Effect of Mineralocorticoid Receptor Blockade in T2D
Effect of Mineralocorticoid Receptor Blockade in T2D
Individuals with T2DM, aged 18–70 years, were enrolled in a double-blind, randomized, controlled study (clinicaltrials.gov NCT00865124). Exclusion criteria included the following: coronary, cerebrovascular, or peripheral vascular or renal disease (estimated glomerular filtration rate <60 mL/min/1.73 m); bronchospastic lung disease; gout if not on hydrochlorothiazide (HCTZ); serum potassium >5.0 mmol/L; current smoker; pregnancy; use of potassium-sparing diuretics, oral contraceptives, hormone replacement therapy, or rosiglitazone; uncontrolled hypertension (systolic blood pressure [BP] >160 mmHg or diastolic BP >100 mmHg); ACEI intolerance; systolic BP <105 mmHg off antihypertensive therapy; and other major medical illnesses. Partners HealthCare Institutional Review Board approved the protocol, and all participants provided written informed consent.
Participants completed a 3-month run-in phase followed by a baseline assessment, randomization to drug treatment, and posttreatment assessment. With initiation of the 3-month run-in, participants were placed on enalapril 20 mg daily and tapered off other antihypertensive medications except amlodipine 5–10 mg daily that was added for systolic BP ≥140 mmHg. Antidiabetic medications were adjusted to achieve a goal hemoglobin A1C (HbA1c) ≤7%. Simvastatin 20 mg daily was added for direct LDL >100 mg/dL if participant was statin tolerant not on a statin. Participants measured BP and blood glucose daily and communicated readings to study staff weekly.
Four days prior to and during the 2-day in-patient admission, participants consumed a caffeine-free, isocaloric diet (250 mmol/day Na, 100 mmol/day K, 1,000 mg/day Ca, 300 mg/day Mg, and at least 30% carbohydrate by calories). Participants stopped amlodipine 36 h prior to admission, and antidiabetic medications were adjusted to avoid hypoglycemia. Upon admission after an overnight fast, supine BP was measured every 5 min for 30 min, and the average was used for analysis. Blood samples were collected for HbA1c, glucose, and lipids, and 24-h urine collection for sodium, creatinine, and aldosterone was initiated. Participants underwent echocardiography for assessment of diastolic function, cardiac PET scan for determination of CFR (ratio of adenosine-stimulated to rest MBF), and cardiac MRI scan to determine left ventricular (LV) mass index and myocardial extracellular volume using techniques described previously. The following morning, after being supine and fasting from midnight onwards, blood was drawn for potassium, sodium, plasma renin activity, angiotensin II, and aldosterone. Assays were performed as previously described; angiotensin II was measured using ALPCO Immunoassay (Salem, NH).
Participants without evidence of cardiac ischemia or prior myocardial infarction on baseline imaging were randomized 1:1:1 to 6 months of add-on daily therapy with one of three treatments: spironolactone 25 mg, HCTZ 12.5 mg with KCl 10 mEq, or matching placebo. To accommodate a funding reduction and considering the study rationale where the primary outcome was the effect of spironolactone versus HCTZ on CFR, the placebo arm was stopped after 80% of participants were randomized. All participants and study staff (except Investigational Drug Service, which was responsible for randomization) were blinded to treatment. Plasma potassium was measured at 1, 2, 4, 8, 16, and 24 weeks. A posttreatment assessment, which was identical to the baseline assessment, was completed at 6 months.
Comparisons of treatment arms for demographic and other baseline variables were performed using Wilcoxon rank sum tests or χ tests. The primary outcome was CFR, and the overall analysis framework was a repeated measures ANCOVA covering baseline and 6-month visit data. Spironolactone versus HCTZ was considered primary in the design, and HCTZ and placebo were expected to be similar. In addition to baseline CFR, covariates were selected from among those associated with vascular function (e.g., statin use, HbA1c, BMI, race, and age). All subsets were tested, retaining only those covariates contributing significantly to the multiple variable model. Diastolic function (E/e'), as a measure of the impact of CFR on cardiac function, was a secondary outcome. Data are presented as means ± SD. All statistical analyses were performed with SAS version 9.3 (SAS Institute, Cary, NC).
