- •In adult patients with CF and at least one copy of F508del, treatment with the triple CFTR modulator was associated with significant improvement of glucose tolerance.
- •ELX/TEZ/IVA significantly improved FEV1, weight, sweat chloride, and in 48.5% the glucose tolerance without an increase of insulin and C-Peptide secretion.
- •Insulin sensitivity as estimated by the HOMA-IR and Matsuda-Index did not change significantly.
- •Inflammatory and proinflammatory markers such as CRP, IgE and IgG significantly declined after treatment initiation consistent with the hypothesis that the triple modulator therapy may improve glucose tolerance indirectly, e.g. by reducing inflammation.
The novel triple CFTR modulator therapy Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) improves lung function, body mass index (BMI), sinus clearance, and quality of life in patients with cystic fibrosis. Whether treatment with ELX/TEZ/IVA is associated with improved glucose tolerance is unknown.
This cohort study included adults with CF and at least one copy of F508del.. Study assessments before treatment and at least 3 months after ELX/TEZ/IVA initiation included an oral glucose tolerance test (OGTT) with glucose and insulin measurements, BMI, lung function test, and sweat chloride levels. We used an analysis of response profiles to calculate changes in outcomes.
33 patients (27.8 ± 6.3 years; 73% male; 64% F508del homozygous) were included. After a median of 184 [IQR, 107 - 278] days following treatment initiation 16 (48.5%) patients improved their glucose tolerance category, while 13 (39.4%) remained unchanged and 4 (12.1%) deteriorated. Overall, 60, 90 and 120 min OGTT glycemia decreased significantly from 11.9 ± 2.7 mmol/l to 10.6 ± 2.8 mmol/l (p = 0.012), 10.4 ± 3.0 mmol/l to 8.4 ± 3.6 mmol/l (p = 0.002) and 7.3 ± 3.1 mmol/l to 5.7 ± 3.0 mmol/l (p = 0.012). HbA1c levels also improved significantly, from 5.50±0.24% to 5.39±0.25% (p = 0.039).
In adult patients with CF and at least one copy of F508del, treatment with the triple CFTR modulator was associated with possible improvement of glucose tolerance without increases of insulin secretion. Early initiation of treatment as assessed through long-term prospective trials is mandatory to demonstrate if decreased glucose control is preventable or even reversible.
Abbreviations:AUC (Area under the curve), CF (Cystic fibrosis), CFRD (Cystic fibrosis related diabetes mellitus), CFTR (Cystic fibrosis transmembrane conductance regulator), CRP (C-reactive protein), ELX/TEZ/IVA (Elexacaftor/Tezacaftor/Ivacaftor), FDA (Food and drug administration), FEV1 (Forced expiratory volume in 1 second), HOMA-IR (Homeostasis model assessment of insulin resistance), Ig (Immunglobulin), IGI (Insulinogenic index), IGT (Impaired glucose tolerance), INDET (Indeterminate glucose tolerance), IVA (Ivacaftor), LUM/IVA (Lumacaftor/Ivacaftor), NGT (Normal glucose tolerance), OGTT (Oral glucose tolerance test), PEX (pulmonary exacerbations), pwCF (Patients with cystic fibrosis), SD (Standard deviation)
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Published online: January 19, 2023
Accepted: January 11, 2023
Received in revised form: January 10, 2023
Received: September 24, 2022
Publication stageIn Press Corrected Proof
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