Clinical trial NCT00865124: Role of Mineralocorticoid Receptor in Diabetic Cardiovascular Disease
Official title: Role of Mineralocorticoid Receptor in Diabetic Cardiovascular Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Type 2 Diabetes Mellitus
Vascular Disease
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2009-03-19
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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:

1. spironolactone
2. hydrochlorothiazide (HCTZ) plus potassium
3. 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.


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.

Primary outcomes:
measure: Change in Coronary Flow Reserve From Baseline to 6 Months
timeFrame: Baseline and six months
Secondary outcomes:
measure: Change in Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function
timeFrame: Baseline and six months
measure: Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function (With Angiotensin II)
timeFrame: Baseline and six months
measure: Change in Renal Plasma Flow
timeFrame: Baseline and six months
Other outcomes:
Locations:
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
Study officials:
affiliation: Brigham and Women's Hospital
name: Gail K Adler, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.