BACKGROUND:Malnutrition, inflammation, limited exercise, and low muscle mass increase the risk of cystic fibrosis (CF) bone disease (CFBD). Additionally, dysfunction of the CF transmembrane conductance regulator (CFTR) directly affects bone-forming cells. Elexacaftor/Tezacaftor/Ivacaftor (ETI) could influence these aspects. We examined the impact of ETI on bone health in Danish people with CF. METHODS:This nationwide cohort study evaluated changes in bone status in adults with CF after ETI treatment. Dual energy X-ray absorptiometry (DXA) was used to assess bone mineral density Z-scores in lumbar spine, femoral neck, and total hip. To assess calcium metabolism, plasma levels of vitamin D, calcium, and parathyroid hormone (PTH) were evaluated. Data were collected from 2 years pre- to 3.5 years post-ETI initiation, comparing pre-ETI levels with 1-, 2- and 3-year post-ETI measurements. Data were analyzed using linear mixed effects regression models and subgroup interaction analyses. RESULTS:197 Danish adults with CF were included in the study, contributing 435 DXA scans. Mean change from pre-ETI period (95%CI) in femoral neck and total hip Z-scores showed a decrease by year 3 of -0.16 (-0.31; -0.01; p=0.04) and -0.15 (-0.30; <0.01; p=0.05), respectively, while lumbar spine showed a slight increase of 0.13 (-0.05, 0.31; p=0.15). Vitamin D levels initially decreased but subsequently increased by 8.9 nmol/L (4.5-13.3; p<0.01) by year 3 as compared to pre-ETI levels. Calcium and PTH levels remained stable. CONCLUSION:After 3 years of ETI treatment in Danish adults with CF, no clinically significant changes in bone health or calcium metabolism were observed.

BACKGROUND:Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity in cystic fibrosis (CF). After the introduction of modulator therapy, extended life expectancy and altered nutritional status may have changed the landscape of CFRD. This study aimed to evaluate the current CFRD management in Denmark. METHODS:In a nationwide, cross-sectional study, we included all individuals in Denmark diagnosed with CFRD, defined by insulin use, ≥2 abnormal OGTTs (2-h glucose ≥11.1 mmol/L), or elevated HbA1c (>48 mmol/mol). The cohort was identified using the Danish CF Registry, including all CF cases in Denmark. Health records were reviewed to validate diagnoses and extract data on treatment regimens and glycemic control. RESULTS:We identified 151 people with CFRD, with a prevalence of 40% in adults with CF and 1% in adolescents. Among them, 7% used insulin pumps, 41% used basal-bolus treatment, 11% used only basal or mixed insulin, 6% used only bolus insulin, 33% did not use insulin or oral antidiabetics, and 2% used combinations or had missing data on treatment regimen. Median HbA1c was 48 mmol/mol, with 10% having HbA1c ≥ 70 mmol/mol. Continuous glucose monitoring (CGM) users (44%) had a median time in range of 70% and median time below range of 1%. No cases of severe hypoglycemia were recorded in the year before data collection. CONCLUSIONS:In the Danish CFRD cohort glycemic control was generally good, although some remained severely dysregulated. While insulin remains the only antidiabetic treatment, the role of oral antidiabetics is likely to expand in the post-modulator era.

In 2024-2025, the Cystic Fibrosis Foundation (US) and Cystic Fibrosis Trust (UK) hosted an International CFRD Consortium round-table webinar series for basic science, translational, and clinical researchers with the goal of sharpening mechanistic understanding of CFRD pathogenesis and prioritizing therapeutic development. This review summarizes the research priorities identified in the International CFRD Consortium, including (i) further investigation into the role of pancreatic fibrosis, vascular abnormalities, and α-cell dysfunction in the development of CFRD; (ii) the creation and refinement of novel animal and human cell- and tissue-based models to understand the complex interplay of exocrine and endocrine cells in the CF pancreas; (iii) development and validation of circulating and imaging biomarkers, together with dynamic glucose testing to explore β-cell function and kinetics in people with CF across the dysglycemia spectrum; and (iv) prospective clinical studies to guide CFRD treatment options and investigate the changing landscape of aging, increasing prevalence of obesity and diabetes and their complications in the era of cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Collectively, these priorities aim to accelerate transition from mechanism to intervention and expand evidence-based care for people with CF at risk of, or living with, CFRD.

