Free Fatty Acids-Induced Hypertension in Obese Subjects (Aim #2)

Overview

The purpose of this study is to see if salsalate, an Nuclear factor-kappaB (NF-κB) mediated inflammation inhibitor, or carvedilol, an α- and β-blocker, will protect against free fatty acid induced hypertension, insulin resistance, endothelial dysfunction, inflammation and oxidative stress, and autonomic dysfunction in obese normotensive subjects.

Full Title of Study: “Free Fatty Acids-Induced Hypertension, Endothelial Dysfunction, Inflammation, Insulin Resistance, and Autonomic Dysfunction in Lean and Obese Subjects (Aim #2)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: Double (Participant, Investigator)
  • Study Primary Completion Date: March 2011

Detailed Description

During postprandial lipemia, dietary triglycerides transported by intestinal chylomicrons are hydrolyzed by lipoprotein lipase lining the vascular bed, with subsequent release of FFA for transport across the endothelium. Whether the intermittent flux of FFA has the same impact as the i.v. lipid infusion will be examined. Decreased endothelial function has been reported after a single or long-term dietary high fat load in normal subjects; however, others have found no effects on brachial artery vasoreactivity. Our preliminary studies indicate that high oral fat loads (60 g) resulted in higher FFA levels and BP changes, and reduced FMD compared to low fat load (25 g).

Interventions

  • Drug: Salsalate
    • Salsalate 750 mg
  • Drug: Carvedilol
    • Carvedilol 3.125 mg
  • Drug: Placebo
    • One tablet
  • Drug: Intralipid 20%
    • 24-hour infusion of Intralipid 20% solution at 20 mL/h (96 g/24 h)

Arms, Groups and Cohorts

  • Experimental: Salsalate
    • Obese, normotensive, healthy subjects will receive an intravenous (IV) administration of Intralipid 20% for 24 hours, and then one salsalate 750 mg tablet twice daily for two weeks. If the subject has no side effects, the dose will be increased to two salsalate 750 mg tablets twice daily for the remaining four weeks. The subjects will then receive another 24-hour IV administration of Intralipid 20% at the 6-week point.
  • Experimental: Carvedilol
    • Obese, normotensive, healthy subjects will receive an intravenous (IV) administration of Intralipid 20% for 24 hours, and then one carvedilol 3.125 mg tablet twice daily for two weeks. If the subject has no side effects, the dose will be increased to two carvedilol 3.125 mg tablets twice daily for the remaining four weeks. The subjects will then receive another 24-hour IV administration of Intralipid 20% at the 6-week point.
  • Placebo Comparator: Placebo
    • Obese, normotensive, healthy subjects will receive an intravenous (IV) administration of Intralipid 20% for 24 hours, and then one placebo tablet twice daily for two weeks. The dose will be increased to two placebo tablets twice daily for the remaining four weeks. The subjects will then receive another 24-hour IV administration of Intralipid 20% at the 6-week point.

