Salsalate an Effective Add-on for Type 2’s

The salicylate drug salsalate may be an effective add-on therapy for poorly controlled type 2 diabetes….

In a 1-year randomized, controlled trial involving 286 patients already taking one to three medications for diabetes, adding daily oral salsalate consistently reduced hemoglobin A_1c and fasting glucose levels, as well as improving other cardiometabolic risk factors.

The magnitude of the treatment effect was similar to that reported for other add-on diabetes therapies currently in use.

The treatment was well tolerated, no serious adverse events occurred, and there was no evidence of gastrointestinal adverse effects. However, some changes in renal function and cholesterol levels "require continued evaluation before salsalate can be recommended for widespread use in type 2 diabetes," the investigators noted.

Dr. Allison B. Goldfine of Harvard Medical School, Boston, and her associates performed the clinical trial after proof-of-principle studies showed that salsalate reduced blood glucose, triglycerides, free fatty acids, and C-reactive protein concentrations; improved glucose utilization; and increased circulating insulin and adiponectin levels. Their trial was intended to assess the magnitude and durability of the drug’s glycemic efficacy, as well as its tolerability, when taken for 1 year.

The study patients treated at 21 U.S. sites were adults who were aged 75 years or younger and who had HbA_1c levels of 7.0%-9.5% and were already being managed with lifestyle modification, metformin, insulin, secretagogues, and/or dipeptidyl peptidase-4 inhibitors, alone or in combination. They were randomly assigned to add three daily doses of either salsalate (3 g daily for 2 weeks, then 3.5 g daily) or matching placebo to their drug regimen for 48 weeks.

Patients maintained stable doses of lipid-lowering and hypertension medications whenever possible for the course of the study. They were followed frequently to assess safety factors, treatment adherence, and treatment response.

The primary efficacy outcome was change in HbA_1c level at 48 weeks. The salsalate group’s mean level was 0.37 percentage points lower than the control group’s, a significant difference. Moreover, the difference between the two study groups in HbA_1c levels was significant at all of the frequent assessments, including the initial assessment after just 4 weeks of treatment.

In addition, the mean HbA_1c level was 0.33 percentage points lower in the salsalate group at the end of the study than it had been at baseline, a significant difference. In contrast, the mean HbA_1c level was essentially unchanged over time in the control group, with a mean, nonsignificant increase of 0.04 percentage points at week 48.

The magnitude of the treatment benefit was greatest among patients who had the highest HbA_1c levels at baseline. For every 1% increase in baseline HbA_1c, the mean reduction in HbA_1c was 0.43 percentage points, the investigators said.

At the conclusion of the study, more patients receiving salsalate (41%) had achieved 0.5 percentage points or greater decreases in HbA_1c levels than those receiving placebo (23%).

Consistent with these changes in HbA_1c, fasting glucose levels also showed significant improvement only in the patients receiving salsalate.

Published online July 1, 2013, in Annals of Internal Medicine.