BACKGROUND:Elexacaftor/Tezacaftor/Ivacaftor (ETI) has raised concerns about liver-related side effects. This study evaluated changes in liver function tests (LFTs) and the prevalence of hepatotoxicity over two years of ETI treatment in a nationwide cohort of Danish people with cystic fibrosis (pwCF) METHODS: Changes in LFTs were assessed in pwCF aged ≥12 years, including those with pre-existing hepatic impairment, using data from the Danish CF Registry (2016-2025). Statistical analyses included piecewise linear mixed models for long-term changes and descriptive analysis of abnormal LFTs to assess hepatotoxicity. RESULTS:A total of 331 pwCF were included. Compared to pre-ETI levels, alanine aminotransferase (ALT) levels were significantly elevated at six months post-ETI but stabilized and approached pre-ETI levels by 24 months. Alkaline phosphatase (ALP) levels were lower at all timepoints, with a statistically significant decrease at 24 months. Gamma-glutamyl transferase (GGT) levels were consistently lower post-ETI. The prevalence of abnormal ALT, ALP, and GGT was initially higher post-ETI, peaking at one month, then steadily declining to pre-treatment values within two years. Three individuals (0.9 %) had signs of severe hepatotoxicity with ALT >5x upper limit of normal (ULN) and bilirubin >2xULN post-ETI. Among those with pre-existing hepatic impairment and those with unexpected liver complications post-ETI 5/7 and 5/8, respectively, reached the full ETI dose. CONCLUSION:ALT levels almost normalized, while GGT and ALP levels declined within two years of ETI treatment. Reassuringly, severe hepatotoxicity was rare, suggesting that close monitoring may suffice for managing mild to moderate hepatotoxicity in pwCF.

INTRODUCTION:Elexacaftor/tezacaftor/ivacaftor (ETI) is a breakthrough therapy for cystic fibrosis (CF). We aimed to assess ETI's real-world impact on peripheral airway disease assessed as ventilation distribution inhomogeneity using nitrogen multiple breath washout (N2MBW) in children aged 6-17 years. Additionally, we compared the two outcomes, lung clearance index (LCI), and ventilation distribution efficiency (VDE), as VDE is considered to adjust for a theoretical overestimation of lung disease when using LCI. METHODS:This nationwide study included data from N2MBW performed during routine clinical care. Linear mixed effect regression was used to assess changes in LCI and VDE after 12 months of ETI treatment. Subgroup analyses included baseline age (6-11 vs. 12-1 years) and disease severity (normal-moderate vs. severe-very severe). RESULTS:We included 131 children (78% homozygous for F508del mutation, mean [SD] age 11.5 [3.4]), and 339 N2MBW tests. The median (range) number of tests per child was 3 (1-10). The estimated mean (95% CI) 12-months post-ETI improvement in LCI and VDE were 1.7 units (-2.1; -1.2, p < 0.001) and 2.1%-point (1.6; 2.6, p < 0.001), respectively. Similar LCI and VDE improvements were observed across age groups. Using VDE, fewer children were categorized with very severe lung disease, and the ETI-effect did not differ between the severity groups, unlike LCI. CONCLUSION:Our research demonstrates that ETI treatment significantly improves lung function, as measured by N2MBW, in Danish children and adolescents with CF. VDE improvements were consistent across age and disease severity groups. In contrast, LCI revealed larger effect estimates for those with severe to very-severe lung impairment.

