The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial

Abstract

Background: Salsalate, a nonacetylated prodrug of salicylate, has been shown to decrease blood glucose concentration in small studies.

Objective: To compare the efficacy and safety of salsalate at different doses in patients with type 2 diabetes.

Design: Parallel randomized trial with computer-generated randomization and centralized allocation. Patients and investigators, including those assessing outcomes and performing analyses, were masked to group assignment. (ClinicalTrials.gov registration number: NCT00392678)

Setting: 3 private practices and 14 universities in the United States.

Patients: Persons aged 18 to 75 years with fasting plasma glucose concentrations of 12.5 mmol/L or less (< or = 225 mg/dL) and hemoglobin A1c (HbA1c) levels of 7.0% to 9.5% treated by diet, exercise, and oral medication at stable doses for at least 8 weeks.

Intervention: After a 4-week, single-masked run-in period, patients were randomly assigned to receive placebo or salsalate in dosages of 3.0, 3.5, or 4.0 g/d for 14 weeks (27 patients each) in addition to their current therapy.

Measurements: Change in HbA1c was the primary outcome. Adverse effects and changes in measures of coronary risk and renal function were secondary outcomes.

Results: Higher proportions of patients in the 3 salsalate treatment groups experienced decreases in HbA1c levels of 0.5% or more from baseline (P = 0.009). Mean HbA1c changes were -0.36% (P = 0.02) at 3.0 g/d, -0.34% (P = 0.02) at 3.5 g/d, and -0.49% (P = 0.001) at 4.0 g/d compared with placebo. Other markers of glycemic control also improved in the 3 salsalate groups, as did circulating triglyceride and adiponectin concentrations. Mild hypoglycemia was more common with salsalate; documented events occurred only in patients taking sulfonylureas. Urine albumin concentrations increased in all salsalate groups compared with placebo. The drug was otherwise well tolerated.

Limitation: The number of patients studied and the trial duration were insufficient to warrant recommending the use of salsalate for type 2 diabetes at this time.

Conclusion: Salsalate lowers HbA1c levels and improves other markers of glycemic control in patients with type 2 diabetes and may therefore provide a new avenue for treatment. Renal and cardiac safety of the drug require further evaluation.

Primary funding source: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

Figure 1. Study flow diagram

* Participant who did not receive medication was excluded; participant who withdrew because of tinnitus was included in analysis.

Figure 2. Changes in circulating metabolic measures, by study group

All data are provided as unadjusted mean changes. Each data point represents the mean value for all patients examined. We analyzed 27 patients at baseline in each group. This decreased to 26 patients in the 4.0-g/d group at 4 weeks; 26 and 25 patients in the 3.5- and 4.0-g/d groups, respectively, at 8 weeks; and 26 patients in the placebo and 3.5-g/d groups and 25 in the 4.0-g/d group at 14 weeks (Figure 1). We used the Holm procedure to adjust for multiple comparisons in all cases. FBG = fasting blood glucose; HbA_1c = hemoglobin A_1c; HDL = high-density lipoprotein. A. Trends in HbA_1c level over time. The F test for the overall effect of treatment group was significant (P = 0.003) as was each pairwise test between placebo and salsalate (P = 0.02, 0.02, and 0.001 for the 3.0-g/d, 3.5-g/d, and 4.0-g/d groups, respectively). B. Trends in FBG concentration over time. To convert results from mg/dL to mmol/L, multiply by 0.0555. C. Trends in glycated albumin level over time. D. Trends in adiponectin concentration over time. The F test for each overall effect in panels B, C, and D was significant (P < 0.001), as was each pairwise test between placebo and salsalate (P < 0.001 for all doses). E. Trends in triglyceride concentration over time. The F test for the overall effect of treatment group was significant (P = 0.005). Each pairwise test between placebo and salsalate was significant (P = 0.002, 0.02, and 0.03 for the 3.0-g/d, 3.5-g/d, and 4.0-g/d groups, respectively). To convert results from mg/dL to mmol/L, multiply by 0.0113. F. Trends in total–HDL cholesterol ratio over time. This ratio did not change (P = 0.55).