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Cystic fibrosis-related diabetes – the latest 

28th June 2023
3D human lungs

Modern treatment means that people with cystic fibrosis are living longer, healthier lives. However, this welcome news brings a challenge – more people are also living with cystic fibrosis-related diabetes (CFRD) and need to manage two serious chronic conditions. There are many unanswered questions around the pathophysiology, treatment and outcomes of CFRD, which is why a high-level workshop, the findings of which are reported in a recent issue Diabetes Care, has set out some research priorities. Dr Susan Aldridge reports.

Cystic fibrosis (CF) is a recessive disorder resulting from mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) channel. This protein is highly expressed in the lungs, intestines, pancreatic and hepatobilary ducts, and its loss in CF leads to disruption of salt, bicarbonate and water movement, resulting in progressive organ dysfunction. The lungs are particularly vulnerable, with recurrent infections and worsening lung function, which often leads to early death or requirement for a lung transplant. Malnutrition, liver disease and pancreatic exocrine insufficiency also feature. 

CFRD is a common complication, occurring in 20% of teenagers with CF and up to half of adults. It arises from insulin insufficiency and has been associated with worse lung function and increased mortality. Despite decades of research, a clear understanding of the underlying pathophysiology of CFRD remains elusive, mainly because of the lack of a reliable animal model system to study. However, that is changing, thanks to the recent discovery of new animal models of CFRD and the introduction of new tools and reagents allowing detailed studies of human pathology specimens. Now researchers can investigate the chain of events in CFRD pathogenesis with unprecedented granularity. 

Meanwhile, CF care is being transformed by the availability of modulator therapies that can partly restore function. The most active of these, known as highly effective modulator therapies (HEMT), result in dramatic improvements in lung function, CF symptoms, disease stability and nutritional status, although their impact on the endocrine manifestations of CF are largely unknown. 

In light of these developments, the National Institute of Diabetes and Digestive and Kidney Diseases and the Cystic Fibrosis Foundation (CFF) sponsored a CFRD Scientific Workshop in June 2021 to share research data and identify knowledge gaps that can be used to inform research priorities going forward. Some of the highlights of the meeting are summarised below. 

The biological underpinnings of CFRD

It is well established that the main cause of CFRD is reduced insulin secretion, which is observed even in people with CF who do not have diabetes. The presence of CFRD is tightly linked to pancreatic insufficiency (PI). Histopathologic studies on human CF pancreases suggest the endocrine component is spared, relative to extensive loss of exocrine tissue, loss of beta cell mass, altered islet composition with increased non-beta cells, and expression of inflammatory molecules. Determining how CF exocrine pancreatic disease impairs islet function, including the role of local factors, such as altered islet vasculature, should be a research priority.

Factors outside the pancreas may also affect beta cell function in CF. For instance, incretin secretion and incretin response are impaired. How these affect the development of CFRD is another important research question. Then there is the cellular localisation of the CFTR gene in the pancreas, where studies have shown only minimal expression in beta cells in a normal pancreas. Research into which CFTR-expressing cell types are essential to maintaining proper islet function should also be a priority. This should include identifying the developmental stages during which CFTR function is vital for the long-term prevention of CFRD. Understanding the biology underlying CFRD may not only help identify targeted treatments and preventative approaches, but also yield information that could be relevant to other forms of diabetes. 

CFRD screening and diagnosis

How best to screen for and diagnose CFRD remains a challenge. Currently, screening involves an annual oral glucose tolerance test (OGTT). Abnormal glucose tolerance is common in CF, but rates of progression vary and studies are looking at the role of the one-hour OGTT and peak glucose just before the two-hour mark in predicting the emergence of CFRD. 

Adherence to the current screening guidelines is poor but, increasingly, continuous glucose monitoring (CGM) is being used to investigate dysglycaemia in people with CF. Research into screening should focus on which CGM metrics are most useful for screening and alternatives, such as blood spots and breath or sputum testing for novel biomarkers. The optimal age to start yearly screening is another issue that needs investigating. 

Workshop participants would also like to see prospective longitudinal studies into the clinical effects of early dysglycaemia in CF and research into the optimal OGTT glucose thresholds for predicting CFRD and relevant clinical outcomes. A further priority is studies into the early pathophysiology of CFRD and the drivers of disease progression, as well as the timing and type of interventions that may prevent or delay this progression. 

Nutrition and CFRD

In CF, nutritional status is strongly linked to both lung function and survival. Current dietary recommendations are to consume an unrestricted, high-calorie, high-fat diet to offset the fat malabsorption that is a feature of the condition. However, the introduction of HEMT has resulted in weight and BMI improvements and this has made the traditional CF diet look poor-quality – one that is too high in saturated fats and sugars and, in itself, a risk factor for glucose intolerance and diabetes, at least in the non-CF population. This has led many CF centres to adapt their dietary guidelines accordingly and the CFF will be updating theirs. 

However, CFRD differs from its pathophysiology compared with other types of diabetes. It is not known what impact diet has on onset or progression of the condition. There is also a small but rising prevalence of overweight and obesity among those with CF, particularly as life expectancy increases, and so the impact of this also needs to be investigated. However, underweight in adults and lack of healthy growth in children is still prevalent in those with CF and these are risk factors for CFRD. 

Therefore, research should focus on the impact of diet and the quality of macronutrients on the risk for CFRD and its management. The calorie, macronutrient and micronutrient needs among those on HEMT should also be determined. And specific dietary recommendations should also be developed for those who have overweight or obesity as well as those who are underweight or have growth failure. 

