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Role of Mineralocorticoid Receptor in Diabetic Cardiovascular Disease

Primary Purpose

Type 2 Diabetes Mellitus, Vascular Disease

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Spironolactone

Hydrochlorothiazide + potassium

Placebo

About this trial

This is an interventional treatment trial for Type 2 Diabetes Mellitus

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

age 18-70 years
type 2 diabetes mellitus
with or without hypertension

Exclusion Criteria:

ischemic changes on resting electrocardiogram,
clinical evidence of heart disease (angina, heart failure, unstable angina),cerebrovascular or peripheral vascular disease,
significant cardiac arrhythmias,
aortic stenosis,
2nd or 3rd degree atrio-ventricular block, sinus node disease, or symptomatic bradycardia,
bronchospastic lung disease with active wheezing,
known hypersensitivity to adenosine,
hemoglobin A1C (HbA1c) > 8.5%, *
gout (If not already taking HCTZ),
the use of Rosiglitazone,**
estimated glomerular filtration rate (eGFR) < 60 ml/min,
serum potassium > 5.0 mmol/L,
use of potassium-sparing diuretics,**
current smoker,*
pregnancy,
renal disease not related to diabetes mellitus,
uncontrolled hypertension, systolic blood pressure (BP) >160 mm Hg and diastolic BP >100 mm Hg,*
use of cyclic hormone replacement therapy
past intolerance of angiotensin-converting enzyme (ACE) inhibitor therapy
other major medical illnesses. Participants with evidence of a previous myocardial infarction on the first adenosine-stimulated positron emission tomography (PET) study will be withdrawn from the study.
Screening systolic blood pressure < 105 mm Hg off of anti-hypertensive medications
- Participants can enroll in study and proceed with in-patient evaluations if during the run-in period adjustments of medications, diet and habits lead to improved glucose control [equivalent to HbA1c <8.5%, controlled hypertension and cessation of smoking.
  - Participants who are currently taking these medications will not qualify for a screening visit. If medications were recently stopped by the participant's physician, he or she may be screened but the baseline assessment protocol must occur 3 months after stopping.

Sites / Locations

Brigham and Women's Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Placebo Comparator

Arm Label

Spironolactone (mineralocorticoid receptor [MR] blockade)

Hydrochlorothiazide + potassium

Placebo capsule

Arm Description

Outcomes

Primary Outcome Measures

Change in Coronary Flow Reserve From Baseline to 6 Months

Coronary flow reserve (CFR), or myocardial perfusion reserve, was assessed via cardiac positron emission tomography (PET). CFR is the ratio of adenosine-stimulated blood flow through myocardium to resting blood flow through myocardium. An improvement in coronary flow reserve is beneficial.

Secondary Outcome Measures

Change in Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function

Diastolic function was assessed via tissue doppler imaging (TDI) by echocardiography to determine left ventricular diastolic function before and after 6 months of treatment.

Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function (With Angiotensin II)

Diastolic function was assessed via tissue doppler imaging (TDI) by echocardiography to determine left ventricular diastolic function before and after 6 months of treatment; and in response to acute administration (3 nanograms/kg/min for 60 min) of the vasoactive agent, Angiotensin II.

Change in Renal Plasma Flow

Renal vasculature was assessed by examining renal plasma flow, or para-aminohippurate (PAH) clearance, basally and in response to acute administration (3 nanograms/kg/min for 60 min) of the vasoactive agent, Angiotensin II.

Full Information

NCT ID

NCT00865124

First Posted

March 17, 2009

Last Updated

May 19, 2017

Sponsor

Brigham and Women's Hospital

Collaborators

National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI)

1. Study Identification

Unique Protocol Identification Number

NCT00865124

Brief Title

Role of Mineralocorticoid Receptor in Diabetic Cardiovascular Disease

Official Title

Role of Mineralocorticoid Receptor in Diabetic Cardiovascular Disease

Study Type

Interventional

2. Study Status

Record Verification Date

May 2017

Overall Recruitment Status

Completed

Study Start Date

September 2008 (undefined)

Primary Completion Date

August 2013 (Actual)

Study Completion Date

May 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Brigham and Women's Hospital

