Triple combination cystic fibrosis transmembrane receptor modulator effects on glycaemia and insulin kinetics in cystic fibrosis with and without diabetes

BACKGROUND: Greater insight into the effects of cystic fibrosis (CF) transmembrane modulators such as elexacaftor-tezacaftor-ivacaftor (ETI) on glucose metabolism can support a more dynamic and individualised approach to CF-related dysglycaemia. AIM: To assess changes in glycemia, body weight and pulmonary function in adults with CF with and without cystic fibrosis related diabetes (CFRD) following ETI. METHODS: This single-centre retrospective cohort study included adults with at least one F508del mutation (23 with CFRD, 38 without CFRD). Exploratory outcomes were HbA1c and total daily insulin doses in the CFRD group and glucose and insulin profiles (0-120 min oral glucose tolerance test [OGTT]), HOMA2-derived indices of insulin resistance (IR), secretion (%S), and β-cell function (%B) in the non-CFRD group. Pulmonary function and weight were assessed in both groups. RESULTS: Mean age was 33.8 ± 10.0 years (CFRD) and 32.8 ± 8.8 years (non-CFRD), with median ETI exposure of 12.3 and 13.4 months, respectively. In the CFRD cohort, HbA1c decreased non-significantly (6.6% to 6.1%, p = 0.2) with no significant change in insulin dose (0.28 to 0.20 IU/kg/day, p = 0.1). In non-CFRD participants, ETI significantly reduced 1- and 2-hour OGTT glucose levels (9.6 vs. 9.2 mmol/L at 1 h, p < 0.01; 6.1 vs. 4.8 mmol/L at 2 hours, p = 0.01), with 13/38 participants improving OGTT classification; no progression to CFRD occurred. Lung function improved in both groups. CONCLUSIONS: Adults with at least one F508del mutation, ETI was associated with a clinically relevant reduction in HbA1c in those with CFRD and improved glucose tolerance in those without, supporting favourable metabolic effects beyond established respiratory benefits.