Angiotensin II Blockade and Inflammation in Obesity

NCT01684748 | Completed Phase 4 Results DMC

• 1 other identifier: arbfat
• Study Type: interventional
• Target: 20
• Locations: 0 countries
• Sites: N/A

Brief Summary

Overweight and obesity, which afflicts \~65% of the U.S. population and more than 1 billion people worldwide, increases the risk of developing hypertension. Activation of the renin angiotensin system (RAS) is an important mechanism by which obesity leads to hypertension. In addition to its vasoconstricting and sodium retaining actions, angiotensin II also has potent pro-inflammatory actions including macrophage infiltration and expression of proinflammatory cytokines in target tissues. Adipose tissue and skeletal muscle appear to be a key sites for the generation of proinflammatory cytokines. Although angiotensin II receptor blockade reduces inflammation in many tissues, the effects on adipose tissue and skeletal muscle in humans are not clear. Importantly, the chronic low grade inflammatory state that accompanies obesity complicates hypertension by contributing to insulin resistance and accelerating cardiovascular disease. Therefore, the general aim of the present proposal will be to determine the influence of angiotensin II receptor blockade on adipose tissue and skeletal muscle inflammation and its relation to improvements in insulin sensitivity, if observed, in obese hypertensive humans. To address these aims, 44 obese (BMI\>30 kg/m2) hypertensive (BP\>140 systolic and/or 90 diastolic) individuals (age=50-65 years) will be randomized to receive 8 weeks of either the angiotensin II receptor antagonist, olmesartan medoxomil, or no treatment in a crossover manner. Subcutaneous adipose tissue and skeletal muscle biopsies will be obtained and insulin sensitivity (intravenous glucose tolerance tests) will be assessed at baseline and following 8 weeks of each intervention. A two week washout period will separate the interventions.

Conditions

Overweight; Obese; Prehypertension; Hypertension

Keywords

angiotensin II; obesity; diabetes

Outcome Measures

Primary Outcomes (1)

• Insulin Sensitivity by Intravenous Glucose Tolerance Testing (Change Over Time)

  Data collected from the intravenous glucose tolerance tests included blood concentrations of glucose and insulin. Glucose was measured immediately on a YSI glucose analyzer and insulin was measured via ELISA colormetric kits once all study samples were collected. To analyze changes in insulin sensitivity, the MINMOD software was used. The MINMOD software uses Bergman's minimal model to determine insulin sensitivity during an intravenous glucose tolerance test. Both glucose and insulin values were inserted at each timepoint collected (33 in total over the 3-hour protocol) and the software was run to generate the insulin sensitivity value at baseline and post-test. This information was then used to calculate the change of insulin sensitivity from baseline to post-testing after each 8-week intervention.

  Baseline testing to post-testing after 8-week intervention

Other Outcomes (1)

• Collagen Gene Expression in Skeletal Muscle (Change Over Time)

  Baseline testing to post-testing after 8-week intervention

Study Arms (2)

Olmesartan Medoxomil first, then No Drug

EXPERIMENTAL

During the First Intervention (8 weeks), subjects will be provided with daily 20 mg of olmesartan for the first 2 weeks. Subjects receive additional daily doses of 40 mg olmesartan for the remainder of the study period (6 weeks). The dose remains at 20 mg per day, however, if BP falls below 110/70 during the first 2 weeks. In addition, subjects will continue taking the drug during the 2-week follow-up testing period. Subjects will then proceed to the Washout period (2 weeks). During the Second Intervention (8 weeks), no drug will be administered to the subjects.

Drug: Olmesartan medoxomil

No Drug first, then Olmesartan Medoxomil

EXPERIMENTAL

During the First Intervention (8 weeks), no drug will be administered to the subjects. Subjects will then proceed to the Washout period (2 weeks). During the Second Intervention (8 weeks), subjects will be provided with daily 20 mg of olmesartan for the first 2 weeks. Subjects then receive daily doses of 40 mg olmesartan for the remainder of the study period (6 weeks). The dose remains at 20 mg per day, however, if BP falls below 110/70 during the first 2 weeks. In addition, subjects will continue taking the drug during the 2-week follow-up testing period.

Drug: Olmesartan medoxomil

Interventions

Olmesartan medoxomil DRUG

Crossover intervention comparing antihypertensive medication to no drug intervention.

Also known as: Benicar

No Drug first, then Olmesartan Medoxomil; Olmesartan Medoxomil first, then No Drug

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years of age
• Weight stable for previous 6 months (+2.0kg)
• Sedentary to recreationally active
• Willing to be randomized to treatment or placebo
• Verbal and written informed consent
• Approved for participation by Medical Director (Jose Rivero, M.D.)

You may not qualify if:

• Blood pressure outside stated range
• Diabetes or taking diabetes medications
• Total cholesterol \>6.2 mmol/L; triglycerides \>4.5 mmol/L
• Past or current ischemic heart disease, stroke, respiratory disease, endocrine or metabolic disease, neurological disease, or hematological-oncological disease
• Evidence of renal insufficiency; GFR\< 60 ml/min\*
• Medications (including but not limited to antihypertensives, statins or other with anti-inflammatory actions) or antioxidant vitamins or supplements
• Known allergy or hypersensitivity to olmesartan or any of its components
• Pregnant or planning to become pregnant

Sponsors & Collaborators

• Virginia Polytechnic Institute and State University: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

MeSH Terms

Conditions

Overweight; Obesity; Prehypertension; Hypertension; Diabetes Mellitus

Interventions

Olmesartan Medoxomil

Condition Hierarchy (Ancestors)

Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Vascular Diseases; Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Tetrazoles

Results Point of Contact

• Title: Elaina Marinik, Ph.D.
• Organization: Virginia Polytechnic Institute & State University

emarinik@vt.edu

5402318299

Study Officials

• Kevin P. Davy, Ph.D.

  Virginia Polytechnic Institute and State University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: September 6, 2012
• First Posted: September 13, 2012
• Study Start: February 1, 2009
• Primary Completion: August 1, 2011
• Study Completion: August 1, 2011
• Last Updated: January 3, 2018
• Results First Posted: January 12, 2015

Record last verified: 2017-12