Aldosterone and the Metabolic Syndrome

Phase 1

Completed

• Conditions: Diabetes Mellitus; Metabolic Diseases; Glucose Metabolism Disorders; Endocrine System Diseases
• Interventions: 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)

• Registration Number: NCT01103245
• Lead Sponsor: Vanderbilt University Medical Center

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.

Study Timeline

• Study Start: 2010-03
• Study First Submitted: 2010-04-12
• Study First Submitted QC: 2010-04-13
• Study First Posted: 2010-04-14
• Primary Completion: 2012-07
• Study Completion: 2013-09
• Results First Submitted: 2017-04-19
• Status Verified: 2018-03
• Results First Submitted QC: 2018-03-26
• Last Update Submitted: 2018-03-26
• Results First Posted: 2018-11-05
• Last Update Posted: 2018-11-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 69

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
HCTZ plus ALI 150 then ALI 300	Aliskiren 300 mg (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
HCTZ plus ALI 150 then ALI 150 and SPL 25	Aliskiren 150 mg (ALI 150)	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
HCTZ plus SPL 25 then ALI 150 and SPL 25	Aliskiren 150 mg (ALI 150)	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
HCTZ plus ALI 150 then ALI 300	Aliskiren 150 mg (ALI 150)	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
HCTZ plus SPL 25 then ALI 150 and SPL 25	Spironolactone (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
HCTZ plus ALI 150 then ALI 150 and SPL 25	Spironolactone (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
HCTZ plus SPL 25 then SPL 50	Spironolactone (SPL 25)	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
HCTZ plus SPL 25 then SPL 50	Spironolactone 50 mg (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
HCTZ plus ALI 150 then ALI 150 and SPL 25	Hydrochlorothiazide (HCTZ)	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
HCTZ plus SPL 25 then SPL 50	Hydrochlorothiazide (HCTZ)	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
HCTZ plus ALI 150 then ALI 300	Hydrochlorothiazide (HCTZ)	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
HCTZ plus SPL 25 then ALI 150 and SPL 25	Hydrochlorothiazide (HCTZ)	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

Primary Outcome Measures

Name	Time	Method
Plasma Insulin	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	at the end of each 1 month study period ( 3 times in total)	Fasting plasma glucose, measured during hyperglycemic clamp

Trial Locations

Locations (1)

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States