Angiotensin II Blockade and Inflammation in Obesity

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.

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Key information

Conditions

Overweight Body Weight Cardiovascular Diseases Diabetes Mellitus Endocrine System Diseases Glucose Metabolism Disorders Hypertension Metabolic Diseases Nutrition Disorders Nutritional and Metabolic Diseases Obese Obesity Overnutrition Pathological Conditions, Signs and Symptoms Prehypertension Signs and Symptoms Vascular Diseases

Age range

18 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

18-75 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.)

Exclusion criteria

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

Treatment and study plan

olmesartan medoxomil

Drug

Crossover intervention comparing antihypertensive medication to no drug intervention.

Other names: Benicar

Primary outcomes

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

Time frame: Baseline testing to post-testing after 8-week intervention

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.

Other outcomes

Collagen Gene Expression in Skeletal Muscle (Change Over Time)

Time frame: Baseline testing to post-testing after 8-week intervention

RNA extraction and quantification were determined using an RNeasy Mini Fibrous Kit and DNase I treatment (Qiagen, Valencia, CA, USA) in accordance to the manufacturer's directions for mRNA extraction. Quantitative real-time polymerase chain reaction (qRT-PCR) measured the expression of collagen III using an ABI PRISM 7900 Sequence Detection System instrument and TaqMan Universal PCR Master Mix according to the manufacturer's instructions (Applied Biosystems, Foster City, CA, USA). Relative gene expression levels were determined using the number of cycles necessary to reach threshold and results were normalized to cyclophilin B RNA levels.

Sponsors and collaborators

Lead sponsor

Virginia Polytechnic Institute and State University

Other

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

Registry information

Official study title

Angiotensin II Blockade and Adipose Tissue Inflammation in Obesity

Acronym: ARB

Important dates

Study start: 2009
Primary completion: 2011
Study completion: 2011
First posted: Sep 13, 2012
Registry last updated: Jan 3, 2018

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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