Treatment of Cardiovascular Disorders with Salicylates

Joslin Diabetes Center, Inc.
posted on 03/09/2009

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Inflammation participates in the pathogenesis of insulin resistance, type 2 diabetes and cardiovascular disease, and weight gain and obesity are known to be accompanied by activation of at least two inflammatory pathways in adipose tissue and liver: the JNK pathway and the NF-êB pathways. Both pathways increase the production of proinflammatory cytokines and chemokines and promote recruitment of macrophages to adipose tissue. The salicylate family of compounds have long been known to be capable of lowering blood glucose levels in diabetic patients, and have recently been shown to act by inhibiting the NF-êB pathway. The inventors have extensively studied the possible use of nonacetylated salicylate compounds for the treatment of metabolic and CV disorders, and have developed a body of clinical and preclinical data which provide proof of concept for such therapeutic uses. In particular, the inventors have found that administration of high doses of non-acetylated forms of salicylate, (such as salsalate or trilisate) is useful for preventing or retarding development of type 2 diabetes (T2D) in obese subjects (JDP-106), and for preventing or retarding the development or progression of cardiovascular diseases, e.g., atheroma formation (JDP-109). Salsalate or other nonacetylated salicylates can be used as a novel treatment for insulin resistance and type 2 diabetes, and to treat or prevent CV disease. The salicylates, and salsalate in particular, have been used for decades in human therapeutics, and are known to have very favorable human safety profiles. The inventors’ proof-of-principle clinical studies have shown that salsalate, in safe and tolerable doses, reduces glycemia, improves lipid homeostatis, and may improve inflammatory cardiovascular risk indexes in overweight individuals. More extensive clinical trials are now underway, which could provide support for ultimate FDA approval for such therapies.