Preservation of β-cell Function in Pancreatic Insufficient Cystic Fibrosis With Highly Effective CFTR Modulator Therapy

Elexacaftor/Tezacaftor/Ivacaftor (ETI; Trikafta™) enhances aberrant cystic fibrosis transmembrane conductance regulator (CFTR) function and may improve the insulin secretory defects associated with a deterioration in clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF).This longitudinal case-control study assessed changes in β-cell function and secretory capacity measures over two visits in individuals with PI-CF who were initiated on ETI after the baseline visit (2012-2018) and 1) restudied between 2019-2021 (ETI group) vs. 2) those restudied between 2015-2018 and not yet treated with CFTR modulator therapy (controls).Nine ETI participants (mean ± SD age 25 ± 5 years) and eight matched controls were followed up after median(IQR) 5(4-7) and 3(2-3) years, respectively (p < 0.01), with ETI initiation a median of 1 year before follow-up. Clinical outcomes, glucose-potentiated arginine (GPA) and mixed-meal tolerance test (MMTT) measures were assessed with comparisons of within and between group change by non-parametric testing.Glucose-potentiated insulin and C-peptide responses to GPA deteriorated in controls but not the ETI group, with C-peptide changes different between groups (p < 0.05). Deterioration in basal proinsulin secretory ratio was observed in controls but improved, as did the maximal arginine-induced proinsulin secretory ratio, in the ETI group (p < 0.05 for all comparisons). During MMTT, early insulin secretion improved as evidenced by more rapid insulin secretory rate kinetics.ETI preserves β-cell function in CF through effects on glucose-dependent insulin secretion, proinsulin processing and meal-related insulin secretion. Further work should determine whether early intervention with ETI can prevent deterioration of glucose tolerance in PI-CF.