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Protocol for systematic review of evidence on the determinants and influence of early glycaemic control in childhood-onset type 1 diabetes
Systematic Reviewsvolume 4, Article number: 159 (2015)
Landmark studies in adult-onset type 1 diabetes (T1D) populations indicate that improved glycaemic control through use of intensive insulin therapy is strongly associated with reduced risk for the development of diabetes-related complications and mortality in later years. However, it is unclear whether these associations can be extrapolated to childhood-onset T1D, given the influence of other important biological and psychosocial determinants of glycaemic control, particularly during adolescence. The aims of the review are (1) to investigate the impact of early glycaemic control (within the first 2 years after diagnosis) on subsequent glycaemic trends and risk of complications during the life course of childhood-onset T1D and (2) to identify the predictors of early glycaemic control in children and young people (0–25 years).
The methods used in this study are systematic identification, review and mapping of quantitative (intervention and observational) and qualitative literature; assessing the effect and predictors of early glycaemic control in T1D (diagnosed ≤18 years) on risk or prevalence of later complications. An iterated search strategy, with no language or period restrictions, was applied to identify studies from six electronic databases. This will be supplemented by hand-searching (reference lists and contacting authors of studies meeting the inclusion criteria). Studies assessing glycaemic control within the first 2 years of diagnosis in children (at baseline) will be quality-assessed against predefined criteria and mapped descriptively to future health outcomes. Extracted data will be analysed and synthesised using narrative and forest plots or harvest plots for quantitative evidence and thematic analyses for qualitative studies. To get a deeper understanding of the predictors of early glycaemic control in reducing complications in childhood and adult life, we will integrate qualitative and quantitative evidence using mixed methods or parallel synthesis approach.
These linked reviews will be the first to systematically investigate the effects of early glycaemic control and integrate both the quantitative and qualitative evidence on predictors of early glycaemic control in childhood-onset T1D in reducing future diabetes complications. This will help identify and map current research and inform development of effective future interventions.
Systematic review registration
Recent studies indicate a reduction of life expectancy by over a decade, in people diagnosed with type 1 diabetes (T1D) [1–3]. Given the duration of glycaemic exposure, the risk for diabetes-related vascular diseases is likely to be greater in childhood-onset compared to adult-onset T1D [3–6]. The burden of T1D greatly impacts upon the quality of life of children and their families [7, 8]. These poor outcomes have been highlighted by health policy advisers  and are of relevance given the increasing worldwide incidence of childhood T1D [10–14], and in those aged under 5 years, in whom both prognosis and burden of disease are likely to be even worse [15–18]. The strongest modifiable predictor of complications in T1D patients is glycaemic control, which is measured as haemoglobin A1c levels (HbA1c) [19–22]. Use of intensive insulin therapy in young children is associated with better glycaemic control (i.e. lower HbA1c levels) .
Results from a recent systematic review of 18 clinical trials (with a total of 2254 T1D participants and a mean follow-up duration across studies varying between 1 and 25 years) showed that targeting intensive glycaemic control (four or more insulin injections per day or insulin pump therapy) did not improve all-cause mortality, but it reduced the relative risk of the composite macrovascular outcomes (0.63; confidence interval (CI) 0.41 to 0.96; P = 0.03) and diabetic nephropathy (0.37; CI 0.27 to 0.50; P < 0.00001), when compared to management with conventional insulin regimens (i.e. three or less insulin injections per day) . However, the review could not assess the effect of targeting intensive glycaemic control on patients younger than 18 years and no macrovascular or microvascular outcomes were reported in the four small trials (sample sizes between 14 and 34), three of which included newly diagnosed T1D patients under 18 years, probably due to the short follow-up period of up to 1.5 years [25–28].
An updated Cochrane review with 12 trials (with a mean follow-up duration across studies varying between 1 and 6.5 years) concluded that tight glycaemic control (compared to less intense treatment targets) was beneficial in younger patients (age not specified), at early stages of disease (retinopathy: RR 0.27 (95 % CI 0.18 to 0.42); P < 0.00001; nephropathy: RR 0.56 (95 % CI 0.46 to 0.68); P < 0.00001; neuropathy: RR 0.35 (95 % CI 0.23 to 0.53); P < 0.00001) . However, this review contained just one trial in young children aged 6–15 years with diabetes duration of 1–2 years , and most of the other included trials were conducted in the 1980s, when use of insulin pump therapy was less widespread.
