The evolving understanding of cystic fibrosis-related diabetes in the highly effective modulator therapy era: a scoping review

Abstract

Cystic fibrosis-related diabetes (CFRD) is a unique form of diabetes that shares features with both type 1 and type 2 diabetes and is most often characterised by transient postprandial hyperglycaemia as a consequence of delayed first-phase insulin release. In the last decade, new developments in the form of highly effective modulators have transformed the landscape of cystic fibrosis (CF) care and life expectancy. As CFRD is one of the most common complications of CF, there is a growing and urgent need to better understand how to optimise CFRD diagnosis and management across the continuum. In this review, we examine recent advancements in the understanding of CF dysglycaemia and CFRD monitoring and treatment, and synthesise the growing body of literature on post-market findings on how glycaemic management changes in response to modulator therapy.

Graphical Abstract

Supplementary Information

The online version contains a slide of the figure for download available at 10.1007/s00125-025-06653-7.

Introduction

Cystic fibrosis (CF) is an autosomal recessive disorder caused by a defect in the CF transmembrane conductance regulator (CFTR) channel, manifesting as a multi-system disease with a significant burden of morbidity and mortality risk [1]. One of the most common complications of CF is CF-related diabetes (CFRD), the prevalence of which doubles every decade by the third decade of life [2]. Historically, CFRD has been associated with a worse clinical trajectory of progressive deteriorating lung function, more frequent pulmonary exacerbations, poorer nutrition status and higher mortality risk [3, 4]. However, over the last decade, CFTR-targeted therapies, termed modulators, have revolutionised the care of CF, with the latest commercially available generation of CFTR modulators, elexacaftor plus tezacaftor plus ivacaftor (ETI), projected to greatly enhance the life expectancy of eligible people with CF, rivalling that of the non-CF population [5]. While the seminal Phase III clinical trials primarily focused on pulmonary outcomes, post-marketing and observational data are emerging on how ETI or other highly effective modulator therapy (HEMT) can impact other CF-related complications, including CF dysglycaemia or CFRD. Coupled with the rapidly evolving landscape of diabetes technologies and management, many questions around CFRD care in the era of modulator therapy have been raised. In this scoping review, we review the understanding of CFRD pathophysiology and its treatment, emerging diabetes technologies and the impact of CFTR modulator therapies on CF dysglycaemia.

Methodology

This scoping review focuses on the latest available evidence (January 2021 to March 2025) relating to CFRD in the new modulator era since our previous review carried out in 2021 [3]. A concept-based search strategy was employed, building on the earlier review [3]. An electronic search was conducted of existing literature (using MEDLINE and Google Scholar databases) and was limited to studies that were conducted/published in English. The concept-based search included keywords such as ‘CFRD’, ‘CFTR modulators’, ‘cystic fibrosis and diabetes’, ‘continuous glucose monitoring’, ‘insulin pump’ and ‘CFRD complications’. As the intention of the scoping review was to highlight emerging research, published abstracts were included and noted. Review articles were also included. Exclusion criteria were studies based on people with CF who were pregnant or had post-transplant-diagnosed diabetes (as these may represent other forms of diabetes), research related to pancreatic insufficiency, animal models and CFRD screening. A total of 235 abstracts published between 1 January 2021 and 1 March 2025 were identified (as of June 2025), of which 91 went on to full review after title and abstract screening. This review did not assess study quality or bias. Data were not confirmed with individual investigators.

CFRD

Based on pre-ETI estimates, up to 50% of people with CF will be diagnosed with CFRD over the course of their lifetime [6, 7], making this the most common non-pulmonary complication of CF [2]. The increased lifespan of people with CF, in part due to the success of ETI, and improved CFRD screening have led to an increase in CFRD diagnoses [7, 8]. The most notable risk factors for CFRD include older age, more severe CFTR mutations, poor nutrition, reduced lung capacity, persistent inflammation and exacerbations, female sex, pregnancy, pancreatic insufficiency, a family history of type 2 diabetes, lower lung function and a history of comorbid enteral nutrition need, allergic bronchopulmonary aspergillosis and liver disease [5, 9, 10].

CF dysglycaemia screening and diagnosis

The screening modality of choice for CFRD has become controversial. The general consensus from guidelines worldwide recommends the use of the 2 h 75 g OGTT performed on an annual basis to screen for CFRD starting at the age of 10 years [5, 11, 12] (Table 1). Should the 2 h OGTT glucose be ≥11.1 mmol/l (≥200 mg/dl), a repeat OGTT confirming the result would be diagnostic of CFRD (criteria for CFRD diagnosis are summarised in Table 2) [13]. However, the OGTT has been criticised for being cumbersome and unacceptable to patients, and typical adherence to screening is suboptimal [14, 15]. Consequently, alternative tools for CFRD screening, such as fructosamine [16–18], 1 h OGTT [19], 1,5-anhydroglucitol [17, 20] and HOMA [21–23] have been explored with variable predictive success in replacing the 2 h OGTT.

Table 1.

