NSAID Lowers Glucose Levels in Type 2 Diabetes

Chronic low-grade inflammation found in many patients with diabetes

Salsalate, a generic non-steroidal anti-inflammatory drug (NSAID) used to treat arthritis, significantly lowered blood glucose levels and decreased inflammatory mediators in patients with type 2 diabetes. Further research is needed to understand the side effects of this agent in patients with diabetes, the study authors noted in the July 2 issue of Annals of Internal Medicine.

“Epidemiologic studies have suggested that a low-grade, chronic inflammation is present in patients who have diabetes, and precedes and predicts the development of diabetes in people who do not yet have the disease,” said lead author Allison B. Goldfine, MD, Associate Professor at Harvard Medical School and Section Head of Clinical Research at Joslin Diabetes Center, Boston, Massachusetts. “Our study adds to a growing body of science to demonstrate that one can specifically target this low-grade inflammation to improve metabolism in patients with diabetes,” she said.

The study involved 286 participants with poorly controlled type 2 diabetes (A1C 7.0%-9.5%; mean A1C, 7.85%) despite treatment with diabetes medications, exercise, and dietary changes. None of the patients were taking insulin. The patients were randomized to salsalate 3.5 g per day or placebo in addition to their regular diabetes medications (ie, metformin, insulin secretagogue, or dipeptidyl peptidase-4 inhibitor, alone or in combination) for 48 weeks. Patients who were currently on insulin, thiazolidinediones, glucagon-like peptide-1 agonists, NSAIDs, warfarin, or uricosuric agents were not eligible for the trial.

At 48 weeks, the salsalate group had a 37% lower mean change in A1c level compared to the placebo group (-0.53% vs -0.21%; P<0.001). In addition, the mean decrease in fasting glucose level was 15 mg/dL greater in the salsalate group than the placebo group (P<0.001). Furthermore, patients in the salsalate group were more likely to experience dose reductions and discontinuations in their other diabetes medications (62% vs 13% in the placebo group). The anti-inflammatory effect of the agent was demonstrated by reductions in circulating leukocyte, neutrophil, and lymphocyte counts.

“Preclinical studies do not find similar glucose lowering effects for other NSAID that target inhibition of cyclooxygenase (COX) enzymes,” Dr. Goldfine said.

Commentary on the Findings

“It is an interesting study and in patients who are almost at goal, salsalate might help them get to goal in a relatively economic fashion,” said Thomas Weida, MD, former director of the American Academy of Family Physicians Board of Directors, and family physician at Penn State College of Medicine/Milton S. Hershey Medical Center, Henley, Pennsylvania.

He noted that adherence rates were high in this group and the average A1C of 7.85% suggests that many patients had well-controlled diabetes. Thus, he said, “It would be interesting to see what the results would be in a group that had a higher average hemoglobin A1C.” In addition, he suggested that the findings might not be applicable to the general population, as this study group was primarily comprised of white and black patients of upper middle age.

Furthermore, Dr. Weida noted that the reduction in A1C associated with salsalate was modest and is comparable to that of other agents. For example, he wondered whether high-dose aspirin—which also is inexpensive—might have the same effect. 

Side Effects Profile

“Salsalate’s major side effect is tinnitus [experienced by 11% in this study], which was reversible with reduction of the dose of medication or stopping the drug,” Dr. Goldfine said. The salsalate group showed a significant increase in weight (1.3 kg), LDL cholesterol level (8.49 mg/dL), and urinary albumin-creatinine ratio (2.3 mcg/mg; P<0.001) compared with the placebo group. “The clinical significance of these changes in blood and urine tests are not clear, as the magnitude of change is very small,” Dr. Goldfine noted.

“We are conducting studies in patients who have stable coronary artery disease to evaluate the effects of salsalate on atherosclerosis and whether salsalate reduces progression of plaque in the coronary arteries. We hope these studies will help inform us more about cardiovascular safety,” Dr. Goldfine said. She added that other studies are investigating additional anti-inflammatory approaches to treat or prevent diabetes and cardiovascular disease, and encouraged readers of DiabeticLifestyle.com to “look for clinical research sites in their area and consider participation in research studies that may lead to better understanding and treatments of their health conditions.”

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