Salsalate Shows Promise in Treating Type 2 Diabetes

Norra MacReady

March 17, 2010

March 17, 2010 — Treatment with salsalate lowers levels of hemoglobin A1c (HbA1c) and improves markers of glycemic control and coronary risk in people with type 2 diabetes, according to a new study published in the March 16 issue of the Annals of Internal Medicine.

"This study was small, but if a larger trial confirms the findings, salsalate may offer diabetic patients another treatment option," write the authors, led by Allison B. Goldfine, MD, from the Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts.

The hypoglycemic effects of sodium salicylate, an anti-inflammatory agent, have been known for over a century. Aspirin, or acetylsalicylic acid, also can lower blood glucose, but doctors are reluctant to prescribe it for diabetes because in high doses aspirin is associated with bleeding and gastrointestinal irritation. The authors pilot-tested salsalate, a prodrug form of salicylate with a long track record of safety and efficacy in treating arthritis, in people with diabetes and found that it "reduced blood glucose, triglyceride, free fatty acid and C-reactive protein concentrations; improved glucose utilization; and increased circulating insulin and adiponectin concentrations in small proof-of-concept studies." Encouraged by these findings, the authors conducted this study, the Targeting Inflammation Using Salsalate in Type 2 Diabetes trial.

The patients, recruited from 3 private practices and 14 university sites around the United States, were type 2 diabetics ranging in age from 18 to 74 years, with fasting blood glucose concentrations of 12.5 mmol/L or less (≤225 mg/dL) and HbA1c levels of 7.0% to 9.5% at screening. Their usual treatment was diet and exercise alone or with oral medication. Each patient was randomly assigned to 1 of 4 groups: salsalate in dosages of 3.0, 3.5, or 4.0 g/day or a placebo. The patients remained on their other medications for the duration of the study. The treatment period lasted 14 weeks, with evaluations at 2, 4, 8, and 14 weeks after randomization. There were 25 to 27 patients in each group.

Compared with the placebo group, more patients in each of the 3 salsalate groups experienced a drop in HbA1c level of 0.5% or more from baseline (P = .009 overall), with the biggest change seen in the group receiving the highest dose. Patients taking salsalate also experienced significant improvements in other measures of glycemic control, such as fasting glucose concentration (P < .001 compared with placebo) and glycated albumin level (P < .001 compared with placebo), as well as plasma triglyceride concentration (P = .002 compared with placebo).

The most commonly observed adverse effect was hypoglycemia, which was mild and easily managed in most cases. Signals for renal safety were "mixed," the authors write. Urine albumin concentrations increased, but they were measured only once during the study and may vary depending on other factors such as dietary salt and protein intake, exercise, and time of day. Small increases in creatinine level and estimated glomerular filtration rate were observed in patients taking salsalate in a dose of 3.5 g/day, but the significance of these findings is unclear. Overall, these observations are consistent with the safety profile observed in people taking long-term high doses of salsalate for rheumatologic conditions.

The trial's main limitation was its small size, the authors write. They are now conducting a longer, larger trial to further establish the safety and efficacy of salsalate in the management of people with type 2 diabetes.

These findings also may offer further insight into the pathogenesis of diabetes, the investigators write. "Because of salsalate's anti-inflammatory effects, our results suggest that inflammation plays a role in the pathogenesis of type 2 diabetes and that anti-inflammatory therapy may therefore be useful for treating diabetes."

Caraco Pharmaceutical provided drug and placebo for the trial, Lifescan provided home glucose monitoring supplies, and Mercodia provided insulin assay kits. The authors have disclosed no relevant financial relationships.

Ann Intern Med. 2010;152:346-357. Abstract