BACKGROUND & AIMS:Weight gain after elexacaftor/tezacaftor/ivacaftor (ETI) initiation among people with cystic fibrosis (CF) has been widely reported. How these weight changes compare with pre-existing trends, how they compare with linear growth, if they persist over time, and how they affect body composition have yet to be investigated. We assessed changes in body mass, linear growth, and body composition after ETI initiation. METHODS:Anthropometric data from people with CF in the Danish CF Registry were collected from 5 years pre-ETI initiation to 2 years post. Linear mixed-effects models with linear splines were used to assess changes in body mass index (BMI) in adults, and in BMI-for-age z-score (BMZ) and height-for-age z-score (HAZ) in children. Fat and fat-free mass from dual-energy X-ray absorptiometry (DXA) were compared using paired t-tests in adults. RESULTS:We included 392 people with CF. Among 154 children, BMZ was stable 5 years pre-ETI. Mean (95%CI) BMZ increased from -0.22 (-0.37, -0.07) at ETI initiation to 0.24 (0.05, 0.43) 2 years later. BMZ increased at a continuously higher rate post-ETI initiation compared to pre-ETI. HAZ increased by 0.05 (0.01, 0.09) per year pre-ETI, then remained stable post-ETI initiation, with no change from ETI initiation (0.12 (-0.03, 0.26)) to 2 years post-ETI. Among 238 adults, BMI increased by 0.05 (0.004, 0.10) kg/m2 per year pre-ETI. BMI increased from 22.55 (22.08, 23.02) kg/m2 at ETI initiation to 23.75 (23.25, 24.25) kg/m2 after 2 years, but the annual rate of change returned to pre-ETI trends after 9 months. In a subset of 115 adults with available DXA data, mean fat mass index increased by 0.68 kg/m2 (0.01, 1.35) 1 year post-ETI initiation, with no significant gain of fat-free mass index. CONCLUSIONS:Children with CF continued to increase their BMZ 2 years post-ETI initiation, while HAZ remined stable. The rate of change in BMI returned to pre-ETI trends among adults with CF. Adult BMI gains were primarily driven by an increase of fat mass.

Cystic fibrosis-related diabetes (CFRD) affects up to 60% of adults with CF and contributes to poorer clinical outcomes, including accelerated lung decline and increased mortality. CFRD is often diagnosed late, with limited mechanistic insight and few tools for early detection. We profiled serum-derived exosomes from individuals, 173 with CF, across two independent cohorts (Australia and Denmark), stratified by oral glucose tolerance test (OGTT) into normal (NGT), impaired (IGT), and CFRD groups. In a longitudinal subset, matched samples were collected before and after CFTR modulator therapy. Exosomes were isolated via size-exclusion chromatography and validated by NTA and TEM. Label-free proteomics and small RNA sequencing were used to profile exosomal cargo. Multi-analyte classifiers were identified using machine learning, with internal cross-validation. Exosomal profiles captured a continuum of metabolic dysfunction, with distinct signatures in CFRD including elevated PTPN1, MYO5A, and VWF (insulin resistance/hepatic dysfunction), and reduced 14-3-3ζ (β-cell dysfunction). miRNA profiles reinforced these trends, with CFRD exosomes enriched in miR-375-3p, miR-122-5p, and miR-1260a/b. CFTR modulator therapy partially reversed proteomic and transcriptomic markers of insulin resistance and hepatic dysfunction but failed to regulate β-cell-associated signatures. Machine learning models achieved high classification performance (AUC = 0.83), identifying robust multi-omic panels predictive of glucose tolerance state. This study provides the first comprehensive exosome-based multi-omics and machine learning framework for CFRD. Our findings show that serum exosomes hold promise as diagnostic and therapeutic biomarkers for early detection and monitoring of CFRD in precision CF care. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported in part by an Australian National Health and Medical Research Council grant (NHMRC_APP1188987), CFRD-SRC-019 Grant (CF Trust), and Vertex Innovation Grant (2018), Sydney Childrens Hospitals Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics approval was granted by the Sydney Childrens Hospital Network (HREC16-SCHN-120) and Danish Ethical Committee (H-16022305-H19085530) and written informed consent was obtained from all participants. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors or are contained in the manuscript.

