(580) Preservation of β-cell Function in Pancreatic Insufficient Cystic Fibrosis with Highly Effective CFTR Modulator therapy.

Background: Cystic fibrosis-related diabetes is common with pancreatic insufficient cystic fibrosis (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 (E/T/I; Trikafta) on β-cell function have not been assessed.

Methods: We retrospectively assessed changes in GPA measures performed on two visits in individuals with PI-CF without diabetes and who were 1) initiated on E/T/I after the baseline visit (2012-2018) (E/T/I group) and followed-up between 2019-2021 vs. 2) those followed-up between 2015-2018 and not yet treated with CFTR modulator therapy (controls). Non-parametric analyses were performed assessing within and between group changes by Wilcoxon matched pairs and Mann-Whitney U tests, respectively.

Results: 9 E/T/I participants (mean±SD age 25±5 years) and 8 matched controls were followed up after a median (IQR) 5.3 (3.7-6.6) and 2.7 (1.9-2.9) years, respectively (p< 0.01), with E/T/I initiation 1.2 (0.6-1.3) years before the follow-up visit. All but 1 individual (control) had at least one copy of delF508 with two copies in 67% E/T/I group vs. 38% control group, p=0.23. Weight and BMI increased in both groups, but by more in the E/T/I group (p< 0.05). Lung function assessed by percentage predicted forced vital capacity (FVC) improved in the E/T/I group (p< 0.05) but not controls (between group change, p=0.01). No difference was observed in forced expiratory volume (FEV1). Serial oral glucose tolerance test glucose improved in the E/T/I group (p< 0.01, repeated measures ANOVA) but not controls who demonstrated deterioration in oral glucose tolerance test status categorization (p< 0.05). No difference in HbA1c was observed between groups.

Acute insulin and C-peptide responses to glucose-potentiated arginine deteriorated in controls (p< 0.05) but not in the E/T/I group, with the C-peptide changes different between groups (p< 0.05). A trend towards lower fasting proinsulin response was seen in the E/T/I group (p=0.07). Deterioration in the basal proinsulin secretory ratio was observed in the controls (p< 0.05, between group change, p< 0.05) but improved together with the maximal response in the E/T/I group (p< 0.05).

Conclusions: E/T/I 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 E/T/I can prevent deterioration of glucose tolerance in PI-CF.

Acknowledgements: This work was supported by Public Health Service research grants [R01 DK97830 (to AK and MRR), K23 DK107937 (to SS), UL1 TR001878 (University of Pennsylvania Center for Human Phenomic Science), and P30 DK19525 (University of Pennsylvania Diabetes Research Center)] from the National Institutes of Health.

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