Impact of elexacaftor/tezacaftor/ivacaftor on glucose tolerance in adolescents with cystic fibrosis
Authors: Galderisi Alfonso , Weiss Laurence , Besançon Alix , Stremler Nathalie , Reix Philippe , Wizla Nathalie , Lustre Aline , Rames Cinthia , Tatopoulos Aurelie , Perisson Caroline , Dalphin Marie-Laure , Troussier Françoise , Houdouin Véronique , Bessaci Katia , Cosson Laure , Gabsi Asma , Corvol Harriett , Deneuville Eric , Storni Véronique , Ramel Sophie , Bui Stéphanie , Heraud Marie-Christine , Remus Natascha , Huet Frédéric , Scalbert Manuella , Mely Laurent , Gachelin Elsa , Giannantonio Marie , Letierce Alexia , Sahki Djouher , Marguet Christophe , Bonnel Anne-Sophie , Sermet-Gaudelus Isabelle ,   the MODUL CF group, Baravalle Melisande , Barboura Mahassen , Barzic Audrey , Benhalla Lilia , Bennour Khadidja , Bessaci Katia , Bessou Antoine , Bihouee Thiphaine , Bonnel Anne-Sophie , Bouleghem Nesrine , Bui Stéphanie , Chedevergne Frédérique , Corvol Harriet , Cosson Laure , Couderc Laure , Dalphin Marie-Laure , De carli Paola , Deneuville Eric , Foucaud Pierre , Gabsi Asma , Gachelin Elsa , Hassani Fatiha , Houdouin Veronique , Huet Frédéric , Jamin Marie , Kaba Kadiatou , Labbe Guillaume , Languepin Jane , Laurans Muriel , Lerena Cathy , Letierce Alexia , Livrozet Clotilde , Marguet Christophe , Mely Laurent , Messaoudi Rania , Mittaine Marie , Ohlmann Camille , Perisson Caroline , Perrin Thomas , Piccini-bailly Carole , Rames Cinthia , Reix Philippe , Remus Natascha , Ronayette Anna , Sahki Djouher , Scalbert Manuela , Sermet Isabelle , Socchi Floriane , Stremler Nathalie , Tatopoulos Aurélie , Thouvenin Guillaume , Toin Tom , Troussier Françoise , Weiss Laurence , Werck-Galois Marie Christine , Wizla Nathalie 
Published: February 2025

Abstract

Background
Highly effective CFTR modulators, such as elexacaftor/tezacaftor/ivacaftor (ETI), herald a new era in therapeutic strategy of cystic fibrosis (CF). ETI impact on glucose tolerance remains controversial.

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, 31 with AGT. The baseline characteristics of the two groups were similar except for a higher glucose level at 1 and 2-h OGTT in the AGT group. ETI induced an increase in BMIz-score and in Forced Expiratory Volume in 1 second (FEV1) (p&lt;0.001). After 12 months, participants with NGT did not experience any change of 1-h and 2-h glucose. By contrast, those with AGT displayed a reduction of 2-h glucose at M12 (p=0.006). 15out of the 31 (48%) adolescents in the AGT group reversed to NGT but 9/75 (17%) in the NGT group progressed to AGT. 3 participants with CF related diabetes at baseline reversed to AGT. 1-hour glucose concentrations at or above 8.7 mmol/L (157mg/dL) during baseline OGTT had 80% sensitivity to identify those with AGT at 12 months (OR 1.51 [1.20, 1.92], p=0.001). 20 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. 1-hour glucose during the OGTT helps to detect risk for AGT after ETI treatment.