Comparison of guideline recommendations for screening criteria for CFRD

Screening scenario	US 2010 guidelines [13]	Australian 2013 guidelines [68]	ISPAD 2022 guidelines [12]	Canadian 2025 guidelines [5]
Asymptomatic at baseline
HbA1c	No	No	No	Yes HbA1c used as a first step in screening Only perform 2 h OGTT if HbA1c ≥37 mmol/mol (>5.5%) Skip this step if HbA1c unreliable in a given individual (i.e. transfusion dependency)
2h 75 g OGTT (fasting + 2 h reading)	Yes Gold standard	Yes Gold standard	Yes Gold standard	Yes In second step of screening, for confirmation
Age at start of screening	10 years	10 years	10 years	10 years
Frequency of screening	Annually	Annually	Annually, but every 3–5 years is reasonable if pancreatic sufficient	Annually
During acute illness or during systemic steroid use	Use fasting glucose and 2 h postprandial blood glucose monitoring for 48 h If elevated, verify with certified laboratory testing	Use fasting glucose and 2 h postprandial blood glucose monitoring If elevated, verify with certified laboratory testing	Use fasting glucose and 2 h postprandial blood glucose monitoring for 48 h If elevated, verify with certified laboratory testing	Four times per day (including fasting glucose and 2 h postprandial) blood glucose monitoring for 72 h If elevated, verify with certified laboratory testing
While on continuous drip enteral feeding	Mid-feed and immediate post-feed SMBG at feeding initiation and then monthly If elevated, verify with certified laboratory testing	Mid-feed and immediate post-feed SMBG, every month If elevated, verify with certified laboratory testing	Mid-feed and immediate post-feed SMBG at feeding initiation If elevated, verify with certified laboratory testing	Mid-feed and immediate post-feed SMBG at feeding initiation for 72 h If elevated, verify with certified laboratory testing
Pregnancy	Screen at pre-pregnancy or early pregnancy Screen for GDM at 12–16 weeks and at 24–28 weeks using 2 h 75 OGTT with blood glucose measures at 0, 1 and 2 h Third 2 h OGTT at 6–12 weeks post-partum if GDM was diagnosed	Screen at pre-pregnancy or early pregnancy Screen for GDM at 24–28 weeks and again 6–12 weeks post-partum if GDM was diagnosed	Screen for GDM at 12–16 weeks and at 24–28 weeks Third 2 h OGTT at 6–12 weeks post-partum if GDM was diagnosed	Screen for GDM at 12–16 weeks and again at 24–28 weeks using the 2 h 75 g OGTT No post-partum testing required given the ongoing surveillance post-partum per CF protocol above
Pre-transplantation	2 h 75 g OGTT pre-transplant if not performed in the last 6 months	2 h 75 g OGTT pre-transplant if not performed in the last 6 months	2 h 75 g OGTT pre-transplant if not performed in the last 6 months	2 h 75 g OGTT pre-transplant if not performed in the last 6 months

GDM, gestational diabetes mellitus

Table 2.

Diagnostic criteria for CFRD

Diagnostic test	Diagnostic criteria
Most common
Random plasma glucose	>11.1 mmol/l (>200 mg/dl) + classical symptoms of diabetes (polyuria and polydipsia)
2 h OGTT glucose	≥11.1 mmol/l (≥200 mg/dl)
Other tests
FBGa	≥7 mmol/l (≥126 mg/dl)
HbA1c	≥48 mmol/mol (≥6.5%)
On enteral feeds
Random plasma glucose	≥11.1 mmol/l (≥200 mg/dl) during or after feedings on two separate days
During acute illness
FBG	≥7 mmol/l (≥126 mg/dl)
2 h postprandial plasma glucose	≥11.1 mmol/l (≥200 mg/dl) and persisting for 48 h
During pregnancy
75 g OGTT	FBG ≥5.1 mmol/l (≥92 mg/dl), 1 h glucose ≥10.0 mmol/l (≥180 mg/dl) and 2 h glucose ≥8.5 mmol/l (≥153 mg/dl)

Table adapted from Coriati et al [5] and Khare et al [10]

^aFBG alone is not recommended for CFRD screening

FBG, fasting blood glucose

The simpler standard tool to assess plasma glucose in general diabetes, HbA_1c, was historically unreliable given increased erythrocyte turnover in people with CF, possibly stemming from elevated systemic inflammation and differences in CF metabolism, resulting in HbA_1c possibly underestimating the true glycaemic state in people with CF [24]. However, HbA_1c may now have a role to play in the screening algorithm for CFRD in adults, either as the sole first-step screening tool (only those with HbA_1c >37 mmol/mol [>5.5%] would need a 2 h OGTT [25]), an approach that was adopted by the 2025 Canadian CFRD guideline (although not other international guidelines; Table 1) [5], or as a combination first-step screening tool with HOMA-B [26]. Regarding diagnosis, the HbA_1c cutoff of 48 mmol/mol (6.5%) is the recommended diagnostic threshold for CFRD, consistent with other forms of diabetes.

There has been recent interest in the role that continuous glucose monitoring (CGM) could play in the detection of early glucose abnormalities in people with CF, both adults and the paediatric population [27]. Glycaemic abnormalities identified by CGM despite a normal OGTT are associated with reduced lung function [28, 29] delayed recovery during an exacerbation [30] and reduced BMI [31]. These abnormalities are also inversely correlated with time above range (TAR) for glucose and lower plasma insulin during OGTT screening [32], suggesting that CGM may identify individuals who are at risk of worsening CF outcomes prior to CFRD diagnosis. As CGM-identified glycaemic abnormalities in people with CF with normal glucose tolerance (NGT) appear to predict future lung function [33, 34] and BMI [35], the possibility that CGM may offer early diagnosis of CF dysglycaemia prior to CFRD diagnosis has been raised [36–38]. However, this has not been consistently reported [35]. While the discrepancies may be attributable to differences in sensor technologies, how glycaemic excursion is defined or confounding study design, it remains unclear how clinically relevant CGM abnormalities are and how they might be used in a screening population. The role that CGM can play in the diagnosis of CFRD has also been explored and the thresholds for the percentage of time spent above 2 h OGTT cutoffs are associated with 87–90% sensitivity and 95% specificity for predicting CFRD [39]. However, this has not been consistently shown [40]. As such, CGM remains an adjunct tool in the screening and diagnosis of CFRD.

