ESPE Abstracts

Background: CFRD is a unique subtype of diabetes mellitus, distinct from type 1 and type 2, harbouring β-cell dysfunction and β-cell loss and insulin resistance. Modulator therapies directly target the underlying defect of CF, modulating or correcting the function of the CFTR gene (mutation-specific). Few studies investigated the effect of modulators on CFRD and glucose metabolism. We performed an observational study on the short-term effects of the triple-modulator-therapy elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on glucose tolerance in people with CF.

Methods: 16 adolescents with CF (homozygous or heterozygous F508-CFTR variant) underwent oral glucose tolerance tests (OGTT) before and four- six weeks after initiating ELX/TEZ/IVA therapy. A continuous glucose monitoring (CGM) system was used three days before until seven days after starting ELX/TEZ/IVA. OGTT results were categorised into normal glucose tolerance (NGT), indeterminate glucose tolerance (INDET), a combined group of impaired fasting glucose/impaired glucose tolerance (IGT) and CFRD. In terms of CGM measurements, we calculated the percentage of time of glucose levels within the following categories: Very low (≤ 2.7 mmol/L), low (≥ 2.8 and ≤ 3.3 mmol/L), normal (≥ 3.4 and ≤ 7.7 mmol/L), high (≥ 7.8 and ≤ 11.1 mmol/L), and very high (≥ 11.2 mmol/L). People with known CFRD were excluded.

Results: OGTT results were available from 15 adolescents. Before ELX/TEZ/IVA treatment, OGTTs resulted in two new diagnoses of CFRD; six participants were categorised as having IGT, two as INDET and five as NGT. OGTT categories improved after initiating ELX/TEZ/IVA (P=0.02): no participant fell into the category CFRD, two into the category IGT, four into INDET and nine into NGT. Glucose levels of OGTT improved at 60, 90 and 120 min (P< 0.05), whereas fasting glucose did not change. Eleven participants successfully performed CGM measurements. We did not find a difference in the percentage of the respective glucose level time before and after ELX/TEZ/IVA initiation. No episodes of hypoglycaemia (very low and low category) were observed after starting ELX/TEZ/IVA. Episodes of hyperglycaemia were similar before and after starting ELX/TEZ/IVA treatment (3.0% [IQR 0.6 - 4.46] vs 1.2% [IQR 0.84- 2.08].

Conclusions: Shortly after initiating ELX/TEZ/IVA therapy, glucose tolerance measured by OGTT improved in people with CF. This pilot study indicates that ELX/TEZ/IVA treatment has beneficial effects on the endocrine pancreatic function and might prevent or at least postpone future CFRD.