Salsalate Therapy to Reduce Insulin Resistance and Cardiovascular Risk

January 10, 2020 updated by: VA Office of Research and Development

The hypothesis is that salsalate therapy may be an effective and safe method to modulate inflammation in metabolically-critical tissues and thus reduce insulin resistance and its related complications.

The objectives of the study are to (1) determine whether salsalate therapy improves insulin resistance in subjects with IGT and changes in glucose area under the curve following a standard oral glucose tolerance test (OGTT); (2) determine whether salsalate therapy reduces a) plasma levels of a variety of well established inflammatory proteins and b) mononuclear cell inflammatory activity to provide evidence of reduced systemic and tissue inflammation, respectively; and (3)also determine whether salsalate therapy improves parameters of cardiovascular disease risk, including features of metabolic syndrome (fasting glucose, triglycerides, HDL, and blood pressure) as well as endothelial dysfunction.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Recent studies demonstrate an important role for sub-acute, chronic inflammation in the development of insulin resistance, type 2 diabetes mellitus (T2 DM) and cardiovascular disease (CVD). A broad body of data indicate that obesity and high fat or "Western" diets activate sub-acute inflammatory processes in fat and liver tissue as well as in mononuclear cells. The inflammatory mediators produced by these tissues and cells promote the development of insulin resistance both locally and at distant sites such as skeletal muscle. These same inflammatory mediators may also increase the risk for CVD. Work from our labs indicate that Nuclear Factor-kappa B (NF-kB), an inflammatory master switch for a multitude of proinflammatory genes and pathways, is activated in fat and liver by obesity and high fat diets. We have also noted similar NF-kB activation in monocytes and macrophages in similar conditions of nutritional excess. It has become evident that salicylates inhibit the NF-kB regulatory protein IKKB (inhibitor of Kappa B Kinase) and we have subsequently demonstrated their ability to downregulate NF-kB activation in each of these above tissues in animals. Moreover, by inhibiting the IKKB/NF-kB pathway, salicylates appear to ameliorate insulin resistance and its associated metabolic abnormalities and potentially provide a new approach for pharmacologic treatment of T2 DM as well as individuals with conditions such as impaired glucose intolerance (IGT) to prevent their progression to diabetes. Preliminary results from a two-week trail is T2 DM patients indicated that high-dose aspirin(ASA,~7g/day) improved glucose metabolism and associated risk factors. While this was as important first step towards proof-of-principle, the risk of severe gastrointestinal bleeding associated with high-dose ASA precludes broader use. Salicylate in its prodrug form of salsalate(Disalcid), is much safer than ASA(as it does not irritate the gastric mucosa nor alter bleeding times). We have now conducted several preliminary short-term in individuals with IGT or T2 DM as well in obese insulin resistant subjects and have demonstrated that salsalate in doses of 3.5-4.5g/d provides similar blood salicylate levels as high dose ASA and induces similar clinical and metabolic benefits over the 2-4 weeks study duration. Therefore, in vitro, animal and human clinical studies all support the concept that inhibiting the IKKB/NF-kB pathway with salsalate is a feasible approach to reducing insulin resistance. This study will more fully characterize the metabolic benefits of high dose salsalate therapy.

Study Type

Interventional

Enrollment (Actual)

71

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Arizona
      • Phoenix, Arizona, United States, 85012
        • Carl T. Hayden VA Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Male and female veterans between the age of 21-75 who have IFG (impaired fasting glucose) and/or IGT

Exclusion Criteria:

  • any diabetes therapy in the prior 12-months period
  • any acute illness
  • Ongoing high dose aspirin or Salsalate Therapy
  • history of GI bleeding
  • hearing problems
  • poor vascular access, prior pancreatitis, uncontrolled hypertension, pregnancy, renal disease or anemia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo
Matching placebo
Drug: Placebo
Participants were randomized to 12-week treatment matching the active salsalate arm.
Active Comparator: Salsalate Therapy
Salsalate
Drug: Salsalate
Participants were randomized to 12-week treatment with up to 4 g/day.
Other Names:
  • Disalcid
  • Mono-Gesic
  • Salflex
  • Salsitab
  • Amigesic
  • Anaflex
  • Argesic-SA
  • Marthritic

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Systemic Glucose Disposal- Glucose Infusion Rates
Time Frame: 3 months
Participants were admitted to the Clinical Research Units at 06:00-08:00 hours after an overnight fast. Euglycaemic-hyperinsulinaemic clamps were conducted at baseline and at the end of the study. Because salsalate therapy appears to decrease insulin clearance leading to higher circulating insulin levels during the clamp, we reduced the infusion rate of insulin in the active treatment arm by 20% (from 100 to 80 mUm-2 min-1) at the study end. Insulin solutions were prepared by the site pharmacist so that study staff remained blinded to drug assignment. Whole-body insulin sensitivity was estimated from glucose infusion rate (GIR) during last 30 min of insulin infusions.
3 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Glucose Area Under the Curve in These Subjects
Time Frame: 3 months
3 months
Plasma CRP
Time Frame: 8 and 12 weeks
Plasma C-reactive protein was measured by PVAHS clinical laboratory. Data are reported as change from baseline at 8 and 12 weeks.
8 and 12 weeks
Endothelial Function
Time Frame: Baseline and 12 weeks
Endothelial-mediated arterial responses using peripheral arterial tonometry (PAT; Itamar Medical, Caesarea, Israel).
Baseline and 12 weeks
Plasma Interleukin 6
Time Frame: 8 and 12 weeks
Plasma IL-6 was measured by ELISA. Data are reported as change from baseline at 8 and 12 weeks.
8 and 12 weeks
Plasma sVCAM
Time Frame: 8 and 12 weeks
Plasma soluble VCAM was measured by ELISA. Data are reported as change from baseline at 8 and 12 weeks.
8 and 12 weeks
Plasma Adiponectin
Time Frame: 8 and 12 weeks
Plasma soluble Adiponectin was measured by ELISA. Data are reported as change from baseline at 8 and 12 weeks.
8 and 12 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

VA Office of Research and Development

Collaborators

Joslin Diabetes Center

Investigators

  • Principal Investigator: Peter Reaven, MD, Carl T. Hayden VA Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2007

Primary Completion (Actual)

August 1, 2010

Study Completion (Actual)

September 1, 2010

Study Registration Dates

First Submitted

May 26, 2006

First Submitted That Met QC Criteria

May 26, 2006

First Posted (Estimate)

May 29, 2006

Study Record Updates

Last Update Posted (Actual)

January 21, 2020

Last Update Submitted That Met QC Criteria

January 10, 2020

Last Verified

January 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CLIN-011-05F

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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