Aldosterone and the Metabolic Syndrome: Renin Inhibition Versus Mineralocorticoid Receptor (MR) Antagonism
Overview
- Phase
- Phase 1
- Intervention
- Hydrochlorothiazide (HCTZ)
- Conditions
- Metabolic Diseases
- Sponsor
- Vanderbilt University Medical Center
- Enrollment
- 69
- Locations
- 1
- Primary Endpoint
- Plasma Insulin
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
The purpose of this study is to determine the effects of mineralocorticoid receptor (MR) antagonism and renin inhibition on glucose metabolism in humans.
Detailed Description
The purpose of this study is to determine the effects of mineralocorticoid receptor (MR) antagonism and renin inhibition on fasting blood glucose and glucose-stimulated insulin secretion in humans.
Investigators
James Matt Luther
Assistant Professor of Medicine
Vanderbilt University Medical Center
Eligibility Criteria
Inclusion Criteria
- •Subjects meeting all of the following conditions will be included in the study:
- •Ambulatory subjects, 18 to 70 years of age, inclusive
- •For female subjects, the following conditions must be met:
- •postmenopausal status for at least 1 year, or
- •status-post surgical sterilization, or
- •if of childbearing potential, utilization of adequate birth control and willingness to undergo urine beta-hcg testing prior to drug treatment and on every study day.
- •A seated or supine systolic blood pressure greater than 130/85 on three separate measurements at least 15 minutes apart
- •Metabolic Syndrome as defined by the presence of \> 3 of the following:
- •Hypertension as characterized by having Systolic Blood Pressure \> 140 mm Hg and Diastolic Blood Pressure \> 90 mm Hg.
- •Impaired Glucose Tolerance (Fasting Plasma Glucose \> 100 mg/dL)
Exclusion Criteria
- •Subjects presenting with any of the following will not be included in the study:
- •Diabetes type 1 or type 2, a fasting glucose of greater than 110 mg/dL or the use of anti-diabetic medication
- •Use of hormone replacement therapy
- •Statin therapy
- •Breast-feeding
- •Cardiovascular disease such as prior myocardial infarction, presence of angina pectoris, significant arrhythmia, congestive heart failure \[Left Ventricular (LV) hypertrophy acceptable\], deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy
- •Treatment with anticoagulants
- •History of serious neurologic disease such as cerebral hemorrhage, stroke, seizure, or transient ischemic attack
- •History or presence of immunological or hematological disorders
- •Diagnosis of asthma requiring use of inhaled beta agonist \>1 time per week
Arms & Interventions
HCTZ plus ALI 150 then ALI 300
Hydrochlorothiazide (HCTZ) 12.5mg daily for 1 month then HCTZ 12.5mg daily plus Aliskiren 150 mg (ALI 150) daily for 1 month then HCTZ 12.5mg daily plus Aliskiren 300mg ((ALI 300) for 1 month
Intervention: Hydrochlorothiazide (HCTZ)
HCTZ plus ALI 150 then ALI 300
Hydrochlorothiazide (HCTZ) 12.5mg daily for 1 month then HCTZ 12.5mg daily plus Aliskiren 150 mg (ALI 150) daily for 1 month then HCTZ 12.5mg daily plus Aliskiren 300mg ((ALI 300) for 1 month
Intervention: Aliskiren 150 mg (ALI 150)
HCTZ plus ALI 150 then ALI 300
Hydrochlorothiazide (HCTZ) 12.5mg daily for 1 month then HCTZ 12.5mg daily plus Aliskiren 150 mg (ALI 150) daily for 1 month then HCTZ 12.5mg daily plus Aliskiren 300mg ((ALI 300) for 1 month
Intervention: Aliskiren 300 mg (ALI 300)
HCTZ plus ALI 150 then ALI 150 and SPL 25
HCTZ 12.5mg daily for 1 month then HCTZ 12.5mg daily plus Aliskiren 150 mg daily for 1 month then HCTZ 12.5mg daily plus Aliskiren 150 mg daily and Spironolactone 25mg (SPL 25) daily for one month
Intervention: Hydrochlorothiazide (HCTZ)
HCTZ plus ALI 150 then ALI 150 and SPL 25
HCTZ 12.5mg daily for 1 month then HCTZ 12.5mg daily plus Aliskiren 150 mg daily for 1 month then HCTZ 12.5mg daily plus Aliskiren 150 mg daily and Spironolactone 25mg (SPL 25) daily for one month
Intervention: Aliskiren 150 mg (ALI 150)
HCTZ plus ALI 150 then ALI 150 and SPL 25
HCTZ 12.5mg daily for 1 month then HCTZ 12.5mg daily plus Aliskiren 150 mg daily for 1 month then HCTZ 12.5mg daily plus Aliskiren 150 mg daily and Spironolactone 25mg (SPL 25) daily for one month
Intervention: Spironolactone (SPL 25)
HCTZ plus SPL 25 then SPL 50
HCTZ 12.5mg daily for 1 month then HCTZ 12.5mg daily plus Spironolactone 25 mg (SPL 25) daily for 1 month then HCTZ 12.5mg daily plus Spironolactone 50 mg daily for one month
Intervention: Hydrochlorothiazide (HCTZ)
HCTZ plus SPL 25 then SPL 50
HCTZ 12.5mg daily for 1 month then HCTZ 12.5mg daily plus Spironolactone 25 mg (SPL 25) daily for 1 month then HCTZ 12.5mg daily plus Spironolactone 50 mg daily for one month
Intervention: Spironolactone (SPL 25)
HCTZ plus SPL 25 then SPL 50
HCTZ 12.5mg daily for 1 month then HCTZ 12.5mg daily plus Spironolactone 25 mg (SPL 25) daily for 1 month then HCTZ 12.5mg daily plus Spironolactone 50 mg daily for one month
Intervention: Spironolactone 50 mg (SPL 50)
HCTZ plus SPL 25 then ALI 150 and SPL 25
HCTZ 12.5mg daily for 1 month then HCTZ 12.5mg daily plus Spironolactone 25 mg daily for 1 month then HCTZ 12.5mg daily plus Aliskiren 150 mg daily and Spironolactone 25 mg daily for one month
Intervention: Hydrochlorothiazide (HCTZ)
HCTZ plus SPL 25 then ALI 150 and SPL 25
HCTZ 12.5mg daily for 1 month then HCTZ 12.5mg daily plus Spironolactone 25 mg daily for 1 month then HCTZ 12.5mg daily plus Aliskiren 150 mg daily and Spironolactone 25 mg daily for one month
Intervention: Aliskiren 150 mg (ALI 150)
HCTZ plus SPL 25 then ALI 150 and SPL 25
HCTZ 12.5mg daily for 1 month then HCTZ 12.5mg daily plus Spironolactone 25 mg daily for 1 month then HCTZ 12.5mg daily plus Aliskiren 150 mg daily and Spironolactone 25 mg daily for one month
Intervention: Spironolactone (SPL 25)
Outcomes
Primary Outcomes
Plasma Insulin
Time Frame: at the end of each 1 month study period ( 3 times in total)
A Hyperglycemic clamp was performed once during each study period to assess glucose stimulated insulin secretion. Glucose is infused intravenously to maintain blood glucose near 200 mg/dL to stimulate insulin secretion. During this time plasma insulin levels were measured and the insulin response is reported as the incremental increase over the first 10 minutes of glucose administration.
Plasma Glucose
Time Frame: at the end of each 1 month study period ( 3 times in total)
Fasting plasma glucose, measured during hyperglycemic clamp