Also, evidence from landmark studies indicates that improved glycaemic control in T1D through use of intensive insulin therapy is strongly associated with reduced complications risk and mortality [19, 31, 32]. Results from the Diabetes Control and Complications Trial (DCCT), a multicenter, randomised controlled clinical trial of 1441 people (including 195 adolescents) with T1D (1983–1993), provided evidence that early intensive glycaemic control conferred a significant reduction in risk of microvascular and macrovascular complications compared to conventional treatment, an effect which continued in subsequent years even after equalisation of metabolic control [21, 31, 33, 34]. Importantly, reduced mortality was also observed with the use of early intensive versus conventional insulin therapy use (43 deaths versus 64 deaths respectively among 1429 participants; hazard ratio 0.67 (95 % CI 0.46–0.99)) after 27 years from entry into the trial . All-cause mortality was significantly higher among those with higher mean HbA1c levels (hazard ratio (HR) = 1.56 (95 % CI 1.35–1.81 per 10 % relative increase in HbA1c); P < 0.001) and with renal disease (HR = 8.51(95 % CI 4.45–16.27); P < 0.001) during the 27-years of follow-up [33, 35].
Other studies have also suggested the beneficial effects of early glycaemic control in preventing future complications [36, 37]. Therefore, it appears that maintaining lower HbA1c levels in the early years after diagnosis may be beneficial in adults for reducing future risk of complications, regardless of subsequent glycaemic control over the course of diabetes duration. Diabetologists use the term “metabolic memory” for these observations. However, the DCCT contained only 195 adolescents (13 to 17 years of age at entry), with T1D duration of 38 ± 20 months at the start of the trial . Hence, the effect of insulin intensification from or near to diagnosis has not been robustly assessed in childhood-onset T1D. It would be important to note that adult outcomes cannot be extrapolated to childhood due to important biological and psychosocial determinants such as puberty, insulin resistance and adolescent risk-taking behaviours that are less relevant in adults .
Furthermore, some reports indicate that very early HbA1c level track with future glycemic control, i.e. low or high HbA1c levels within the first few months of diagnosis associate with low or high HbA1c levels in later years, an effect which can persist for almost a decade [31, 40–43]. These studies were from USA and Europe, but the age range, duration of T1D, treatment and follow-up varied across studies. Additionally, the use of intensive insulin therapy in early childhood T1D is increasing but is not universal . Also, many well-documented population-based registries lack robust and comparable data on glycemic control .
Our review will investigate whether HbA1c levels in the first 2 years following diagnosis of T1D in children predicts future risk of complications and will quantify the extent to which the level of glycaemia in the first 2 years of diabetes tracks in adulthood/with increasing diabetes duration. We will also investigate the predictors of early glycaemic control and how these may influence the paediatric TID management plan. Our analyses may highlight a need for a change in early care processes in children with T1D, by providing an argument for more intensive diabetes treatments than are currently undertaken.
We will undertake two linked systematic reviews answering two main research questions, namely:
Is higher early HbA1c (within 2 years of T1D diagnosis) associated with later complications in child-onset T1D patients (childhood-onset T1D defined as onset ≤18 years)?
What factors at diagnosis or soon after are associated with higher early HbA1c?
We will follow the methods for conducting systematic reviews, as described by the Evidence for Policy and Practice Information (EPPI) and Co-ordinating Centre . The review process will be in four phases. Phase 1 (completed): iterative scoping stage to define the research question, refine the search strategy and outline the inclusion/exclusion and quality assessment criteria. This was followed by identification of literature by searching of electronic databases. Phase 2: descriptive mapping and synthesis of existing evidence by number, types and quality attributes of research studies on the topic. Phase 3: detailed data extraction and in-depth synthesis of quantitative studies . Phase 4: thematic analysis of qualitative literature , followed by integration of these findings with the quantitative evidence by using parallel synthesis or mixed method approach . This methodology of using qualitative research to explain quantitative evidence will provide a deeper understanding of the predictors influencing early glycaemic control in children and young people.
After a number of initial iterative scoping searches, with input from experts in the field, the search strategy was refined to maximise sensitivity and specificity in capturing key publications. Three sets of search terms were used (see search strategy in Table 1) relating to population (children and young people diagnosed with TID), exposure (terms to capture observational, intervention, qualitative studies and review articles relating to early diabetes control) and outcome (complications, mortality or metabolic memory).
Six electronic databases (Medline and Embase (via OVID), Web of Science (via Thomson Reuters), Cinhal (via EBSCO), Scopus (via Elsevier) and Cochrane Library) were double-searched in parallel (by VMP and HC to minimise study selection bias) in December 2014, without time period or language restrictions, by using a combination of free text and Thesaurus or Mesh terms (see Additional file 1: Electronic database search strategy.pdf). All identified articles from individual databases (Medline, n = 13,039; Embase, n = 645; Web of Science, n = 2323; Cinahl, n = 984; Scopus, n = 1540 and Cochrane, n = 3242) were imported into an endnote file and de-duplicated, which resulted in 17,915 articles for further review. This will be supplemented by hand-searching reference lists and contacting authors of included studies and relevant reviews (see Fig. 1 for a flow diagram of the study selection process).
