Assessment of Renin Inhibition on Insulin Sensitivity, Diastolic Function and Aortic Compliance

This study is an investigation of the effect of commonly prescribed anti-hypertensive agents on insulin sensitivity, diastolic function and aortic compliance. The aims of the study are as follows:

Specific Aim 1: To determine in insulin resistant, hypertensive subjects if renin inhibition for 12 weeks modifies glucose homeostasis and insulin sensitivity.

To accomplish this specific aim, we will use three approaches: a fasting HOMA Index; and a three hour glucose tolerance test. Only hypertensive subjects with insulin resistance, as assessed by HOMA index will be enrolled in the study. Insulin resistance will be assessed basally and after twelve weeks of treatment with either a calcium channel blocker with placebo, or calcium channel blocker with a renin inhibitor, or a calcium channel blocker with a renin inhibitor and an angiotensin receptor antagonist.

Specific Aim 2: To determine in insulin resistant, hypertensive subjects if renin inhibition for 12 weeks modifies diastolic function and aortic compliance response to dietary sodium intake.

The same protocol and subjects will be used as defined in Specific Aim 1. Myocardial relaxation velocity (tissue Doppler imaging at the mitral annulus) and aortic compliance (characteristic aortic impedance) will be measured at baseline and then after acute and chronic renin inhibition:

1. Acute effect of renin inhibition: Hemodynamic measurements will be obtained on both high and low dietary sodium intake conditions (~1 week each) before and after a single dose of a renin inhibitor.
2. Chronic effect of renin inhibition: Hemodynamic measurements will be obtained at baseline and after 12 weeks of each of the three drug treatment arms above.

The study lasts 12 weeks and plans to study 45 hypertensive adults over the next two years.

Study Overview

• Status: Terminated
• Conditions: Insulin Sensitivity; Diastolic Function; Aortic Compliance
• Intervention / Treatment: Drug: Valsartan and Aliskiren; Drug: Aliskiren; Drug: Amlodipine

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men and women, 18-70 years old
• BMI =/< 35
• BP: BP > 145/95 on no BP medication or on 3 or less BP medications
• HOMA =>2.5
• Any race

Exclusion Criteria:

• 4 or more BP medications
• Intolerance or known prior adverse history from taking the medications amlodipine, aliskiren or valsartan
• BP >170/110 on screening exam
• Alcohol intake >12 oz per week
• Current smoking
• Recreational drug use
• Known or suspected secondary hypertension
• Known history of coronary artery disease, cerebrovascular disease or congestive heart failure
• History or known kidney disease (eGFR <50cc/min)
• Diabetes or current metformin use, or HbA1c >=6.5% on screen
• Steroid use (oral or inhaled, chronic or within the past 6 months)
• Clinically significant screening lab abnormalities (See attached "Screening Labs Acceptable Ranges")
• Evidence of ischemia or heart block on screening electrocardiogram (greater than type I-second degree heart block, left bundle branch block, or ST-T wave changes in 2 or more contiguous leads).
• Acute hospitalizations including surgery in the past 6 months
• Chronic use of non-steroidal anti-inflammatory or narcotic medications
• Women who are pregnant or nursing, or wish to become pregnant and/or who can not agree or tolerate two forms of birth control during the study period:

Acceptable birth control methods for use in this study are:

• hormonal methods, such as birth control pills, patches, injections, vaginal ring, or implants
• barrier methods (such as a condom or diaphragm) used with a spermicide (a foam, cream, or gel that kills sperm)
• intrauterine device (IUD)
• abstinence (no sex)
• Significant concomitant medical illnesses (cancer, chronic active immunological conditions, etc.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Aliskiren	Drug: Aliskiren; Aliskiren 150 mg daily for 10 weeks, force titrated after initial 2 weeks.
Placebo Comparator: Valsartan and Aliskiren; Valsartan 150 mg and Aliskiren (150 mg followed by force titration to 300 mg)	Drug: Valsartan and Aliskiren; Subject taking combination of valsartan and aliskiren.
Placebo Comparator: Placebo Group; Only taking Amlodipine	Drug: Amlodipine; Taking Amlodipine as prescribed by MD for management of high blood pressure.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Insulin Sensitivity by HOMA at 12 Weeks	The difference (change) in HOMA calculated as Baseline HOMA minus 12-week HOMA value	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aortic Compliance	Characteristic aortic imedeance, dynes x s/cm5	12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulse Wave Velocity	Measure of pulsewave velocity cm/s	12 weeks

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Jonathan Williams, MD, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: December 1, 2010
• First Submitted That Met QC Criteria: December 1, 2010
• First Posted (Estimate): December 2, 2010

Study Record Updates

• Last Update Posted (Actual): February 13, 2018
• Last Update Submitted That Met QC Criteria: January 18, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Hyperinsulinism; Hypersensitivity; Insulin Resistance; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Amlodipine; Valsartan
• Other Study ID Numbers: 2010p001286