Introduction: Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis (CF) and is associated with worse outcome. CFRD arises from reduced β-cell function and mass: abnormalities of early-phase insulin release progress to overt CFRD as a consequence of exocrine dysfunction and pancreatic fibrosis. The chloride channel defect can be modified using CF transmembrane conductance regulator (CFTR) targeted drugs: ivacaftor increases channel opening and improves lung function in G551D mutations; lumacaftor increases the number of channels and in combination (ivacaftor/lumicaftor) improves pulmonary end-points in the common F508del gene defect.
Case 1: Female CF patient homozygous F508del (25yrs) with exocrine insufficiency and CFRD on insulin pump therapy. Over 8-weeks of ivacaftor/lumicaftor, her daily insulin dose fell (16.1iu basal + bolus 1iu:CHO10g to 11iu basal only) with improvement in HbA1c (10.1 to 8.4%) and %predFEV1 (2%). Glucometer readings demonstrated a lower fasting mean glucose level (11.6±2.8mmol/l to 7.8±3.7mmol/l; p=0.009) and similar post-prandial levels (8.3±5.5mmol/l to 6.4±2.2mmol/l; p=0.2) despite cessation of bolus insulin.
Case 2: Male CF patient homozygous F508del (56yrs) with exocrine insufficiency and long-standing (>30yrs) CFRD, treated with subcutaneous glargine (28iu) and aspart (2:CHO15g) commenced ivacaftor/lumicaftor. Over 10-weeks of treatment there was improvement in %predFEV1 (2%), but no improvement in HbA1c (7.7 to 8.6%) or change of insulin regimen.
Conclusion: CFTR-modifiers may improve CFRD via an effect on the CFTR, which is present on the β-cell and is implicated in physiological insulin release. Three cases with G551D have reported improvement of CFRD following ivacaftor. This is the first report of the effect ivacaftor/lumicaftor on CFRD in F508del: Case 1 demonstrates improvement, which may result from enhancement of CFTR function in the β-cell; Case 2 has no response consistent with loss of β-cell mass in long-standing CFRD. This novel observational data supports the role of CFTR in insulin secretion.