Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial

Abstract

Background: Short-duration studies show that salsalate improves glycemia in type 2 diabetes mellitus (T2DM).

Objective: To assess 1-year efficacy and safety of salsalate in T2DM.

Design: Placebo-controlled, parallel trial; computerized randomization and centralized allocation, with patients, providers, and researchers blinded to assignment. (ClinicalTrials.gov: NCT00799643).

Setting: 3 private practices and 18 academic centers in the United States.

Patients: Persons aged 18 to 75 years with fasting glucose levels of 12.5 mmol/L or less (≤225 mg/dL) and hemoglobin A1c (HbA1c) levels of 7.0% to 9.5% who were treated for diabetes.

Intervention: 286 participants were randomly assigned (between January 2009 and July 2011) to 48 weeks of placebo (n = 140) or salsalate, 3.5 g/d (n = 146), in addition to current therapies, and 283 participants were analyzed (placebo, n = 137; salsalate, n = 146).

Measurements: Change in hemoglobin A1c level (primary outcome) and safety and efficacy measures.

Results: The mean HbA1c level over 48 weeks was 0.37% lower in the salsalate group than in the placebo group (95% CI, -0.53% to -0.21%; P < 0.001). Glycemia improved despite more reductions in concomitant diabetes medications in salsalate recipients than in placebo recipients. Lower circulating leukocyte, neutrophil, and lymphocyte counts show the anti-inflammatory effects of salsalate. Adiponectin and hematocrit levels increased more and fasting glucose, uric acid, and triglyceride levels decreased with salsalate, but weight and low-density lipoprotein cholesterol levels also increased. Urinary albumin levels increased but reversed on discontinuation; estimated glomerular filtration rates were unchanged.

Limitation: Trial duration and number of patients studied were insufficient to determine long-term risk-benefit of salsalate in T2DM.

Conclusion: Salsalate improves glycemia in patients with T2DM and decreases inflammatory mediators. Continued evaluation of mixed cardiorenal signals is warranted.

Figure 1. Study flow diagram

All data were used through trial completion or point of withdrawal for patients with a baseline HbA_1c measurement. Two participants withdrew after randomization but before the blood draw; 1 additional participant did not have baseline HbA_1c measurement from the laboratory. Percentages may not sum to 100 due to rounding. HbA_1c = hemoglobin A_1c.

Figure 2. Glycemic effects of salsalate

HbA_1c (A) and FBG (C) levels are graphed as unadjusted means and 95% CIs. In panel A, the numbers of participants analyzed for the primary end point of HbA_1c levels at each time point are displayed below study week. Mild hypoglycemia events (B) and notifications for hyperglycemia (D) sent to the primary caregivers are based on HbA_1c levels >10.5% before week 24 and >9.5% after week 24. Participants could have >1 mild hypoglycemic event or exceed the hyperglycemic threshold >1 time during the trial. FBG = fasting blood glucose; HbA_1c = hemoglobin A_1c.

Figure 3. Mean values and 95% CIs for leukocyte count (A), hematocrit (B), neutrophil count (C), adiponectin level (D), lymphocyte count (E), and LDL cholesterol level (F)

LDL = low-density lipoprotein.

Figure 4. Renal effects of salsalate

ACR = albumin–creatinine ratio; DC = discontinued; eGFR = estimated glomerular filtration rate; IQR = interquartile range; MDRD = Modification of Diet in Renal Disease; NS = not significant. A. Median changes and IQRs for urinary ACR. Error bars represent the IQRs. The 2.3-μg/mg between-group difference in ACR reported in the text and values reported in Table 2 were obtained by back-transformation of log-transformed data for ACR because ACR was not normally distributed. B. Mean changes and 95% CIs in circulating uric acid levels. C and D. ACRs for the 23 participants receiving placebo (C) and 33 receiving salsalate (D) who were asked to return at week 56, after 8-week washout period, because ACR or blood pressure was elevated at week 48. Lines are median values; shaded areas are 25th through 75th quartiles. E and F. Mean changes and 95% CIs for eGFRs, using creatinine concentrations and the MDRD equation (E) or cystatin C concentrations (F).