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TINSAL-T2D: Salsalate lowered glucose in patients with type 2 diabetes
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PHILADELPHIA — New data from the 1-year TINSAL-T2D trial showed that an anti-inflammatory drug related to aspirin and salicylate approved for the treatment of joint pain — salsalate — has glucose-lowering properties and potential cardiovascular benefits.
Steven Shoelson, MD, PhD, associate director of research at the Joslin Diabetes Center and researcher for the Targeting Inflammation Using Salsalate for Type 2 Diabetes (TINSAL-T2D) trial said salicylic acid (Durasal, Elorac; Salex, Coria Laboratories) was first used to treat a patient aged 56 years with diabetes and obesity in 1876. The patient was treated for more than a week with high doses of salicylic acid, the same dose that was shown to be effective for joint pain, he said.
“This is actually the case study that we were very interested in and spent the last decade repeating and reproducing,” Shoelson said during a presentation. “We first did this with animals trying to see if there was an effect, thinking that this growing interest in inflammation as potential pathogenic mediator might be targetable by an anti-inflammatory and here we had an anti-inflammatory drug that had been shown already historically to work in a diabetic patient. So we did reinvestigate this.”
TINSAL-T2D
In the NIH-sponsored trial, Shoelson and colleagues enrolled patients aged 18 to 75 years at 21 centers around the country. They excluded 312 patients and 326 entered the run-in phase. Of those, 286 patients (mean age, 56 years; 55% male) were randomly assigned to salsalate 3.5 g per day in three doses (n=146) or placebo (n=140).
Patients were on an exercise and diet regimen and were already using as many as three oral agents. Eighty-eight percent were using metformin; 52%, insulin secretagogue; 15%, DPP-4 inhibitors; and 0.3%, alpha-glucosidase inhibitors. Patients were overweight with a baseline BMI of 33.3; an average HbA1c of 7.7%; fasting glucose of 151 mg/dL; total cholesterol of 165 mg/dL; and triglycerides of 157 mg/dL.
Results revealed a 0.24% decrease in HbA1c (P≤.001); an 11 mg/dL decrease in fasting blood glucose (P<.001); an increase in insulin (P=.003); and a decrease in C-peptide (P≤.02) after 48 weeks, as compared with placebo. Minimal weight gain was reported (2.2 lbs or 1 kg), LDL increased gradually (8 mg/dL) and HDL remained unchanged during the course of the study. There was a small increase in urinary albumin (1.8 mcg/mg creatinine) that was reversible when the drug was discontinued and no effect on renal filtration. There were no changes in BP, and there was no evidence of bleeding. Some measures of liver function improved.
CV effects
Allison B. Goldfine, MD, head of Clinical, Behavioral and Outcomes Research at Joslin Diabetes Center and an associate professor of medicine at Harvard Medical School, said there were also pertinent findings other than salsalate’s glucose-lowering properties. Anti-inflammatory properties were evident by the lowering of circulating total white blood cell counts, neutrophils and lymphocytes, she said.
Additionally, researchers are currently looking at the 21% increase in adiponectin and 11% decrease in uric acid, which could provide potential cardioprotective qualities and mitigate the increase in cholesterol, they said.
“We’re very interested in looking at what will happen to the atherosclerotic plaque burden as an early marker for whether or not there is a balance between the cardio-renal risk factors and actual plaque,” Goldfine told Endocrine Today. “The preclinical animal models look extremely promising that salicylates would actually reduce the leukocyte adhesion and plaque development. If that’s true, then the balance of these risks and benefits may become very favorable. We’re in the process, and we’re fully enrolled in a trial to look at salsalate in patients with stable coronary artery disease. In about 2.5 years we’ll know. If that looks very promising, then I think that would really seed a full cardiovascular outcome trial.”
Questions remain
Cyrus Desouza, MBBS, associate professor of internal medicine and chief of endocrinology at the University of Nebraska Medical Center, and researcher in the TINSAL-T2D trial, said results were encouraging in terms of treatment for diabetes and prevention of CVD.
“Any means by which you can reduce inflammation would logically help reduce incidence for cardiovascular disease, and maybe progression to diabetes,” Desouza said in an interview. “Although the HbA1c-lowering was not as much as anticipated, I think the importance is the overall picture of decreased inflammation, and perhaps cardiovascular protection. But I think we need to do a larger trial to be able to prove the cardiovascular benefits within the diabetes population.”– by Samantha Costa
For more information:
- Shoelson S. Inflammation in type 2 diabetes and results of the TINSAL-T2D trial. Presented at: the American Diabetes Association’s 72nd Scientific Sessions; June 8-12, 2012; Philadelphia.