Aldosterone and the Metabolic Syndrome

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.

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