Effects of modulator therapies on endocrine complications in adults with cystic fibrosis: a narrative review.

Publisher: Australasian Medical Publishing Co Country of Publication: Australia NLM ID: 0400714 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1326-5377 (Electronic) Linking ISSN: 0025729X NLM ISO Abbreviation: Med J Aust Subsets: MEDLINE

Publication: : Pyrmont, NSW : Australasian Medical Publishing Co.
Original Publication: Sydney : Australasian Medical Pub. Co.

Cystic Fibrosis*/complications ; Cystic Fibrosis*/drug therapy ; Cystic Fibrosis*/genetics ; Diabetes Mellitus, Type 2*/drug therapy; Pregnancy ; Female ; Adult ; Humans ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/therapeutic use ; Mutation ; Quality of Life

Cystic fibrosis is a monogenic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which transports chloride ions in secretory organs. Modulator therapies are small molecules that correct CFTR dysfunction and can lead to a wide range of benefits for both pulmonary and extrapulmonary complications of cystic fibrosis. With advancements in airway, antimicrobial and nutritional therapies and now introduction of modulator therapies, most people living with cystic fibrosis in Australia are now adults. For adults with cystic fibrosis, endocrine manifestations such as cystic fibrosis-related diabetes, metabolic bone disease, and reproductive health are becoming increasingly important, and emerging evidence on the endocrine effects of CFTR modulator therapies is promising and is shifting paradigms in our understanding and management of these conditions. The management of cystic fibrosis-related diabetes will likely need to pivot for high responders to modulator therapy with dietary adaptions and potential use of medications traditionally reserved for adults with type 2 diabetes, but evidence to support changing clinical care needs is currently lacking. Increased attention to diabetes-related complications screening will also be required. Increased exercise capacity due to improved lung function, nutrition and potentially direct modulator effect may have a positive impact on cystic fibrosis-related bone disease, but supporting evidence to date is limited. Fertility can improve in women with cystic fibrosis taking modulator therapy. This has important implications for pregnancy and lactation, but evidence is lacking to guide pre-conception and antenatal management. Provision of multidisciplinary clinical care remains ever-important to ensure the emergence of endocrine and metabolic complications are optimised in adults with cystic fibrosis.
(© 2023 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Ahern S, Salimi F, Caruso M, et al. Australian Cystic Fibrosis Data Registry annual report. Melbourne: Monash University, 2021. https://cysticfibrosis.org.au/wp-content/uploads/2023/05/2021-ACFDR-Annual-Report.pdf (viewed Sept 2023).
Li W, Soave D, Miller MR, et al. Unraveling the complex genetic model for cystic fibrosis: pleiotropic effects of modifier genes on early cystic fibrosis-related morbidities. Hum Genet 2014; 133: 151-161.
Velard F, Delion M, Le Henadd C, et al. Cystic fibrosis and bone disease: defective osteoblast maturation with the F508del mutation in cystic fibrosis transmembrane conductance regulator. Am J Respir Crit Care Med 2014; 189: 746-748.
Wong PY. CFTR gene and male fertility. Mol Hum Reprod 1998; 4: 107-110.
Xue R, Gu H, Qiu Y, et al. Expression of cystic fibrosis transmembrane conductance regulator in ganglia of human gastrointestinal tract. Sci Rep 2016; 6: 30926.
Colombo C. Liver disease in cystic fibrosis. Curr Opin Pulm Med 2007; 13: 529-536.
Haq I, Almulhem M, Soars S, et al. Precision medicine based on CFTR genotype for people with cystic fibrosis. Pharmgenomics Pers Med 2022; 15: 91-104.
Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365: 1663-1672.
Accurso FJ, Rowe SM, Clancy JP, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med 2010; 363: 1991-2003.
Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 2015; 373: 220-231.
Jia S, Taylor-Cousar JL. Cystic fibrosis modulator therapies. Annu Rev Med 2023; 74: 413-426.
Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med 2019; 381: 1809-1819.
Heijerman HGM, et al. Efficacy and safety of the elexacaftor/tezacaftor/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.
Gavioli EM, Guardado N, Haniff F, et al. A current review of the safety of cystic fibrosis transmembrane conductance regulator modulators. J Clin Pharm Ther 2021; 46: 286-294.
Moran A, Brunzell C, Cohen RC, et al. Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care 2010; 33: p. 2697-2708.
Middleton PG, Wagenaar M, Matson AG, et al. Australian standards of care for cystic fibrosis-related diabetes. Respirology 2014; 19: 185-192.
Olesen HV, Drevinek P, Gulmans VA, et al. Cystic fibrosis related diabetes in Europe: prevalence, risk factors and outcome; Olesen et al. J Cyst Fibros 2020; 19: 321-327.
Finkelstein SM, Wielinski CL, Elliott GR, et al. Diabetes mellitus associated with cystic fibrosis. J Pediatr 1988; 112: 373-377.
Kwong E, Desai S, Chong L, et al. The impact of cystic fibrosis-related diabetes on health-related quality of life. J Cyst Fibros 2019; 18: 734-736.
Moran A, Dunitz J, Nathan B, et al. Cystic fibrosis-related diabetes: current trends in prevalence, incidence, and mortality. Diabetes Care 2009; 32: 1626-1631.
Adler AI, Shine BSF, Chamnan P, et al. Genetic determinants and epidemiology of cystic fibrosis-related diabetes: results from a British cohort of children and adults. Diabetes Care 2008; 31: 1789-1794.
Blackman SM, Hsu S, Ritter SE, et al. A susceptibility gene for type 2 diabetes confers substantial risk for diabetes complicating cystic fibrosis. Diabetologia 2009; 52: 1858-1865.
Marshall BC, Butler SM, Stoddard M, et al. Epidemiology of cystic fibrosis-related diabetes. J Pediatr 2005; 146: 681-687.
Hull RL, Gibson RL, McNamara S, et al. Islet interleukin-1β immunoreactivity is an early feature of cystic fibrosis that may contribute to β-cell failure. Diabetes Care 2018; 41: 823-830.
Hicks R, Marks BE, Oxman R, Moheet A. Spontaneous and iatrogenic hypoglycemia in cystic fibrosis. J Clin Transl Endocrinol 2021; 26: 100267.
Hameed S, Morton JR, Jaffé A, et al. Early glucose abnormalities in cystic fibrosis are preceded by poor weight gain. Diabetes Care 2009; 33: 221-226.
Schwarzenberg SJ, Thomas W, Olsen TW, et al. Microvascular complications in cystic fibrosis-related diabetes. Diabetes Care 2007; 30: 1056-1061.
Sandouk Z, Nachawi N, Simon R, et al. Coronary artery disease in patients with cystic fibrosis - a case series and review of the literature. J Clin Transl Endocrinol 2022; 30: 100308.
Moran A, Pillay K, Becker D, et al. ISPAD clinical practice consensus guidelines 2018: management of cystic fibrosis-related diabetes in children and adolescents. Pediatr Diabetes 2018; 19 (Suppl): 64-74.
Lam GY, Doll-Shankaruk M, Dayton J, et al. The use of fructosamine in cystic fibrosis-related diabetes (CFRD) screening. J Cyst Fibros 2018; 17: 121-124.
Kumar S, Pallin M, Soldatos G, Teede H. Comparison of continuous glucose monitoring to reference standard oral glucose tolerance test for the detection of dysglycemia in cystic fibrosis: a systematic review. J Clin Transl Endocrinol 2022; 30: 100305.
Piona C, Volpi S, Zusi C, et al. Glucose tolerance stages in cystic fibrosis are identified by a unique pattern of defects of beta-cell function. J Clin Endocrinol Metab 2021; 106: 1793-1802.
Bessonova L, Volkova N, Higgins M, et al. Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor. Thorax 2018; 73: 731-740.
Bellin MD, Laguna T, Leschyshyn J, et al. Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study. Pediatr Diabetes 2013; 14: 417-421.
Kelly A, De Leon DD, Sheikh S, et al. Islet hormone and incretin secretion in cystic fibrosis after four months of ivacaftor therapy. Am J Respir Crit Care Med 2018; 199: 342-351.
Tsabari R, Elyashar HI, Cymberknowh MC, et al. CFTR potentiator therapy ameliorates impaired insulin secretion in CF patients with a gating mutation. J Cyst Fibros 2016; 15: e25-e27.
Volkova N, Moy K, Evans J, 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.
Barry PJ, Banerjee A, Horsley A, et al. 182 Impact of ivacaftor on glycaemic health in patients carrying the G551D mutation. J Cyst Fibros 2015; 14: S104.
Christian F, Thierman A, Shirley E, et al. Sustained glycemic control with ivacaftor in cystic fibrosis-related diabetes. J Investig Med High Impact Case Rep 2019; 7: 2324709619842898.
Gaines H, Jones KR, Lim J, et al. Effect of CFTR modulator therapy on cystic fibrosis-related diabetes. J Diabetes Complications 2021; 35: 107845.
Hayes D, McCoy KS, Sheikh SI. Resolution of cystic fibrosis-related diabetes with ivacaftor therapy. Am J Respir Crit Care Med 2014; 190: 590-591.
Misgault B, Chatron E, Reynaud Q, et al. Effect of one-year lumacaftor-ivacaftor treatment on glucose tolerance abnormalities in cystic fibrosis patients. J Cystic Fibros 2020; 19: 712-716.
Moheet A, Beisand D, Zhang L, et al. Lumacaftor/ivacaftor therapy fails to increase insulin secretion in F508del/F508del CF patients. J Cyst Fibros 2021; 20: 333-338.
Thomassen JC, Mueller MI, Alejandre Alcazar MA, et al. Effect of lumacaftor/ivacaftor on glucose metabolism and insulin secretion in Phe508del homozygous cystic fibrosis patients. J Cyst Fibros 2018; 17: 271-275.
Li A, Vigers T, Pyle L, et al. Continuous glucose monitoring in youth with cystic fibrosis treated with lumacaftor-ivacaftor. J Cyst Fibros 2019; 18: 144-149.
Scully KJ, Marchetti P, Sawicki GS, et al. The effect of elexacaftor/tezacaftor/ivacaftor (ETI) on glycemia in adults with cystic fibrosis. J Cyst Fibros 2022; 21: 258-263.
Korten I, Kieninger E, Krueger L, 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; 10: 852551.
Steinack C, et al. Improved glucose tolerance after initiation of elexacaftor/tezacaftor/ivacaftor in adults with cystic fibrosis. J Cyst Fibros 2023; 22: 722-729.
Chan CL, Granados A, Moheet A, et al. Glycemia and β-cell function before and after elexacaftor/tezacaftor/ivacaftor in youth and adults with cystic fibrosis. J Clin Transl Endocrinol 2022; 30: 100311.
Merjaneh L, Hasan S, Kasim N, Ode KL. The role of modulators in cystic fibrosis related diabetes. J Clin Transl Endocrinol 2021; 27: 100286.
Carrion A, Borowitz DS, Freedman SD, et al. Reduction of recurrence risk of pancreatitis in cystic fibrosis with ivacaftor: case series. J Pediatr Gastroenterol Nutr 2018; 66: 451-454.
Kounis I, Lévy P, Rebours V. Ivacaftor CFTR potentiator therapy is efficient for pancreatic manifestations in cystic fibrosis. Am J Gastroenterol 2018; 113: 1058-1059.
Johns JD, Rowe SM. The effect of CFTR modulators on a cystic fibrosis patient presenting with recurrent pancreatitis in the absence of respiratory symptoms: a case report. BMC Gastroenterol 2019; 19: 123.
Kelsey R, et al. Cystic fibrosis-related diabetes: pathophysiology and therapeutic challenges. Clin Med Insights Endocrinol Diabetes 2019; 12: 1179551419851770.
Bellin MD, Laguna T, Leschyshyn J, et al. Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study. Pediatr Diabetes 2013; 14: 417-421.
Poore TS, Taylor-Cousar JL, Zemanick ET. Cardiovascular complications in cystic fibrosis: a review of the literature. J Cyst Fibros 2022; 21: 18-25.
Onady GM, Stolfi A. Drug treatments for managing cystic fibrosis-related diabetes. Cochrane Database Syst Rev 2020; (10): CD004730.
Kumar S, Soldatos G, Ranasinha S, et al. Continuous glucose monitoring versus self-monitoring of blood glucose in the management of cystic fibrosis related diabetes: a systematic review and meta-analysis. J Cyst Fibros 2023; 22: 39-49.
Aris RM, Renner JB, Winders AD, et al. Increased rate of fractures and severe kyphosis: sequelae of living into adulthood with cystic fibrosis. Ann Intern Med 1998; 128: 186-193.
Cairoli E, Eller-Vainicher C, Morlacchi LC, et al. Bone involvement in young adults with cystic fibrosis awaiting lung transplantation for end-stage respiratory failure. Osteoporos Int 2019; 30: 1255-1263.
Sermet-Gaudelus I, et al. European cystic fibrosis bone mineralisation guidelines. J Cyst Fibros 2011; 10 (Suppl): S16-S23.
King SJ, Topliss DJ, Kotsimbos T, et al. Reduced bone density in cystic fibrosis: DeltaF508 mutation is an independent risk factor. Eur Respir J 2005; 25: 54-61.
Sermet-Gaudelus I, Delion M, Durieu I, et al. Bone demineralization is improved by ivacaftor in patients with cystic fibrosis carrying the p.Gly551Asp mutation. J Cyst Fibros 2016; 15: e67-e69.
Jacquot J, Abdallah D, Jourdain ML, et al. Cystic fibrosis related bone disease - alterations in blood monocytes of G551D-bearing cystic fibrosis patients undergoing treatment with ivacaftor. Proceedings of the American Thoracic Society 2018 International Conference; San Diego (USA), 2018. https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2018.197.1_MeetingAbstracts.A3665 (viewed Sept 2023).
Le Heron L, Guillaume C, Velard F, et al. Cystic fibrosis transmembrane conductance regulator (CFTR) regulates the production of osteoprotegerin (OPG) and prostaglandin (PG) E2 in human bone. J Cyst Fibros 2010; 9: 69-72.
Conwell LS, Chang AB. Bisphosphonates for osteoporosis in people with cystic fibrosis. Cochrane Database Syst Rev 2014; (3): CD002010.
Leifke E, Friemert M, Heilmann M, et al. Sex steroids and body composition in men with cystic fibrosis. Eur J Endocrinol 2003; 148: 551-557.
Hughan KS, Daley T, Rayas MS, et al. Female reproductive health in cystic fibrosis. J Cyst Fibros 2019; 18: S95-S104.
Siwamogsatham O, Stephens K, Tangpricha V. Evaluation of teriparatide for treatment of osteoporosis in four patients with cystic fibrosis: a case series. Case Rep Endocrinol 2014; 2014: 893589.
Crow HM, Graves L, Anabtawi A. Romosozumab used to treat a patient with cystic fibrosis-related osteoporosis. Am J Med Sci 2022; 364: 461-465.
Putman MS, Greenblatt LB, Bruce M, et al. The effects of ivacaftor on bone density and microarchitecture in children and adults with cystic fibrosis. J Clin Endocrinol Metab 2021; 106: e1248-e1261.
Wright BA, Ketchen NK, Rasmussen LN, et al. Impact of elexacaftor/tezacaftor/ivacaftor on vitamin D absorption in cystic fibrosis patients. Pediatr Pulmonol 2022; 57: 655-657.
Tangpricha V. Correction of the gene defect in cystic fibrosis: is it too late for bone? J Clin Endocrinol Metab 2021; 106: e2359-e2361.
Smith HC. Fertility in men with cystic fibrosis assessment, investigations and management. Paediatr Respir Rev 2010; 11: 80-83.
Tournier A, Murris M, Prevotat A, et al. Fertility of women with cystic fibrosis: a French survey. Reprod Biomed Online 2019; 39: 492-495.
Stead RJ, Hodson ME, Batten JC, et al. Amenorrhoea in cystic fibrosis. Clin Endocrinol (Oxf) 1987; 26: 187-195.
Tizzano EF, Silver MM, Chitayat D, et al. Differential cellular expression of cystic fibrosis transmembrane regulator in human reproductive tissues. Clues for the infertility in patients with cystic fibrosis. Am J Pathol 1994; 144: 906.
Blohm F, Fridén B, Milsom I. A prospective longitudinal population-based study of clinical miscarriage in an urban Swedish population. BJOG 2008; 115: 176-183.
Junior G, et al. Maternal and perinatal outcomes in pregnant women with cystic fibrosis. Rev Bras Ginecol Obstet 2019; 41: 230-235.
Jelin AC, Sharshiner R, Caughey AB. Maternal co-morbidities and neonatal outcomes associated with cystic fibrosis. J Matern Fetal Neonatal Med 2017; 30: 4-7.
Girault A, Blanc J, Gayet V, et al. Maternal and perinatal outcomes of pregnancies in women with cystic fibrosis--A single centre case-control study. Respir Med 2016; 113: 22-27.
Patel EM, Swamy GK, Heine RP, et al. Medical and obstetric complications among pregnant women with cystic fibrosis. Am J Obstet Gynecol 2015; 212: 98.e1-9.
Kroon MAGM, Akkerman-Nijland AM, Rottier BL, et al. Drugs during pregnancy and breast feeding in women diagnosed with cystic fibrosis - an update. J Cyst Fibros 2018; 17: 17-25.
Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry - annual data report 2021. Bethesda (MD), CFF: 2021. https://www.cff.org/sites/default/files/2021-11/Patient-Registry-Annual-Data-Report.pdf (viewed Aug 2023).
Jones G, Harris EJ, Dyce P, et al. Enhanced fertility - an unforeseen consequence of ivacaftor therapy? Poster presented at 28th North American Cystic Fibrosis Conference, Atlanta (USA); 9-11 October 2014. https://onlinelibrary.wiley.com/doi/10.1002/ppul.23108 (viewed Sept 2023).
Jones GH, Walshaw MJ. Potential impact on fertility of new systemic therapies for cystic fibrosis. Paediatr Respir Rev 2015; 16: 25-27.
O'Connor KE, Goodwin DL, NeSmith A, et al. Elexacafator/tezacaftor/ivacaftor resolves subfertility in females with CF: a two center case series. J Cyst Fibros 2021; 20: 399-401.
Ladores S, LA Bray, Brown J. Two unanticipated pregnancies while on cystic fibrosis gene-specific drug therapy. J Patient Exp 2020; 7: 4-7.
Heltshe SL, Godfrey EM, Josephy T, et al. Pregnancy among cystic fibrosis women in the era of CFTR modulators. J Cyst Fibros 2017; 16: 687-694.
Godfrey EM, Mody S, Schwartz MR, et al. Contraceptive use among women with cystic fibrosis: a pilot study linking reproductive health questions to the Cystic Fibrosis Foundation National Patient Registry. Contraception 2020; 101: 420-426.
Taylor-Cousar JL. CFTR modulators: impact on fertility, pregnancy, and lactation in women with cystic fibrosis. J Clin Med 2020; 9: 2706.
Nash EF, Middleton PG, Taylor-Cousar JL. Outcomes of pregnancy in women with cystic fibrosis (CF) taking CFTR modulators - an international survey. J Cyst Fibros 2020; 19: 521-526.
Jain R, Wolf A, Molad M, et al. Congenital bilateral cataracts in newborns exposed to elexacaftor-tezacaftor-ivacaftor in utero and while breast feeding. J Cyst Fibros 2022; 21: 1074-1076.
Kopp BT, Fitch J, Jaramillo L, et al. Whole-blood transcriptomic responses to lumacaftor/ivacaftor therapy in cystic fibrosis. J Cyst Fibros 2020; 19: 245-254.
Clancy JP, Cotton CU, Donaldson SH, et al. CFTR modulator theratyping: current status, gaps and future directions. J Cyst Fibros 2019; 18: 22-34.

Australian Government

Keywords: Cystic fibrosis; Diabetes mellitus, type 2; Endocrinology; Metabolic diseases; Reproduction

126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator)

Date Created: 20231015 Date Completed: 20231122 Latest Revision: 20231124

20231215

10.5694/mja2.52119

37839059