Role of Mineralocorticoid Receptor in Diabetic Cardiovascular Disease

• Spironolactone (Drug): 25 mg capsule daily for 6 months
• Hydrochlorothiazide + potassium (Drug): hydrochlorothiazide (HCTZ) + potassium, 12.5 mg/10 milliequivalents (mEq) capsule daily
• Placebo (Other): Placebo capsule daily

Primary outcomes

• Change in Coronary Flow Reserve From Baseline to 6 Months [Baseline and six 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 outcomes

• Change in Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function [Baseline and six months]: 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) [Baseline and six months]: 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 [Baseline and six months]: 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.

Sex: All, ages: 18 Years to 70 Years

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.

Participant flow

Outcome results

• Change in Coronary Flow Reserve From Baseline to 6 Months (Primary), Mean, ratio: Spironolactone (MR Blockade) 0.33 +/- 0.83; Hydrochlorothiazide + Potassium -0.10 +/- 0.65; Placebo 0.02 +/- 1.03
• Change in Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function (Secondary), Mean, ratio: Spironolactone (MR Blockade) 0.02 +/- 1.61; Hydrochlorothiazide + Potassium 0.06 +/- 1.35; Placebo 0.64 +/- 1.95
• Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function (With Angiotensin II) (Secondary), Mean, ratio: Spironolactone (MR Blockade) 6.67 +/- 1.93; Hydrochlorothiazide + Potassium 6.72 +/- 1.93; Placebo 6.55 +/- 2.24
• Change in Renal Plasma Flow (Secondary), Mean, mL/min/1.73m^2: Spironolactone (MR Blockade) 527 +/- 76; Hydrochlorothiazide + Potassium 508 +/- 82; Placebo 518 +/- 108

Adverse events

Time frame: 6 months

Serious adverse events by term

Other adverse events by term

• Results publication: 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. PMID 30409780
• Results publication: 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. PMID 25125488

• Gail K Adler, MD, PhD, Principal investigator, Brigham and Women's Hospital

NIH grants: R01HL087060