ObjectivesLung disease progression in people with cystic fibrosis (pwCF) varies from one individual to another. Different immunological characteristics have been suggested to explain this variation, and we hypothesised that lung capacity may be associated with the innate immune response in pwCF. In an exploratory study, we aimed to investigate potential links between the innate immune response and lung function in pwCF using the standardised immune function assay TruCulture.MethodsIn a single-centre study with combined cross-sectional and longitudinal data before and after intravenous antibiotics, blood was sampled fromPseudomonas aeruginosa-infected pwCF. Whole blood was analysed by TruCulture to reveal the unstimulated and stimulated cytokine release. Tobit regressions and Spearman's correlations were used to estimate the associations between lung function and cytokine release.ResultsWe included 52 pwCF in the cross-sectional study and 24 in the longitudinal study. In the cross-sectional study, we found that compared to a healthy population, the release of toll-like receptor (TLR)3, TLR4- and TLR7/8-stimulated interferon-γ, and interleukin (IL)-12p40 was reduced. Although TLR3-stimulated IL-1β and IL-6 release increased with lung function, overall, cytokine release did not correlate well with lung function. In the longitudinal study, the cytokine release was modified by antibiotic treatment, but the cytokine release before antibiotic treatment did not associate with changes in lung function after treatment.ConclusionThe stimulated cytokine release could not predict lung function levels or changes in pwCF, but our data indicate that pwCF experience exhaustion in the innate immune response after years of chronic bacterial infection.

BackgroundExcessive inflammation and recurrent airway infections characterize people with cystic fibrosis (pwCF), a disease with highly heterogeneous clinical outcomes. How the overall immune response is affected in pwCF, its relationships with the lung microbiome, and the source of clinical heterogeneity have not been fully elucidated.MethodsPeripheral blood and sputum samples were collected from 28 pwCF and an age-matched control group. Systemic immune cell subsets and surface markers were quantified using multiparameter flow cytometry. Lung microbiome composition was reconstructed using metatranscriptomics on sputum samples, and microbial taxa were correlated to circulating immune cells and surface markers expression.ResultsIn pwCF, we found a specific systemic immune profile characterized by widespread hyperactivation and altered frequencies of several subsets. These included substantial changes in B-cell subsets, enrichment of CD35+/CD49d+ neutrophils, and reduction in dendritic cells. Activation markers and checkpoint molecule expression levels differed from healthy subjects. CTLA-4 expression was increased in Tregs and, together with impaired B-cell subsets, correlated with patients' lung function. Concentrations and frequencies of key immune cells and marker expression correlated with the relative abundance of commensal and pathogenic bacteria in the lungs.ConclusionThe CF-specific immune signature, involving hyperactivation, immune dysregulation with alteration in Treg homeostasis, and impaired B-cell function, is a potential source of lung function heterogeneity. The activity of specific microbes contributes to disrupting the balance of the immune response. Our data provide a unique foundation for identifying novel markers and immunomodulatory targets to develop the future of cystic fibrosis treatment and management.

The aim of this study was to investigate insulin secretion, insulin sensitivity, disposition index and insulin clearance by glucose tolerance status in individuals with cystic fibrosis (CF) and exocrine pancreatic insufficiency. In a cross-sectional study, we conducted an extended (ten samples) OGTT in individuals with pancreatic-insufficient CF (PI-CF). Participants were divided into normal glucose tolerance (NGT), early glucose intolerance (EGI), impaired glucose tolerance (IGT) and CF-related diabetes (CFRD) groups. We used three different oral minimal models to assess insulin secretion, insulin sensitivity and insulin clearance during the OGTT. We evaluated insulin secretion using total secretion (Φ total), first-phase secretion (Φ dynamic) and second-phase secretion (Φ static) from the model, and we estimated the disposition index by multiplying Φ total and insulin sensitivity. Among 61 participants (NGT 21