CFRD continuum

CFRD is not a sudden-onset disease; rather, it represents a continuum from NGT to abnormal glucose tolerance (AGT) that progresses over time, beginning with a blunted first-phase insulin response resulting in postprandial hyperglycaemia to eventual insulin resistance and CFRD (Fig. 1). Under the AGT umbrella, impaired glucose tolerance (IGT) is seen first, defined by a 2 h OGTT of 7.8–11.0 mmol/l (140–199 mg/dl). Indeterminate glycaemia (INDET) is characterised by an abnormal 30–60 min glucose reading (≥11.1 mmol/l [≥200 mg/dl]) but a normal 2 h reading [41]. Conceptually, INDET is considered a pre-CFRD condition, existing in the CFRD continuum between IGT and CFRD. People with CF with IGT or INDET have all been demonstrated to be at an elevated risk of developing CFRD and its complications such as reduced lung function [41]. While less common, isolated impaired fasting glucose (IFG) defined as fasting blood glucose of ≥5.6–6.9 mmol/l (≥100–125 mg/dl) has also been reported, although the clinical significance of this group is less clear and conflicting [42, 43]. At the end of the CF dysglycaemia continuum is CFRD without or with fasting hyperglycaemia.

Fig. 1.

The CFRD continuum (adapted from [13]). Abnormal glucose management can be considered a continuum ranging from NGT to AGT or CF dysglycaemia, encompassing IGT with or without IFG and INDET, where abnormal 1 h but not 2 h glucose tolerance is seen, and then CFRD. Each is associated with a range of potential impacts on lung function (forced expiratory volume in 1 s [FEV₁])/BMI and CFRD outcomes. There is also a growing appreciation for transient abnormal CGM findings in those with NGT or early CF dysglycaemia, although the clinical relevance remains controversial. Management for NGT with CGM abnormalities might include lifestyle modification and random CGM or SMBG. For AGT, a more targeted approach aimed at periods of increased risk (e.g. during oral prednisone use, during acute pulmonary exacerbation/supraphysiological stress, or while on continuous parenteral feeds) might help to identify more severe dysglycaemia. Management of CFRD might include oral glucose-lowering therapy and/or insulin therapy. CFRD w/o FH, CFRD without fasting hyperglycaemia; CFRD w FH, CFRD with fasting hyperglycaemia. This figure is available as a downloadable slide

CFRD pathophysiology

CFRD is a unique form of diabetes that is unlike type 1 diabetes (there is no underlying autoimmune process and initial ketoacidosis is uncommon in CFRD) or type 2 diabetes (CFRD is not typically characterised by an abundance of peripheral adiposity driving insulin resistance and macrovascular disease is rare) [7]. Classical symptoms of diabetes, such as polydipsia or polyuria, are not common in the early stages of CFRD [7]. However, CFRD shares some clinical features with other types of diabetes such as insulin insufficiency, as well as pancreatic inflammation, and fatty infiltration, leading to impaired insulin secretion [9].

The cause of CFRD is not entirely clear, although it is believed to be multifactorial. CFTR dysfunction mediates both exocrine and endocrine pancreatic insufficiency due to partial loss or dysfunction of pancreatic islet cells, resulting in delayed or insufficient insulin secretion [2–5]. As pancreas pathology has been demonstrated to begin in utero, with substantial abnormalities seen by the age of 5 years [44], endocrine pancreatic dysfunction likely begins similarly early in life. Consistently, AGT has been found in infants along with evidence of reduced pancreatic beta cell mass and function (reduced conversion of insulin from proinsulin) in young people with CF [45]. As CF dysglycaemia worsens across the CFRD continuum, a similar drop in beta cell function and insulin sensitivity is seen [45]. Additionally, insulin insufficiency may be further hampered by a reduction in incretin signalling, with reduced glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) [46]. Abnormal glucagon secretion from alpha cells has also been observed, contributing to CF dysglycaemia [47]. Following this loss of first-phase insulin response, over time, insulin resistance may also occur, possibly associated with increased age and chronic systemic inflammation [4, 5], even in absence of peripheral obesity.

Given that beta cell dysfunction is thought to begin early in life, it is tempting to speculate that earlier intervention with modulator therapy might curtail CFRD development. As the clinical indication of CFTR modulators (particularly ETI) gains approval for younger age of use, along with a number of reported instances of pregnant CF-carrier women receiving ETI for the treatment of meconium ileus in CF foetuses [48–50] or the growing rates of pregnant women with CF continuing on ETI throughout pregnancy and into the lactation period [51, 52] allowing for treatment-levels of ETI exposure to their foetuses and newborns, undoubtedly there will be data to come on whether CFTR modulation can prevent the pathogenic mechanisms of CFRD development from occurring altogether.

Complications of CFRD

Relevant CF outcomes, such as impaired lung function, increased pulmonary exacerbations, increased catabolism and weight decline, and fourfold increase in mortality risk, are clear complications of CFRD development [3, 4, 53]. Microvascular complications have also been well documented in people with CFRD, manifesting with classical diabetes-related complications such as albuminuria, nephropathy, retinopathy and neuropathy [54, 55]. These microvascular changes result in greater cognitive impairment (executive function and processing speed) [56], vision defects [57], gastroparesis and gastrointestinal symptoms [58] and reduced lean muscle mass [59]. Conversely, macrovascular complications have been identified rarely but can occur in people with CFRD, as documented in case reports and small case series [54, 55, 60–63]. People with CFRD have been found to have higher arterial stiffness, compared with people with CF without CFRD and healthy control individuals [64]. Collectively, these studies suggest that CFRD may also be a risk factor for coronary arterial changes leading to macrovascular complications. In addition, as people with CF on ETI are expected to live longer [65], cardiovascular risks associated with general ageing combined with a more prolonged history of CFRD and insulin resistance are expected to increase the cumulative risk of macrovascular complications [63]. Additionally, the traditional high-fat diet recommended for people with CF coupled with the well-reported dramatic weight gain seen within the first year of initiation of ETI [66, 67] may further augment the risk of CVD [63].

CFRD treatment

CFRD treatment aims to optimise glucose management to avoid long-term microvascular, pulmonary and nutritional complications [7]. It requires diabetes education, a multidisciplinary team approach and lifestyle modifications [12] such as nutritional changes, physical activity and medication management, including oral glucose-lowering agents or insulin (Fig. 1). Table 3 provides an overview of CFRD treatment as outlined by four CFRD guidelines.

Table 3.

