KEY POINTS
- CFRD account for morbidity and mortality increase in paediatric patients with cystic fibrosis.
- OGTT is the gold standard diagnostic procedure for early diagnosis of CFRD and other glucose metabolism abnormalities.
- CGM is useful in the treatment monitoring phase but to date has no standardized diagnostic value.
- Insulin therapy is the first treatment recommendation for children and adolescents with CFRD.
- Recent CTFR-modulating therapies have shown promising impact on glucose control in children with CFRD.
INTRODUCTION
Cystic fibrosis is an autosomal recessive disorder due to mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes the CFTR protein. The most common cystic fibrosis-associated mutation is the delta F508, a deletion of phenylalanine at residue 508 of the CFTR gene [1]. A dysfunction of the CFTR protein induces abnormalities in the sodium chloride cotransport channel in epithelial cells, especially in the respiratory and gastrointestinal systems. Liver impairment, respiratory disease and exocrine pancreatic insufficiency are, therefore, mainly responsible for the symptoms associated with cystic fibrosis [2,3].
When pancreatic fibrotic damage progresses, a partial insufficiency of the endocrine function of the pancreas can also occur with consequent derangement of glucose metabolism [4].
The pathophysiology of CFRD is complex and multifactorial; insulin secretion deficiency and peripheral insulin resistance coexist together and several factors such as genetic predisposition, nutritional status and inflammation cooperate in causing glucose metabolism abnormalities in cystic fibrosis patients.
Several forms of alteration of glucose metabolism exist in cystic fibrosis and they can occur at different points in the course of the disease. In fact, there are forms of full-blown diabetes and forms of prediabetes in which the early alterations of glucose metabolism converge together [5▪▪].
The aim of the present work is to revisit the most recent literature on this topic and to detail the most up-to-date procedures in terms of diagnosis and therapy of alterations of glucose metabolism in the course of CF.
DIAGNOSIS
The diagnosis of cystic fibrosis-related diabetes (CFRD) is based on the same diagnostic criteria valid for other forms of diabetes; these criteria still refer to the position statement of 2010, supported by the major diabetes scientific societies, the American Diabetes Association, the Cystic Fibrosis Foundation and the Paediatric Endocrine Society [6].
The main procedure for diagnosing CFRD or other disorders of glucose metabolism is the Oral Glucose Tolerance Test (OGTT), which remains the diagnostic gold standard despite the recent advent of Continuous Glucose Monitoring (CGM) systems; this latter is spreading very rapidly in the context of a more complex management of all forms of diabetes; however, to date, there is still no strong evidence to hypothesize the use of CGM for diagnostic purposes. In fact, CGM has proven to be very useful in managing and guiding diabetes therapy, but broad-spectrum studies on large populations are needed to hypothesize its diagnostic use as a replacement for the OGTT [7,8▪]. Furthermore, even the diagnostic threshold of 6.5% (48 mmol/mol) of glycosylated haemoglobin (HbA1c) is not unanimously recognized in the context of glucose alterations of cystic fibrosis; in fact, unlike what is established in other forms of diabetes, lower or normal levels of HbA1c do not exclude the diagnosis of CFRD [9].
Therefore, the OGTT maintains its particular relevance in the field of glucose alterations in cystic fibrosis as individuals affected by cystic fibrosis very rarely has complete and persistent euglycemia; even in the presence of a normal fasting glucose or a normal 2 h OGTT glucose level, frequently in patients with cystic fibrosis intermediate increases in glucose during the OGTT are present. There is consensus to screen children with cystic fibrosis with the OGTT from 10 years of age. Screening with OGTT is recommended once a year.
