Beta cell function and insulin sensitivity during elexacaftor/tezacaftor/ivacaftor therapy in people with cystic fibrosis

Laura Zazzeron¹Valeria Grancini^2*Maddalena Trombetta³Gianfranco Alicandro¹Maria Linda Boselli³Irene Cogliati²Giovanna Mantovani²Andrea Gramegna⁴Francesco Blasi⁴Riccardo C Bonadonna³Emanuela Orsi²Valeria Daccò¹

• ¹Mother and Child Department, Cystic Fibrosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
• ²Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
• ³Endocrinology, Diabetes and Metabolism, Department of Medicine, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
• ⁴Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Milan, Italy

Background: Cystic fibrosis-related diabetes (CFRD) is the most common extra-pulmonary complication in adults with cystic fibrosis (CF) and is primarily driven by progressive beta-cell dysfunction. The impact of CFTR modulators, particularly elexacaftor/tezacaftor/ivacaftor (ETI), on glucose metabolism remains incompletely understood. This study aimed to assess the effect of ETI on beta-cell function and insulin sensitivity in people with CF (pwCF) without a history of CFRD. Methods: We conducted a prospective study involving pwCF who underwent oral glucose tolerance tests (OGTT) at baseline (prior to ETI initiation) and at 6 and 18 months after starting ETI therapy. Mathematical modelling of OGTT data was used to assess beta-cell function through two physiologically distinct components of insulin secretion: derivative control (DC), reflecting the early insulin secretory response to changes in plasma glucose, and proportional control (PC), representing the insulin secretory response to prevailing glucose concentrations. PC was expressed as the stimulus–response relationship between plasma glucose and insulin secretion rate (ISR) at predefined glucose levels (4.0, 5.5, 8.0, and 11.0 mmol/L). Insulin sensitivity was estimated using the oral glucose insulin sensitivity (OGIS) index. Results: Sixty-eight pwCF (median age 20 years) were included. At baseline, 8 (11.8%) had impaired fasting glucose and 15 (22.1%) had impaired glucose tolerance. These proportions remained stable over time, with no new cases of diabetes. Plasma glucose at 120 minutes post-OGTT and ISR at 5.5 mmol/L glucose decreased significantly at both 6 and 18 months. ISR at 5.5 mmol/L glucose also decreased at 18 months, whereas DC, ISR at higher glucose levels, and OGIS values did not significantly change over time. Conclusions: ETI therapy was not associated with reversal of existing glucose tolerance abnormalities but may contribute to preservation of beta-cell function and insulin sensitivity. This is supported by stable DC values over time, in contrast to the progressive decline typically observed in CF populations.