Comparison of guideline treatment recommendations for CFRD

Treatment	US 2010 guidelines [13]	Australian 2013 guidelines [68]	ISPAD 2022 guidelines [12]	Canadian 2025 guidelines [5]
Pharmacotherapy
Insulin	Individuals with CFRD are insulin insufficient and, based on available data, insulin is the only recommended treatment	Insulin is the only recommended treatment for CFRD	People with CFRD should be treated with insulin therapy	In children, insulin is the first-line and only therapy In individuals who are underweight, who have difficulty maintaining body weight and/or who are experiencing pulmonary decline, insulin is first-line therapy
Repaglinide	Not recommended	Oral agents are not as effective as insulin in improving outcomes and are not recommended outside clinical research trials	In certain cases (e.g. refusal of insulin therapy in asymptomatic individuals diagnosed by annual screening but without fasting hyperglycaemia) a trial of oral glucose-lowering agents could be considered under close observation	In some adults with CFRD who prefer alternative options to insulin, non-insulin glucose-lowering agents may be considered; repaglinide may be used as an alternative to insulin to improve postprandial glucose levels and HbA1c
Metformin	Not recommended	Oral agents are not as effective as insulin in improving outcomes and are not recommended outside clinical research trials	Other oral diabetes drugs such as metformin are in use in individual cases in single CF centres. However, there remains inadequate information to recommend the use of these drugs	May be considered as a weight-neutral glucose-lowering agent with low risk of hypoglycaemia
Sulfonyureas	Not recommended	Oral agents are not as effective as insulin in improving outcomes and are not recommended outside clinical research trials	Not mentioned	Not recommended because of high risk of hypoglycaemia
Sitagliptin, GLP-1 receptor agonists, SGLT2i agents	Not mentioned	Oral agents are not as effective as insulin in improving outcomes and are not recommended outside clinical research trials	Other oral diabetes drugs such as sitagliptin and empagliflozin are in use in individual cases in single CF centres. However, there remains inadequate information to recommend the use of these drugs	May be considered if weight loss would be beneficial or if cardiorenal risk is increased
Non-pharmacotherapy
Monitoring	HbA1c measurement is recommended quarterly Should conduct SMBG testing at least three times a day	HbA1c measurement is recommended quarterly Should conduct SMBG testing at least three times a day CGM is under investigation	HbA1c measurement is recommended quarterly Should perform SMBG at least four times a day CGM may be used as an alternative to SMBG	HbA1c monitored every 3–6 months Those not on pharmacological therapy: SMBG for 3–4 days or CGM for 10–14 days may be used every 6 months as an adjunct to HbA1c monitoring
Dietary	Evidence-based guidelines for nutritional management are recommended	Education regarding the high energy requirements due to respiratory disease, recurrent infections and the need for exercise regimens is important	Medical nutrition therapy is essential but should follow CF guidelines for dietary therapy, with individualisation	High-energy, high-fat diet but this should be tailored to the individual’s target weight Newly diagnosed or those not meeting glycaemic targets should receive counselling by a dietitian
Physical activity	Should be advised to do moderate aerobic exercise for at least 150 min per week	Exercise and physiotherapy routines may need adjustment given their impact on blood glucose absorption and metabolism	Should be advised to do moderate aerobic exercise for at least 150 min per week	Should participate in regular physical activity including combined exercise programmes (aerobic and resistance)

Table adapted from Moran et al [13]; Middleton et al [121]; Ode et al [12]; and Coriati et al [5]

SGLT2i, sodium–glucose cotransporter 2 inhibitor

Insulin

National and international guidelines indicate that insulin is considered first-line therapy for people with CFRD, and is the only pharmacotherapy for children [5, 12, 13, 68]. In particular, it is suggested that people with CFRD who are underweight, who struggle to maintain their body weight or who display pulmonary decline begin treatment with insulin [5]. While insulin remains the primary treatment for CFRD, there is growing interest in the role of oral glucose-lowering agents and non-insulin injectables [69]. For individuals requiring intensive insulin therapy, insulin pump therapy, including partial closed-loop therapies may be appropriate [12]. Additionally, for those requiring intensive insulin therapy, CGM should be considered [5].

Repaglinide

The 2025 Canadian guideline recommended repaglinide as an alternative to insulin therapy for individuals that are without weight loss, pulmonary decline or persistent hyperglycaemia and have limitations impacting their ability to take insulin [5] based on recent RCT evidence [70]. The 2022 ISPAD CFRD guideline did not endorse repaglinide use in children and adolescents, given contradictory findings to the earlier CFRDT trial [71] and some concerns around high dropout rates in the more recent trial [12]. Nevertheless, in Canadian practice, healthcare professionals caring for adults with CF self-reported repaglinide as the most common prescribed alternative to insulin [72]. Of note, the use of repaglinide may increase the risk of hepatic toxicity when co-prescribed with ETI and thus careful monitoring is required when both treatments are used concurrently [73].

Dipeptidyl peptidase-4 inhibitors

Recently, dipeptidyl peptidase-4 (DPP-4) inhibitors have been increasingly explored for their use in people with CFRD. A series of observational studies have highlighted the efficacy of sitagliptin as primary therapy or as an adjunct to insulin for CFRD, consistently demonstrating improvements in time in range (TIR) and reduced glucose variability as measured by CGM, although improvements in weight or HbA_1c are inconsistent [74, 75]. The longer-term efficacy and tolerability of sitagliptin for up to 5–10 years has been identified in one case series of three people with CFRD [76]. Finally, a trial of sitagliptin in 26 adults with AGT demonstrated improved early insulin secretion, glucagon suppression and increased mixed-meal tolerance test response for intact GLP-1 and GIP, over 6 months compared with placebo [77]. However, sitagliptin did not impact glucose tolerance in this trial [77]. DPP-4 inhibitor use in people with CFRD requires careful consideration given the reported increased risk of pancreatitis in the general population [78], as well as renal and liver derangements in people with CF [79].