Research Design and Methods
Patient Population
Individuals with T2DM, aged 18–70 years, were enrolled in a double-blind, randomized, controlled study (clinicaltrials.gov NCT00865124). Exclusion criteria included the following: coronary, cerebrovascular, or peripheral vascular or renal disease (estimated glomerular filtration rate <60 mL/min/1.73 m); bronchospastic lung disease; gout if not on hydrochlorothiazide (HCTZ); serum potassium >5.0 mmol/L; current smoker; pregnancy; use of potassium-sparing diuretics, oral contraceptives, hormone replacement therapy, or rosiglitazone; uncontrolled hypertension (systolic blood pressure [BP] >160 mmHg or diastolic BP >100 mmHg); ACEI intolerance; systolic BP <105 mmHg off antihypertensive therapy; and other major medical illnesses. Partners HealthCare Institutional Review Board approved the protocol, and all participants provided written informed consent.
Study Procedures
Participants completed a 3-month run-in phase followed by a baseline assessment, randomization to drug treatment, and posttreatment assessment. With initiation of the 3-month run-in, participants were placed on enalapril 20 mg daily and tapered off other antihypertensive medications except amlodipine 5–10 mg daily that was added for systolic BP ≥140 mmHg. Antidiabetic medications were adjusted to achieve a goal hemoglobin A1C (HbA1c) ≤7%. Simvastatin 20 mg daily was added for direct LDL >100 mg/dL if participant was statin tolerant not on a statin. Participants measured BP and blood glucose daily and communicated readings to study staff weekly.
Baseline and 6-Month Assessment Protocol
Four days prior to and during the 2-day in-patient admission, participants consumed a caffeine-free, isocaloric diet (250 mmol/day Na, 100 mmol/day K, 1,000 mg/day Ca, 300 mg/day Mg, and at least 30% carbohydrate by calories). Participants stopped amlodipine 36 h prior to admission, and antidiabetic medications were adjusted to avoid hypoglycemia. Upon admission after an overnight fast, supine BP was measured every 5 min for 30 min, and the average was used for analysis. Blood samples were collected for HbA1c, glucose, and lipids, and 24-h urine collection for sodium, creatinine, and aldosterone was initiated. Participants underwent echocardiography for assessment of diastolic function, cardiac PET scan for determination of CFR (ratio of adenosine-stimulated to rest MBF), and cardiac MRI scan to determine left ventricular (LV) mass index and myocardial extracellular volume using techniques described previously. The following morning, after being supine and fasting from midnight onwards, blood was drawn for potassium, sodium, plasma renin activity, angiotensin II, and aldosterone. Assays were performed as previously described; angiotensin II was measured using ALPCO Immunoassay (Salem, NH).
Drug Treatment
Participants without evidence of cardiac ischemia or prior myocardial infarction on baseline imaging were randomized 1:1:1 to 6 months of add-on daily therapy with one of three treatments: spironolactone 25 mg, HCTZ 12.5 mg with KCl 10 mEq, or matching placebo. To accommodate a funding reduction and considering the study rationale where the primary outcome was the effect of spironolactone versus HCTZ on CFR, the placebo arm was stopped after 80% of participants were randomized. All participants and study staff (except Investigational Drug Service, which was responsible for randomization) were blinded to treatment. Plasma potassium was measured at 1, 2, 4, 8, 16, and 24 weeks. A posttreatment assessment, which was identical to the baseline assessment, was completed at 6 months.
Statistical Methods
Comparisons of treatment arms for demographic and other baseline variables were performed using Wilcoxon rank sum tests or χ tests. The primary outcome was CFR, and the overall analysis framework was a repeated measures ANCOVA covering baseline and 6-month visit data. Spironolactone versus HCTZ was considered primary in the design, and HCTZ and placebo were expected to be similar. In addition to baseline CFR, covariates were selected from among those associated with vascular function (e.g., statin use, HbA1c, BMI, race, and age). All subsets were tested, retaining only those covariates contributing significantly to the multiple variable model. Diastolic function (E/e'), as a measure of the impact of CFR on cardiac function, was a secondary outcome. Data are presented as means ± SD. All statistical analyses were performed with SAS version 9.3 (SAS Institute, Cary, NC).
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