Glucagon‐like peptide‐1 receptor agonists in adults with cystic fibrosis‐related diabetes: Rationale and emerging evidence

Cystic fibrosis (CF) is the most common autosomal recessive genetic disorder among Caucasians, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.1 More than 2000 CFTR variants have been identified; the F508del mutation is most common.2 A mutation in the CFTR gene leads to defective chloride channels, causing increased mucus viscosity and impaired clearance. CFTR is highly expressed in airway epithelia and pancreatic ductal epithelial cells, and the disease is characterized by progressive obstructive pulmonary disease and exocrine pancreatic insufficiency. Remarkable improvements in nutrition, respiratory care, newborn screening, and CFTR modulator therapies have significantly extended life expectancy, with survival often exceeding 50 years in developed countries.1 Cystic fibrosis-related diabetes (CFRD) is the most common extra-pulmonary complication in adults with CF.3 Its prevalence increases with age, reaching 40%–50% in adulthood.4 CFRD is a distinct subtype of diabetes mellitus, characterized by delayed first-phase insulin secretion that leads to postprandial hyperglycaemia despite normal fasting glucose in many patients. While insulin therapy is often necessary shortly after diagnosis, the progression to insulin deficiency is slower and less complete than in type 1 diabetes.5 Insulin remains the primary treatment6; however, the evolving landscape of CFRD marked by changing CF phenotypes, rising rates of overweight and obesity, and emerging evidence of preserved beta-cell reserve,5, 7 warrants exploring the potential of adjunctive agents for additional benefits such as improved glycaemic and weight control and reduced insulin dosing. Glucagon-like peptide-1 (GLP-1)-based therapies enhance glucose-dependent insulin secretion, inhibit glucagon secretion, slow gastric emptying, and promote satiety.8 In this commentary, we explore the potential of GLP-1 receptor agonists as a novel therapeutic option for adults with CFRD who have overweight or obesity. CFRD is a complex, multifactorial endocrine disorder whose precise pathophysiological mechanisms remain an area of active investigation. Initial hypotheses attributed CFRD primarily to the progressive loss of pancreatic beta-cells secondary to exocrine pancreatic insufficiency, and current evidence suggests that beta-cell secretory dysfunction can originate from inflammatory processes within the exocrine pancreas.9 Insulin deficiency constitutes the central pathophysiological feature of CFRD and is characterized by a delayed first-phase insulin secretion, attributable to impaired exocytosis of preformed insulin vesicles, and an overall attenuated insulin secretory peak.9 In vitro studies show inconsistent findings on CFTR expression in beta-cells and its impact on insulin secretion.6 The direct involvement of CFTR in islet cell function is indicated by research in mice and human islets, which demonstrates reduced GLP-1-augmented glucose-potentiated insulin secretion when CFTR is inhibited.10 In addition, accumulating evidence underscores the significant role of dysregulated incretin signalling in the pathogenesis of CFRD.5 An impaired incretin effect, potentially resulting from diminished beta-cell secretory capacity or reduced sensitivity to incretins, has been consistently documented.11, 12 Earlier studies have reported lower circulating levels of GLP-1 in individuals with CFRD compared to normoglycemic healthy controls.13 Nonetheless, a recent study in patients with CFRD revealed that, despite the absence of hyposecretion of the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), a diminished insulinotropic response was still observed.14 Consequently, the loss of the incretin effect, despite seemingly adequate circulating incretin levels, suggests that reduced insulinotropic activity of these hormones significantly contributes to postprandial hyperglycaemia in individuals with CFRD. Further supporting the possibility of receptor-level defects, a recent study found that in the CFRD pancreas, intra-islet GLP-1 levels are not significantly reduced and may even be slightly elevated. However, beta-cell GLP-1 receptor protein expression is markedly lower, despite unchanged GLP-1 receptor transcripts, indicating a post-transcriptional or post-translational defect.15 These findings suggest novel targets for improving beta-cell function in CFRD, such as restoring GLP-1 receptor protein levels or modulating downstream signalling to compensate for diminished receptor expression. Furthermore, evidence suggests that in individuals with CF and abnormal glucose tolerance, GLP-1 (but not GIP) can improve glucose-dependent insulin secretion without impacting the maximal secretory capacity of beta-cells, as demonstrated by the study from Nyirjesy et al.16 This study specifically examined the impact of GLP-1 and GIP on alpha- and beta-cell function in individuals with CF, pancreatic insufficiency, and abnormal glucose tolerance. Their findings showed that GLP-1 significantly augmented glucose-dependent insulin secretion, indicating preserved beta-cell reserve within this cohort. However, GIP administration failed to elicit an increase in second-phase insulin secretion, even during hyperglycemia.16 Investigating the diminished insulinotropic effect of GIP in these individuals may provide valuable insights into the pathogenesis of CFRD. Additionally, these findings suggest that GLP-1 receptor agonists could be a useful treatment for CFRD. Rapid gastric emptying appears to aggravate postprandial hyperglycaemia in CF.17 In pancreatic-insufficient adolescents with CF, pancreatic enzyme replacement therapy significantly attenuated