Metformin

Traditionally, the risk of gastrointestinal side effects and weight loss has precluded the use of metformin in people with CFRD [78]. With improvements in weight in the ETI era, there is now renewed interest in this drug. There is early evidence that metformin may be a possible adjunct to allow dose reduction of insulin therapy while improving HbA_1c, albuminuria and pulmonary exacerbation rates [80]. However, this finding was confounded by a significant portion of the study cohort concurrently starting ETI, so it is not clear whether the improvements can be entirely attributable to metformin use. Dewdney et al reported the use of metformin in four people with CFRD in a retrospective analysis and their mean C-peptide levels were >900 pmol/l, compared with the cohort mean of 750 pmol/l, raising the possibility that metformin might be more suitable for a subgroup of people with CFRD with a greater endogenous level of insulin [81].

GLP-1 receptor agonists

GLP-1 agonists have been rising in popularity in general diabetes treatment but have not been as explored in people with CFRD given the historically reduced BMI in this population. Correspondingly, the handful of studies exploring the use of GLP-1 agonists in people with CFRD were conducted in individuals who were concurrently overweight. As people with CFRD often experience a decreased incretin effect [78], GLP-1 agonists should theoretically improve the effects of this metabolic imbalance. The published literature have identified efficacy in reducing/normalising weight, improving glycaemic management and stabilising/improving lung function while individuals who were insulin-dependent experienced a reduction in their daily insulin requirements, although the HbA_1c was inconsistently improved [82–85]. However, the potential side effects of nausea, vomiting and possibility of pancreatitis [78] are important considerations, particularly in the CF population. Nevertheless, with the observed rise in BMI post-ETI initiation, there may be a growing role for GLP-1 agonists in people with CFRD.

Technology and CFRD management

Technological advances in diabetes management, such as CGM and insulin delivery devices, along with an emerging role for predictive algorithms, have also been explored in the management of CFRD. A survey of 120 individuals with CF and family members found that the majority of people with CFRD and their caregivers have used CGM and hold a generally positive opinion of this technology [27]. In contrast, the survey indicated insulin pumps are less commonly used and generally have a lower acceptability rating by people with CFRD.

CGM

In addition to the role of CGM in screening for CFRD as discussed above, CGM has been adopted into clinical care of people with CFRD based on studies that identified the utility of CGM to guide treatment decisions [28, 86] and documented sensitivity to identify expected glycaemic excursions during pulmonary exacerbations [87, 88]. Minimal high-quality data exist comparing the superiority of CGM to self-monitoring of blood glucose (SMBG), although a recent meta-analysis suggested that CGM use may possibly improve HbA_1c control after at least 6 weeks of use when compared with SMBG [89]. Coupled with the general patient preference for and acceptance of CGM [90], the recent Canadian Guidelines on CFRD recommended the use of CGM to direct therapy [5].

Insulin pumps and automated insulin delivery systems

Insulin pumps and automated insulin delivery (AID) systems have demonstrated evidence of improvements in lean body mass, postprandial glucose management and HbA_1c (with insulin pump use [91]) and improved overall glycaemic management (with sensor-augmented pump [CGM combined with insulin pump] use) [92]. Most recently, AID systems, devices that combine CGM with automatically adjusted insulin pump with or without a predictive algorithm to provide supplemental insulin, have been tested for use in people with CFRD (summarised in Table 4). Use of an AID system in eight people with CFRD demonstrated a decline in HbA_1c in all five individuals who underwent testing, and improved TIR without impacting the time below range (TBR) compared with prior CGM plus manual insulin titration, and may have accounted for lung function improvement or stabilisation and BMI improvement in some participants [93]. Yusuf et al also reported a reduction in HbA_1c and improved average glucose and TIR in 12 people with CFRD using the AID system [94]. Similarly, AID use was associated with good tolerability and satisfaction in two people with CFRD with low total daily insulin requirement over 2 years [95] and increased TIR and lowered mean glucose, TAR and glycaemic variability, without impacting TBR in 13 adults and adolescents with CFRD compared with CGM plus manual insulin titration at 1 and 3 months [96]. Another case series of 14 people with CFRD using AID systems for 6 months also demonstrated significant improvements in HbA_1c, glucose management indicator and TIR [97]. However, a retrospective pilot study of ten people with CFRD using an AID system failed to demonstrate a statistically significant improvement in TIR or TAR over 1 year of use despite reduction in HbA_1c, glycaemic variability and insulin requirements [98].

Table 4.

Impact of insulin pumps and AID systems on CF glycaemic outcomes

Reference	N in study	Adults/paediatrics	Impact on CF glycaemic outcomes	Key points
Scully et al (2022) [96]	13	Both	Improvement	Increase in TIR Decrease in mean glucose, time in hyperglycaemic range and glycaemic variability
Grancini et al (2023) [92]	46	Adults	Improvement	Improved HbA1c, mean glucose, TIR and fat-free mass
Yaseen and Slattery (2024) [93]	8	Adults	Improvement	Decline in HbA1c Increase in TIR and BMI
Grancini et al (2024) [95]	2	Adults	No data	Off-label use Improvement in quality of life and treatment satisfaction
Grancini et al (2024) [97]	14	No data	Improvement	Improvement in HbA1c and TIR
Bassi et al (2024) [98]	10	Adults	Improvement	Reduction in HbA1c and insulin requirement
Sherwood et al (2024) [99]	20	Adults	Improvement	Improvement in TIR and mean glucose
Yusuf et al (2025) [94]	12	Adults	Improvement	Improvement in mean glucose and TIR

The latest generation of AID devices, the insulin-only iLet bionic pancreas, is being studied in people with CFRD (ClinTrials.gov registration no. NCT06449677). People with CFRD using the bionic pancreas demonstrated superior glucose management without compromising TBR compared with those with usual care [99], thus establishing safety and efficacy to warrant the current ongoing Phase III study of this device in people with CFRD. Additionally, a clinical trial is currently being conducted to determine whether hybrid closed-loop glucose management (using the CamAPS system) is better than insulin therapy with CGM for people with CFRD (ClinicalTrials.gov registration no. NCT05562492). With these ongoing studies, the use of insulin pumps and AID devices is expected to become more realistic in the future care of people with CFRD.

