Glycemia and Insulin Secretion in Cystic Fibrosis 2 Years after Elexacaftor/Tezacaftor/Ivacaftor: PROMISE-ENDO

Background Elexacaftor/tezacaftor/ivacaftor (ETI) is a highly effective therapy that improves lung disease in people with cystic fibrosis (pwCF), but its effect on glucose tolerance and insulin secretion is unclear. Methods PROMISE is a multicenter prospective, observational study of ETI in pwCF ≥12 years and at least one F508del allele. The PROMISE Endocrine substudy (PROMISE-ENDO) enrolled participants at 10 CF Centers where hemoglobin A1c (HbA1c) was collected and 3-hour oral glucose tolerance tests (OGTT) conducted to examine glucose tolerance, glucose excursions, and insulin secretory rates (deconvolution of C-peptide) and sensitivity (oral minimal model) prior to ETI and 12 to 18 months and 24-30 months following ETI initiation. Longitudinal mixed effects models were used to test within-subject ETI effects. Results At baseline, 79 participants completed OGTTs (39 [49%] male, median [IQR] age 19.6 [14.7, 27.3] years, BMI z-score 0.12 [-0.51, 0.65]). At 12-18 months n = 68 and at 24-30 months n = 58 completed OGTTs. At 24-30 months, fasting glucose (mg/dL) decreased (94 [92, 96] to 90 [88, 93], P =. 02) in the subset not on insulin therapy (n = 61), but no differences in 1-hour or 2-hour glucose were found. HbA1c decreased from 5.8% (5.6%, 5.9%) to 5.5% (5.4%, 5.6%), P <. 001 by 24-30 months. Although insulin sensitivity (mU/L-1 min-1) decreased (8.4 [7.2, 9.5] vs 6.8 [5.8, 7.9], P =. 03), no changes in oral disposition index were found, P =. 14. Conclusion After 2 years of ETI, fasting glucose and HbA1c showed modest decreases. Glucose tolerance varied, and overall measures of insulin secretion did not deteriorate.