 (0.4)
4 Month, serum ca	9.1 (0.4)	9.3 (0.3)

5. Secondary Outcome

Title	HbA1C
Description	HbA1c percentage assessed by turbidimetric inhibition immunoassay for hemolyzed whole blood
Time Frame	0, 2, and 4 month

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Vitamin D
Arm/Group Description	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	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
Measure Participants	44	50
HbA1c 0 month	7.0 (1.2)	7.0 (1.2)
HbA1c 2 month	7.4 (1.8)	6.9 (1.2)
HbA1c 4 month	7.4 (1.9)	7.0 (1.1)

6. Secondary Outcome

Title	Vitamin D
Description	25(OH) Vitamin D assess by liquid chromatography with tandem mass spectrometry
Time Frame	0, 2, and 4 Month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Vitamin D
Arm/Group Description	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	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
Measure Participants	44	50
0 Month, Vitamin D	46.1 (15.9)	40.1 (11.9)
2 Month, Vitamin D	37.7 (16.0)	40.7 (11.3)
4 Month, Vitamin D	44.5 (18.2)	42.7 (17.1)

7. Secondary Outcome

Title	hsCRP
Description	High sensitivity C-reactive protein assessed by particle-enhanced immunoturbidimetric assay
Time Frame	0, 2, and 4 Month

Outcome Measure Data

Analysis Population Description

Several subjects were unable to give a sample at various time points.

Arm/Group Title	Placebo	Vitamin D
Arm/Group Description	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	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
Measure Participants	44	50
0 Month, hsCRP	3.7 (3.0)	6.0 (7.0)
2 Month, hsCRP	3.6 (2.9)	5.9 (6.6)
4 Month, hsCRP	4.2 (4.0)	6.7 (8.5)

8. Secondary Outcome

Title	Fasting Glucose
Description	Serum fasting glucose assessed by hexokinase method
Time Frame	0, 2, and 4 Month

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Vitamin D
Arm/Group Description	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	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
Measure Participants	44	50
0 Month, Fasting Glucose	126.7 (34.5)	123.3 (39.1)
2 Month, Fasting Glucose	137.4 (57.6)	124.9 (51.0)
4 Month, Fasting Glucose	138.4 (55.2)	128.7 (42.4)

9. Secondary Outcome

Title	Urine Calcium to Creatinine Ratio.
Description	Urine calcium to creatinine ratio assessed by spectrophotometry
Time Frame	0, 2 and 4 Months

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Vitamin D
Arm/Group Description	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	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
Measure Participants	44	50
0 Month, ca to creatinine ratio	69.8 (49.8)	88.1 (94.8)
2 Month, ca to creatinine ratio	102.3 (80.1)	114.1 (62.5)
4 Month, ca to creatinine ratio	89.9 (80.9)	134.5 (106.5)

Adverse Events

Time Frame	The subjects in the placebo and vitamin D arm were monitored for adverse events from enrollment through completion which was over a course of 4 months.
Adverse Event Reporting Description	Adverse events were not collected or assessed from the the non-intervention blood collection arm.
Arm/Group Title	Placebo		Vitamin D
Arm/Group Description	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		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
All Cause Mortality
	Placebo		Vitamin D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		0/50 (0%)
Serious Adverse Events
	Placebo		Vitamin D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		0/50 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Vitamin D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		0/50 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.