Salsalate Therapy to Reduce Insulin Resistance and Cardiovascular Risk

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Salsalate Therapy to Reduce Insulin Resistance and Cardiovascular Risk

Conditions
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Atherosclerosis, Cardiovascular Disease, Inflammation, Insulin Resistance, Noninsulin-dependent Diabetes Mellitus

Intervention / Treatment
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* Drug: Salsalate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Matching placebo | Drug: Placebo<br>* Participants were randomized to 12-week treatment matching the active salsalate arm.<br>|
| Active Comparator: Salsalate Therapy<br>Salsalate | Drug: Salsalate<br>* Participants were randomized to 12-week treatment with up to 4 g/day.<br>* Other names: Salsitab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Systemic Glucose Disposal- Glucose Infusion Rates | 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 |  | 3 months | 
| Plasma CRP | 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 | Endothelial-mediated arterial responses using peripheral arterial tonometry (PAT; Itamar Medical, Caesarea, Israel). | Baseline and 12 weeks | 
| Plasma Interleukin 6 | 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 | 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 | Plasma soluble Adiponectin was measured by ELISA. Data are reported as change from baseline at 8 and 12 weeks. | 8 and 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiovascular Disease, Inflammation, Insulin Resistance, Type 2 DM