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The Impact of Reducing Inflammation on Vascular Function in the Metabolic Syndrome

This study has been completed.
Sponsor:
Information provided by:
Brigham and Women's Hospital
ClinicalTrials.gov Identifier:
NCT00762827
First received: September 26, 2008
Last updated: June 24, 2011
Last verified: June 2011
  Purpose

The purpose of the study is to test whether salsalate,an aspirin-like drug, can improve blood vessel function by reducing inflammation caused by insulin resistance, making the development of blockages less common.

We also want to see if salsalate will

  1. Change the way blood vessels expand and/or
  2. Improve the ability of cells to use blood sugar for energy.

Condition Intervention Phase
Metabolic Syndrome
Drug: Salsalate
Drug: Placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: The Impact of Reducing Inflammation on Vascular Function in the Metabolic Syndrome

Resource links provided by NLM:


Further study details as provided by Brigham and Women's Hospital:

Primary Outcome Measures:
  • The purpose of the study is to test whether salsalate can improve blood vessel function by reducing inflammation caused by insulin resistance, making the development of blockages less common. [ Time Frame: once every 8 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • We also want to see if salsalate will change the way blood vessels expand and/or improve the ability of cells to use blood sugar for energy [ Time Frame: once every 8 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 150
Study Start Date: November 2005
Study Completion Date: June 2011
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1
Salsalate
Drug: Salsalate
4 grams daily for 28 days
Placebo Comparator: 2
Placebo
Drug: Placebo
Matching Placebo

Detailed Description:

To test the hypothesis that reductions in intracellular inflammation will restore insulin-mediated and endothelium-dependent vasodilation in subjects with the metabolic syndrome.

Recent demographic trends indicate a dramatic growth in the incidence of obesity and insulin resistance in the United States, highlighting a population at increased risk for the complications of atherosclerosis. The metabolic syndrome, identified as through a collection of risk factors, is associated with increases in adiposity and insulin resistance. Insulin resistance, typically characterized by impaired skeletal muscle glucose uptake, affects tissues other than skeletal muscle, including liver, adipose, and blood vessels. In experimental animal models and humans with insulin resistance, disturbances in insulin signaling consistently lead to decreased bioavailability of endothelium-derived nitric oxide and impaired endothelium-dependent vasodilation. The impact of abnormal insulin signaling on vascular endothelium has not been well characterized in humans in vivo.

Basic studies suggest that insulin receptor medicated activation of the PI 3-kinase pathway is important for normal endothelial nitric oxide synthase function. Abnormalities demonstrated in the metabolic syndrome alter signaling at multiple sites within this pathway, particularly phosphorylation of the serine residue of the insulin receptor substrate. Excess free fatty acid liberation by adipose tissue impairs insulin signaling and activates protein kinase C beta and Inhibitor kappa B kinase beta. Each of these pathobiological disturbances, including excess FFA, heightened PKC-beta activation, and increased inflammatory transcription factor activation serine phosphorylate IRS, cause endothelial dysfunction in humans, and are potential therapeutic targets. Data defining the pathophysiology of endothelial insulin resistance and the importance of these candidate mechanisms in patients is lacking.

The applicants will determine whether inhibition of IKKbeta by salsalate improves endothelium-dependent vasodilation as a consequence of restored endothelial insulin signaling and serine 1177 phosphorylation of eNOS in patients with metabolic syndrome.

  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • 3 out of 5 of the following:

    • abdominal obesity
    • elevated fasting blood sugar (100 mg/dL< glucose < 126 mg/dL)
    • low HDL
    • elevated fasting blood triglycerides ( > 150 mg/dL)
    • hypertension (BP > 130/85 mm HG)

Exclusion Criteria:

  • * LDL cholesterol >190 mg/dL

    • cigarette smoking within 1 year
    • renal insufficiency (creatinine > 1.4 mg/dl)
    • blood dyscrasia, or hepatic dysfunction (ALT > 2x upper limit of normal)
    • pregnancy
    • no evident atherosclerosis or vascular disease
    • will have a normal cardiovascular examination
    • history of gastrointestinal problems including: gastrointestinal bleed dyspepsia gastroesophageal reflux disease (GERD)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00762827

Locations
United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Brigham and Women's Hospital
Investigators
Principal Investigator: Joshua A Beckman, MD Brigham and Women's Hospital
  More Information

No publications provided by Brigham and Women's Hospital

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Joshua A. Beckman, MD, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT00762827     History of Changes
Other Study ID Numbers: 2005-P-001875
Study First Received: September 26, 2008
Last Updated: June 24, 2011
Health Authority: United States: Institutional Review Board

Keywords provided by Brigham and Women's Hospital:
Excess body weight
High blood pressure
High levels of cholesterol
High blood sugar levels

Additional relevant MeSH terms:
Inflammation
Metabolic Syndrome X
Syndrome
Disease
Glucose Metabolism Disorders
Hyperinsulinism
Insulin Resistance
Metabolic Diseases
Pathologic Processes

ClinicalTrials.gov processed this record on November 27, 2014