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

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.

Conflict of interest statement

Duality of interest The authors declare that there is no duality of interest associated with this manuscript.

Figures

Fig. 1

Flow chart of participant enrollment, randomisation and analysis. EHC, euglycaemic–hyperinsulinaemic clamp

Fig. 2

Fasting concentrations of plasma glucose (a), C-peptide (b), insulin (c) and NEFA (d). Data are means ± SE. *p

Fig. 3

Responses of plasma glucose (a, b), insulin (c, d), C-peptide (e, f) and NEFA (g, h) to a 2 h OGTT following placebo (a, c, e, g) or salicylate (b, d, f, h) treatment. Inserts (a, b) represent incremental AUC changes in glucose at 0, 8 and 12 weeks. Data are means ± SE. *p †p < 0.05, week 12 (black circles) vs baseline; ‡p < 0.05, ‡‡‡p < 0.001, salsalate vs placebo, repeated measures ANCOVA adjusted for site

Fig. 4

(a) GIR during the euglycaemic–hyperinsulinaemic clamp (EHC) at baseline and after 12 weeks’ treatment with salsalate or placebo. (b) Average insulin concentrations during last 30 min of EHC. (c, d) Metabolic clearance of insulin in the fasting state (c) and during the EHC (d). Data are means ±SE; *p**p< 0.01, within group comparison of week 12 (black bars) vs baseline (white bars); †††p< 0.001, salsalate vs placebo; repeated measures ANCOVA adjusted for site

Fig. 5

Spearman correlation between follow-up plasma salicylate levels and changes (follow-up minus baseline) in fasting glucose (r = −0.54, p = 0.002). Follow-up was defined as the average of week 8 and 12 values

Fig. 6

(a) NF-κB activity in the subcutaneous abdominal adipose tissue (AT) at baseline (white bars) and after 12 weeks’ (black bars) treatment with salsalate or placebo. Data are means ± SE; *p ††p < 0.01, salsalate vs placebo; repeated measures ANCOVA adjusted for site. (b) Spearman correlation between follow-up plasma salicylate levels and change (follow-up minus baseline) in adipose tissue NF-κB activity (r = −0.53, p = 0.02). AU, arbitrary units