Thus, six different groups of glucose metabolism alterations are identified in cystic fibrosis children and adolescents [5▪▪,10] that need to be well identified in order to reduce cystic fibrosis morbidity and mortality. These six classes are based on the fasting, intermediate and 2 h OGTT glucose values and are as follows:
- (1) Impaired fasting glucose (IFG)
- (2) Abnormal glucose tolerance (AGT)
- (3) Impaired glucose tolerance (IGT)
- (4) CFRD without fasting hyperglycaemia (CFRD-FH-)
- (5) CFRD with fasting hyperglycaemia (CFRD-FH+)
- (6) Indeterminate hyperglycaemia (INDET)
Table 1 shows the glycometabolic characteristics of each class.
Table 1 -
Different groups of glucose abnormalities in cystic fibrosis patients
| Classes |
Fasting glucose |
2 h OGTT glucose |
Intermediate OGTT glucose |
| IFG |
>100/>5.6 |
<140/<7.8 |
<140/<7.8 |
| AGT |
<126/<7 |
<140/<7.8 |
≥140/≥7.8 |
| IGT |
<126/<7 |
140–199/7.8–11 |
|
| CFRD-FH-
|
<126/<7 |
≥200/≥11.1 |
|
| CFRD-FH+
|
≥126/≥7 |
≥200/≥11.1 |
|
| INDET |
<126/<7 |
<140/<7.8 |
≥200/≥11.1 |
Glucose values are expressed in mg/dl/mmol/l. AGT, abnormal glucose tolerance; CFRD-FH+, CFRD with fasting hyperglycaemia; CFRD-FH-, CFRD without fasting hyperglycaemia; INDET, indeterminate hyperglycaemia; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; OGTT, Oral Glucose Tolerance Test.
THERAPY
Before we begin to describe the different treatment options for CFRD and cystic fibrosis-associated prediabetes, an important premise needs to be made: the therapy of the different forms of glucose derangement has a favourable impact not only on strictly metabolic outcomes but also, and above all, on the morbidity and complications associated with cystic fibrosis. In particular, a favourable impact on pulmonary function, growth, nutritional status and the recurrence of respiratory infections has been demonstrated [11–13].
NUTRITIONAL TREATMENT
Nutritional treatment of CFRD may be useful, but it is not believed to be sufficient in the absence of an adequate pharmacological approach. A hypercaloric and hyperproteic diet without restriction of carbohydrates, fats and salt is recommended for children and adolescents with CFRD [14]. These recommendations are based on the fundamental assumption that diabetes itself adversely affects the nutritional status of patients with cystic fibrosis and that, unlike in long-standing type 1 and type 2 diabetes, patients with CFRD have no high cardiovascular risk. In fact, the nutritional recommendations for children and adolescents with CFRD must adhere to the general nutritional recommendations indicated in cystic fibrosis and are profoundly different from those given in type 1 diabetes [15].
ORAL HYPOGLYCEMIC AGENTS
A recent article illustrated the results of a Canadian survey, in order to understand the established habits in clinical practice in the treatment of children and adults with CFRD; this survey highlighted that the paediatric practitioners are more inclined and prefers to use insulin in the treatment of CFRD, while adult practitioners use also repaglinide [16]. The efficacy and safety of repaglinide in the treatment of children and adolescents older than 10 years of age with CFRD have been evaluated in a relatively recent article [17]; the authors of this multicentre, open-label, randomized trial concluded that using repaglinide for glucose control in children and adolescents with CFRD is as efficacious and well tolerated as insulin therapy. Also the ‘Cochrane Database of Systematic Reviews’ did not find relevant differences between insulin and repaglinide in the treatment of hyperglycaemia and other clinical aspects associated with CFRD. The ‘Cochrane Database of Systematic Reviews’ also assessed the emerging evidences on other oral hypoglycaemic medications and encourages investigators to evaluate the efficacy, safety and treatment adherence of other OHAs as well as metformin, glitazones, dipeptidyl-peptidase 4 (DPP4) inhibitors, GLP1 agonist and SGLT2 inhibitors. As regards the use of GLP1 analogues, to date there are precautions justified by the risk of pancreatitis that these molecules can rarely induce. Nevertheless, the use of insulin in the treatment of CFRD in childhood is widely supported and recommended by various national and international guidelines [18,19].
