Long-term Elexacaftor/Tezacaftor/Ivacaftor therapy improves glucose tolerance and lowers insulin concentrations in cystic fibrosis.

OBJECTIVE: Cystic fibrosis-related diabetes (CFRD) is common in cystic fibrosis (CF). While elexacaftor/tezacaftor/ivacaftor (ETI) improves clinical outcomes, effects on glucose metabolism are unclear. We assessed the impact of ETI on glucose tolerance and insulin during oral glucose tolerance tests (OGTTs) in people with CF. METHODS: OGTT data from 101 individuals (median age 23 years) were analyzed retrospectively within a 10-year window (5 years pre- to 5 years post-ETI). Tests performed before ETI (n=378) and during ETI (n=199) were classified as normal glucose tolerance (NGT), impaired fasting glucose (IFG), indeterminate glycaemia (INDET), impaired glucose tolerance (IGT), or CFRD. RESULTS: Compared with pre-ETI values, mean OGTT glucose decreased (p=0.015) and insulin concentrations declined (p<0.001) during ETI, with significant glucose changes after 60 and 90 minutes and insulin after 30, 60, 90 and 120 minutes. The distribution of glucose metabolism categories during ETI differed by age (p=0.004): adolescents (<20 years) more often had INDET than adults (33% vs 22%), whereas adults (≥20 years) more frequently had IGT (20.6% vs 11.0%). Insulin sensitivity improved, with significant changes in Matsuda index (-0.65, p=0.017). CONCLUSIONS: ETI therapy is associated with improved glucose tolerance and lower insulin concentrations on OGTT, suggesting metabolic benefits of CFTR modulation. Ongoing monitoring of glycaemic status-particularly in adolescents-is warranted to clarify evolving glucose regulation in the ETI era.