Clinical trial NCT00330733: Salsalate Therapy to Reduce Insulin Resistance and Cardiovascular Risk
Official title: Salsalate Therapy to Reduce Insulin Resistance and Cardiovascular Risk
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Atherosclerosis
Cardiovascular Disease
Inflammation
Insulin Resistance
Noninsulin-dependent Diabetes Mellitus
Keywords: Cardiovascular Disease
Inflammation
Insulin Resistance
Type 2 DM
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: Joslin Diabetes Center
First posted: 2006-05-29
Enrollment: 71
Sex: ALL
Minimum age (years): 21
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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 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

Primary outcomes:
measure: Change in Systemic Glucose Disposal- Glucose Infusion Rates
timeFrame: 3 months
Secondary outcomes:
measure: Glucose Area Under the Curve in These Subjects
timeFrame: 3 months
measure: Plasma CRP
timeFrame: 8 and 12 weeks
measure: Endothelial Function
timeFrame: Baseline and 12 weeks
measure: Plasma Interleukin 6
timeFrame: 8 and 12 weeks
measure: Plasma sVCAM
timeFrame: 8 and 12 weeks
measure: Plasma Adiponectin
timeFrame: 8 and 12 weeks
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Carl T. Hayden VA Medical Center
state: Arizona
Study officials:
affiliation: Carl T. Hayden VA Medical Center
name: Peter Reaven, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Goldfine AB, Conlin PR, Halperin F, Koska J, Permana P, Schwenke D, Shoelson SE, Reaven PD. A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance. Diabetologia. 2013 Apr;56(4):714-23. doi: 10.1007/s00125-012-2819-3. Epub 2013 Jan 31.