Type 2 Diabetes: Glycemic Control Improved With Salsalate

Marlene Busko

July 05, 2013

Salsalate, which has been used for decades to treat inflammation in rheumatoid arthritis, was well-tolerated and lowered glycosylated hemoglobin (HbA1C) levels in patients with inadequately controlled type 2 diabetes, according to results from a 1-year trial.

At a dose of 3.5 g/day, mean HbA1C levels decreased by 0.37% more in patients randomly assigned to the drug than those assigned to placebo, which is comparable, the researchers state, to the effect of other more expensive oral diabetes drugs taken with metformin. Salsalate also improved levels of some cardioprotective markers.

However, the drug was linked with modest, but reversible, increased urinary albumin levels, as well as increased low-density lipoprotein cholesterol, which "require[s] continued evaluation before salsalate can be recommended for widespread use in [type 2 diabetes mellitus]," write study authors Allison B. Goldfine, MD, from the Joslin Diabetes Center in Boston, Massachusetts, and the Targeting Inflammation Using Salsalate in Type 2 Diabetes (TINSAL-T2T) study team.

The work was published in the July 2 issue of the Annals of Internal Medicine.

Cyrus V. Desouza, MD, from the University of Nebraska Medical School in Omaha, who was not involved in this research, said that he agrees with the authors. "There is a possibility that salsalate could be used as an antidiabetic drug in the future," he told Medscape Medical News."It does reasonably lower HbA1c, although not very powerfully, [and] it might have [beneficial] cardiovascular effects, which are yet to be proven."

New Use for an Ancient Drug?

Salicylate has been used to treat inflammation since ancient times, and salsalate, a prodrug form of salicylate, has been used to treat rheumatoid arthritis for about 50 years, Dr. Desouza said. About 10 years ago, researchers began investigating whether this inexpensive, generic, antiinflammatory agent might lower blood glucose in type 2 diabetes.

The National Institutes of Health sponsored TINSAL-T2D, and findings from a short, dose-ranging study were published in 2010. The current, larger study extends this work.

In TINSAL-T2D, 286 patients aged 18 to 75 years (mean age, 55.8 years) who had inadequately controlled type 2 diabetes (HbA1c levels of 7% - 9.5%) were randomly assigned to 48 weeks of either salsalate 3.5 g in 3 divided doses or placebo. Most patients were being treated with metformin (88.1%), about 52% were receiving an insulin secretagogue, and 15% were receiving a dipeptidyl peptidase 4 inhibitor. Nearly 41% were receiving a single diabetes drug, whereas 49% were receiving dual therapy; only a few were being treated with triple therapy (5.6%) or lifestyle modification alone (4.5%).

Salsalate reduced HbA1c levels at all times, even though patients taking it were more likely to reduce their other diabetes medications. At 48 weeks, patients in the salsalate group had a mean drop in HbA1c level of 0.33%, which was 0.37% greater than that seen in patients in the placebo group (P < .001). "This is comparable to the effect of a couple of other [more expensive] drugs on the market," Dr. Desouza noted.

Hypoglycemia was seen in 41 patients receiving salsalate vs 23 receiving placebo (P = .036), largely in patients also receiving sulfonylureas. Tinnitus, an expected adverse effect of high-dose salicylates, was not significantly different between the 2 groups: 16 (11%) patients receiving salsalate and 7 (5%) receiving placebo reported this adverse effect (P = .082). There were no reports of gastrointestinal bleeding.

The study supports the hypothesis that inflammation plays a role in diabetes. Compared with patients in the placebo group, patients taking salsalate had greater decreases in the inflammatory markers leukocytes, neutrophils, and lymphocytes.

Patients receiving salsalate also had significant improvements in adiponectin and uric acid, markers of cardiometabolic risk, as well as in triglycerides compared with those receiving placebo. In contrast, they had increased total and low-density lipoprotein cholesterol levels with no change in high-density lipoprotein cholesterol compared with patients receiving placebo. Their urinary albumin levels increased (which reversed when the drug was discontinued), and yet they did not have any change in glomerular filtration rate.

"What is the significance of all these [cardiovascular and renal] markers going up and down? Ultimately, you have to have a cardiovascular outcome trial to find out," Dr. Desouza added, in agreement with the study authors. "The next step would be to do a...long-term [safety and] efficacy trial before [salsalate] can be used as a medication" in this population, he concluded.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, which participated in study design and data interpretation. Caraco Pharmaceutical Laboratories provided salsalate and placebo, LifeScan provided glucometers and test strips, and Mercodia provided insulin assay materials. Full conflict-of-interest information can be found on the journal's Web site.

Ann Intern Med. 2013;159:1-12. Abstract

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