9-OR: ADA Presidents' Select Abstract: Targeting Inflammation with Salsalate in Type 1 Diabetes Neuropathy (TINSAL-T1DN Trial)

Introduction & Objective: Diabetic peripheral neuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) are highly prevalent complications of diabetes without effective disease-modifying treatments. Chronic inflammation and the NFkB pathway have emerged as important mechanisms. We aimed to assess the effectiveness and safety of salsalate, a NFkB blocker, in individuals with type 1 diabetes (T1D) and DPN.

Methods: This was a phase 2/3, randomized, double-blind clinical trial of salsalate 3 grams daily vs placebo for 12 months. The primary outcome was the change in intraepidermal nerve fiber density (IENFD) at the distal thigh at 12 months. Secondary outcomes included IENFD at distal leg, nerve conduction studies and measures of CAN (standardized cardiovascular autonomic reflex tests, heart rate variability). Linear regressions were used to assess percent changes in all outcomes between groups.

Results: Fifty-five participants with T1D (mean age 51±12 years, baseline HbA1c 8.4±1.7%, duration 29±14 years) and mild to moderate DPN completed the trial. No significant differences were found in the primary outcome after 12 months. However, positive trends were noted in several secondary outcomes (salsalate vs placebo): sural amplitude (15% vs -10%; p=0.058), sural nerve conduction velocity (9% vs -4%; p=0.16), and measures of CAN (root mean square of the differences of successive RR intervals 34% vs 7%, expiration/inspiration ratio 6% vs -1%, and the 30:15 ratio 19% vs -5%) (p >0.05 for all). After adjusting for age, gender, diabetes duration, HbA1c, BMI, baseline IENFD at distal leg and thigh, sural amplitude significantly improved (31%; p= 0.031) with salsalate.

Conclusion: In this small T1D cohort, salsalate treatment did not significantly change IENFD at distal thigh at 12 months. Trends toward improvement in the sural amplitude and other outcomes suggest salsalate’s potential as a disease-modifying therapy in T1D neuropathy, necessitating larger trials.