Aldosterone and the Metabolic Syndrome

Study Overview
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Brief Summary
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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
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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.

Official Title
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Aldosterone and the Metabolic Syndrome: Renin Inhibition Versus Mineralocorticoid Receptor (MR) Antagonism

Conditions
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Metabolic Diseases, Diabetes Mellitus, Endocrine System Diseases, Glucose Metabolism Disorders

Intervention / Treatment
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* Drug: Hydrochlorothiazide (HCTZ)
* Drug: Aliskiren 150 mg (ALI 150)
* Drug: Spironolactone (SPL 25)
* Drug: Aliskiren 300 mg (ALI 300)
* Drug: Spironolactone 50 mg (SPL 50)


Participation Criteria
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Eligibility Criteria
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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) Increased triglyceride level > 150mg/dL Decreased levels of High-Density Lipoprotein (HDL) cholesterol For males, less than 30 mg/dL For females, less than 40 mg/dL Waist circumference For males, greater than 40 inches. For females, greater than 35 inches. 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 Pregnancy 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 Clinically significant gastrointestinal impairment that could interfere with drug absorption Impaired hepatic function [aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) >1.5 x upper limit of normal range] Impaired renal function [estimated glomerular filtration rate (eGFR) of <60ml/min] as determined by the four-variable Modification of Diet in Renal Disease (MDRD) equation, where serum creatinine (Scr) is expressed in mg/dl and age in years: eGFR (ml/min/1.73m2)=175 • Scr-1.154 • age-0.203 • (1.212 if black) • (0.742 if female) Hematocrit <35% Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult, such as arthritis treated with non-steroidal antiinflammatory drugs Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in 1 month) Treatment with lithium salts History of alcohol or drug abuse Treatment with any investigational drug in the 1 month preceding the study Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study Screening plasma potassium <3.2 mmol/L or use of chronic potassium supplements for the treatment of hypokalemia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: HCTZ plus ALI 150 then ALI 300<br>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 | Drug: Hydrochlorothiazide (HCTZ)<br>* HCTZ 12.5mg daily<br>* Other names: HCTZ;Drug: Aliskiren 150 mg (ALI 150)<br>* Aliskiren 150mg daily<br>* Other names: Tekturna;Drug: Aliskiren 300 mg (ALI 300)<br>* Aliskiren 300mg daily<br>* Other names: Tekturna;|
| Active Comparator: HCTZ plus ALI 150 then ALI 150 and SPL 25<br>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 | Drug: Hydrochlorothiazide (HCTZ)<br>* HCTZ 12.5mg daily<br>* Other names: HCTZ;Drug: Aliskiren 150 mg (ALI 150)<br>* Aliskiren 150mg daily<br>* Other names: Tekturna;Drug: Spironolactone (SPL 25)<br>* spironolactone 25mg daily<br>* Other names: Aldactone;|
| Active Comparator: HCTZ plus SPL 25 then SPL 50<br>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 | Drug: Hydrochlorothiazide (HCTZ)<br>* HCTZ 12.5mg daily<br>* Other names: HCTZ;Drug: Spironolactone (SPL 25)<br>* spironolactone 25mg daily<br>* Other names: Aldactone;Drug: Spironolactone 50 mg (SPL 50)<br>* Spironolactone 50 mg daily<br>* Other names: Aldactone;|
| Active Comparator: HCTZ plus SPL 25 then ALI 150 and SPL 25<br>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 | Drug: Hydrochlorothiazide (HCTZ)<br>* HCTZ 12.5mg daily<br>* Other names: HCTZ;Drug: Aliskiren 150 mg (ALI 150)<br>* Aliskiren 150mg daily<br>* Other names: Tekturna;Drug: Spironolactone (SPL 25)<br>* spironolactone 25mg daily<br>* Other names: Aldactone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Insulin | 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. | at the end of each 1 month study period ( 3 times in total) | 
| Plasma Glucose | Fasting plasma glucose, measured during hyperglycemic clamp | at the end of each 1 month study period ( 3 times in total) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glucose, Insulin