Advertisement

Improved glucose tolerance after initiation of Elexacaftor / Tezacaftor / Ivacaftor in adults with cystic fibrosis

  • Carolin Steinack
    Correspondence
    Corresponding author at: University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland.
    Affiliations
    Department of Pulmonology, Center of Lung Transplantation, Center of Adult Cystic Fibrosis, Interventional Lung Center, University Hospital Zurich, Zurich, Switzerland
    Search for articles by this author
  • Matthias Ernst
    Affiliations
    Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich and University of Zurich, Zurich, Switzerland
    Search for articles by this author
  • Felix Beuschlein
    Affiliations
    Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich and University of Zurich, Zurich, Switzerland

    Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University Munich, Munich, Germany
    Search for articles by this author
  • René Hage
    Affiliations
    Department of Pulmonology, Center of Lung Transplantation, Center of Adult Cystic Fibrosis, Interventional Lung Center, University Hospital Zurich, Zurich, Switzerland
    Search for articles by this author
  • Maurice Roeder
    Affiliations
    Department of Pulmonology, Center of Lung Transplantation, Center of Adult Cystic Fibrosis, Interventional Lung Center, University Hospital Zurich, Zurich, Switzerland
    Search for articles by this author
  • Macé M. Schuurmans
    Affiliations
    Department of Pulmonology, Center of Lung Transplantation, Center of Adult Cystic Fibrosis, Interventional Lung Center, University Hospital Zurich, Zurich, Switzerland
    Search for articles by this author
  • Christoph Schmid
    Affiliations
    Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich and University of Zurich, Zurich, Switzerland
    Search for articles by this author
  • Thomas Gaisl
    Affiliations
    Department of Pulmonology, Center of Lung Transplantation, Center of Adult Cystic Fibrosis, Interventional Lung Center, University Hospital Zurich, Zurich, Switzerland
    Search for articles by this author
Published:January 19, 2023DOI:https://doi.org/10.1016/j.jcf.2023.01.004

      Highlights

      • 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.

      Abstract

      Background

      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.

      Methods

      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.

      Results

      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).

      Conclusion

      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.

