Inflammatory pathway to diabetes may be interrupted by salicylates

Salsalate may represent a novel treatment to lower blood glucose in patients withtype 2 diabetes. Promising results from the dose-ranging first stage of theTargeting Inflammation Using Salsalate for Type 2 Diabetes (TINSAL-T2D) studysupport the larger stage 2 of the study to evaluate the effects of salsalate onblood glucose control over 48 weeks, says Allison Goldfine, MD.

Low-grade chronic inflammation has gained recognition as participating in thepathogenesis of insulin resistance and type 2 diabetes, says Dr. Goldfine, directorof clinical research at the Joslin Diabetes Center, Boston, MA. From animalresearch, it was discovered that the inflammatory pathway regulated by nuclearfactor-kappa beta is activated in obesity and diabetes. This pathway is inhibited bysalicylates, demonstrating that the effects of obesity are mediated throughinflammation.

Salsalate is a nonsteroidal anti-inflammatory drug marketed in the United Statesfor the treatment of arthritic pain. It does not inhibit cyclo-oxygenase andtherefore is free of the bleeding side effects associated with aspirin.

In stage 1 of TINSAL-T2D, the effects of salsalate in dosages of 3.0 g, 3.5 g,and 4.0 g per day were compared to placebo in a double-masked fashion in 108patients with type 2 diabetes inadequately controlled by their current treatment.Their hemoglobin A_1c (HbA_1c) at study entry needed to be 7.0% to9.5%. One third of patients were on two or more oral therapies at baseline.

HbA_1c level at 16 weeks, the primary endpoint, was reduced significantly with all three dosages of salsalate compared to placebo(p=0.02 for the 3.0 g and 3.5 g per day vs placebo; p=0.001 for 4.0 gper day vs placebo).

Modest hypoglycemia developed more often in patients treated with 3.5 g per dayof salsalate, but occurred only in those patients treated concomitantly withsulfonylureas. "These events led to adjustments in concomitant medications forpatient safety," says Dr. Goldfine. "A significant proportion of patients requiredreductions in their concomitant medications for those in the salsalate arm."

Fasting blood glucose levels were also reduced significantly with all threedosages (p<0.001 for all dosages vs placebo).

In patients randomized to active treatment, there was a modest increase infasting insulin levels, no change in C-peptide concentrration (consistent withsalsalate's modest effect on insulin clearance previoulsy demonstrated), a reductionin circulating triglycerides, no significant change in blood pressure (but a trendtoward an increase in systolic blood pressure [SBP] of about 1.8 mmHg), and nochange in weight.

According to Dr. Goldfine, the slight but nonsignificant increase in SBP willneed to be examined further.

There were significant reductions in uric acid in all three treatment groups, amodest increase in serum creatinine only in the 3.5-g dose of salsalate, no changein cystatin c levels or creatinine clearance at any dosage, and a modest increase inurinary microalbumin excretion with all dosages.

Stage 2 of the study is exploring the 3.5-g dose of salsalate in more than 500patients with type 2 diabetes over 52 weeks. Enrollment is ongoing, says Dr.Goldfine.