INSULIN THERAPY
Insulin is the recommended therapy for children and adolescents with CFRD [6,20], although to date there are still few randomized controlled trials that compared the different insulin regimes, especially during developmental age. There is unanimous agreement in deeming extreme personalization of insulin therapy necessary in this context. Tailored insulin therapy must take into account the degree of hyperglycaemia and the time of day (fasting or postprandial) in which the hyperglycaemic events primarily occur. Furthermore, considering the different insulin formulations available (Table 2), it is advisable to adequately choose the most appropriate therapeutic regimen.
Table 2 -
Different insulin kinetics
| Insulin |
Peak of action |
Maximum duration of action |
| Lisproa
|
2 h |
5 h |
| Asparta
|
2 h |
5 h |
| Glulisinea
|
2 h |
5 h |
| Regularb
|
4 h |
4 h |
| Glargine U100c
|
None |
24 h |
| Detemirc
|
None |
20 h |
| Degludecd
|
None |
36 h |
| Glargine U300d
|
None |
36 h |
aRapid-acting insulin analogues.
bRegular insulin.
cFirst-generation basal insulin.
dSecond-generation basal insulin.
Depending on the ‘glycaemic phenotype’, the insulin regimen indicated can vary from exclusive basal insulin (especially indicated for the CFRD-FH+ forms) to the classic basal-bolus insulin treatment regimens in which prandial insulin is added to the basal insulin at each meal usually using rapid insulin analogues. Glargine insulin (U100) is the most studied insulin together with the NPH insulin, currently no longer used. To date, no efficacy and safety data are available on glargine U300 and Degludec insulins, while comparable efficacy data are available for rapid-acting insulin analogues and regular insulin [10].
Children affected by CFRD are usually more insulin-sensitive as compared with their peers with type 1 diabetes [21]; insulin resistance is a feature that usually occurs later in the course of the disease or during periods of infectious exacerbations or steroid treatment. Consequently, compared with children with type 1 diabetes, the daily insulin requirement is usually lower; due to these considerations, starting the insulin treatment with a basal insulin dose of 0.2 IU/kg/day and/or with a prandial insulin dose of 0.05–0.1 IU/kg before each main meal is recommended [10].
An effective and well tolerated alternative to intensive multiinjection insulin therapy is treatment with insulin pumps; there is little evidence in the literature in this regard [22], but a recent contribution in this field [23] has highlighted how the treatment with automatic insulin delivery systems of adolescents and young adults with CFRD is extremely effective in terms of glycometabolic control, significantly improving all glycaemic control parameters.
FUTURE DIRECTIONS
Recently, the advent of CFTR-modulating therapies with Elexacaftor, Tezacaftor and Ivacaftor has allowed for further increase the life expectancy of patients with cystic fibrosis. These new therapies have proven effective in improving the respiratory function, the nutritional status and the infectious risk of patients (adults and paediatric) with cystic fibrosis, especially in those with the Delta F508 mutation (90% of people with cystic fibrosis). Growing interest is also emerging about the role of CFTR modulators on glycometabolic aspects. In particular, the triple therapy with Elexacaftor–Tezacaftor–Ivacaftor (ETI) has shown promising impact on glucose control in children with CFRD [24▪▪,25▪▪].
CONCLUSION
CFRD represents the most frequent nonrespiratory complication of cystic fibrosis and accounts for a substantial increase in mortality. Early diagnosis and treatment of CFRD and/or other forms of glucose metabolism derangement is essential in order to achieve a solid improvement of respiratory function, nutritional status and quality of life. Correct clinical phenotyping of glucose metabolism alterations, nutritional approach, early insulin treatment and new therapies with CFTR modulators will further improve life expectancy and quality of life of children and adolescents affected by cystic fibrosis.
Acknowledgements
None.
Financial support and sponsorship
This work was supported by the Italian Ministry of Health with “Current Research funds”.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
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