Collaborators

National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Aldosterone is a significant mediator of cardiovascular injury associated with heart failure and the cardiovascular benefits of mineralocorticoid receptor blockade are additive to those of angiotensin converting enzyme inhibitors or angiotensin II (ANGII) receptor blockers. This study will test the hypothesis that mineralocorticoid receptor (MR) antagonists exert beneficial cardiovascular effects, specifically by decreasing vascular injury and improving vascular function. A randomized, double-blind study will be conducted, in which participants with Type 2 Diabetes Mellitus will undergo a series of assessments to test heart, blood vessel, and kidney function at baseline, and after 2 and 6 months of treatment with one of the following drugs: spironolactone hydrochlorothiazide (HCTZ) plus potassium placebo In the event of insufficient funds, randomization to the placebo arm will be stopped and primary assessment of outcomes will occur at baseline and after 6 months of treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Type 2 Diabetes Mellitus, Vascular Disease

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

69 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Spironolactone (mineralocorticoid receptor [MR] blockade)

Arm Type

Experimental

Arm Title

Hydrochlorothiazide + potassium

Arm Type

Active Comparator

Arm Title

Placebo capsule

Arm Type

Placebo Comparator

Intervention Type

Drug

Intervention Name(s)

Spironolactone

Intervention Description

25 mg capsule daily for 6 months

Intervention Type

Drug

Intervention Name(s)

Hydrochlorothiazide + potassium

Intervention Description

hydrochlorothiazide (HCTZ) + potassium, 12.5 mg/10 milliequivalents (mEq) capsule daily

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

Placebo capsule daily

Primary Outcome Measure Information:

Title

Change in Coronary Flow Reserve From Baseline to 6 Months

Description

Time Frame

Baseline and six months

Secondary Outcome Measure Information:

Title

Change in Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function

Description

Diastolic function was assessed via tissue doppler imaging (TDI) by echocardiography to determine left ventricular diastolic function before and after 6 months of treatment.

Time Frame

Baseline and six months

Title

Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function (With Angiotensin II)

Description

Time Frame

Baseline and six months

Title

Change in Renal Plasma Flow

Description

Time Frame

Baseline and six months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: age 18-70 years type 2 diabetes mellitus with or without hypertension Exclusion Criteria: ischemic changes on resting electrocardiogram, clinical evidence of heart disease (angina, heart failure, unstable angina),cerebrovascular or peripheral vascular disease, significant cardiac arrhythmias, aortic stenosis, 2nd or 3rd degree atrio-ventricular block, sinus node disease, or symptomatic bradycardia, bronchospastic lung disease with active wheezing, known hypersensitivity to adenosine, hemoglobin A1C (HbA1c) > 8.5%, * gout (If not already taking HCTZ), the use of Rosiglitazone,** estimated glomerular filtration rate (eGFR) < 60 ml/min, serum potassium > 5.0 mmol/L, use of potassium-sparing diuretics,** current smoker,* pregnancy, renal disease not related to diabetes mellitus, uncontrolled hypertension, systolic blood pressure (BP) >160 mm Hg and diastolic BP >100 mm Hg,* use of cyclic hormone replacement therapy past intolerance of angiotensin-converting enzyme (ACE) inhibitor therapy other major medical illnesses. Participants with evidence of a previous myocardial infarction on the first adenosine-stimulated positron emission tomography (PET) study will be withdrawn from the study. Screening systolic blood pressure < 105 mm Hg off of anti-hypertensive medications Participants can enroll in study and proceed with in-patient evaluations if during the run-in period adjustments of medications, diet and habits lead to improved glucose control [equivalent to HbA1c <8.5%, controlled hypertension and cessation of smoking. Participants who are currently taking these medications will not qualify for a screening visit. If medications were recently stopped by the participant's physician, he or she may be screened but the baseline assessment protocol must occur 3 months after stopping.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Gail K Adler, MD, PhD

Organizational Affiliation

Brigham and Women's Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Brigham and Women's Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

30409780

Citation

Haas AV, Rosner BA, Kwong RY, Rao AD, Garg R, Di Carli MF, Adler GK. Sex Differences in Coronary Microvascular Function in Individuals With Type 2 Diabetes. Diabetes. 2019 Mar;68(3):631-636. doi: 10.2337/db18-0650. Epub 2018 Nov 8.

Results Reference

derived

PubMed Identifier

25125488

Citation

Garg R, Rao AD, Baimas-George M, Hurwitz S, Foster C, Shah RV, Jerosch-Herold M, Kwong RY, Di Carli MF, Adler GK. Mineralocorticoid receptor blockade improves coronary microvascular function in individuals with type 2 diabetes. Diabetes. 2015 Jan;64(1):236-42. doi: 10.2337/db14-0670. Epub 2014 Aug 14.

Results Reference

derived

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Role of Mineralocorticoid Receptor in Diabetic Cardiovascular Disease

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