Hypertension, Obese, Overweight, Prehypertension
Conditions
Keywords
angiotensin II, obesity, diabetes
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.
Interventions
DRUGOlmesartan medoxomil
Crossover intervention comparing antihypertensive medication to no drug intervention.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Virginia Polytechnic Institute and State University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Sensitivity by Intravenous Glucose Tolerance Testing (Change Over Time) | 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
| Measure | Time frame | Description |
|---|---|---|
| Collagen Gene Expression in Skeletal Muscle (Change Over Time) | 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. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Olmesartan Medoxomil First, Then No Drug 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.
Olmesartan medoxomil | 8 |
| No Drug First, Then Olmesartan Medoxomil 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. | 8 |
| Total | 16 |
Baseline characteristics
| Characteristic | No Drug First, Then Olmesartan Medoxomil | Olmesartan Medoxomil First, Then No Drug | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 8 Participants | 15 Participants |
| Age, Continuous | 49.75 years STANDARD_DEVIATION 14.2 | 49.25 years STANDARD_DEVIATION 9.8 | 49.5 years STANDARD_DEVIATION 11.8 |
| Body fat | 39.8 Percentage of fat STANDARD_DEVIATION 13.5 | 43.9 Percentage of fat STANDARD_DEVIATION 10.5 | 41.8 Percentage of fat STANDARD_DEVIATION 12.1 |
| Body mass index | 31.5 kg/m2 STANDARD_DEVIATION 6.8 | 34.5 kg/m2 STANDARD_DEVIATION 7 | 33.0 kg/m2 STANDARD_DEVIATION 6.9 |
| Body weight | 90.4 kg STANDARD_DEVIATION 17.7 | 102.3 kg STANDARD_DEVIATION 20.9 | 96.3 kg STANDARD_DEVIATION 19.7 |
| Diastolic blood pressure | 80.1 mmHg STANDARD_DEVIATION 7.9 | 81.0 mmHg STANDARD_DEVIATION 5.1 | 80.6 mmHg STANDARD_DEVIATION 6.4 |
| Glucose | 99.1 mg/dL STANDARD_DEVIATION 13.8 | 95.8 mg/dL STANDARD_DEVIATION 10.8 | 97.4 mg/dL STANDARD_DEVIATION 12 |
| HDL cholesterol | 55.1 mg/dL STANDARD_DEVIATION 29 | 45.5 mg/dL STANDARD_DEVIATION 9.8 | 50.3 mg/dL STANDARD_DEVIATION 21.5 |
| LDL cholesterol | 131.3 mg/dL STANDARD_DEVIATION 22.4 | 129.9 mg/dL STANDARD_DEVIATION 34.9 | 130.6 mg/dL STANDARD_DEVIATION 31.2 |
| Region of Enrollment United States | 8 participants | 8 participants | 16 participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 8 Participants |
| Systolic blood pressure | 140.6 mmHg STANDARD_DEVIATION 12.8 | 133.7 mmHg STANDARD_DEVIATION 10.1 | 137.2 mmHg STANDARD_DEVIATION 11.7 |
| Total cholesterol | 207.8 mg/dL STANDARD_DEVIATION 20.9 | 199.5 mg/dL STANDARD_DEVIATION 38.2 | 203.7 mg/dL STANDARD_DEVIATION 30.1 |
| Total fat mass | 34.6 kg STANDARD_DEVIATION 14.7 | 43.1 kg STANDARD_DEVIATION 15.1 | 38.8 kg STANDARD_DEVIATION 15 |
| Triglycerides | 106.8 mg/dL STANDARD_DEVIATION 50.9 | 120.6 mg/dL STANDARD_DEVIATION 68.5 | 113.7 mg/dL STANDARD_DEVIATION 53.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 16 | 0 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 |
Outcome results
Primary
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.
Time frame: Baseline testing to post-testing after 8-week intervention
Population: Results of insulin sensitivity by intravenous glucose tolerance (IVGTT) testing are reported per intervention (Olmesartan Medoxomil and No drug). Only 10 of the 16 study participants who participated in all or some of the study measurements opted to complete or had sufficient data to analyze for each pre- and post-intervention (4 total) IVGTT.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olmesartan Medoxomil | Insulin Sensitivity by Intravenous Glucose Tolerance Testing (Change Over Time) | 0.253 mu/L/min | Standard Deviation 2.7 |
| No Drug Intervention | Insulin Sensitivity by Intravenous Glucose Tolerance Testing (Change Over Time) | -0.804 mu/L/min | Standard Deviation 2.2 |
Other Pre-specified
Collagen Gene Expression in Skeletal Muscle (Change Over Time)
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.
Time frame: Baseline testing to post-testing after 8-week intervention
Population: Results are reported for the Olmesartan Medoxomil intervention only; there was insufficient RNA yield for the majority of participants during the no drug treatment. Only 7 of the 16 study participants who participated in the study measurements had sufficient data to analyze the pre- and post-intervention skeletal muscle biopsy tissues.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olmesartan Medoxomil | Collagen Gene Expression in Skeletal Muscle (Change Over Time) | Pre-Olmesartan medoxomil | 1491 Arbitrary unit (AU) | Standard Error 510 |
| Olmesartan Medoxomil | Collagen Gene Expression in Skeletal Muscle (Change Over Time) | Post-Olmesartan medoxomil | 774 Arbitrary unit (AU) | Standard Error 271 |