Effect of Elexacaftor/Tezacaftor/Ivacaftor on Glucose Tolerance in Adolescents With Cystic Fibrosis.

Abstract

Context: Highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators, such as elexacaftor/tezacaftor/ivacaftor (ETI), herald a new era in therapeutic strategy of cystic fibrosis (CF). ETI's effect on glucose tolerance remains controversial.

Objective: The study was undertaken to evaluate the effect of ETI treatment on glucose tolerance in youths with CF.

Methods: All the participants underwent a baseline oral glucose tolerance test (OGTT) before ETI initiation (M0) and 12 months (M12), and at 24 months if possible. The cohort was stratified in two subgroups based on the baseline OGTT: normal glucose tolerance (NGT) and abnormal glucose tolerance (AGT) defined by impaired fasting glucose or impaired glucose tolerance or diabetes not requiring insulin treatment.

Results: We included 106 adolescents with CF (age 14.1 ± 1.5 years), 75 with NGT, and 31 with AGT. The baseline characteristics of the two groups were similar except for a higher glucose level at 1- and 2-hour OGTT in the AGT group. ETI induced an increase in body mass index z score and in forced expiratory volume in 1 second (FEV1) (P < .001). After 12 months, participants with NGT did not experience any change of 1-hour and 2-hour glucose. By contrast, those with AGT displayed a reduction of 2-hour glucose at M12 (P = .006). Fifteen out of the 31 (48%) adolescents in the AGT group reversed to NGT but 9 of 75 (17%) in the NGT group progressed to AGT. Three participants with CF-related diabetes at baseline reversed to AGT. One-hour glucose concentrations at or above 8.7 mmol/L (157 mg/dL) during baseline OGTT had 80% sensitivity to identify those with AGT at 12 months (odds ratio 1.51; [1.20-1.92]; P = .001). Twenty participants had a 24-month OGTT that confirmed preserved insulin secretion.

Conclusion: ETI may improve glucose tolerance in adolescents with CF by preserving insulin secretion. One-hour glucose during the OGTT helps to detect risk for AGT after ETI treatment.