344-OR: Slowed Metabolic Decline after Oral Insulin (OI) in Relatives at High Risk for Type 1 Diabetes (T1D)

Abstract

We assessed whether OI slowed metabolic decline after 1 yr of treatment among highest risk relatives who participated in the Diabetes Prevention Trial-Type 1 (DPT1) and TrialNet (TN) T1D prevention trials for OI. As published, with a diagnosis of T1D as the endpoint, both OI trials (7.5 mg/day) were negative overall. However, subgroup analyses suggested efficacy for those at high risk in each trial (DPT1: higher titer of insulin autoantibodies; TN: lower first-phase insulin response). Thus, we assessed whether OI slowed metabolic decline among the OI trial participants at highest risk, defined by DPT1 Risk Scores over a 6.75 threshold (DPTRS; OGTT C-peptide and glucose, age, and BMI), above which T1D risk increases sharply as DPTRS increases. Of 73% in DPT1 and 89% in TN with 1 yr OGTTs, 32% in DPT1 (90/282; age: 8.7±4.8 yrs) and 35% in TN (118/340; age: 6.9±3.3 yrs) were in the highest risk groups (3 yr risks: 56% in DPT-1; 55% in TN). In the analysis, area under curve (AUC) C-peptide increased from baseline to 1 yr in both OI groups (DPT1: p<0.01; TN: p<0.05) but not in the placebo groups, while AUC glucose increased more in the placebo groups (DPT1: p<0.01; TN: p<0.01) than in the OI groups (DPT1: p<0.05; TN: n.s.). Consistent with those changes, in both trials the 1 yr AUC C-peptide/AUC glucose ratio (x100; AUC ratio) was greater in the OI group than in the placebo group [DPT1: 2.86±1.06 vs. 2.42±1.03 (ng/ml)/(mg/dl); TN: 3.06±1.13 vs. 2.57±0.96 (ng/ml)/(mg/dl); p-value<0.05 for each (baseline adjusted)]. For DPT1 and TN combined (no interaction for treatment between trials), the p-value for the AUC ratio difference was <0.001. Of those with DPTRS <6.75 (3 yr risk: 24% for both DPT1 and TN), the AUC ratio did not differ between OI and placebo. In conclusion, when DPTRS was >6.75 metabolic outcomes at 1 yr appeared similarly favorable for OI in the DPT1 and TN trials, suggesting OI slows insulin decline in those at high risk for T1D. Moreover, metabolic measures could be useful endpoints for T1D prevention trials. Disclosure J. Sosenko: None. J.P. Palmer: None. M.J. Haller: Advisory Panel; Self; SAB Biotherapeutics, Inc. J.S. Skyler: Advisory Panel; Self; Abvance Therapeutics, ADOCIA, Avotres, Boehringer Ingelheim Pharmaceuticals, Inc., Dance Biopharm Holdings, Inc., Immunomolecular Therapeutics, Intrexon, Oramed Pharmaceuticals, Orgenesis Inc., Sanofi, Tolerion, Inc., Viacyte, Inc. Board Member; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. Consultant; Self; Novo Nordisk A/S. Research Support; Self; Tolerion, Inc. Stock/Shareholder; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. A. Pugliese: None. D. Schatz: None.