CFTR modulators and CF dysglycaemia

CFTR modulators are a class of medications that have been designed to target defects in the CFTR protein, with proven efficacy in improving lung function, reducing pulmonary exacerbation rates, reducing gastrointestinal issues and improving weight [7]. The first generation of modulators includes ivacaftor (Kalydeco), a potentiator drug that improves the channel function of CFTR and is used in a small subset of people with CF who have a gating defect. The second generation of modulators includes the combination therapy of ivacaftor plus corrector lumacaftor (LUM-IVA; Orkambi) or ivacaftor plus corrector tezacaftor (TEZ-IVA; Symdecko). Since the corrector compounds target CFTR misfolding, the most common genetic cause of which is the CF mutation F508del, more than 80% of people with CF worldwide are now eligible for these therapies. The third generation of modulators is ETI therapy, combining tezacaftor with ivacaftor plus additional corrector elexacaftor (Trikafta); ETI has superior efficacy in lung function improvement compared with prior generations of modulators and as such is the most common modulator used currently. Since these highly effective modulators have been on the market, a growing body of observational data has raised the tantalising possibility that these drugs may also improve CF dysglycaemia, particularly in individuals with AGT prior to the development of CFRD. While evidence related to the impact of CFTR modulators on dysglycaemia is still emerging, early studies have demonstrated the ability of modulators to improve ion and fluid transport in pancreatic epithelium, although inflammation was not meaningfully reduced in one animal study [100]. A second animal study however, demonstrated improved pancreatic exocrine function with CFTR modulator administration [101]. Additionally, CFTR modulator administration may have an impact on beta cell function through improvements in insulin secretion and proinsulin processing [102]. However, whether modulators are acting through a direct (previously beta cell CFTR has been shown to modulate glucose and Cl⁻ efflux leading to membrane signalling cascades required for insulin secretion) [103] or indirect mechanism (CFTR dysfunction results in indirect beta cell mass and function loss by inducing pancreatic autodigestion and inflammation, leading to insufficient islet activity) [100, 102, 104] is unclear at this time given the controversy that remains around the role of CFTR in beta cells dysfunction. Nevertheless, it has been hypothesised that CFTR therapy may decelerate the deterioration in glycaemic management in people with CF over time [105]. Thus, how CFTR modulators might impact the development or trajectory of CFRD is of significant research interest. Table 5 provides a summary of the evidence on the impact of CFTR modulator therapy on CF dysglycaemia.

Table 5.

Summary of recent evidence (post 2021) on the impact of CFTR modulator therapy on CF dysglycaemia

Reference	N in study	Adults/paediatrics	Impact on CF dysglycaemia	Key points
LUM-IVA
Moheet et al (2021) [116]	39	Both	No impact	No improvement in insulin secretion or glucose tolerance
Cohen et al (2024) [105]	15	Both	Improvement	Decrease in 120 min OGTT
TEZ-IVA
Lurquin et al (2023) [118]	15	Adults	Mixed	Decrease in insulin doses, although HOMA indices did not change Positive effect on BMI and FEV1
Ekblond et al (2023) [119]	55	Adults	No impact	No improvement in glucose tolerance or insulin secretion, although HOMA for insulin resistance demonstrated a non-significant decline
ETI
Chan et al (2022) [130]	20	Mixed	Mixed	No significant differences in glucose tolerance, glucose AUC or frequently sampled OGTT glucose concentrations Median C-peptide index increased and HOMA2-IR increased HbA1c decreased and CGM variables did not change
Scully et al (2022) [123]	23	Adults	Improvement	Average glucose, % time spent above 11.1 mmol/l (200 mg/dl), and peak sensor glucose decreased and % TIR increased No change in CGM measured or reported hypoglycaemia
Korten et al (2022) [124]	16	Paediatrics	Improvement	OGTT categories improved, glucose levels of OGTT improved at 60, 90 and 120 min, fasting glucose and CGM measures did not change
Petersen et al (2022) [127]	134	Adults	Improvement	In people with CFRD random glucose and HbA1c were decreased post ETI In people with CF BMI and BP increased
Steinack et al (2023) [125]	33	Adults	Improvement	48.5% improved their glucose tolerance category, 39.4% remained unchanged and 12.1% deteriorated OGTT glucose levels decreased and HbA1c levels improved significantly
Nielsen et al (2024) [126]	321	Mixed	Mixed	HbA1c declined significantly People with CFRD also experienced a decline in HbA1c, with no change in insulin use, weekly number of hypoglycaemic events or CGM indices
Chan et al (2025) [131]	79	Mixed	Mixed	Fasting glucose decreased in those not on insulin, with no difference in 1 h or 2 h glucose HbA1c and insulin sensitivity decreased
Galderisi et al (2025) [128]	106	Paediatrics	Mixed	AGT did not change at 1 h or 2 h, although the AGT had a non-statistically significant reduction at 2 h 15/31 in the AGT group reversed to NGT and 9/75 in the NGT group progressed to AGT Three people with CFRD reversed to AGT
Appelt et al (2025) [129]	90	Adults	Improvement	Significant reductions in glucose concentrations at 60, 90 and 120 min, HbA1c and insulin levels during ETI treatment

FBG, fasting blood glucose; FEV₁, forced expiratory volume in 1 s

Ivacaftor

Several large retrospective database analyses using the UK and US CF registries found a trend of reduced CFRD prevalence over 2, 3 and 5 years of ivacaftor use when compared with individuals who were modulator-naive [106, 107]. Correspondingly, a number of studies demonstrated improvements in OGTT values (with those meeting CFRD diagnosis transitioning to IGT range or normalisation of those with IGT) post ivacaftor therapy, along with improvements in insulin AUC values, early phase C-peptide response [108–110] and insulin requirement [111]. These observations raise the possibility that ivacaftor may improve beta cell function, resulting in enhanced early phase insulin. Although this mechanistic hypothesis has not been consistently demonstrated [111–114], glycaemic outcome (as measured by OGTT values) appears to be improved in people with CF on ivacaftor.

