828-P: Preservation of ß-Cell Function in Pancreatic Insufficient Cystic Fibrosis (CF) with Highly Effective CFTR Modulator Therapy

CF related diabetes is common with pancreatic insufficient CF (PI-CF) . Highly effective modulator therapy enhances aberrant CF transmembrane conductance regulator (CFTR) function and improves pulmonary and nutritional status. Ivacaftor therapy for indicated CFTR mutations enhanced insulin secretion to glucose-potentiated arginine (GPA) testing; however the effects of elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta™) on β-cell function have not been assessed. We retrospectively compared changes in GPA measures performed on two visits in individuals with PI-CF without diabetes and who were 1) initiated on ETI after the baseline visit (ETI group) vs. 2) not treated with CFTR modulator therapy (controls) . ETI participants (mean±SD age 27±9 years) and 8 matched controls were followed up after a median (IQR) 5.8 (3.7-6.7) and 2.7 (1.9-3.0) years, respectively (p=0.001) , with ETI initiation 1.1 (0.2-1.2) years before the follow-up visit. Weight increased in both groups, but by more in the ETI group (p<0.01) . No differences in lung function or HbA1c were observed; however, improvement in oral glucose tolerance test 2-hour glucose was observed in the ETI group (p<0.05) that was different by trend from the change seen in controls (p=0.09) . Acute insulin and C-peptide responses to glucose-potentiated arginine deteriorated in controls (p<0.05) but not in the ETI group, while C-peptide changes differed between groups (p<0.05) . A trend towards lower acute proinsulin response was seen in the ETI group (p=0.07) with the change different between groups (p<0.05) . Deterioration in the proinsulin secretory ratio was observed in the control (p<0.05) but not the ETI group (between group change, p=0.01) . ETI therapy appears to preserve β-cell function in CF through effects on glucose-dependent insulin secretion and proinsulin processing. Further work should determine whether early intervention with ETI can prevent deterioration of glucose tolerance in PI-CF. Disclosure A.Flatt: None. M.R.Rickels: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Consultant; L-Nutra Inc. A.Kelly: Research Support; vTv Therapeutics. S.Sheikh: None. A.J.Peleckis: None. K.Gallagher: None. P.Alvarado: None. D.Hadjiliadis: Advisory Panel; AstraZeneca, Research Support; Mylan N.V. D.Stefanovski: None. R.J.Gallop: None. R.C.Rubenstein: None. Funding Public Health Service research grants (RDK97830; K23 DK107937; UL1 TR001878) and National Institutes of Health (P30 DK19525) .