Sweat chloride concentration, a diagnostic feature in cystic fibrosis (CF), reflects CF transmembrane conductance regulator (CFTR) activity. CFTR modulator therapies, especially elexacaftor/tezacaftor/ivacaftor (ETI), has improved CF outcomes. We report nationwide, real‐world data on sweat chloride concentration in people with CF (pwCF) with and without modulator therapies. All Danish pwCF with a minimum of one F508del allele were included. Sweat chloride measurements were stratified by genotype and modulator treatment. Differences were assessed using mixed‐effects models. We included 977 sweat chloride measurements from 430 pwCF, 71% of which were F508del homozygous. Heterozygous and homozygous ETI‐treated pwCF had an estimated mean sweat chloride concentration of 43 mmol/L (95% confidence interval: 39; 48) and 43 mmol/L (39; 47), respectively—48% and 59% lower than those without treatment. High variation in concentrations remained regardless of treatment status. Despite ETI treatment, 27% heterozygous and 23% homozygous pwCF had elevated concentrations (≥60 mmol/L). These real‐world data confirm a substantial decrease in sweat chloride concentration during modulator treatment, especially ETI, where mean concentrations halved. However, large variation remained, including persistently high concentrations. These findings emphasize the potential of sweat chloride concentration as a treatment response biomarker and the need to explore its heterogeneity and relationship with clinical outcomes.

BackgroundPeople living with cystic fibrosis in Denmark had early, universal access to triple modulator treatment with elexacaftor/tezacaftor/ivacaftor. Close monitoring allowed us to assess the impact of treatment on lung function and progression of lung disease in an unselected nationwide cystic fibrosis population from 6 years of age.MethodsData were analysed using linear mixed-effect models to assess changes in levels and annual rates of change (slopes) in percent predicted (pp) forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and forced expiratory flow at 25–75% of FVC (ppFEF25–75%) between the 12 months pre-treatment and treatment periods. Subgroup analyses assessed the impact of elexacaftor/tezacaftor/ivacaftor among those with/without previous modulator treatment, normal/mild/moderate/severe lung disease at treatment initiation, children/adults and birth cohorts.ResultsWe included 392 people living with cystic fibrosis with a median (interquartile range) 12 (nine to 15) spirometry measurements per person. The mean (95% CI) improvement in ppFEV1was 13.0 (11.3–14.6) 12 months after initiation of elexacaftor/tezacaftor/ivacaftor treatment. The annual rate of change improved from −1.4 (−2.1 – −0.6) ppFEV1in the pre-treatment year to 2.7 (1.8–3.5) ppFEV1per year during treatment. Similarly, ppFVC increased by 8.0 (7.1–8.9) and FEF25–­75%by 19.5 (17.0–21.9).ConclusionsUsing high-resolution data from a nationwide real-world setting, our study documents the impact of elexacaftor/tezacaftor/ivacaftor on lung function across subgroups based on age, disease severity and treatment history. These findings point towards a new period of consistent lung function improvement among people living with cystic fibrosis on elexacaftor/tezacaftor/ivacaftor.

Cystic fibrosis (CF) care in Denmark has been characterized by close monitoring and pre-emptive treatment of lung disease and other CF-related complications. Continuous evaluation through data collection and commitment to clinical research has incrementally improved outcomes. This approach has been in line with best practices set forth by European Standards of Care but has also gone beyond Society standards particularly pertaining to early treatment with high-dose combination antimicrobial therapy. Despite a high prevalence of severe CF variants, lung function has been among the best in Europe. In this review, the Danish approach to management of CF prior to the introduction of new CF modulator treatment is explained and benchmarked. Downsides to the Danish approach are discussed and include increased burden of treatment, risk of antimicrobial resistance, side-effects and costs.

