Impact of CFTR Modulators on Beta-Cell Function in Children and Young Adults with Cystic Fibrosis

Abstract

Background: To date, no consistent data are available on the possible impact of CFTR modulators on glucose metabolism. The aim of this study was to test the hypothesis that treatment with CFTR modulators is associated with an improvement in the key direct determinants of glucose regulation in children and young adults affected by Cystic Fibrosis (CF). Methods: In this study, 21 CF patients aged 10–25 underwent oral glucose tolerance test (OGTT) before and after 12–18 months of treatment with Lumacaftor/Ivacaftor or Elexacaftor-Ivacaftor-Tezacaftor. β-cell function (i.e., first and second phase of insulin secretion measured as derivative and proportional control, respectively) and insulin clearance were estimated by OGTT mathematical modelling. Insulin sensitivity was estimated by the Oral Glucose Sensitivity Index (OGIS). The dynamic interplay between β-cell function, insulin clearance and insulin sensitivity was analysed by vector plots of glucose-stimulated insulin bioavailability vs. insulin sensitivity. Results: No changes in glucose tolerance occurred after either treatment, whereas a significant improvement in pulmonary function and chronic bacterial infection was observed. Beta cell function and insulin clearance did not change in both treatment groups. Insulin sensitivity worsened in the Lumacaftor/Ivacaftor group. The analysis of vector plots confirmed that glucose regulation was stable in both groups. Conclusions: Treatment of CF patients with CFTR modulators does not significantly ameliorate glucose homeostasis and/or any of its direct determinants.

Efficacy and Safety of Elexacaftor-Tezacaftor-Ivacaftor in the Treatment of Cystic Fibrosis: A Systematic Review

“…The results showed no significant change in β-cell DC, PC, insulin clearance, and insulin sensitivity after the triple therapy. Only HbA 1 c was significantly reduced in these patients ( p = 0.04) [ 26 ].…”

“…Finally, Piona et al, in their observational pilot study, noted that five of the 21 participants, aged 22 ± 7.4 years, with Phe508del/Other genotype, and ALD (ppFEV 1 < 40%) had an increase in ppFEV 1 to 49 ± 11.27 ( p < 0.041), FVC to 4.17 ± 0.95 lt ( p < 0.014) and a decrease in SCC to 30.33 ± 11.72 mmol/lt ( p < 0.002) from baseline, after 12–18 months of ELX/TEZ/IVA treatment [ 26 ].…”

Post-approval studies with the CFTR modulators Elexacaftor-Tezacaftor—Ivacaftor

“…Studies on the impact of ELX/TEZ/IVA on glucose homeostasis yielded conflicting outcomes. Continuous glucose monitoring (CGM) and oral glucose tolerance tests (OGTT) did not detect any difference in glucose patterns after several months of ELX/TEZ/IVA therapy in three studies (Chan et al, 2022;Crow et al, 2022;Piona et al, 2022). In contrast, glucose patterns again assessed by CGM or OGTT improved in three other studies (Korten et al, 2022;Scully et al, 2022;Steinack et al, 2023).…”

Highly effective cystic fibrosis transmembrane conductance (regulator) modulator therapy: shifting the curve for most while leaving some further behind

“…ETI's effects on the development of CF related diabetes (CFRD) is more difficult to characterize. Though some studies show improvements in some indices of glucose control [11][12][13], it is unclear if HEMT will delay or prevent the development of CFRD. pwCF report significant improvement in general health related quality of life (QoL) metrics [14], which is quite apparent to those of us providing care for pwCF.…”