Endocrine Abstracts

Introduction: Cystic fibrosis-related diabetes (CFRD) is a common complication among people with cystic fibrosis (pwCF), contributing to significant morbidity and mortality. The introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators has markedly improved pulmonary outcomes and quality of life in pwCF. However, the impact of these modulators — particularly the combination therapy Elexacaftor/Tezacaftor/Ivacaftor (ETI) — on glucose metabolism remains unclear and controversial. This study aimed to evaluate changes in oral glucose tolerance following ETI initiation in a relatively large cohort.

Methods: We conducted a retrospective, observational, single-center study involving pwCF receiving ETI therapy aged 10 years and older. All participants underwent 2-hour oral glucose tolerance testing (OGTT) prior to starting ETI and again at 12 and 24 months post-initiation. Participants were stratified into three subgroups based on baseline glucose tolerance: normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and CFRD (managed with diet al one or <10 IU/day of insulin). Secondary outcomes included absolute changes in body weight, evaluation of excessive weight gain (≥10 kg) (only in ≥18 years), and absolute changes in HbA1c, at two years after starting ETI.

Results: We included 68 pwCF with a median age of 23 (IQR 18-31) years. At baseline, 38 (56%) patients had NGT, 17 (26%) IGT, and 13 (19%) CFRD. Among those with NGT at baseline, 29/38 (76%) remained stable. Deterioration of OGTT was observed in 9/38 subjects (24%); of which eight developed IGT and one CFRD. Of those with baseline IGT, 11/17 subjects (65%) showed an improvement in OGTT with 9 subjects having NGT after one year. However, five of them experienced a reversal to IGT at year two. 2/17 IGT subjects (12%) developed CFRD. Among those with baseline CFRD, 5/13 (38%) experienced improved OGTT results at year one. Three reverted to NGT and two to IGT, although CFRD returned in one case at year 2. Bodyweight was assessed in 54 adult pwCF demonstrating an overall significant weight gain at year two (median 4 [IQR 0.9-6.8] kg vs. baseline; P <0.001). Excessive weight gain was present in 11 cases (20%). Absolute weight gain did not differ between subjects with deteriorated glucose tolerance and those who maintained stable or improved glucose tolerance. However, all subjects who developed IGT gained weight. Development of CFRD was accompanied by excessive weight gain in two subjects. All three subjects developing CFRD carried homozygosity for the F508del mutation. In the total cohort, median HbA1c decreased from 5.5% (IQR 5.2-5.8) to 5.1% (IQR 5.1-5.6) at year two (P <0.001).

Conclusion: ETI may improve glucose tolerance in pwCF. However, this effect is heterogeneous, appears to diminish over time and may be abolished by excessive weight gain. Preventing excessive weight gain associated with ETI therapy may therefore lower the risk for deterioration of glucose tolerance and development of CFRD, especially in high-risk subjects.

Keywords: Cystic fibrosis, Bodyweight, CFRD, CFTR-modulator, glucose metabolism