Article

Diabetologia

, Volume 56, Issue 4, pp 714-723

First online:

A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance

  • A. B. GoldfineAffiliated withDepartment of Medicine, Joslin Diabetes Center, Harvard Medical School
  • , P. R. ConlinAffiliated withDepartment of Medicine, Boston VA Health Care System, Brigham and Women’s Hospital
  • , F. HalperinAffiliated withDepartment of Medicine, Joslin Diabetes Center, Harvard Medical School
  • , J. KoskaAffiliated withResearch Department, Phoenix VA Health Care System
  • , P. PermanaAffiliated withResearch Department, Phoenix VA Health Care System
  • , D. SchwenkeAffiliated withResearch Department, Phoenix VA Health Care System
  • , S. E. ShoelsonAffiliated withDepartment of Medicine, Joslin Diabetes Center, Harvard Medical School
  • , P. D. ReavenAffiliated withDepartment of Medicine, Phoenix VA Health Care SystemDepartment of Medicine, University of Arizona Email author 

Abstract

Aims/hypothesis

Chronic sub-acute inflammation contributes to the pathogenesis of type 2 diabetes mellitus and cardiovascular disease. High doses of salicylate reduce inflammation, glucose and triacylglycerols, and may improve insulin sensitivity, suggesting therapeutic potential in impaired fasting glucose and/or impaired glucose tolerance. This trial aimed to evaluate the effect of salsalate vs placebo on insulin resistance and glycaemia in impaired fasting glucose and/or impaired glucose tolerance.

Methods

We conducted a 12 week, two-centre, randomised, placebo-controlled study to evaluate the effect of salsalate (up to 4 g/day) vs placebo on systemic glucose disposal. Secondary objectives included treatment effects on glycaemia, inflammation and cardiovascular risk factors. Seventy-eight participants with impaired fasting glucose and/or impaired glucose tolerance from two VA healthcare systems were enrolled. Randomisation assignment was provided by the coordinating center directly to site pharmacists, and participants and research staff were blinded to treatment assignment.

Results

Seventy-one individuals were randomised to placebo (n = 36) or salsalate (n = 35). Glucose disposal did not change in either group (salsalate 1% [95% CI −39%, 56%]; placebo 6% [95% CI −20%, 61%], p = 0.3 for placebo vs salsalate). Fasting glucose was reduced by 6% during the study by salsalate (p = 0.006) but did not change with placebo. Declines in glucose were accompanied by declines in fasting C-peptide with salsalate. Insulin clearance was reduced with salsalate. In the salsalate group, triacylglycerol levels were lower by 25% (p = 0.01) and adiponectin increased by 53% (p = 0.02) at the end of the study. Blood pressure, endothelial function and other inflammation markers did not differ between groups. Adipose tissue nuclear factor κB (NF-κB) activity declined in the salsalate group compared with placebo (−16% vs 42%, p = 0.005), but was not correlated with metabolic improvements. The frequency of tinnitus was low but tended to be higher with salsalate therapy (n = 4 vs n = 2).

Conclusions/interpretation

In summary, salsalate therapy was well tolerated, lowered fasting glucose, increased adiponectin and reduced adipose tissue NF-κB activity. These changes were not related to changes in peripheral insulin sensitivity, suggesting additional mechanisms for metabolic improvement.

Trial registration

ClinicalTrials.gov NCT00330733

Funding

Office of Research and Development, Medical Research Service, Department of Veterans Affairs and NIH K24 DK63214

Keywords

Adipose tissue Cardiovascular risk factors Endothelial function Impaired glucose tolerance Inflammation Insulin resistance Salicylates