Impact of Elexacaftor/Tezacaftor/Ivacaftor on Glucose Tolerance and Abnormal Glucose Metabolism: A Phase 3b, Open-Label Clinical Trial.

Rationale: Abnormal glucose metabolism is a common complication in people with cystic fibrosis (CF), and those with impaired glucose tolerance (IGT) or CF-related diabetes (CFRD) have increased disease burden. Elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) is safe and effective for people with CF ≥2 years of age with ELX/TEZ/IVA-responsive CFTR (CF transmembrane conductance regulator) mutations; however, efficacy on glycemic control has not been studied. Objectives: To evaluate the impact of ELX/TEZ/IVA on glucose tolerance in people with CF who have IGT or CFRD. Methods: In this phase 3b, open-label study, ELX/TEZ/IVA was administered for 48 weeks to participants ≥12 years of age, heterozygous for F508del and a minimal function CFTR mutation, with either IGT or CFRD. Measurements and Main Results: Sixty-nine participants received ELX/TEZ/IVA. The primary endpoint was change in blood glucose concentration after a 2-hour oral glucose tolerance test from baseline to the average of Week 36 and Week 48; participants had a mean change of -35.0 mg/dl (95% confidence interval [CI], -49.2 to -20.7 mg/dl; P < 0.0001) (-1.9 mmol/L [95% CI, -2.7 to -1.2 mmol/L]). Secondary endpoints were the proportion of participants with improvement in dysglycemia categorization (CFRD, IGT, normal glucose tolerance) at Week 48 and safety. Among participants with abnormal glucose tolerance at baseline, 37.7% (95% CI, 24.8 to 52.1) had improvements in dysglycemia categorization at Week 48. Overall, 35.5% of participants had normal glucose tolerance at Week 48 compared with 13.0% at baseline. Safety was consistent with the established safety profile of ELX/TEZ/IVA. Conclusions: ELX/TEZ/IVA treatment led to clinically meaningful improvements in blood glucose regulation, with significant within-group decreases in blood glucose concentrations after oral glucose tolerance testing and improved dysglycemia categorization in people with CF with early IGT or CFRD. Clinical trial registered with www.clinicaltrials.gov (NCT04599465).