Joslin Study Shows Anti-Inflammatory Drug May Prevent Type 2 Diabetes
Inexpensive Medication May Also Treat Type 2 Diabetes, Slow Heart Disease
BOSTON – Jan. 28, 2008 -- Researchers at the Joslin Diabetes Center are reporting that an inexpensive anti-inflammatory drug similar to aspirin, salsalate, may prevent type 2 diabetes by lowering blood glucose and reducing inflammation.
The study, which appears in the February issue of Diabetes Care, is a small, proof-of-principal clinical trial, but is promising enough to spur three more trials to see if the drug, salsalate, can also treat diabetes by lowering blood glucose, slow the progression of coronary artery disease in those with metabolic syndrome, and perhaps prevent diabetes in those at high risk.
"This is exciting because salsalate has a good safety profile after many years of use, is inexpensive to make and appears to have the potential to lower blood glucose," said Allison B. Goldfine, M.D., lead researcher on the study, Director of Clinical Research at Joslin and Assistant Professor at Harvard Medical School. "It may be useful in preventing diabetes."
While it has long been known that high doses of aspirin could reduce blood glucose levels, the risk of stomach bleeding is too high to allow for this treatment to be used, she said. It has also been known for several years that inflammatory markers and proteins are elevated in people with diabetes and that aspirin can reduce inflammation, she noted.
Animal studies had shown aspirin could be effective, but since it could not safely be used in humans at high doses, the researchers thought about designing a new drug. Goldfine suggested trying salsalate, a non-steroidal, anti-inflammatory medication that is similar to aspirin but does not cause bleeding in patients at risk for diabetes. The inexpensive drug has been used for decades to treat arthritis.
The double-masked, placebo-controlled study of 20 obese young adults found that salsalate substantially reduced blood glucose levels as well as inflammation, and, as a result, may cut their risk of developing type 2 diabetes.
"Our study was the first to look at the metabolic changes that occur when you give salsalate to obese people who have not yet developed diabetes and we’re really encouraged by what we found," she said.
The study found that those who took 4 grams of salsalate per day for one month reduced fasting glucose levels by 13 percent and levels of C-reactive protein, a marker for inflammation, by 34 percent. Earlier studies have implicated inflammation in the development of type 2 diabetes and heart disease.
The proof-of-principal study concludes that salsalate reduces glycemia and may improve inflammatory cardiovascular risk indexes in the obese. The findings support the hypothesis that chronic inflammation contributes to obesity-related abnormal blood glucose and suggests that targeting inflammation may provide a therapy for diabetes prevention.
This study was funded by grants from the National Institutes of Health; the Joslin Diabetes and Endocrinology Research Center; a Joslin Eli Lilly Fellowship Grant; and the Clinical Investigator Training Program of Harvard-MIT Health Sciences and Technology-Beth Israel Deaconess Medical Center, in collaboration with Pfizer Inc., and Merck & Company, Inc.
Other researchers participating in the study were Amy Fleischman, M.D., MMSc; Steven E. Shoelson, M.D., Ph.D.; and Raquel Bernier, B.S.
Additional Salsalate Trials
The encouraging results from this proof-of-principal study have prompted several related studies.
Dr. Goldfine is the principal investigator in one study that targets inflammation using salsalate in patients with metabolic syndrome, assessing effects of coronary artery plaque volume. This project is funded by the National Heart, Lung and Blood Institute and will begin enrollment in winter 2008. There is a lifestyle intervention arm to this study being run by Dr. Ernest Schaefer of The Jean Mayer USDA Human Nutrition Center on Aging at Tufts University and Dr. Francine Welty of Beth Israel Deaconess Medical Center.
The lifestyle study, called Targeting INflammation using SALsalate to prevent CardioVascular Disease (TINSAL-CVD), will look at the effects of lifestyle intervention (diet, exercise and omega-3 fatty acid supplement) or salsalate compared to placebo to reduce progression or promote regression of hard and soft coronary artery calcification as assessed by multi-detector CT angiography, a relatively new method to image the coronary arteries. Patients are randomized to lifestyle, salsalate or placebo with images of the coronary arteries at baseline and after 30 months of intervention.
A second study being headed by Drs. Goldfine and Shoelson is using salsalate in patients with type 2 diabetes to target inflammation and thus lower blood glucose. This study, called TINSAL-T2D, is ongoing and is funded by the National Institute of Diabetes and Digestive and Kidney Diseases.
A third study headed by Dr. Goldfine and Dr. Peter Reaven of the Carl T. Hayden VA Medical Center in Phoenix targets inflammation using salsalate in patients with impaired glucose tolerance to improve insulin sensitivity. This study, called TINSAL-IGT, is ongoing and is funded by the VA.
The various studies using salsalate in connection with treatment and prevention of diabetes stem from work initiated at Joslin dating back to the 1990s when the molecular target of high dose aspirin was identified. Dr. Shoelson, who holds the Helen and Morton Adler Chair and is Head of the Section on Cellular and Molecular Physiology at Joslin, was the first to demonstrate the importance of this inflammatory pathway, IKK/NFkB, in animal models of diet-induced obesity and diabetes. These "bench" studies showed the benefits of aspirin in improving metabolism in these animals.
These ongoing studies, including the one being reported today, show the progress that has been made in taking these lab studies and bringing them to patients in a relatively short period of time. After Shoelson’s initial discovery, some had considered looking to develop a new drug to target IKK/NFkB, since it was known that aspirin had too great a risk of bleeding. But Goldfine came up with the idea of trying salsalate, a drug already developed and on the market.
"This was important to speed the bench to bedside observations as much of the pharmacokinetic and long-term safety data is established," she said. "Although the drug was around, no one ever thought of using it in diabetes/metabolic syndrome."
Drugs currently available to treat diabetes do not directly target the IKK/NFkB pathway. As a result, these studies promise to lead to some novel therapies for the disease.