      Keywords

      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)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Cystic Fibrosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Heijerman H.G.M.
        • McKone E.F.
        • Downey D.G.
        • Van Braeckel E.
        • Rowe S.M.
        • Tullis E.
        • et al.
        Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial.
        Lancet. 2019; 394: 1940-1948
        • Ramsey B.W.
        • Davies J.
        • McElvaney N.G.
        • Tullis E.
        • Bell S.C.
        • Drevinek P.
        • et al.
        A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.
        N Engl J Med. 2011; 365: 1663-1672
        • Middleton P.G.
        • Mall M.A.
        • Drevinek P.
        • Lands L.C.
        • McKone E.F.
        • Polineni D.
        • et al.
        Elexacaftor-Tezacaftor-Ivacaftor for cystic fibrosis with a single Phe508del allele.
        N Engl J Med. 2019; 381: 1809-1819
        • Taylor-Cousar J.L.
        • Munck A.
        • McKone E.F.
        • van der Ent C.K.
        • Moeller A.
        • Simard C.
        • et al.
        Tezacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del.
        N Engl J Med. 2017; 377: 2013-2023
        • Sergeev V.
        • Chou F.Y.
        • Lam G.Y.
        • Hamilton C.M.
        • Wilcox P.G.
        • Quon B.S.
        The Extrapulmonary effects of cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis.
        Ann Am Thorac Soc. 2020; 17: 147-154
        • Elder D.A.
        • Wooldridge J.L.
        • Dolan L.M.
        • DA D'Alessio
        Glucose tolerance, insulin secretion, and insulin sensitivity in children and adolescents with cystic fibrosis and no prior history of diabetes.
        J Pediatr. 2007; 151: 653-658
        • Olesen H.V.
        • Drevinek P.
        • Gulmans V.A.
        • Hatziagorou E.
        • Jung A.
        • Mei-Zahav M.
        • et al.
        Cystic fibrosis related diabetes in Europe: prevalence, risk factors and outcome.
        J Cyst Fibros. 2020; 19 (Olesen et al): 321-327
        • Hameed S.
        • Morton J.R.
        • Jaffe A.
        • Field P.I.
        • Belessis Y.
        • Yoong T.
        • et al.
        Early glucose abnormalities in cystic fibrosis are preceded by poor weight gain.
        Diabetes Care. 2010; 33: 221-226
        • Bismuth E.
        • Laborde K.
        • Taupin P.
        • Velho G.
        • Ribault V.
        • Jennane F.
        • et al.
        Glucose tolerance and insulin secretion, morbidity, and death in patients with cystic fibrosis.
        J Pediatr. 2008; 152 (5 e1): 540-545
        • Koch C.
        • Rainisio M.
        • Madessani U.
        • Harms H.K.
        • Hodson M.E.
        • Mastella G.
        • et al.
        Presence of cystic fibrosis-related diabetes mellitus is tightly linked to poor lung function in patients with cystic fibrosis: data from the European Epidemiologic Registry of Cystic Fibrosis.
        Pediatr Pulmonol. 2001; 32: 343-350
        • Ntimbane T.
        • Krishnamoorthy P.
        • Huot C.
        • Legault L.
        • Jacob S.V.
        • Brunet S.
        • et al.
        Oxidative stress and cystic fibrosis-related diabetes: a pilot study in children.
        J Cyst Fibros. 2008; 7: 373-384
        • Colombo C.
        • Foppiani A.
        • Bisogno A.
        • Gambazza S.
        • Dacco V.
        • Nazzari E.
        • et al.
        Lumacaftor/ivacaftor in cystic fibrosis: effects on glucose metabolism and insulin secretion.
        J Endocrinol Invest. 2021; 44: 2213-2218
        • Bellin M.D.
        • Laguna T.
        • Leschyshyn J.
        • Regelmann W.
        • Dunitz J.
        • Billings J.
        • et al.
        Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study.
        Pediatr Diabetes. 2013; 14: 417-421
        • Moheet A.
        • Beisang D.
        • Zhang L.
        • Sagel S.D.
        • VanDalfsen J.M.
        • Heltshe S.L.
        • et al.
        Lumacaftor/ivacaftor therapy fails to increase insulin secretion in F508del/F508del CF patients.
        J Cyst Fibros. 2021; 20: 333-338
        • Misgault B.
        • Chatron E.
        • Reynaud Q.
        • Touzet S.
        • Abely M.
        • Melly L.
        • et al.
        Effect of one-year lumacaftor-ivacaftor treatment on glucose tolerance abnormalities in cystic fibrosis patients.
        J Cyst Fibros. 2020; 19: 712-716
        • Volkova N.
        • Moy K.
        • Evans J.
        • Campbell D.
        • Tian S.
        • Simard C.
        • et al.
        Disease progression in patients with cystic fibrosis treated with ivacaftor: data from national US and UK registries.
        J Cyst Fibros. 2020; 19: 68-79
        • Moran A.
        • Pillay K.
        • Becker D.
        • Granados A.
        • Hameed S.
        • Acerini C.L.
        ISPAD Clinical Practice Consensus Guidelines 2018: management of cystic fibrosis-related diabetes in children and adolescents.
        Pediatr Diabetes. 2018; 19: 64-74
        • Green A.
        • Kirk J.
        Guidelines Development G. Guidelines for the performance of the sweat test for the diagnosis of cystic fibrosis.
        Ann Clin Biochem. 2007; 44: 25-34
        • Coriati A.
        • Ziai S.
        • Azar M.
        • Berthiaume Y.
        • Rabasa-Lhoret R.
        Characterization of patients with cystic fibrosis presenting an indeterminate glucose tolerance (INDET).
        J Cyst Fibros. 2016; 15: 127-132
        • Boudreau V.
        • Coriati A.
        • Hammana I.
        • Ziai S.
        • Desjardins K.
        • Berthiaume Y.
        • et al.
        Variation of glucose tolerance in adult patients with cystic fibrosis: what is the potential contribution of insulin sensitivity?.
        J Cyst Fibros. 2016; 15: 839-845
        • Wareham N.J.
        • Phillips D.I.
        • Byrne C.D.
        • Hales C.N.
        The 30 min insulin incremental response in an oral glucose tolerance test as a measure of insulin secretion.
        Diabet Med. 1995; 12: 931
        • Matsuda M.
        • DeFronzo R.A.
        Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp.
        Diabetes Care. 1999; 22: 1462-1470
        • Matthews D.R.
        • Hosker J.P.
        • Rudenski A.S.
        • Naylor B.A.
        • Treacher D.F.
        • Turner R.C.
        Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.
        Diabetologia. 1985; 28: 412-419
        • Korten I.
        • Kieninger E.
        • Krueger L.
        • Bullo M.
        • Fluck C.E.
        • Latzin P.
        • et al.
        Short-term effects of Elexacaftor/Tezacaftor/Ivacaftor combination on glucose tolerance in young people with cystic fibrosis-an observational pilot study.
        Front Pediatr. 2022; 10852551
      1. Modeling the Mean: Analyzing Response Profiles. Applied Longitudinal Analysis 2011. p. 105–41.

        • Barry P.J.
        • Plant B.J.
        • Nair A.
        • Bicknell S.
        • Simmonds N.J.
        • Bell N.J.
        • et al.
        Effects of ivacaftor in patients with cystic fibrosis who carry the G551D mutation and have severe lung disease.
        Chest. 2014; 146: 152-158
        • Moheet A.
        • Moran A.
        New concepts in the pathogenesis of cystic fibrosis-related diabetes.
        J Clin Endocrinol Metab. 2022; 107: 1503-1509
        • Merjaneh L.
        • Hasan S.
        • Kasim N.
        • Ode K.L.
        The role of modulators in cystic fibrosis related diabetes.
        J Clin Transl Endocrinol. 2022; 27100286
        • Sun X.
        • Yi Y.
        • Xie W.
        • Liang B.
        • Winter M.C.
        • He N.
        • et al.
        CFTR Influences Beta Cell Function and Insulin Secretion Through Non-Cell Autonomous Exocrine-Derived Factors.
        Endocrinology. 2017; 158: 3325-3338
        • Petersen M.C.
        • Begnel L.
        • Wallendorf M.
        • Litvin M.
        Effect of elexacaftor-tezacaftor-ivacaftor on body weight and metabolic parameters in adults with cystic fibrosis.
        J Cyst Fibros. 2022; 21: 265-267
        • Scheuing N.
        • Holl R.W.
        • Dockter G.
        • Hermann J.M.
        • Junge S.
        • Koerner-Rettberg C.
        • et al.
        High variability in oral glucose tolerance among 1,128 patients with cystic fibrosis: a multicenter screening study.
        PLoS ONE. 2014 Nov 13; 9e112578