Salsalate, an Anti-Inflammatory, Reduces Blood Glucose in Type 2 Diabetics

June 11, 2012

June 11, 2012 (Philadelphia, Pennsylvania) — An anti-inflammatory agent used for decades to relieve pain, tenderness, swelling, and stiffness caused by rheumatoid arthritis has now been shown to reduce blood glucose levels in individuals with type 2 diabetes. Salsalate, a prodrug that is converted to salicylic acid, reduced HbA1c levels in a group of patients well controlled with other diabetes medications and resulted in a reduction in dosages with these other antidiabetes agents, report investigators.

The catch, however, is that salsalate increased LDL-cholesterol levels an average of 8 mg/dL over the course of the one-year study. Presenting the results here at the American Diabetes Association (ADA) 2012 Scientific Sessions , lead investigator Dr Steven Shoelson (Joslin Diabetes Center, Boston, MA) said that while the reduction in blood glucose levels is a positive sign, especially in a group of well-treated and well-controlled patients, studies will be needed to get a handle on the risks associated with the LDL-cholesterol increase.

"We actually don't know all the benefits, and we probably don't know all the risks, because we haven't done the kind of trial that gathers this information," Shoelson told heartwire during a press conference announcing the results. "Nowadays, we're getting more and more used to diabetes drugs, as they get closer to market, undergoing a phase 4 clinical trial looking at cardiovascular end points. We have not done that yet, but that would be the logical way to assess the full risks and benefits of this drug."

Salsalate is a precursor of salicylate, a drug derived from plants that has been used as a pain medication or anti-inflammatory drug for thousands of years. More than 10 years ago in studies attempting to understand how diabetes occurs, the researchers observed an increase in inflammation associated with weight gain leading to the development of diabetes, and this suggested that an anti-inflammatory agent might be effective to lower blood glucose levels. A 12-week dose-ranging study published in 2010 showed that salsalate reduced HbA1c levels by approximately 0.5% at the highest doses.

In this newest study, which is sponsored by the National Institutes of Health (NIH), the researchers compared the use of 3.5 g of salsalate daily with placebo in 286 patients with type 2 diabetes. In total, HbA1c levels were reduced 0.24%, an absolute reduction the researchers believe is artificially small given that patients in the study were currently being treated with diabetes medications, as well as exercise and diet. Patients, in fact, had a baseline HbA1c level of 7.5%, said Shoelson, but many patients had their medication dosages lowered when salsalate was added. In contrast, those treated with placebo had increases in the dosages of their other diabetes medications. Treatment with salsalate also reduced triglyceride levels as well as white blood cells, neutrophil, and lymphocyte counts.

Regarding the adverse effects, patients treated with salsalate gained 2.2 lbs more than the placebo-treated patients and experienced an 8-mg/dL increase in LDL-cholesterol levels. Urinary albumin increased 1.8 µg per mg of creatinine, but there were no changes in the glomerular filtration rate.

"We did see some signals with this drug that does lead us to a little bit of concern about it," said Shoelson. "There is a small elevation of albumin in the urine and a small elevation in LDL cholesterol in the bloodstream. Those counter the positive benefits that we see with blood glucose and triglycerides, so as we move forward we'll have to evaluate these signals as well. Many drugs do have safety issues, and we have to come to grips with the risk/benefit ratio and decide whether or not it is a good for particular sets of patients."

Speaking to the findings, Dr Myrlene Staten (National Institutes of Diabetes and Digestive and Kidney Disease [NIDDKD], Bethesda, MD), who was not involved in the analysis, noted the elevations in albuminuria in the urine and elevations in LDL cholesterol were transient and disappeared once the drug was stopped. She said the NIDDK wanted to sponsor the study because it was an excellent example of moving research from the bench to the clinic, especially for an inexpensive, generic drug that lacks financial backing from the pharmaceutical industry.

Interestingly, given the availability of salsalate on the market for rheumatoid arthritis, patients can begin taking the medication today if they wanted, something Shoelson and Staten strongly discourage.

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