Clinical Trial Outcome Measures

Primary Measures

  • Change in Systolic Blood Pressure.
    • Time Frame: Pre-dose (Baseline), within 4 hours at Baseline visit
    • Systolic blood pressure is the amount of pressure the heart generates when pumping blood through the arteries to the body. Current guidelines identify normal systolic blood pressure as lower than 120 mmHg. Blood pressure was measured in triplicate with a manual cuff prior to and every 4 hours during the 24-hour infusion with subjects in supine position. Change is the difference in systolic blood pressure at the baseline visit from pre-dosing with Intralipid to 4 hours during Intralipid infusion.
  • Change in Systolic Blood Pressure
    • Time Frame: Pre-dose (Baseline), within 8 hours at Baseline visit
    • Systolic blood pressure is the amount of pressure the heart generates when pumping blood through the arteries to the body. Current guidelines identify normal systolic blood pressure as lower than 120 mmHg. Blood pressure was measured in triplicate with a manual cuff prior to and every 4 hours during the 24-hour infusion with subjects in supine position. from Change is the difference in systolic blood pressure at the baseline visit from pre-dosing with Intralipid to 8 hours during Intralipid.
  • Change in Systolic Blood Pressure
    • Time Frame: Pre-dose (Baseline), within 12 hours at Baseline visit
    • Systolic blood pressure is the amount of pressure the heart generates when pumping blood through the arteries to the body. Current guidelines identify normal systolic blood pressure as lower than 120 mmHg. Blood pressure was measured in triplicate with a manual cuff prior to and every 4 hours during the 24-hour infusion with subjects in supine position. Change is the difference in systolic blood pressure at the baseline visit from pre-dosing with Intralipid to 12 hours during Intralipid infusion.
  • Change in Systolic Blood Pressure
    • Time Frame: Pre-dose (Baseline), within 16 hours at Baseline visit
    • Systolic blood pressure is the amount of pressure the heart generates when pumping blood through the arteries to the body. Current guidelines identify normal systolic blood pressure as lower than 120 mmHg. Blood pressure was measured in triplicate with a manual cuff prior to and every 4 hours during the 24-hour infusion with subjects in supine position. Change is the difference in systolic blood pressure at the baseline visit from pre-dosing with Intralipid to 16 hours during Intralipid infusion.
  • Change in Systolic Blood Pressure
    • Time Frame: Pre-dose (Baseline), within 20 hours at Baseline visit
    • Systolic blood pressure is the amount of pressure the heart generates when pumping blood through the arteries to the body. Current guidelines identify normal systolic blood pressure as lower than 120 mmHg. Blood pressure was measured in triplicate with a manual cuff prior to and every 4 hours during the 24-hour infusion with subjects in supine position. Change is the difference in systolic blood pressure at the baseline visit from pre-dosing with Intralipid to 20 hours during Intralipid infusion.
  • Change in Systolic Blood Pressure
    • Time Frame: Pre-dose (Baseline), within 24 hours at Baseline visit
    • Systolic blood pressure is the amount of pressure the heart generates when pumping blood through the arteries to the body. Current guidelines identify normal systolic blood pressure as lower than 120 mmHg. Blood pressure was measured in triplicate with a manual cuff prior to and every 4 hours during the 24-hour infusion with subjects in supine position. Change is the difference in systolic blood pressure at the baseline visit from pre-dosing with Intralipid to 24 hours during Intralipid infusion.
  • Change in Systolic Blood Pressure
    • Time Frame: Pre-dose (Week 6), within 4 hours at Week 6 visit
    • Systolic blood pressure is the amount of pressure the heart generates when pumping blood through the arteries to the body. Current guidelines identify normal systolic blood pressure as lower than 120 mmHg. Blood pressure was measured in triplicate with a manual cuff prior to and every 4 hours during the 24-hour infusion with subjects in supine position. Change is the difference in systolic blood pressure at Week 6 from pre-dosing with Intralipid to 4 hours during Intralipid infusion.
  • Change in Systolic Blood Pressure
    • Time Frame: Pre-dose (Week 6), within 8 hours at Week 6 visit
    • Systolic blood pressure is the amount of pressure the heart generates when pumping blood through the arteries to the body. Current guidelines identify normal systolic blood pressure as lower than 120 mmHg. Blood pressure was measured in triplicate with a manual cuff prior to and every 4 hours during the 24-hour infusion with subjects in supine position. Change is the difference in systolic blood pressure from at Week 6 from pre-dosing with Intralipid to 8 hours during Intralipid infusion.
  • Change in Systolic Blood Pressure
    • Time Frame: Pre-dose (Week 6), within 12 hours at Week 6 visit
    • Systolic blood pressure is the amount of pressure the heart generates when pumping blood through the arteries to the body. Current guidelines identify normal systolic blood pressure as lower than 120 mmHg. Blood pressure was measured in triplicate with a manual cuff prior to and every 4 hours during the 24-hour infusion with subjects in supine position. Change is the difference in systolic blood pressure at Week 6 from pre-dosing with Intralipid to 12 hours during Intralipid infusion.
  • Change in Systolic Blood Pressure
    • Time Frame: Pre-dose (Week 6), within 16 hours at Week 6 visit
    • Systolic blood pressure is the amount of pressure the heart generates when pumping blood through the arteries to the body. Current guidelines identify normal systolic blood pressure as lower than 120 mmHg. Blood pressure was measured in triplicate with a manual cuff prior to and every 4 hours during the 24-hour infusion with subjects in supine position. Change is the difference in systolic blood pressure at Week 6 from pre-dosing with Intralipid to 16 hours during Intralipid infusion.
  • Change in Systolic Blood Pressure
    • Time Frame: Pre-dose (Week 6), within 20 hours at Week 6 visit
    • Systolic blood pressure is the amount of pressure the heart generates when pumping blood through the arteries to the body. Current guidelines identify normal systolic blood pressure as lower than 120 mmHg. Blood pressure was measured in triplicate with a manual cuff prior to and every 4 hours during the 24-hour infusion with subjects in supine position. Change is the difference in systolic blood pressure at Week 6 from pre-dosing with Intralipid to 20 hours during Intralipid infusion.
  • Change in Systolic Blood Pressure
    • Time Frame: Pre-dose (Week 6), within 24 hours at Week 6 visit
    • Systolic blood pressure is the amount of pressure the heart generates when pumping blood through the arteries to the body. Current guidelines identify normal systolic blood pressure as lower than 120 mmHg. Blood pressure was measured in triplicate with a manual cuff prior to and every 4 hours during the 24-hour infusion with subjects in supine position. Change is the difference in systolic blood pressure at Week 6 from pre-dosing with Intralipid to 24 hours during Intralipid infusion.
  • Change in Flow-mediated Dilation
    • Time Frame: Pre-dose (Baseline), within 12 hours at Baseline visit
    • The change in endothelium-dependent vascular reactivity will be measured by flow-mediated dilation (FMD) of the brachial artery using a high-resolution vascular ultrasound with a 10-MHz linear array transducer. FMD is expressed as the percentage increase in diameter at the baseline visit from pre-dosing with Intralipid to 12 hours during Intralipid infusion.
  • Change in Flow-mediated Dilation
    • Time Frame: Pre-dose (Baseline), within 24 hours at Baseline visit
    • The change in endothelium-dependent vascular reactivity will be measured by flow-mediated dilation (FMD) of the brachial artery using a high-resolution vascular ultrasound with a 10-MHz linear array transducer. FMD is expressed as the percentage increase in diameter at the baseline visit from pre-dosing with Intralipid to 24 hours during Intralipid infusion
  • Change in Flow-mediated Dilation
    • Time Frame: Pre-dose (Week 6), within 12 hours at Week 6 visit
    • The change in endothelium-dependent vascular reactivity will be measured by flow-mediated dilation (FMD) of the brachial artery using a high-resolution vascular ultrasound with a 10-MHz linear array transducer. FMD is expressed as the percentage increase in diameter at the Week 6 visit from pre-dosing with Intralipid to 12 hours during Intralipid infusion.
  • Change in Flow-mediated Dilation
    • Time Frame: Pre-dose (Week 6), within 24 hours at Week 6 visit
    • The change in endothelium-dependent vascular reactivity will be measured by flow-mediated dilation (FMD) of the brachial artery using a high-resolution vascular ultrasound with a 10-MHz linear array transducer. FMD is expressed as the percentage increase in diameter at the Week 6 visit from pre-dosing with Intralipid to 24 hours during Intralipid infusion