LUM-IVA

In a retrospective study of 15 adults and adolescents with CF (aged 13–37 years), pre- compared with post-LUM-IVA initiation showed significant improvement in OGTT values in the majority of participants, such that those who were in the CFRD range improved to AGT and those with AGT improved to NGT [105]. Similarly, Misgault et al reported that half of the enrolled people with CF with AGT normalised to NGT range on repeat OGTT 1 year post LUM-IVA [115]. However, no significant improvements in OGTT, insulin secretion, CGM metrics, HbA_1c or fasting glucose were observed in other small case series involving only adults [116] or children with CF [117]. It is unclear why there are discrepant findings regarding the impact of LUM-IVA on CF dysglycaemia, although heterogeneity of the duration of LUM-IVA use or differences in the distribution of the stage of CF dysglycaemia studied may account for some of these discrepancies.

TEZ-IVA

There is a paucity of literature on the impact of TEZ-IVA on CF dysglycaemia. Lurquin et al conducted a recent study involving 15 people with CF without CFRD on TEZ-IVA (one changed to ETI during the study) and found significant weight and lung function improvement with no significant changes in HbA_1c or HOMA indices (including HOMA-B, HOMA-S [insulin sensitivity] and HOMA-BxS [combined insulin sensitivity and secretion]) [118]. Comparatively, a 21 month study of 55 people with CF (37 treated mainly with TEZ-IVA and 18 untreated) failed to demonstrate any significant change in glucose tolerance, insulin or C-peptide level over time in participants with NGT, AGT or CFRD, although HOMA-IR was lower in the TEZ-IVA-treated group, suggesting that insulin sensitivity could be improved despite no impact on overall blood glucose [119].

ETI

Most published literature on CFTR modulators and CF dysglycaemia involves ETI since ETI is the most effective modulator in improving lung function, reducing pulmonary exacerbations and increasing BMI [120–122] and therefore is the most widely used. For individuals with NGT or AGT, improvements in CGM metrics (mean glucose, peak sensor glucose and TAR), with no change in TBR or the burden of symptoms of hypoglycaemia [123], have been reported with at least 3–12 months of ETI use. Likewise, OGTTs have been reported to normalise among 50% of individuals with AGT [124] with another study finding that 48% of the adult participants demonstrated improved glucose tolerance along with improvements in HbA_1c [125]. HbA_1c or random glucose improvement 1 year post ETI has also been identified by a large Danish retrospective registry study [126] and others [127]. A recent study in 23 people with CF comparing CGM readings pre-ETI and 3–12 months post-ETI initiation identified reduced mean glucose levels, TAR and peak sensor glucose with ETI therapy, while TIR increased [123]. There were no changes in CGM-reported or self-reported hypoglycaemia events. Improvements were noted across the CFRD continuum but these were most marked in people with CFRD. Similarly, a large study of adolescents with CF (75 NGT, 31 AGT) found that those with AGT demonstrated a reduction in 2 h OGTT values and nearly half reversed to NGT after 12 months of ETI therapy [128]. Of note, 17% of the NGT group moved to the AGT group. Finally, Appelt et al conducted a recent pairwise comparison of pre-ETI and 1.5 years post-ETI initiation in 90 people with CF and found significant reductions in insulin levels, HbA_1c and glucose levels, although there were no CF dysglycaemia classification changes that resulted [129]. In contrast, Chan et al studied 20 adolescents and adults with CF who had NGT or AGT on average 10 months post-ETI initiation and found no significant differences in glucose tolerance, glucose AUC or OGTT values, despite an increase in BMI, median C-peptide index and HbA_1c [130]. Similar findings were reported from a separate follow-up study at 24–30 months post-ETI initiation led by the same lead author [131].

For people with CFRD, the evidence for improvement in glycaemic management secondary to ETI is more consistent, although less promising. Some have identified a possible ‘honeymoon phenomenon’ post-ETI initiation of reduced insulin requirements in the first 3–6 months [132–134] but this typically rebounded back to pre-ETI insulin requirements by 1 year [135]. Consistently, in the aforementioned large Danish study, subgroup analysis of people with CFRD (n=26) showed no corresponding change in insulin requirement or CGM metrics (average glucose, CV in glucose, and TBR or TAR) [126]. A similar lack of change in CGM metrics or insulin requirement in people with CFRD was noted by a number of studies conducted worldwide at up to 6 months post-ETI initiation [136, 137], with the lack of change remaining after up to 3 years of treatment [138].

The lack of change in insulin requirement in people with CFRD, or conflicting results in OGTT improvement across the CFRD continuum post ETI, may possibly be due to differences in insulin sensitivity and resistance in these studies, potentially related to increasing fat mass in some individuals but not others post ETI [65]. A study of eight adolescents with CF found that after approximately 11 months of ETI use, weight significantly increased, as did fat mass [139]. Insulin secretion and insulin resistance also significantly increased, while BMI and muscle mass remained unchanged. The reduction in insulin sensitivity [131] and the increase in fat mass [137] has been identified by others as well. Thus, it may be argued that ETI may improve glycaemic management in all people with CF but the rise in weight secondary to ETI may counterbalance any gains by increasing peripheral insulin resistance. This raises the possible need to re-examine the literature by stratifying people with CF post-ETI initiation based on BMI, or more specifically, fat mass change, to predict the impact of ETI therapy on CF dysglycaemia and CFRD.

