The Effects of Salsalate on Glycemic Control in Patients With Type 2 Diabetes

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 (≤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.

Macrophages and islet inflammation in type 2 diabetes

“…TNF-α inhibitors and salsalate, a prodrug of salicylic acid with inhibitory effects on the NF-κB pathway, have also been tested in T2D [60][61][62][63]. The positive results seen in these studies are consistent with the concept of targeting inflammation to treat T2D.…”

Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes

“…Salsalate, prodrug of salicylate, which unlike aspirin and sodium salicylate does not lead to bleeding risk, can improve insulin sensitivity and glucose control in prediabetic and T2DM patients with a good safety profile [74,75]. More particularly, a large randomized trial, the Targeting Inflammation with Salsalate in Type 2 Diabetes (TINSAL-T2D) trial, concluded that salsalate improves glucose control in T2DM patients with decrease in fasting glucose and glycated haemoglobin levels and enhances lipid profile [75]. These data suggest that NF-κB pathways may represent a novel therapeutic target for prevention and treatment of T2DM.…”

Association of subclinical inflammation with deterioration of glycaemia before the diagnosis of type 2 diabetes: the KORA S4/F4 study

“…Data from epidemiological studies have demonstrated that increased levels of proinflammatory immune mediators and decreased levels of the anti-inflammatory adipokine adiponectin precede the onset of diabetes by many years [1][2][3]. Several approaches to attenuate subclinical inflammation in type 2 diabetes have improved glycaemic control [4][5][6][7][8], underscoring the clinical relevance of the inflammatory processes in the regulation of glucose metabolism.…”