The salicylate prodrug salsalate may be an effective add-on therapy for poorly controlled type 2 diabetes, according to a report published online July 1 in Annals of Internal Medicine.

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, said Dr. Allison B. Goldfine of Harvard Medical School, Boston, and her associates.

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. Goldfine and her colleagues 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.

Reductions in and discontinuation of other diabetes medications also were significantly more frequent with salsalate (62%) than with placebo (13%). "Conversely, concomitant diabetes medications were increased and new therapies instituted more frequently for patients receiving placebo (87%) than those receiving salsalate (38%)," Dr. Goldfine and her associates said.

Among the active drug’s anti-inflammatory effects were decreases in circulating leukocytes, neutrophils, and lymphocytes.

Levels of adiponectin, a cardioprotective protein derived from adipocytes, rose by 27% in the salsalate group, compared with the placebo group. Levels of uric acid, which is associated with cardiometabolic disorders and the progression of renal insufficiency, dropped by 18% in the salsalate group, compared with the placebo group.

Salsalate also reduced triglyceride levels. However, the drug increased total and LDL cholesterol levels without altering HDL cholesterol levels. It also increased the urinary albumin-creatinine ratio and increased serum creatinine levels. And it was associated with a 1.3-kg increase in weight.

These modest adverse effects "warrant further assessment," the investigators said.

No serious adverse events were attributed to salsalate. However, the relative risk for mild hypoglycemia was six times greater when salsalate was added to sulfonylureas than when placebo was.

Mild tinnitus was reported by more patients receiving salsalate (11%) than placebo (5%), but it resolved in all patients.

Gastrointestinal adverse effects did not differ between the two study groups, and there was no evidence of GI bleeding. Quality of life also was similar between patients taking salsalate and those taking placebo.

The National Institute of Diabetes and Digestive and Kidney Diseases funded the study. Caraco Pharmaceutical Laboratories provided the salsalate and placebo, but it had no other role in the study.

Add-on salsalate improved poorly controlled type 2 diabetes