Salsalate Therapy to Reduce Insulin Resistance and Cardiovascular Risk
Condition: Atherosclerosis; Cardiovascular Disease; Inflammation; Insulin Resistance; Noninsulin-dependent Diabetes Mellitus
MeSH terms: Cardiovascular Diseases; Atherosclerosis; Insulin Resistance; Diabetes Mellitus, Type 2; Inflammation
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

Intervention name(s): Salsalate; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Participants were randomized to 12-week treatment with up to 4 g/day.; Participants were randomized to 12-week treatment matching the active salsalate arm.
Other intervention name(s): Amigesic; Anaflex; Argesic-SA; Disalcid; Marthritic; Mono-Gesic; Salflex; Salsitab
Intervention MeSH terms: Salicylsalicylic acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Cardiovascular Disease; Inflammation; Insulin Resistance; Type 2 DM