Targeting Inflammation With Salsalate in Type 1 Diabetes Neuropathy-TINSAL -T1DN

Diabetic neuropathy (DN) is the most common chronic complication of diabetes, affecting up to50% of individuals with type 1 diabetes (T1DM). DN is a progressive disease, leading to severe morbidity and staggering health care costs. Patients experience poor quality of life due to pain, loss of sensation leading to poor balance, falls and eventual foot deformities with high rates of ulcerations and amputations. While not as commonly diagnosed as DN, cardiovascular autonomic neuropathy (CAN) carries equal morbidity with patients experiencing orthostasis, arrhythmias and premature death).

Despite the high morbidity associated with DN, most randomized clinical trials evaluating therapies for established DN have been disappointing. To date there is no pathogenetic treatment for this condition. The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive control designed to achieve near-normal glycemia is essential in reducing the risk of DN development in type 1 diabetes (8, 9). However, attainable intensive glycemic control, although necessary, is insufficient to prevent adverse nervous system effects, justifying a therapeutic need to identify new drug targets to treat DN early in its course. One such new therapeutic target is inflammation. Multiple pre-clinical and clinical studies demonstrate a pathogenic role for inflammation, especially cytokine production, in the disease course of DN and CAN. This suggests that agents with known anti-inflammatory properties, such as salicylates, may prevent the development of DN and the pain associated with DN. Salsalate, a pro-drug form of salicylate, is a FDA approved drug commonly indicated for relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis and related rheumatic disorders. In vitro and in vivo studies and human trials have shown that salicylate therapy is effective in controlling low grade inflammation in diabetes by inhibition of the inhibitor of the κB kinase (IKKβ)/NF-κB pathway. It has a large margin of safety (unlike other salicylates), and a low cost. There is also extensive experience with long-term human use of salsalate.

Several studies show that salsalate causes no greater intestinal occult blood loss than placebo and has no suppressive effects on renal prostaglandin production in contrast to aspirin or NSAIDs. The recently published NIDDK-funded "Targeting Inflammation Using Salsalate in Type 2 Diabetes (TINSAL-T2D)" trial confirmed salutary effects of 3.5 gram/day salsalate on markers of inflammation, glucose control and overall safety after 48 weeks patients with type 2 diabetes. The Investigators' initial NIDDK funded R03 (DK 094499) grant confirmed the safety and feasibility of targeting inflammation with salsalate treatment in T1DM subjects with DN. The Investigators' current study builds upon and expands their initial promising results and will either confirm or refute the therapeutic efficacy of salsalate in a larger T1DM cohort.