ObjectiveWe hypothesized that the insulin-sensitizing adipokine adiponectin (ADP) is upregulated in cystic fibrosis (CF) related diabetes (CFRD) and underweight adults with CF. We aimed to assess correlations between glucose metabolism, body composition and ADP in CF.MethodsWe performed a cross-sectional study among adults with CF at the Copenhagen CF Center. The study included a fasting level of ADP, an oral glucose tolerance test (OGTT), and a dual energy-x-ray absorptiometry scan.ResultsIn total, 115 patients were included of whom 104 had an OGTT performed. Glucose intolerance was not correlated with ADP in multivariable analysis, while increased hepatic insulin resistance (i.e., HOMA-IR) was correlated with reduced ADP levels. ADP declined by 4% (eβ 0.96, 95% CI: 0.94, 0.98), 5% (eβ 0.95, 95% CI: 0.93, 0.98), 9% (eβ 0.91, 95% CI: 0.87, 0.95), and 83% (eβ 0.17, 95% CI: 0.08, 0.37) for each one unit (kg/m2) increase in body mass index, fat mass index, muscle mass index, and bone mineral content index, respectively.ConclusionsIn CF, ADP was negatively correlated with hepatic insulin resistance as well as low fat, muscle, and bone mass, but not with glucose intolerance. This suggests that malnutrition leads to higher ADP levels in CF.

Sweat chloride concentration, a diagnostic feature in cystic fibrosis (CF), reflects CF transmembrane conductance regulator (CFTR) activity. CFTR modulator therapies, especially elexacaftor/tezacaftor/ivacaftor (ETI), has improved CF outcomes. We report nationwide, real-world data on sweat chloride concentration in people with CF (pwCF) with and without modulator therapies. All Danish pwCF with a minimum of one F508del allele were included. Sweat chloride measurements were stratified by genotype and modulator treatment. Differences were assessed using mixed-effects models. We included 977 sweat chloride measurements from 430 pwCF, 71% of which were F508del homozygous. Heterozygous and homozygous ETI-treated pwCF had an estimated mean sweat chloride concentration of 43 mmol/L (95% confidence interval: 39; 48) and 43 mmol/L (39; 47), respectively—48% and 59% lower than those without treatment. High variation in concentrations remained regardless of treatment status. Despite ETI treatment, 27% heterozygous and 23% homozygous pwCF had elevated concentrations (≥60 mmol/L). These real-world data confirm a substantial decrease in sweat chloride concentration during modulator treatment, especially ETI, where mean concentrations halved. However, large variation remained, including persistently high concentrations. These findings emphasize the potential of sweat chloride concentration as a treatment response biomarker and the need to explore its heterogeneity and relationship with clinical outcomes.

BackgroundElexacaftor/tezacaftor/ivacaftor (ETI) has improved the clinical status of individuals with cystic fibrosis (CF), however, whether ETI impacts glucose tolerance remains unknown. We aimed to study the change in glycated hemoglobin (HbA1c) and CF related diabetes (CFRD) status after initiation of ETI.MethodsWe included individuals ≥12 years treated with ETI in Denmark in a longitudinal observational study. HbA1c was measured at baseline, 3, 6, 9 and 12 months after treatment initiation. Change in HbA1c was assessed in mixed models adjusted for age, sex, glucose tolerance and prior CFTR modulator treatment. In a sub-population with CFRD, we assessed the change in insulin usage, hypoglycemic events and the 30-day continuous glucose monitoring (CGM) parameters (i.e., average blood glucose, time below (≤3.9 mM) and above (>10.0 mM) normal range, and the variation in glucose) after 12 months of treatment.ResultsAmong 321 individuals with CF, HbA1c declined by 2.1 mmol/mol [95 % confidence interval (CI): -2.6; -1.5 mmol/mol] after 3 months and by 2.3 mmol/mol [95 %CI: -2.8; -1.9 mmol/mol] after 12 months of ETI treatment. The decline was independent of glucose tolerance status at baseline. In 26 individuals with CFRD at baseline, the mean decline in HbA1c was 3.6 mmol/mol [95 %CI: -6.9; -0.4 mmol/mol] after 12 months, but we did not observe any change in insulin usage, weekly number of hypoglycemic events or CGM parameters.ConclusionIn the Danish CF cohort, HbA1c declined over 12 months of ETI treatment, however, among a subset with CFRD, we observed no change in insulin usage and CGM glucose levels.

