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

Anneliese J. Flatt, Saba Sheikh, Amy J. Peleckis, Paola Alvarado, Denis Hadjiliadis, Darko Stefanovski, Robert J. Gallop, Ronald C. Rubenstein, Andrea Kelly, Michael R. Rickels

Research output: Contribution to journalArticlepeer-review


Context: Elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta) enhances aberrant cystic fibrosis transmembrane conductance regulator function and may improve the insulin secretory defects associated with a deterioration in clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). Objective: This longitudinal case-control study assessed changes in β-cell function and secretory capacity measures over 2 visits in individuals with PI-CF who were initiated on ETI after the baseline visit (2012-2018) and (1) restudied between 2019 and 2021 (ETI group) vs (2) those restudied between 2015 and 2018 and not yet treated with cystic fibrosis transmembrane conductance regulator modulator therapy (controls). Methods: Nine ETI participants (mean ± SD age, 25 ± 5 years) and 8 matched controls were followed up after a median (interquartile range) 5 (4-7) and 3 (2-3) years, respectively (P < .01), with ETI initiation a median of 1 year before follow-up. Clinical outcomes, glucose-potentiated arginine, and mixed-meal tolerance test measures were assessed with comparisons of within- and between-group change by nonparametric testing. Results: Glucose-potentiated insulin and C-peptide responses to glucose-potentiated arginine deteriorated in controls but not in the ETI group, with C-peptide changes different between groups (P < .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 < .05 for all comparisons). During mixed-meal tolerance testing, early insulin secretion improved as evidenced by more rapid insulin secretory rate kinetics. Conclusion: 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.

Original languageEnglish
Pages (from-to)151-160
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Issue number1
StatePublished - Jan 1 2024


  • cystic fibrosis transmembrane conductance regulator
  • cystic fibrosis-related diabetes
  • highly effective modulator therapy
  • insulin secretion
  • β-cell secretory capacity


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