LB-002 - RESIDUAL C-PEPTIDE IS ASSOCIATED WITH LOWER HYPOGLYCEMIA RISK IN NEW-ONSET TYPE 1 DIABETES – A POOLED ANALYSIS OF 2780 ADULTS AND CHILDREN.

K. Collins¹, A. Lozano¹, F. Walker¹, B. Greeno¹, P. Taylor², P. Senior³, C. Dayan², K. Romero¹, S. Karpen¹, E. Atabakhsh¹; ¹The Critical Path Institute, Tucson, AZ, United States, ²Cardiff University, Cardiff, Wales, United Kingdom, ³University of Alberta, Edmonton, Alberta, Canada.

Background: Preserved endogenous insulin secretion, measured by C-peptide, in individuals with type 1 diabetes (T1D) is associated with better long-term clinical outcomes. However, C-peptide is not yet recognized as a regulatory-grade, clinically meaningful surrogate endpoint. It is challenging to design trials that demonstrate a difference in accepted endpoints (e.g., HbA1c) in new-onset T1D. We sought to explore whether C-peptide is associated with protection from hypoglycemic events and thus have utility as a surrogate endpoint.

Methods: Subject-level data from 2780 pediatric and adult subjects with new-onset T1D ( < 100 days from diagnosis) were pooled from 21 studies (20 clinical trials, 1 observational). Hypoglycemic events in the first year, using existing consensus definitions, was selected as the clinical endpoint. Level 2 ( < 54 mg/dl) and 3 (requiring 3rd party assistance) hypoglycemic events were combined due to the small number of level 3 events. Significance between the frequency of events and time-normalized C-peptide AUC quartiles was determined by the Dunn-Kruskal-Wallis test with multiple comparison correction.

Results: Subjects were stratified into quartiles based on C-peptide levels one year after the start of the study ( < 0.24, 0.24-0.46, 0.46-0.76, >0.76 nmol/L). The frequency of events was lower in the >0.76 group (2.3 events [0.7 95% CI]) compared to the other groups: < 0.24 (5.0 [1.2], p=0.00004), 0.24-0.46 (4.3 [1], p=0.0003), 0.46-0.76 (3.4 [0.9], p=0.02).

Conclusion: Higher C-peptide levels in new-onset T1D is associated with lower risk of hypoglycemic events supporting the utility of C-peptide as a surrogate endpoint for clinical trials. Therapies aimed at preservation of insulin secretion, as measured by C-peptide, may substantially reduce the burden of hypoglycemic events in T1D.