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

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ClinicalTrials.gov Identifier: NCT02406586
Recruitment Status : Completed
First Posted : April 2, 2015
Results First Posted : May 28, 2015
Last Update Posted : May 28, 2015
Sponsor:
Collaborator:
American Diabetes Association
Information provided by (Responsible Party):
Guillermo Umpierrez, Emory University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Hypertension Diabetes Drug: Salsalate Drug: Carvedilol Drug: Placebo Drug: Intralipid 20% Not Applicable

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).

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: Free Fatty Acids-Induced Hypertension, Endothelial Dysfunction, Inflammation, Insulin Resistance, and Autonomic Dysfunction in Lean and Obese Subjects (Aim #2)
Study Start Date : July 2009
Actual Primary Completion Date : March 2011
Actual Study Completion Date : March 2011

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
Drug: Salsalate
Salsalate 750 mg
Other Names:
  • Disalcid
  • NSAID

Drug: Intralipid 20%
24-hour infusion of Intralipid 20% solution at 20 mL/h (96 g/24 h)
Other Name: 20% I.V. Fat Emulsion

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.
Drug: Carvedilol
Carvedilol 3.125 mg
Other Name: Coreg

Drug: Intralipid 20%
24-hour infusion of Intralipid 20% solution at 20 mL/h (96 g/24 h)
Other Name: 20% I.V. Fat Emulsion

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.
Drug: Placebo
One tablet

Drug: Intralipid 20%
24-hour infusion of Intralipid 20% solution at 20 mL/h (96 g/24 h)
Other Name: 20% I.V. Fat Emulsion




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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.

  16. 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 Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. Change in Expression of Inflammatory Biomarkers (Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-12 (IL-12), Tumor Necrosis Factor Alpha (TNF-alpha), and C-Reactive Protein (CRP)) [ Time Frame: Baseline, 6 weeks ]
    IL-1, IL-6, IL-12, TNF-alpha, and CRP are inflammatory biomarkers. Each was measured by using microsphere-based flow cytometric immunoassay. Change is the difference between 6-week inflammatory biomarkers from baseline inflammatory biomarkers.

  5. 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.

  6. 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.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02406586


Locations
United States, Georgia
Grady Memorial Hospital
Atlanta, Georgia, United States, 30303
Sponsors and Collaborators
Emory University
American Diabetes Association
Investigators
Principal Investigator: Guillermo Umpierrez, MD Emory University

Responsible Party: Guillermo Umpierrez, Professor, Emory University
ClinicalTrials.gov Identifier: NCT02406586     History of Changes
Other Study ID Numbers: IRB00009277a
First Posted: April 2, 2015    Key Record Dates
Results First Posted: May 28, 2015
Last Update Posted: May 28, 2015
Last Verified: May 2015

Additional relevant MeSH terms:
Hypertension
Vascular Diseases
Cardiovascular Diseases
Carvedilol
Soybean oil, phospholipid emulsion
Salicylsalicylic acid
Sodium Salicylate
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antihypertensive Agents
Vasodilator Agents
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists
Fat Emulsions, Intravenous
Parenteral Nutrition Solutions
Pharmaceutical Solutions
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors