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

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.


Summary
• 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.

Classification of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in cystic fibrosis
Narrative review and phenotypes means that not all individuals living with the condition benefit.Ivacaftor was the first drug available, but despite promising in vitro results, it is clinically effective in a very small proportion (< 6%) of people with cystic fibrosis who have the G551D or other class III (gating) mutations. 8,9Lumacaftor was discovered next and used in combination with ivacaftor, but bronchospasm, particularly in individuals with severe airflow obstruction, limited its uptake. 10This created opportunity for tezacaftor-ivacaftor, which offered advantages over lumacaftorivacaftor, including fewer drug-drug interactions, better side effect profile, and benefits in those homozygote for the Phe508del mutation. 11However, the clinical benefits of tezacaftor-ivacaftor were modest and high throughput drug discovery continued, eventuating in the most successful synergistic combination yet with elexacaftor-tezacaftor-ivacaftor (ETI).With ETI, remarkable clinical benefits have been demonstrated for the first time in people both homozygous and heterozygous for the Phe508del mutation. 12,13Real-world experiences have further substantiated their benefits, tolerability and safety. 14With ETI approved on the Australian Pharmaceutical Benefits Scheme for all adults since 1 April 2022, those with diminishing pulmonary symptoms have pivoted their attention to extrapulmonary complications.This narrative review aims to summarise modulator effects on the endocrine system, with a focus on cystic fibrosis-related diabetes, metabolic bone disease, and fertility.
We conducted an Ovid MEDLINE and grey literature electronic search on 14 March 2023 to capture studies evaluating effects of currently available modulator therapies on cystic fibrosis-related diabetes, metabolic bone disease, and reproductive health.All study designs that included human in vitro studies were selected.Animal studies were excluded due to inherent challenges and limitations of currently available models.The search strategy is available in the Supporting Information, section 1.

Epidemiology
The term "cystic fibrosis-related diabetes" encompasses a complex spectrum of glucose abnormalities that can be transient or progressive with diagnosis based on specific glucose criteria being met on screening tests. 15,16Epidemiological studies report that the prevalence of cystic fibrosis-related diabetes increases with age, with an estimated 30% of adults affected. 17Both incidence and prevalence are directly proportional to diabetes screening, which may vary across centres.The presence of cystic fibrosis-related diabetes has been associated with higher morbidity and mortality, 18 reduced quality of life, and increased utilisation of health care resources compared with people without diabetes. 19However, with the introduction of aggressive screening and improved clinical management, adverse effects can be minimised. 20

Risk factors
Risk factors for cystic fibrosis-related diabetes include increasing age, female sex, pancreatic insufficiency, cystic fibrosis-related liver disease, and systemic corticosteroid use. 21Individuals with class I and II CFTR gene mutations also appear to be at increased risk of cystic fibrosis-related diabetes. 21Family history of type 2 diabetes may also increase susceptibility. 22

Clinical associations
Adverse clinical outcomes directly linked to the presence of cystic fibrosis-related diabetes include more severe pulmonary disease, increased frequency and severity of pulmonary exacerbations, and presence of multiresistant microorganisms such as Pseudomonas aeruginosa. 23Before modulators, people with cystic fibrosis-related diabetes have also been at a higher risk of compromised nutritional status due to catabolism and ensuing weight loss.

Pathogenesis
The endocrine pancreas contains β islet cells, which are responsible for synthesis and storage of insulin.The exact mechanisms of their dysfunction and loss resulting in insulin deficiency and onset of cystic fibrosis-related diabetes remains unclear.In the exocrine pancreas, dysfunctional CFTR can lead to ductal obstruction and autodigestion of pancreatic ductal and acinar cells.The "bystander hypothesis" postulates collateral damage to β cells and perhaps explains why exocrine pancreatic insufficiency often coexists clinically with cystic fibrosis-related diabetes.The "inflammation hypothesis" suggests that initial structural damage to β cells is accompanied with an exaggerated inflammatory response adding further insult, 24 which may explain insulin resistance seen in cystic fibrosis.Disruption of the incretin 25 axis that regulates release of insulin and glucagon from the pancreatic islet cells, lipid metabolism, gut motility, appetite, body weight, and immune function has also been postulated.

Clinical findings
Clinically, weight loss and declining lung function may be the earliest indicators and precede the onset of glucose abnormalities required to meet the current diagnostic criteria for cystic fibrosisrelated diabetes. 26Post-prandial hyperglycaemia is often the first glycaemic manifestation, with fasting hyperglycaemia a later occurrence.Presence of fasting hyperglycaemia has been linked to increased risk and incidence of microvascular complications. 27ore recently, macrovascular events have also been reported in adults with cystic fibrosis-related diabetes. 28

Screening and diagnosis
Guidelines recommend screening for cystic fibrosis-related diabetes from the age of ten years with an annual oral glucose tolerance test (OGTT) 16,29 (Box 3).The OGTT remains the most sensitive test for the diagnosis of cystic fibrosis-related diabetes (Box 4) and a distinct category called "indeterminate glycaemia" Narrative review (INDET) is used to recognise the mid-OGTT glucose elevations that can be seen in people with cystic fibrosis. 32

Effects of modulator therapies on cystic fibrosis-related diabetes
Ivacaftor monotherapy.In people with cystic fibrosis with normal and impaired glucose tolerance, ivacaftor may reduce progression to cystic fibrosis-related diabetes. 33This effect may be through improved first phase insulin secretion [34][35][36] and overall endogenous insulin production independent of incretin effects. 350][41] Importantly, CFTR genotype appears key to ivacaftor success, 34 with patients homozygous for Phe508del mutation receiving minimal benefit.
Combination modulator therapies.In individuals with impaired glucose tolerance, the use of lumacaftor-ivacaftor has been linked to positive glycaemic outcomes after one year of treatment in people who also demonstrated improved pulmonary and nutritional outcomes. 424][45] Early prospective studies evaluating effects of ETI on continuous glucose monitoring indices, 46 glucose tolerance, 47,48 and weight 49  • Recommendation to perform annual OGTT 29 Indeterminate glycaemia (INDET) < 5.6 < 7.7 • Mid-OGTT plasma glucose > 11.1 mmol/L 32 Impaired glucose tolerance (IGT) 5.6-6.97.8-11.0 • Can be impaired fasting and/or two-hour plasma glucose level 15 Cystic fibrosis-related diabetes without fasting hyperglycaemia < 6.9 ≥ 11.1 • Diagnosis can only be made in the non-pregnant state 15 Cystic fibrosis-related diabetes with fasting hyperglycaemia ≥ 7.0 na • Association with microvascular complications 27 Gestational diabetes (GDM) in cystic fibrosis ≥ 5.1 ≥ 8.5 • One-hour plasma glucose > 10.0 mmol/L also meets diagnostic criteria for GDM • Repeat OGTT post partum recommended to evaluate for cystic fibrosis-related diabetes 15 Narrative review on β cells, and likely other mechanisms are involved.There is some evidence that CFTR modulators may reduce the risk of pancreatitis in cystic fibrosis and may partially restore exocrine pancreatic function, [51][52][53] with favourable pancreatic exocrineendocrine paracrine interactions 54 improving residual β cell function.Suppressed glucagon may also play a role in reducing hyperglycaemia. 40,55The effectiveness of modulator therapies in treating hyperglycaemia in individuals with confirmed cystic fibrosis-related diabetes may depend on available β cells that can be rescued and genotype-modulator interactions.But what is more exciting is the preventive or disease-modifying potential of modulator therapies, with the possibility that early initiation in childhood may preserve both endocrine and exocrine pancreatic function.The correlation between improved pulmonary function and glycaemia is noteworthy and points to possible downgrading of the inflammation cascade and reduction in insulin resistance, either via mechanisms of reducing islet cell and/or systemic inflammation.
Management in the post-modulator era.Management of cystic fibrosis-related diabetes will need to pivot for high responders to modulator therapies, with increasing focus on normalising glycaemia, screening for diabetes-related complications and optimisation of metabolic health parameters, including cardiovascular risk factors. 56Overweight-and obesity-related complications, such as fatty liver, may also become more prevalent. 56These metabolic complications and risks also need to be considered in adults with mild cystic fibrosis phenotypes not receiving modulator therapies.For now, insulin remains the mainstay of treatment due to lack of robust evidence supporting the use of oral antihyperglycaemic agents and non-insulin injectables. 57Incretin-based therapies may be appealing for adults with excess weight gain on ETI, but given lack of safety and efficacy data, initiation should occur within a research context.In addition, improvements in lung function may be associated with reduced energy needs and this will require adaptive dietary changes.Interactions with obesogenic environmental factors and genetic susceptibility to type 2 diabetes will also become relevant.Continuous glucose monitoring will be of great value to guide dietary and pharmacotherapy decisions. 58Use of glycated haemoglobin as a screening tool, particularly in adults with stable lung disease on modulator therapy, will also need to be explored.

Epidemiology
The term "cystic fibrosis-related bone disease" is an umbrella term encompassing both low bone mineral density and/or fragility fractures in people with cystic fibrosis.Fracture rates in adult men and women with cystic fibrosis may be double that of the general population, 59 with fragility fractures affecting an estimated half of all adults with end-stage lung disease. 60Rib and vertebral compression fractures can significantly compromise lung function, and severe osteoporosis can be a barrier to lung transplantation.

Risk factors
Multiple risk factors for cystic fibrosis-related bone disease exist.These include exposure to exogenous glucocorticoids, chronic infection and inflammation, malnutrition, vitamin D deficiency, decreased physical activity, hypogonadism, and presence of diabetes.Currently, dual-energy x-ray absorptiometry (DXA) is recommended for the assessment and monitoring of cystic fibrosis-related bone disease. 61

Pathogenesis
CFTR may be expressed on osteoblasts, osteocytes and chondrocytes and their progenitors, implicating that dysfunction may have direct effects on bone. 62In vitro experiments have demonstrated CFTR dysfunction can increase osteoclast activity, 63 survival and differentiation 64 and can disrupt osteoblast function, 65 resulting in uncoupling of bone remodelling.

Management
The current management of cystic fibrosis-related bone disease involves optimisation of micronutrient status, including fatsoluble vitamin D and K supplementation, ensuring adequate calcium intake, avoidance or minimisation of glucocorticoid therapy, evaluation for modifiable secondary causes, and administration of bone preservation therapies.Bisphosphonates are effective in improving bone mineral density at both the hip and femur, but they have not been shown to significantly reduce fracture rates. 66Intravenous administration may be preferred to minimise the risk of aspiration.Denosumab use has been limited due to risks of hypocalcaemia, infection, and younger age of this population.Reduced sex steroids in both men 67 and women 68 have been described in cystic fibrosis; however, the benefits of hormonal replacement therapy on bone health has not been specifically evaluated.The evidence for anabolic therapy such as teriparatide and romosozumab is limited, 69,70 and these agents are often reserved for individuals with complex fracture history who fail to respond to initial antiresorptive therapies.

Effects of modulators on cystic fibrosis-related bone disease
The clinical evaluation of CFTR modulators on bone health is sparse.Ivacaftor has been demonstrated to improve bone mineral density 63 and cortical bone area, thickness and porosity. 71A pilot study demonstrated that weight gain improved bone mineral density and exercise capacity in nine individuals with cystic fibrosis (mean age, 18.6 years; standard deviation, 4.7 years) who were administered ETI compared with cystic fibrosis controls. 71In addition to potential direct effects of restoring CFTR function on bone health, indirect benefits may include improved absorption of vitamin D from the gastrointestinal tract, 72 increased exercise capacity, improved nutritional state, and reduced infection and inflammation. 73Together, these early findings are encouraging and, given the tolerability and safety of modulator therapies, clinical improvements in cystic fibrosisrelated bone disease should be anticipated.However, optimal clinical management for adults receiving modulator therapy with declining bone mineral density and/or osteoporotic fracture remains unclear, and research is needed to clarify whether adjunct use with currently available bone preservation therapies is safe and efficacious.

Reproductive health
With increasing life expectancy in the post-modulator era, adults with cystic fibrosis may desire fertility.Subfertility and infertility are common in people living with cystic fibrosis and can affect both men and women.

Male infertility
Heterozygosity and homozygosity for Phe508del mutation correlates strongly with male infertility. 74Congenital bilateral

Narrative review
absence of vas deferens leads to azoospermia, often requiring surgical sperm retrieval with intracytoplasmic sperm injection.Male hypogonadism due to chronic illness, growth and pubertal failure may also affect spermatogenesis.In contrast to congenital bilateral absence of vas deferens, whether modifiable factors leading to male hypogonadotropic hypogonadism may be responsive to modulator therapies remains to be seen.

Female infertility
Up to 40% of adult women with cystic fibrosis may experience subfertility, which is higher than the general population. 75enarche in females with cystic fibrosis can be delayed, 76 and secondary amenorrhoea due to chronic illness, malnutrition and low bodyweight are not uncommon.Abnormalities in cervical mucus due to CFTR dysfunction may also contribute to subfertility, with CFTR expressed in the cervical and endometrial epithelium and fallopian tubes. 77Assisted reproductive technologies, such as intrauterine insemination, are used to overcome hostile cervical mucus, and gonadotrophic ovulation induction is offered to women with anovulation.With in vitro fertilisation, pre-implantation genetic testing of partner CFTR mutation carrier status can also be facilitated.

Pregnancy in women with cystic fibrosis
The rates of spontaneous miscarriage in women with cystic fibrosis appear comparable to the general population. 78There is evidence that pregnancy overall does not affect survival in cystic fibrosis; 79 however, higher rates of Caesarean delivery, diabetes, preterm birth, congenital anomalies, 80,81 and pulmonary decline in the mother have been reported. 82

Effects of modulators on fertility
The effects of CFTR modulators on female fertility and fetal and maternal outcomes during pregnancy and lactation have not been studied in clinical trial settings, as pregnancy was often an exclusion criterion. 83The American Cystic Fibrosis Foundation Patient Registry report found pregnancy rates doubled in women of reproductive age in the first year after ETI initiation. 846][87][88][89] This also highlights the need for appropriate contraceptive counselling to avoid unplanned pregnancies, which may be relatively high in this population. 90

Effects of modulators on pregnancy and lactation
CFTR modulator therapies cross the placenta and continued use in pregnancy needs to be balanced with known risks to the mother, especially pulmonary decline, and potentially unknown risks to the fetus.Modulator therapies are also secreted in breastmilk and despite ivacaftor now approved for children above six months of age, safety in lactation remains unclear. 91Currently, case reports 91 and surveys 92 form the primary data source to elicit potential effects of modulator therapies on mothers with cystic fibrosis and their babies.
A recent report of bilateral congenital cataracts in three separate neonates exposed to modulator therapies in utero and while breastfeeding 93 highlights the need for vigilance.The prospective MAYFLOWERS trial (Clini calTr ials.govIdentifier, NCT04828382), which evaluates maternal pulmonary function antenatally together with obstetric and neonatal outcomes in the era of modulators, will hopefully fill this evidence gap.

Future directions
Health care providers involved in caring for adults with cystic fibrosis need to distinguish between those who have had marked clinical response to modulator therapies and non-responders.This will enable appropriate tailoring of clinical management.
People with cystic fibrosis are a heterogenous population and efforts are underway exploring metabolomic analysis and transcriptomics to help us better understand and predict outcomes 94 and move closer to precision medicine.There is also interest in developing models whereby characterisation and classification of CFTR variants will be according to their response to modulator therapies, a process called "theratyping". 95Postapproval, real-world studies such as PROMISE (Clini calTr ials.gov Identifier, NCT04038047) will be integral in informing the cystic fibrosis community about the broader effects of modulator therapies.Currently, most funding for cystic fibrosis research in Australia remains discovery-based and targeted at gene therapy, CFTR modulation, and development of anti-infective agents.Research into the emerging endocrine and metabolic complications in cystic fibrosis is also needed to evaluate whether pharmacotherapies adopted for use in this population are safe and effective, inform evidence-based practice, advocate for equitable access to diabetes technology, and develop integrated models of care that can support clinicians outside dedicated cystic fibrosis centres.Although recent advances in therapeutics have resulted in greater optimism for many adults living with cystic fibrosis, modulator therapies are not a cure, and provision of ongoing complex care in a multidisciplinary setting is still needed.

3 Available screening tests and their applicability for diagnosing cystic fibrosis-related diabetes Screening test Procedure Used for diagnosis of cystic fibrosis-related diabetes
31gestion of 1.75 g/kg up to 75 g of glucose in the fasting state followed by evaluation of plasma blood glucose level at least 0-minute, 60-minute and 120-minute time points• Yes • It is the most validated test with longitudinal data linking Evidence is lacking for cystic fibrosis-specific CGM cut-points31 These limited findings provide interesting insights into the aetiopathogenesis of cystic fibrosis-related diabetes, potential recovery of β cell function, genotype-modulator interactions, and associations with pulmonary outcomes.The data suggest that initiation of modulator therapies may not be associated with immediate glycaemic benefits and that the lag time might extend beyond the time frame it would take to reach steady state.This indicates modulator therapies do not briskly switch