these glucose excursions by slowing gastric emptying and restoring GLP-1 and GIP secretion.18 Furthermore, pre-meal administration of the GLP-1 receptor agonist exenatide normalized postprandial glycemia in young people with CF and impaired glucose tolerance, an effect the authors attributed to delayed gastric emptying.19 Insulin resistance also plays a role, although it is not considered the primary mechanism. In older individuals exhibiting more pronounced glycaemic dysregulation, diminished expression of insulin-sensitive glucose transporter type 4 (GLUT-4) in skeletal muscle and adipose tissue compromises peripheral glucose uptake.20 Chronic hyperglycaemia can further downregulate GLUT-4, potentially exacerbating peripheral insulin resistance. These processes are frequently compounded by poor nutritional status, characterized by reduced lean and adipose tissue mass, pulmonary exacerbations, and concomitant glucocorticoid therapy, all of which contribute to diminished glucose uptake from the circulation.20 Significant advancements in the medical management of CF and CFRD have been made, particularly with the advent of CFTR modulator therapies that can partially restore CFTR function.21 The triple-combination CFTR modulator therapy, elexacaftor/tezacaftor/ivacaftor (ETI), approved in 2019, has demonstrated notable benefits in nutritional status, lung function, and quality of life for patients who carry at least one copy of the F508del CFTR mutation or another responsive mutation.22 Early reports on the effects of CFTR modulators in CFRD showed a considerable reduction in insulin requirements and an increase in body weight following treatment.23 More recently, Chan et al. prospectively examined the impact of ETI on glucose tolerance in 79 individuals with CF aged 12 or older, all carrying at least one F508del mutation. They employed a 3-h oral glucose tolerance test (OGTT) to facilitate mathematical modeling of insulin secretion rate and insulin sensitivity.24 Following up to 2.5 years of ETI treatment, the study revealed a modest but significant reduction in fasting glucose levels, without alterations in overall OGTT glucose levels, despite a partial improvement in insulin secretion dynamics. Simultaneously, a significant decline in insulin sensitivity was observed at the end of the study, alongside a trend towards increased BMI.24 These opposing effects likely explain the overall stable glycaemic status observed in the study. The underlying reasons for any improvement in islet function are still unclear. These could include a compensatory response to changes in peripheral insulin sensitivity, a direct effect of CFTR modulator therapy on the pancreas, or a response to reduced systemic inflammation alleviating “beta-cell toxicity.”25 CF care emphasizes maintaining a healthy weight, as higher BMI is associated with better lung function. For individuals with CF, current recommendations suggest a minimum BMI at the 50th percentile for children and target BMIs of ≥22 kg/m2 for adult females and ≥23 kg/m2 for adult males.26 However, data from 2000 to 2019 show a significant shift: underweight status decreased by 40%, while overweight and obesity increased by over 300% and 400%, respectively.7 Risk factors associated with obesity in CF patients include older age, having at least one allele with a class IV or V CFTR mutation (genetic mutations often associated with milder phenotypes), higher pulmonary function values, and CFTR modulator use.7 In fact, CFTR modulators may contribute to weight gain by improving exocrine pancreas function. Consequently, weight gain in CF is likely multifactorial, potentially resulting from improved dietary intake, reduced energy expenditure, and enhanced nutrient absorption due to pancreatic enzyme therapy.27 Historically, traditional CF care emphasized a high-calorie, high-fat diet to counteract malabsorption and increased energy expenditure.4, 6 However, the expanded use of CFTR modulator therapies has altered the nutritional status of many patients. Underweight and growth faltering remain significant concerns, though, for individuals who are not eligible for or do not respond to modulator therapy due to mutations associated with severe CFTR dysfunction (e.g., two null alleles). Insulin remains the primary treatment for CFRD due to its direct action on the fundamental physiological defect of insufficient insulin secretion.6 Early initiation of insulin therapy has been linked to improved nutritional outcomes and may potentially stabilize pulmonary function by mitigating the harmful effects of hyperglycaemia on lung health.6 In parallel, rapid progress in diabetes technology is expanding treatment options. Continuous glucose monitoring offers real-time data that can enhance the precision of insulin dosing, reduce the incidence of hypoglycaemia, and alleviate the burden of frequent fingerstick testing. Emerging hybrid closed-loop systems automatically adjust basal insulin delivery based on continuous glucose readings, yet still require the user to administer a prandial bolus before each meal. Although these systems appear promising for improving glycaemic control and quality of life,28 larger, long-term trials specifically in CFRD populations are needed. The rising prevalence of overweight and obesity in the CF population, particularly among individuals using CFTR modulators,7 underscores the growing need for non-insulin therapies as alternatives or adjuncts, especially for this subgroup. Considering the impaired incretin effect observed in CFRD and prior findings indicating that GLP-1 can enhance glucose-dependent insulin secretion in CF patients with abnormal glucose tolerance, there is increasing interest in incretin-based therapies for CFRD.16 Recent evidence