Vanzacaftor–tezacaftor–deutivacaftor

The latest generation of CFTR modulators, vanzacaftor–tezacaftor–deutivacaftor, has recently become commercially available in the USA, although not elsewhere at the time of writing. The safety and efficacy profile of vanzacaftor–tezacaftor–deutivacaftor was demonstrated in two randomised, active-controlled, double-blind, Phase III trials of people with CF aged 12 years and older who were homozygous or heterozygous for F508del, finding that this treatment is safe and non-inferior to ETI [140]. Notably, the once-a-day regimen may improve adherence (compared with twice daily treatment required with ETI). Similar to prior Phase III modulator trials, the primary outcome focused on pulmonary endpoints so it remains to be seen how vanzacaftor–tezacaftor–deutivacaftor might impact CF dysglycaemia.

It might be tempting, in light of the reviewed literature above suggestive of differences in glycaemic management with different HEMT use, to conclude that certain HEMT is ‘better’ than another. However, it should be highlighted that the selection of HEMT is based on an individual’s genetic mutations and therefore differences in responses between different modulators should be considered in the context of the differences in an individual’s genetics, particularly for those who remain on ivacaftor vs those who have reason to transition to another HEMT. As nearly all literature on the extrapulmonary impact of HEMT are from observational or post-marketing data, each study population may represent a mixed genotypic cohort and thus any interpretation of the data should be individualised to their unique genotype.

Future directions

There is much potential for research related to CFRD in this new era of HEMT. New diabetes technologies and innovations are evolving rapidly. For example, researchers are exploring the use of the human voice as a non-invasive tool for measuring glucose levels and glycaemic management status in CFRD [141]. Consequently, there is a need for the development of long-term cohort studies to assess the impact of CFTR modulators and CF dysglycaemia on people with CF as they age to understand whether modulators can slow or even halt the development of CFRD. Such endeavours should be a collaborative national and international effort as known determinants of blood glucose, such as diet and access to nutrition, can be regionally different, thus impacting efforts to attribute changes in blood glucose solely to modulator use. This is a particularly relevant consideration since there is a well-reported increase in BMI post-ETI use resulting in increasing incidence of obesity in the CF population [142]. How rising obesity might result in or predispose ageing people with CF to peripheral insulin resistance would further cloud attempts to understand changes in CFRD pathophysiology in the context of modulators. Thus, large-scale efforts spanning nations and regions would be best positioned to answer these complex questions. There is also a need for studies to adequately assess the impact of CFTR modulators on established CFRD [143], examining changes in CGM-based metrics, OGTT values, insulin resistance and sensitivity profiles and focus on a personalised approach to risk stratification of future micro- and macrovascular complications. Additionally, the role of emerging technologies, such as AID systems and non-insulin-based medical and even surgical approaches to CFRD management should be explored in greater detail. A 2023 case report described the use of bariatric surgery to manage obesity in an individual with CF with type 2 diabetes, with the result of remission from diabetes due to extreme weight loss [144]. With the expected increase in BMI in some people with CFRD on ETI, such invasive interventions might become necessary in the future and thus may need to be explored in people with CF. Current research is exploring the application of semaglutide therapy or sodium–glucose cotransporter 2 inhibitors in the management of CFRD in individuals who are overweight or obese (ClinTrials.gov registration no. NCT05788965 and NCT06149793). Optimisation of CFRD understanding and management will undoubtedly become critical in an ageing CF population.

Limitations

This scoping review provides an update on CFRD pathophysiology and treatment, emerging diabetes technologies and the impact of CFTR modulator therapies on CF dysglycaemia, focusing on the explosion of literature since 2021. As CFTR modulator therapy is an important, and evolving area of research, the review is limited to the timespan of the search (January 2021 to June 2025). Additionally, the review was limited to research published in the English language. As with all scoping reviews, risk of bias assessment and quality appraisal of studies included were not conducted.

Conclusion

With the dawning of the HEMT era, people with CF are living longer lives with improved pulmonary outcomes. However, non-pulmonary complications of CF, such as CFRD, are emerging as the next frontier in the journey towards optimisation in the overall health of people with CF. While understanding of CFRD pathophysiology remains in its infancy, emerging observations have fuelled advances in CFRD screening, testing, treatment and monitoring. While HEMT may improve some risk factors for CFRD development (e.g. reduce recurrent pulmonary exacerbation and inflammation, reduce need for systemic corticosteroids), it may also increase other risk factors (e.g. increase in incidence of obesity). Large multinational longitudinal studies will be necessary to provide ongoing insights into the optimal management of the evolving landscape of CFRD.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

AGT

Abnormal glucose tolerance

AID

Automated insulin delivery

CF

Cystic fibrosis

CFRD

CF-related diabetes

CFTR

CF transmembrane conductance regulator

CGM

Continuous glucose monitoring

DPP-4

Dipeptidyl peptidase-4

ETI

Elexacaftor plus tezacaftor plus ivacaftor

GIP

Glucose-dependent insulinotropic polypeptide

GLP-1

Glucagon-like peptide-1

HEMT

Highly effective modulator therapy

IFG

Impaired fasting glucose

IGT

Impaired glucose tolerance

INDET

Indeterminate glycaemia

LUM-IVA

Ivacaftor plus lumacaftor

NGT

Normal glucose tolerance

SMBG

Self-monitoring of blood glucose

TAR

Time above range

TBR

Time below range

TEZ-IVA

Ivacaftor plus tezacaftor

TIR

Time in range

Funding

GYL has received research funding to her institution from Roche Diagnostics, Alberta Lung, the University Hospital Foundation, Long COVID Web and the Canadian Institutes of Health Research (CIHR).

Authors’ relationships and activities

GYL has received honoraria for educational activities from Boehringer Ingelheim, Alberta Lung and Canadian Thoracic Society/Respiplus. However, none of these competing interests are related to the topic of this review. HS declares that there are no relationships or activities that might bias, or be perceived to bias, her work.

Contribution statement

GYL was responsible for conceptualisation, development of methodology, supervision and manuscript writing. HS was responsible for drafting the manuscript, manuscript editing and review. Both authors have read and approved the final manuscript.