Aims The purpose of the study was to further elucidate the pathophysiology of cystic fibrosis (CF)-related diabetes (CFRD) and potential drivers of hypoglycaemia. Hence, we aimed to describe and compare beta cell function (insulin and proinsulin) and alpha cell function (glucagon) in relation to glucose tolerance in adults with CF and to study whether hypoglycaemia following oral glucose challenge may represent an early sign of islet cell impairment. Methods Adults with CF (≥18 years) were included in a cross-sectional study using an extended (-10, -1, 10, 20, 30, 45, 60, 90, 120, 150, and 180 min) or a standard (-1, 30, 60, and 120 min) oral glucose tolerance test (OGTT). Participants were classified according to glucose tolerance status and hypoglycaemia was defined as 3-hour glucose <3.9 mmol/L in those with normal glucose tolerance (NGT) and early glucose intolerance (EGI). Results Among 93 participants, 67 underwent an extended OGTT. In addition to worsening in insulin secretion, the progression to CFRD was associated with signs of beta cell stress, as the fasting proinsulin-to-insulin ratio incrementally increased (p-value for trend=0.013). The maximum proinsulin level (pmol/L) was positively associated with the nadir glucagon, as nadir glucagon increased 6.2% (95% confidence interval: 1.4-11.3%) for each unit increase in proinsulin. Those with hypoglycaemia had higher 60-min glucose, 120-min C-peptide, and 180-min glucagon levels (27.8% [11.3-46.7%], 42.9% [5.9-92.85%], and 80.3% [14.9-182.9%], respectively) and unaltered proinsulin-to-insulin ratio compared to those without hypoglycaemia. Conclusions The maximum proinsulin concentration was positively associated with nadir glucagon during the OGTT, suggesting that beta cell stress is associated with abnormal alpha cell function in adults with CF. In addition, hypoglycaemia seemed to be explained by a temporal mismatch between glucose and insulin levels rather than by an impaired glucagon response.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have been shown to have a beneficial effect on pulmonary function and nutritional status in patients with cystic fibrosis (CF), but the extent to which they affect glucose tolerance is not fully understood. In the current study, we evaluated the change in glucose tolerance and insulin secretion after first‐generation CFTR modulator treatment in adults with CF.

BACKGROUND:Elexacaftor/tezacaftor/ivacaftor (ETI) has improved the clinical status of individuals with cystic fibrosis (CF), however, whether ETI impacts glucose tolerance remains unknown. We aimed to study the change in glycated hemoglobin (HbA1c) and CF related diabetes (CFRD) status after initiation of ETI. METHODS:We included individuals ≥12 years treated with ETI in Denmark in a longitudinal observational study. HbA1c was measured at baseline, 3, 6, 9 and 12 months after treatment initiation. Change in HbA1c was assessed in mixed models adjusted for age, sex, glucose tolerance and prior CFTR modulator treatment. In a sub-population with CFRD, we assessed the change in insulin usage, hypoglycemic events and the 30-day continuous glucose monitoring (CGM) parameters (i.e., average blood glucose, time below (≤3.9 mM) and above (>10.0 mM) normal range, and the variation in glucose) after 12 months of treatment. RESULTS:Among 321 individuals with CF, HbA1c declined by 2.1 mmol/mol [95 % confidence interval (CI): -2.6; -1.5 mmol/mol] after 3 months and by 2.3 mmol/mol [95 %CI: -2.8; -1.9 mmol/mol] after 12 months of ETI treatment. The decline was independent of glucose tolerance status at baseline. In 26 individuals with CFRD at baseline, the mean decline in HbA1c was 3.6 mmol/mol [95 %CI: -6.9; -0.4 mmol/mol] after 12 months, but we did not observe any change in insulin usage, weekly number of hypoglycemic events or CGM parameters. CONCLUSION:In the Danish CF cohort, HbA1c declined over 12 months of ETI treatment, however, among a subset with CFRD, we observed no change in insulin usage and CGM glucose levels.