suggests that dipeptidyl peptidase-4 (DPP4) inhibitors (which prolong endogenous incretin action) may be a promising and well-tolerated treatment option for CFRD, particularly in the early stages of the condition. In a cohort of 23 patients with relatively mild diabetes (21 on monotherapy and 2 on insulin), DPP4 inhibitors significantly improved continuous glucose monitoring metrics, including increased time in target range, reduced time above range, and lower glucose variability, without impacting weight but also without a significant decrease in HbA1c.29 In another case series, sitagliptin maintained satisfactory glucose control for at least 5 years in three patients with CFRD and pancreatic insufficiency.30 These findings indicate that DPP-4 inhibitors may be a reasonable therapeutic strategy, although they are likely more effective in milder cases. In individuals with type 2 diabetes, GLP-1 receptor agonists or the dual GIP/GLP-1 receptor agonist typically lead to a 1% to ≥2% reduction in A1C, along with a 4 to >9 kg decrease in body weight and carry a low risk of hypoglycaemia.31, 32 To date, four reports have described CFRD individuals with overweight or obesity who received GLP-1 receptor agonists (primarily semaglutide) or the dual GIP/GLP-1 receptor agonist tirzepatide for durations ranging from 3 months to over 4 years (Table 1).33-36 Treatment regimens typically involved weekly injections, with semaglutide doses ranging from 0.13 to 2 mg, or tirzepatide doses up to 7.5 mg weekly. In most cases, these treatments led to meaningful improvements in glycaemic control, significant weight loss, more stable glucose profiles on continuous glucose monitoring, and decreased insulin doses. Some patients reduced their prandial insulin doses or completely discontinued insulin. Pulmonary function, measured by forced expiratory volume in one second (FEV1) or percent predicted FEV1, remained stable or improved in most participants, suggesting no adverse impact on lung health and the potential for additional clinical benefits. Interestingly, a previous study found that GLP-1 receptor agonist use in type 2 diabetes with chronic lower respiratory disease (CLRD) was linked to fewer CLRD exacerbations compared to DPP-4 inhibitor users.37 The treatment was generally well tolerated, with reported adverse events being mostly mild and transient. A minority of individuals discontinued treatment due to side effects. For example, Ahmed et al. reported one patient who stopped therapy after two years due to persistent gastrointestinal symptoms, and Park et al. noted four discontinuations, two of which were attributed to severe nausea and vomiting.34, 35 Despite these encouraging findings, GLP-1 receptor agonists remain off-label for CFRD, and the available data are limited to small case series. An ongoing randomized controlled phase 2 trial (NCT04731272) is investigating the effects of dulaglutide on pancreatic islet function and glycaemic control in adults with CF and abnormal glucose tolerance.38 Gnanapragasam et al.33 Single case report Ahmed et al.34 5-patient case series Park et al.35 11-patient observational study CFRD Subset (n = 7): Ayada et al.36 Single case report Nonetheless, the use of GLP-1 receptor agonists in CFRD necessitates careful, individualized evaluation. Given the absence of robust safety data in individuals with a history of acute or recurrent pancreatitis, these agents should be avoided in such cases. Their weight-reducing effect also makes them unsuitable for underweight patients or those with difficulty maintaining target body weight.39 Furthermore, because GLP-1 receptor agonists delay gastric emptying, they may precipitate or worsen gastrointestinal symptoms (e.g., nausea, bloating) in individuals with CF, particularly those with gastrointestinal dysmotility.40 Therefore, these agents should be used with caution and are best avoided in patients who already have a substantial burden of gastrointestinal symptoms. Improved survival and shifting metabolic profiles, notably rising obesity, necessitate a re-evaluation of CFRD treatment strategies beyond standard insulin therapy. Given the increasing heterogeneity of CF, personalized approaches are warranted. GLP-1 and dual GIP/GLP-1 receptor agonists, with their potential to enhance endogenous insulin secretion and support weight management, present a promising yet underexplored option. Large, well-designed clinical trials are urgently needed to definitively establish their safety, efficacy, and optimal use in CFRD. Future studies should stratify adults with CFRD by CFTR genotype, BMI, insulin requirements, and residual beta-cell function to define the ideal candidate for these therapies. Trials must extend beyond short-term glycaemic metrics to include long-term metabolic endpoints (glycaemic control, weight and body composition changes), pulmonary outcomes, and overall health trajectory. Conceptualization: Afif Nakhleh. Data curation: Afif Nakhleh. Formal analysis: Afif Nakhleh. Investigation: Mai Assaliya Naffa, Gida Ayada, Afif Nakhleh. Methodology: Mai Assaliya Naffa, Gida Ayada, Afif Nakhleh. Project administration: Mai Assaliya Naffa, Gida Ayada, Afif Nakhleh. Resources: Mai Assaliya Naffa, Gida Ayada, Afif Nakhleh. Supervision: Afif Nakhleh. Visualization: Afif Nakhleh. Writing—original draft: Mai Assaliya Naffa, Afif Nakhleh. Writing—review and editing: Mai Assaliya Naffa, Gida Ayada, Sagit Zolotov, Naim Shehadeh, Afif Nakhleh. The authors have nothing to report. This study received no external funding. The authors declare no conflicts of interest. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.16516. The raw data supporting the conclusions of this article will be made available by the authors without undue reservation.