Secondary Measures

  • Change in Diastolic Blood Pressure From Baseline to 6 Weeks
    • Time Frame: Baseline, 6 weeks
    • Diastolic blood pressure is the amount of pressure in the arteries when the heart is at rest between beats. Current guidelines identify normal diastolic blood pressure as lower than 80 mmHg. Blood pressure was measured in triplicate with a manual cuff prior to and every 4 hours during the 8 hour infusion with subjects in supine position. Change is the difference between 6-week diastolic blood pressure from baseline diastolic blood pressure.
  • Change in Oxidative Stress Markers.
    • Time Frame: Baseline, 6 weeks
    • Oxidative stress was measured by using liquid chromatography to collect plasma glutathione and glutathione disulfide. Change is the difference between 6-week plasma glutathione and glutathione disulfide from baseline plasma glutathione and glutathione disulfide.
  • Change in Augmentation Index (AIx)
    • Time Frame: Baseline, 6 weeks
    • AIx is a surrogate measure of peripheral arterial resistance and is measured by analysis of the pulse wave at the radial artery. The AIx is calculated as the ratio of the pulse pressure at the second systolic peak to that at the first systolic peak. Change is the difference between 6-week AIx from baseline AIx.
  • Change in Expression of Inflammatory Biomarker Interleukin-6 (IL-6)
    • Time Frame: Baseline, 6 weeks
    • It is measured by using microsphere-based flow cytometric immunoassay. Change is the difference between 6-week level from baseline level.
  • Change in FFA (Free Fatty Acid) Levels From Baseline to 6 Weeks
    • Time Frame: Baseline, 6 weeks
    • Blood samples were collected for measurement of free fatty acids at baseline and 6 weeks after the Intralipid 20% infusion. FFA levels were determined by colorimetric method. Current guidelines identify normal range of FFA level as less than 0.72 mmol/L. Elevated plasma levels of FFA indicate a greater rate of insulin resistance. Change is the difference between 6-week FFA levels from baseline FFA levels.
  • Change in Pulse Wave Velocity (PWV)
    • Time Frame: Baseline, 6 weeks
    • PWV was measured between the carotid and femoral arteries using the SphygmoCor device. Pressure waveforms at the carotid and femoral arteries were acquired using EKG gating. Velocity (distance per time in milliseconds) was calculated using the foot-to-foot method and the distance between the sites was measured manually.
  • Change in Expression of Inflammatory Biomarker C-Reactive Protein (CRP)
    • Time Frame: Baseline, 6 weeks
    • It is measured by using microsphere-based flow cytometric immunoassay. Change is the difference between 6-week inflammatory biomarker level from baseline level.

Participating in This Clinical Trial

Inclusion Criteria

  • Males or females – Obese subjects (body mass index (BMI) ≥ 30 kg/m^2) – 18 and 65 years – Blood pressure reading < 140/80 mm Hg and no prior history of hypertension Exclusion Criteria:

  • History of diabetes mellitus – History of hypertension – Fasting triglyceride levels > 250 mg/dL – Liver disease (ALT 2.5x > upper limit of normal) – Serum creatinine ≥1.5 mg/dL – Smokers, drug or alcohol abuse – Mental condition rendering the subject unable to understand the scope and possible consequences of the study – Female subjects who are pregnant or breast feeding

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 65 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Emory University
  • Collaborator
    • American Diabetes Association
  • Provider of Information About this Clinical Study
    • Principal Investigator: Guillermo Umpierrez, MD, Professor – Emory University
  • Overall Official(s)
    • Guillermo Umpierrez, MD, Principal Investigator, Emory University

Clinical trials entries are delivered from the US National Institutes of Health and are not reviewed separately by this site. Please see the identifier information above for retrieving further details from the government database.

At TrialBulletin.com, we keep tabs on over 200,000 clinical trials in the US and abroad, using medical data supplied directly by the US National Institutes of Health. Please see the About and Contact page for details.