Aldosterone and the Metabolic Syndrome

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

The purpose of this study is to determine the effects of mineralocorticoid receptor (MR) antagonism and renin inhibition on glucose metabolism in humans.

Study Overview

• Status: Completed
• Conditions: Glucose Metabolism Disorders; Metabolic Diseases; Diabetes Mellitus; Endocrine System Diseases
• Intervention / Treatment: Drug: Hydrochlorothiazide (HCTZ); Drug: Aliskiren 150 mg (ALI 150); Drug: Aliskiren 300 mg (ALI 300); Drug: Spironolactone (SPL 25); Drug: Spironolactone 50 mg (SPL 50)

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.

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects meeting all of the following conditions will be included in the study:

  1. Ambulatory subjects, 18 to 70 years of age, inclusive

  2. For female subjects, the following conditions must be met:

     1. postmenopausal status for at least 1 year, or
     2. status-post surgical sterilization, or
     3. 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.
  3. A seated or supine systolic blood pressure greater than 130/85 on three separate measurements at least 15 minutes apart

  4. Metabolic Syndrome as defined by the presence of > 3 of the following:

     1. Hypertension as characterized by having Systolic Blood Pressure > 140 mm Hg and Diastolic Blood Pressure > 90 mm Hg.
     2. Impaired Glucose Tolerance (Fasting Plasma Glucose > 100 mg/dL)
     3. Increased triglyceride level > 150mg/dL

     4. Decreased levels of High-Density Lipoprotein (HDL) cholesterol

        1. For males, less than 30 mg/dL
        2. For females, less than 40 mg/dL

     5. Waist circumference

        1. For males, greater than 40 inches.
        2. For females, greater than 35 inches.

Exclusion Criteria:

• Subjects presenting with any of the following will not be included in the study:

  1. Diabetes type 1 or type 2, a fasting glucose of greater than 110 mg/dL or the use of anti-diabetic medication
  2. Use of hormone replacement therapy
  3. Statin therapy
  4. Pregnancy
  5. Breast-feeding
  6. 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
  7. Treatment with anticoagulants
  8. History of serious neurologic disease such as cerebral hemorrhage, stroke, seizure, or transient ischemic attack
  9. History or presence of immunological or hematological disorders
  10. Diagnosis of asthma requiring use of inhaled beta agonist >1 time per week
  11. Clinically significant gastrointestinal impairment that could interfere with drug absorption
  12. Impaired hepatic function [aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) >1.5 x upper limit of normal range]

  13. 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)

  14. Hematocrit <35%
  15. 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
  16. Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in 1 month)
  17. Treatment with lithium salts
  18. History of alcohol or drug abuse
  19. Treatment with any investigational drug in the 1 month preceding the study
  20. Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study
  21. Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study
  22. Screening plasma potassium <3.2 mmol/L or use of chronic potassium supplements for the treatment of hypokalemia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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	Drug: Hydrochlorothiazide (HCTZ); HCTZ 12.5mg daily; Other Names: HCTZ; Drug: Aliskiren 150 mg (ALI 150); Aliskiren 150mg daily; Other Names: Tekturna; Drug: Aliskiren 300 mg (ALI 300); Aliskiren 300mg daily; Other Names: Tekturna
Active Comparator: 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	Drug: Hydrochlorothiazide (HCTZ); HCTZ 12.5mg daily; Other Names: HCTZ; Drug: Aliskiren 150 mg (ALI 150); Aliskiren 150mg daily; Other Names: Tekturna; Drug: Spironolactone (SPL 25); spironolactone 25mg daily; Other Names: Aldactone
Active Comparator: 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	Drug: Hydrochlorothiazide (HCTZ); HCTZ 12.5mg daily; Other Names: HCTZ; Drug: Spironolactone (SPL 25); spironolactone 25mg daily; Other Names: Aldactone; Drug: Spironolactone 50 mg (SPL 50); Spironolactone 50 mg daily; Other Names: Aldactone
Active Comparator: 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	Drug: Hydrochlorothiazide (HCTZ); HCTZ 12.5mg daily; Other Names: HCTZ; Drug: Aliskiren 150 mg (ALI 150); Aliskiren 150mg daily; Other Names: Tekturna; Drug: Spironolactone (SPL 25); spironolactone 25mg daily; Other Names: Aldactone

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Investigators: Principal Investigator: James M Luther, MD, Vanderbilt University

Publications and helpful links

General Publications

• Ramirez CE, Shuey MM, Milne GL, Gilbert K, Hui N, Yu C, Luther JM, Brown NJ. Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans. Prostaglandins Other Lipid Mediat. 2014 Oct;113-115:38-44. doi: 10.1016/j.prostaglandins.2014.08.001. Epub 2014 Aug 28.

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): September 1, 2013

Study Registration Dates

• First Submitted: April 12, 2010
• First Submitted That Met QC Criteria: April 13, 2010
• First Posted (Estimate): April 14, 2010

Study Record Updates

• Last Update Posted (Actual): November 5, 2018
• Last Update Submitted That Met QC Criteria: March 26, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Insulin; Glucose
• Additional Relevant MeSH Terms: Insulin Resistance; Hyperinsulinism; Metabolic Syndrome; Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Sodium Chloride Symporter Inhibitors; Spironolactone; Hydrochlorothiazide
• Other Study ID Numbers: 091072; 09CRP2261428 (Other Grant/Funding Number: American Heart Association)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No