Dietary interventions for managing glucose abnormalities in cystic fibrosis: a systematic review protocol

There is limited evidence to guide dietary therapy for glucose abnormalities in cystic fibrosis (CF). CF is a chronic, life-limiting, genetic condition, characterised by abnormally thick and dehydrated secretions which lead to organ obstruction, primarily affecting the lungs and the reproductive and digestive systems [1]. Abnormalities in glucose metabolism are common and a spectrum of progressive glucose tolerance abnormalities occur as individuals grow older; indeterminate glycaemia is followed by impaired glucose tolerance (IGT), which affects 20% of 10-year-olds and 82% of the CF population by the age of 30 years [2], before CF-related diabetes (CFRD) eventually develops [3]. CFRD is the most prevalent complication of CF [4], and it is a distinct form of diabetes which occurs in association with pancreatic insufficiency, primarily caused by pancreatic damage. Its pathophysiology is complex and includes the loss of pancreatic islet cells, leading to both insulin and glucagon deficiency, and fluctuating insulin resistance caused by chronic and acute inflammation and infection [4]. CFRD is typically diagnosed in late adolescence or early adulthood [5‐7] and affects approximately 20% of adolescents and up to 50% of adults with CF aged over 40 years [4, 5, 8]. The early stages of CFRD is characterised by normal fasting glucose but over time fasting hyperglycaemia develops [8]. The combination of diabetes and CF leads to increased morbidity and is associated with a sixfold increase in mortality [7, 9‐11]. Fewer than a quarter of people with CFRD survive beyond the age of 30 years, compared with 60% of CF individuals without diabetes [12, 13].

Optimising glycaemic control is known to improve clinical status and pulmonary function and reduce mortality [5]. Insulin therapy is the primary means of controlling glycaemia in CFRD but its role in -pre-diabetes is less clear [14]. The development of diabetes represents the onset of a second chronic disease, adding further complexity to daily CF treatment regimes. Individuals are required to monitor and control their blood glucose concentrations through regular blood glucose testing and daily insulin injections. Treating IGT in CF with insulin is controversial as it increases patient burden but it is not yet known whether early initiation of insulin reduces morbidity and mortality in the longer term [15].

In cystic fibrosis, a high energy intake is required due to increased energy expenditure and malabsorption, malnutrition risk, and gut abnormalities including delayed gastric emptying, altered intestinal motility and liver disease [7]. To date, there are no meta-analyses or randomised controlled trials of dietary intervention to manage glucose abnormalities in CF, and current guidelines are based on clinical consensus rather than empirical evidence [4, 8]. The goal of CFRD dietary management is to achieve and maintain good nutritional status and normalise blood glucose levels. There are important differences between CFRD and non-CF diabetes, which necessitate a unique approach to diagnosis and management [2]. In practice, due to the lack of specific evidence-based guidelines for managing glucose abnormalities in CF, standard CF nutritional recommendations are frequently applied [4, 8]. However, the energy-dense CF diet is typically high in fat and sugar, and high sugar intakes often results in poor glycaemic control in CF patients with glucose abnormalities. As in any clinical group, patients vary in their specific nutritional needs, and as such, dietary management must be tailored to meet these needs. As practice varies, a consistency of approach and nutritional targeting is needed in this vulnerable group.

Low glycaemic index (GI) dietary intervention has demonstrated benefits in non-CF forms of diabetes, including improved insulin sensitivity, glycaemia and quality of life in both type 1 and type 2 diabetes [16], and it is now recommended as part of their dietary management [17‐19]. A systematic review conducted in 2012 to assess understanding of the effect of low GI dietary interventions in young people with CF concluded that there is a dearth of evidence in this area [20]. A scoping search of the literature has revealed that there has been little further research in this field since the 2012 review was conducted. The aim of the current review is to update the 2012 systematic review by Balzer et al. [20], to assess current understanding of glycaemic index dietary intervention in CF and to broaden the scope of their review to include any type of dietary intervention for managing glucose abnormalities in CF. Studies of dietary interventions aimed at improving glycaemic control in individuals over 5 years of age with CF and either IGT or CFRD, will be considered for inclusion. The comparator is standard CF dietary therapy (energy dense, high-fat diet), in addition to insulin therapy for individuals with CFRD. Outcomes will include glycaemic control (primary) and anthropometry and lung function (secondary).

This protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) 2015 reporting guideline [21] (see Additional file 1). The review is registered on PROSPERO International prospective register of systematic reviews (www.​crd.​york.​ac.​uk/​prospero/​); registration number: CRD42018085569. If any amendments to this protocol are required when conducting the review, these will be clearly described in the review article when prepared for publication.

Titles and abstracts will be assessed for eligibility by two members of the review team (LB, RP). Articles that appear to meet the inclusion criteria will be retrieved in full and independently considered for inclusion by two members of the review team (LB, JHS). The reviewers will resolve disagreements in opinion of studies for inclusion through discussion, and the reasons for excluding studies will be recorded.

Data from full-text articles for inclusion will be extracted independently by two reviewers (LB, RP) using a standardised data extraction template. The template will be piloted by both reviewers before starting the review and modified as required to ensure consistency. The following data will be extracted from each study: study design; sample characteristics (size, inclusion/exclusion criteria, sex, age, socioeconomic status); dietary intervention; results (including but not limited to glycaemic control, anthropometric measures, lung function, adherence and acceptability of dietary intervention); analysis methods; study limitations; and funding sources. Disagreements in opinion of data extracted will be resolved through discussion.

A narrative review of the findings from the included studies will be presented, structured around the outcomes reported. Meta-analysis will be performed only if the identified studies are comparable. The primary outcomes of this review will be continuous variables, and we anticipate that mean values will be reported for all continuous outcomes. Results reporting categorical outcomes will be reported separately. Sub-group analysis based on age (children, adults), glucose abnormality (CFRD, IGT), CF control (good control vs poor control) and transplantation (transplant vs no transplant) will be conducted if there are sufficient numbers of comparable studies. Results will be pooled for comparable sub-sets of studies only where possible.

The preliminary scoping search conducted revealed a relatively small number of studies which appeared to be very diverse. Considerable heterogeneity between studies is therefore anticipated. Where there are sufficient studies deemed comparable, in respect of both the dietary intervention and the outcomes under consideration, their individual effect sizes will be illustrated using forest plots together with combined estimates, using random effect models. Study level characteristics (covariates) that might explain any heterogeneity, such as age, nutritional status and CF control, will be documented and reported. Sub-group analyses as outlined above will be undertaken together with meta-regression if indicated.

This systematic review will elucidate current knowledge of the effects of dietary interventions for managing glucose abnormalities in cystic fibrosis and will highlight areas where further research is needed to inform dietary recommendations for this vulnerable clinical population.