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Salsalate Therapy to Reduce Insulin Resistance and Cardiovascular Risk

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00330733
Recruitment Status : Completed
First Posted : May 29, 2006
Results First Posted : April 22, 2014
Last Update Posted : January 21, 2020
Joslin Diabetes Center
Information provided by (Responsible Party):
VA Office of Research and Development

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Atherosclerosis Cardiovascular Disease Inflammation Insulin Resistance Noninsulin-dependent Diabetes Mellitus Drug: Salsalate Drug: Placebo Phase 2 Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 71 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Salsalate Therapy to Reduce Insulin Resistance and Cardiovascular Risk
Study Start Date : January 2007
Actual Primary Completion Date : August 2010
Actual Study Completion Date : September 2010

Resource links provided by the National Library of Medicine

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
Drug: Salsalate
Participants were randomized to 12-week treatment with up to 4 g/day.
Other Names:
  • Amigesic
  • Anaflex
  • Argesic-SA
  • Disalcid
  • Marthritic
  • Mono-Gesic
  • Salflex
  • Salsitab

Primary Outcome Measures :
  1. 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.

Secondary Outcome Measures :
  1. Glucose Area Under the Curve in These Subjects [ Time Frame: 3 months ]
  2. 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.

  3. Endothelial Function [ Time Frame: Baseline and 12 weeks ]
    Endothelial-mediated arterial responses using peripheral arterial tonometry (PAT; Itamar Medical, Caesarea, Israel).

  4. 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.

  5. 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.

  6. 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.

Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

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 identifier (NCT number): NCT00330733

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United States, Arizona
Carl T. Hayden VA Medical Center
Phoenix, Arizona, United States, 85012
Sponsors and Collaborators
VA Office of Research and Development
Joslin Diabetes Center
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Principal Investigator: Peter Reaven, MD Carl T. Hayden VA Medical Center
Publications of Results:
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Responsible Party: VA Office of Research and Development Identifier: NCT00330733    
Other Study ID Numbers: CLIN-011-05F
First Posted: May 29, 2006    Key Record Dates
Results First Posted: April 22, 2014
Last Update Posted: January 21, 2020
Last Verified: January 2020
Keywords provided by VA Office of Research and Development:
Cardiovascular Disease
Insulin Resistance
Type 2 DM
Additional relevant MeSH terms:
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Cardiovascular Diseases
Insulin Resistance
Diabetes Mellitus, Type 2
Pathologic Processes
Glucose Metabolism Disorders
Metabolic Diseases
Arterial Occlusive Diseases
Vascular Diseases
Diabetes Mellitus
Endocrine System Diseases
Salicylsalicylic acid
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents