Salsalate Therapy to Reduce Insulin Resistance and Cardiovascular Risk

This study has been completed.
Sponsor:
Collaborator:
Joslin Diabetes Center
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT00330733
First received: May 26, 2006
Last updated: April 15, 2014
Last verified: April 2014
  Purpose

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 Intervention Phase
Atherosclerosis
Cardiovascular Disease
Inflammation
Insulin Resistance
Noninsulin-dependent Diabetes Mellitus
Drug: Salsalate
Drug: Placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Salsalate Therapy to Reduce Insulin Resistance and Cardiovascular Risk

Resource links provided by NLM:


Further study details as provided by Department of Veterans Affairs:

Primary Outcome Measures:
  • Change in Systemic Glucose Disposal- Glucose Infusion Rates [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    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:
  • Glucose Area Under the Curve in These Subjects [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  • Plasma Levels of a Variety of Inflammatory Proteins [ Time Frame: 8 and 12 weeks ] [ Designated as safety issue: No ]
  • Parameters of Cardiovascular Disease Risk, Including Glucose, Triglycerides, HDL and Blood Pressure [ Time Frame: 8 and 12 weeks ] [ Designated as safety issue: No ]
  • Endothelial Dysfunction [ Time Frame: 8 and 12 weeks ] [ Designated as safety issue: No ]

Enrollment: 71
Study Start Date: January 2007
Study Completion Date: September 2010
Primary Completion Date: August 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Arm 1
Matching placebo
Drug: Placebo
Matching placebo
Active Comparator: Arm 2
Salsalate
Drug: Salsalate
Salsalate therapy

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.

  Eligibility

Ages Eligible for Study:   21 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  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: NCT00330733

Locations
United States, Arizona
Carl T. Hayden VA Medical Center
Phoenix, Arizona, United States, 85012
Sponsors and Collaborators
Joslin Diabetes Center
Investigators
Principal Investigator: Peter Reaven, MD Carl T. Hayden VA Medical Center
  More Information

Publications:
Responsible Party: Department of Veterans Affairs
ClinicalTrials.gov Identifier: NCT00330733     History of Changes
Other Study ID Numbers: CLIN-011-05F
Study First Received: May 26, 2006
Results First Received: December 18, 2013
Last Updated: April 15, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by Department of Veterans Affairs:
Cardiovascular Disease
Inflammation
Insulin Resistance
Type 2 DM

Additional relevant MeSH terms:
Insulin Resistance
Atherosclerosis
Arteriosclerosis
Inflammation
Cardiovascular Diseases
Diabetes Mellitus
Diabetes Mellitus, Type 2
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Arterial Occlusive Diseases
Vascular Diseases
Pathologic Processes
Endocrine System Diseases
Insulin
Sodium Salicylate
Salicylsalicylic acid
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-Inflammatory Agents
Therapeutic Uses
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on September 16, 2014