Effects of HEMT

Advances in CF care, including the use of HEMT, have certainly contributed to improved health and survival. However, the impact of ageing and better nutritional status on the emergence and progression of glucose abnormalities, including CFRD, remain unclear. US and UK registry data show trends towards lower CFRD rates in the years following the introduction of treatment with ivacaftor, one form of HEMT, and other small studies also show improvements in various glucose abnormalities. Further – and longer – studies on the role of HEMT in improving glucose tolerance and delaying (or even preventing) CFRD development are now needed.  

For example, the CFF-funded PROMISE (A Prospective Study to Evaluate Biological and Clinical Effects of Significantly Corrected CFTR Function) endocrine substudy will look at the impact of combination HEMT therapy on glucose excursion, insulin secretion and incretin secretion, using three-hour OGTT at baseline and 12 to 18 and 24 to 30 months after initiating therapy. It will also look at the association of changes in OGTT with changes in BMI, body composition, pulmonary function and several other measures. 

Other important avenues of research include looking at whether the propensity to diabetes persists in people receiving HEMT and whether this predisposition is uncovered by overweight and/or ageing, despite treatment. It would be particularly interesting to clarify whether initiation of HEMT at a young age – even in infancy – has an impact on beta cell survival and diabetes progression.

Healthcare in CFRD

The management of CFRD, including insulin administration, carb counting and glucose monitoring, adds a significant burden to the medical care of people with CF. Glycaemic targets are based upon those for type 1 and type 2 diabetes, but it would be useful to identify CFRD-specific targets, not only to minimise the risk of diabetes complications but also to address CF-specific pulmonary and nutritional outcomes. 

A recent survey of adults with CFRD and parents of children who have the condition suggested that uptake of diabetes technology, including CGM and insulin pumps, is low in this population. Strategies are needed to improve patient education and access, as well as research to confirm efficacy and acceptability. One study has shown that CGM-guided insulin initiation was associated with slowing of pulmonary decline, but there are no other studies on the impact of CGM on health outcomes and quality of life in CFRD. 

Currently, insulin is the only recommended treatment for CFRD as it improves BMI, which has not been observed with other therapies. However, now the overall health of people with CF is improving, while overweight and obesity are also beginning to emerge, it is time to consider the use of non-insulin therapies to treat CFRD. So far, there have been limited studies – with promising results – into GLP-1 receptor agonists and DPP-4 inhibitors. Longer trials are merited, as well as clinical trials on other diabetes therapies. 

Historically, vascular complications were rarely observed in CFRD, probably due to the shortened life span. Now, with HEMT, we will soon have an ageing CF population and this will necessitate closer monitoring for microvascular and macrovascular complications, preferably from a multidisciplinary team. 

Disease burden from diabetes is not well studied in the CF community, particularly with regard to race and ethnicity. In other forms of diabetes, non-Hispanic Black and Hispanic individuals have greater morbidity and mortality than White individuals, but it is not known whether this is also the case with CFRD. Research into the sociodemographic aspects of CFRD could help address health inequalities.  

Finally, CFRD is a complex condition and endocrinologists should have specific training in diagnosing and managing it. Programmes for nurses and dietitian-certified diabetes educators should also be set up, so they can provide multidisciplinary care to the growing paediatric and adult population with CF.  

Lived experience

A young adult with CFRD and the mother of an adult with CFRD joined the workshop to discuss research priorities from their own patient and caregiver perspectives. They spoke of the emotional and mental toll of dealing with two demanding chronic diseases, which are interdependent. When diabetes is not controlled, lung function suffers, while during a pulmonary exacerbation, blood glucose can become unstable. And many CF medications, such as corticosteroids, make blood glucose control particularly challenging. 

Both speakers highlighted lack of access to practitioners’ knowledge about CFRD. Often, endocrinologists were unaware of the difference between CFRD and type 1 and type 2 diabetes, and they may not be included in the CF care team. Diabetes treatment plans may therefore be written without regard for current CF treatment and any added treatment burden or medication interactions, so one priority should be education and training of multidisciplinary practitioners familiar with CFRD, who would become part of the CF care team. 

And, as the CF population ages, research should also focus on prevention and delay of the onset of CFRD at the prediabetes stage, as well as optimising treatments and technologies for those who develop it. Finally, the long-term impact of CFRD should be investigated, with focus on prevention and treatment of any complications.  

In conclusion

Findings from research into the pathophysiology of CF lung disease have led to significant improvements in patient outcomes. Less attention has been given to the extrapulmonary manifestations of the condition, including CFRD. As people with CF are living longer, the number with CFRD is expected to increase accordingly. There are many unanswered questions about CFRD pathogenesis, risk factors for developing it, its impact on both CF and diabetes-related outcomes, and optimal strategies for diagnosis and treatment. 

This workshop focused on some of the latest research into CFRD and highlighted some basic and clinical research priorities. Addressing these could lead to meaningful change in our understanding of the condition and in its diagnosis, management and outcomes. Including the voices of CF community members is critical to ensuring that these priorities actually speak to the needs of those who are affected by CFRD.  

To read this paper, go to: Putman MS, Norris AW, Hull RL, Rickels MR, Sussel L, Blackman SM, Chan CL, Larson Ode K, Daley T, Stecenko AA, Moran A, Helmick MJ, Cray S, Alvarez JA, Stallings VA, Tuggle KL, Clancy JP, Eggerman TL, Engelhardt JF, Kelly A. Cystic Fibrosis–Related Diabetes Workshop: Research Priorities Spanning Disease Pathophysiology, Diagnosis, and Outcomes. Diabetes Care 2023; 46: 1112-1123.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.