Role of Mineralocorticoid Receptor in Diabetic Cardiovascular Disease

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus; Vascular Disease
• Intervention / Treatment: Drug: Spironolactone; Drug: Hydrochlorothiazide + potassium; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo capsule	Other: Placebo; Placebo capsule daily
Experimental: Spironolactone (mineralocorticoid receptor [MR] blockade)	Drug: Spironolactone; 25 mg capsule daily for 6 months
Active Comparator: Hydrochlorothiazide + potassium	Drug: Hydrochlorothiazide + potassium; hydrochlorothiazide (HCTZ) + potassium, 12.5 mg/10 milliequivalents (mEq) capsule daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline and six months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline and six months
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.	Baseline and six months
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.	Baseline and six months

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Gail K Adler, MD, PhD, Brigham and Women's Hospital

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: September 1, 2008
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: March 17, 2009
• First Submitted That Met QC Criteria: March 18, 2009
• First Posted (Estimate): March 19, 2009

Study Record Updates

• Last Update Posted (Actual): June 14, 2017
• Last Update Submitted That Met QC Criteria: May 19, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Vascular Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Sodium Chloride Symporter Inhibitors; Spironolactone; Hydrochlorothiazide
• Other Study ID Numbers: 2007-P-000564; 1R01HL087060-01A2 (U.S. NIH Grant/Contract)