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

• ClinicalTrials.gov Identifier: NCT01252238
• Recruitment Status: Terminated
• First Posted: December 2, 2010
• Results First Posted: September 5, 2013
• Last Update Posted: February 13, 2018
• Sponsor: Brigham and Women's Hospital
• Information provided by (Responsible Party): Jonathan S. Williams, MD, MMSc, Brigham and Women's Hospital

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Insulin Sensitivity; Aortic Compliance; Diastolic Function	Drug: Aliskiren; Drug: Valsartan and Aliskiren; Drug: Amlodipine	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Assessment of Renin Inhibition on Insulin Sensitivity, Diastolic Function and Aortic Compliance
• Study Start Date: June 2010
• Actual Primary Completion Date: December 2012
• Actual Study Completion Date: December 2012

Arms and Interventions

Arm	Intervention/treatment
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.
Experimental: Aliskiren	Drug: Aliskiren; Aliskiren 150 mg daily for 10 weeks, force titrated after initial 2 weeks.
Placebo Comparator: Placebo Group; Only taking Amlodipine	Drug: Amlodipine; Taking Amlodipine as prescribed by MD for management of high blood pressure.

Outcome Measures

Primary Outcome Measures :

1. Change in Insulin Sensitivity by HOMA at 12 Weeks [ Time Frame: 12 weeks ]
   The difference (change) in HOMA calculated as Baseline HOMA minus 12-week HOMA value

Secondary Outcome Measures :

1. Aortic Compliance [ Time Frame: 12 weeks ]
   Characteristic aortic imedeance, dynes x s/cm5

Other Outcome Measures:

1. Pulse Wave Velocity [ Time Frame: 12 weeks ]
   Measure of pulsewave velocity cm/s

Eligibility Criteria

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

Criteria

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.)

Contacts and Locations

Locations

United States, Massachusetts

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02115

Sponsors and Collaborators

Brigham and Women's Hospital

Investigators

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

More Information

• Responsible Party: Jonathan S. Williams, MD, MMSc, Jonathan Williams, MD, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT01252238
• Other Study ID Numbers: 2010p001286
• First Posted: December 2, 2010
• Results First Posted: September 5, 2013
• Last Update Posted: February 13, 2018
• Last Verified: January 2018

Additional relevant MeSH terms:

Insulin Resistance; Hypersensitivity; Immune System Diseases; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Amlodipine; Valsartan; Antihypertensive Agents; Calcium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Vasodilator Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists