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

Metabolic Syndrome Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00762827
• Other study ID #: 2005-P-001875
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: September 26, 2008
• Last updated: June 24, 2011
• Start date: November 2005
• Est. completion date: June 2011

Study information

• Verified date: June 2011
• Source: Brigham and Women's Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 150
• Est. completion date: June 2011
• Est. primary completion date: June 2011
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 85 Years

Eligibility

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)

Study Design

Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Metabolic Syndrome
• Metabolic Syndrome X
• Syndrome

Intervention

Drug:
• Salsalate
4 grams daily for 28 days
• Placebo
Matching Placebo

Locations

Country	Name	City	State
United States	Brigham and Women's Hospital	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Brigham and Women's Hospital

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.		once every 8 weeks	No
Secondary	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		once every 8 weeks	No