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: 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. 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.

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.)