Type 2 Diabetes Mellitus, Vascular Disease
Conditions
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.
Interventions
DRUGHydrochlorothiazide + potassium
hydrochlorothiazide (HCTZ) + potassium, 12.5 mg/10 milliequivalents (mEq) capsule daily
OTHERPlacebo
Placebo capsule daily
DRUGSpironolactone
25 mg capsule daily for 6 months
Sponsors
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Spironolactone (MR Blockade) Spironolactone: 25 mg capsule daily for 6 months | 23 |
| Hydrochlorothiazide + Potassium Hydrochlorothiazide + potassium: hydrochlorothiazide (HCTZ) + potassium, 12.5 mg/10 mEq capsule daily | 24 |
| Placebo Capsule Placebo: Placebo capsule daily | 17 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 2 | 1 | 0 |
| Overall Study | Withdrawn consent | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Spironolactone (MR Blockade) | Hydrochlorothiazide + Potassium | Placebo Capsule | Total |
|---|---|---|---|---|
| Age, Continuous | 56 years STANDARD_DEVIATION 6 | 53 years STANDARD_DEVIATION 7 | 55 years STANDARD_DEVIATION 10 | 54.72 years STANDARD_DEVIATION 7.66 |
| Sex: Female, Male Female | 6 Participants | 11 Participants | 7 Participants | 24 Participants |
| Sex: Female, Male Male | 17 Participants | 13 Participants | 10 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 0 / 25 | 0 / 17 |
| other Total, other adverse events | 6 / 27 | 5 / 25 | 3 / 17 |
| serious Total, serious adverse events | 2 / 27 | 0 / 25 | 0 / 17 |
Outcome results
Primary
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.
Time frame: Baseline and six months
Population: All participants with data available for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Spironolactone (MR Blockade) | Change in Coronary Flow Reserve From Baseline to 6 Months | 0.33 ratio | Standard Deviation 0.83 |
| Hydrochlorothiazide + Potassium | Change in Coronary Flow Reserve From Baseline to 6 Months | -0.10 ratio | Standard Deviation 0.65 |
| Placebo | Change in Coronary Flow Reserve From Baseline to 6 Months | 0.02 ratio | Standard Deviation 1.03 |
Secondary
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.
Time frame: Baseline and six months
Population: All participants with data available for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Spironolactone (MR Blockade) | Change in Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function | 0.02 ratio | Standard Deviation 1.61 |
| Hydrochlorothiazide + Potassium | Change in Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function | 0.06 ratio | Standard Deviation 1.35 |
| Placebo | Change in Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function | 0.64 ratio | Standard Deviation 1.95 |
Secondary
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.
Time frame: Baseline and six months
Population: All participants with data available for this outcome measure at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Spironolactone (MR Blockade) | Change in Renal Plasma Flow | Pre-treatment, PAH clearance, Post-ANGII | 442 mL/min/1.73m^2 | Standard Deviation 75 |
| Spironolactone (MR Blockade) | Change in Renal Plasma Flow | Pre-treatment, PAH clearance, baseline | 527 mL/min/1.73m^2 | Standard Deviation 76 |
| Spironolactone (MR Blockade) | Change in Renal Plasma Flow | 6 months post-treatment, PAH clearance, baseline | 518 mL/min/1.73m^2 | Standard Deviation 97 |
| Spironolactone (MR Blockade) | Change in Renal Plasma Flow | 6 months post-treatment, PAH clearance, Post-ANGII | 423 mL/min/1.73m^2 | Standard Deviation 89 |
| Hydrochlorothiazide + Potassium | Change in Renal Plasma Flow | 6 months post-treatment, PAH clearance, Post-ANGII | 415 mL/min/1.73m^2 | Standard Deviation 61 |
| Hydrochlorothiazide + Potassium | Change in Renal Plasma Flow | Pre-treatment, PAH clearance, baseline | 508 mL/min/1.73m^2 | Standard Deviation 82 |
| Hydrochlorothiazide + Potassium | Change in Renal Plasma Flow | Pre-treatment, PAH clearance, Post-ANGII | 417 mL/min/1.73m^2 | Standard Deviation 49 |
| Hydrochlorothiazide + Potassium | Change in Renal Plasma Flow | 6 months post-treatment, PAH clearance, baseline | 500 mL/min/1.73m^2 | Standard Deviation 80 |
| Placebo | Change in Renal Plasma Flow | 6 months post-treatment, PAH clearance, Post-ANGII | 427 mL/min/1.73m^2 | Standard Deviation 99 |
| Placebo | Change in Renal Plasma Flow | 6 months post-treatment, PAH clearance, baseline | 491 mL/min/1.73m^2 | Standard Deviation 87 |
| Placebo | Change in Renal Plasma Flow | Pre-treatment, PAH clearance, baseline | 518 mL/min/1.73m^2 | Standard Deviation 108 |
| Placebo | Change in Renal Plasma Flow | Pre-treatment, PAH clearance, Post-ANGII | 436 mL/min/1.73m^2 | Standard Deviation 97 |
Secondary
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.
Time frame: Baseline and six months
Population: All participants with data available for this outcome measure at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Spironolactone (MR Blockade) | Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function (With Angiotensin II) | Pre-treatment, E/e', baseline | 6.67 ratio | Standard Deviation 1.93 |
| Spironolactone (MR Blockade) | Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function (With Angiotensin II) | Pre-treatment, E/e', Post-ANGII | 7.09 ratio | Standard Deviation 1.96 |
| Spironolactone (MR Blockade) | Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function (With Angiotensin II) | 6 months post-treatment, E/e', baseline | 6.76 ratio | Standard Deviation 1.57 |
| Spironolactone (MR Blockade) | Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function (With Angiotensin II) | 6 months post-treatment, E/e', Post-ANGII | 6.28 ratio | Standard Deviation 2.53 |
| Hydrochlorothiazide + Potassium | Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function (With Angiotensin II) | 6 months post-treatment, E/e', Post-ANGII | 5.83 ratio | Standard Deviation 2.82 |
| Hydrochlorothiazide + Potassium | Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function (With Angiotensin II) | Pre-treatment, E/e', baseline | 6.72 ratio | Standard Deviation 1.93 |
| Hydrochlorothiazide + Potassium | Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function (With Angiotensin II) | 6 months post-treatment, E/e', baseline | 7.03 ratio | Standard Deviation 1.83 |
| Hydrochlorothiazide + Potassium | Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function (With Angiotensin II) | Pre-treatment, E/e', Post-ANGII | 7.06 ratio | Standard Deviation 1.66 |
| Placebo | Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function (With Angiotensin II) | 6 months post-treatment, E/e', Post-ANGII | 7.48 ratio | Standard Deviation 1.59 |
| Placebo | Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function (With Angiotensin II) | Pre-treatment, E/e', Post-ANGII | 6.70 ratio | Standard Deviation 3.08 |
| Placebo | Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function (With Angiotensin II) | 6 months post-treatment, E/e', baseline | 7.35 ratio | Standard Deviation 2.26 |
| Placebo | Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function (With Angiotensin II) | Pre-treatment, E/e', baseline | 6.55 ratio | Standard Deviation 2.24 |