Inclusion and exclusion criteria
Interventional studies, i.e. randomised control trials (RCTs) and non-RCTs, targeting glycaemic control (within 2 years of diagnosis of T1D in children and young people) and describing an association with health outcomes will be included. Observational, i.e. cohort and cross-sectional studies that quantified the association between early glycaemic control (within 2 years of diagnosis of T1D) AND risk of future complications in children and young people aged 0 to 25 years at baseline, will be included. Qualitative studies that give a deeper background understanding on the predictors of early HbA1c in this age group will also be included.
Our exclusion criteria are as follows: non-human or animal studies, studies with population selected for other diseases/co-morbidities or clinical conditions, studies in adults aged more than 25 years at baseline, studies in other types of diabetes such as type 2 diabetes (T2D) or gestational diabetes. Quantitative studies not reporting clinical outcomes or quantitative studies that measured glycaemic control but did not describe an association with outcome variables will also be excluded. The overlapping eligibility criteria for the reviews are presented as inclusion/exclusion criteria in Table 2.
Study selection procedure
A 10 % proportion (1792) of the total abstracts and titles will be randomly selected and double screened (DC and VMP), based on a piloted screening protocol. Results will be compared to ensure less than 5 % discrepancy between reviewers. Any disagreements will be resolved through discussion and re-examining of abstract. Following which, all 17,915 abstracts and titles will be screened independently (VMP). Full texts of abstracts appearing to meet the inclusion criteria will be ordered for further review and data extraction. Descriptive mapping of existing evidence will be undertaken to establish gaps in evidence-base and to ascertain that there is sufficient data meriting review.
Data extraction and quality assessment
A data extraction Excel spread sheet will be piloted to ensure consistency of data extraction between reviewers. One of the reviewers (VMP) will then systematically review and extract detailed data of all studies meeting the inclusion criteria. A proportion of the studies will be double-reviewed by a second reviewer, and any differences will be discussed and resolved. Details of data will be extracted according to study designs, i.e. interventional, observational and qualitative (see Table 3).
Included studies will be systematically quality-assessed against pre-set quality criteria by using standard quality assessment checklists designed by the EPPI centre for specific (intervention, observational and qualitative) study designs (see Table 4).
Extracted data will be analysed and synthesised using a narrative and either forest plots or harvest plots (for quantitative evidence) and thematic analyses (for qualitative studies). To get a deeper understanding of the predictors of early glycaemic control in reducing complications in childhood and adult life, we will integrate qualitative and quantitative evidence using mixed methods or parallel synthesis approach.
Meta analyses will be attempted to synthesise data from RCTs and Non-RCTs, assessed with low risk of bias and the results presented as forest plots . Subgroup analyses by intervention type will be undertaken, subject to data type and quality.
Harvest plots  will be used to summarise data if meta-analysis/meta-regression is not possible. The evidence will be presented as bar charts and symbols. Colour (black, dark grey and light grey) of bar will represent quality of study, with lighter bars representing studies of low quality. Height of bar will indicate the study size, and position of the bar will summarise the direction and strength of the association (++, +, 0, −, −−). Categorical and continuous outcome variable results will be consistently recoded, such that a single or double + symbolises higher risk for complications, and a single or double − symbolises a lower risk for complications [52, 53].
Evidence from qualitative studies will be synthesised thematically, and the results will be integrated with the quantitative evidence using the parallel synthesis or mixed methods approach [54, 55]. Recommendations for future interventions and policy decisions will be drawn by interpreting quantitative findings, using the themes identified from qualitative studies.
The importance of diabetes-related complications may be underestimated. Data from the 2010–2011 National Paediatric Diabetes Audit (NPDA) showed that only 5.8 % of all children and young persons with diabetes are recorded as having received all the National Institute for Health and Care Excellence (NICE) recommended care processes aimed at reducing risk of chronic complications . This percentage increased to 16.1 % in the 2013–2014 NPDA, which may reflect the incentivising effect of the recent introduction of the best practice tariff for paediatric diabetes care in the UK . However, this percentage of optimum service delivery still compares unfavourably to adults with diabetes (>60 % received all recommended care processes during the 2011–2012 and 2012–2013 National Diabetes Audits (NDA)) and is very low when compared internationally [16, 58].
In a clinic setting, aiming for tight glycaemic targets remains difficult to achieve, outside of a clinical trial. The mean HbA1c level in the intensively treated group participating for more than 20 years ago in the DCCT was lower than the HbA1c levels in most patients today [59, 60]. The intensive group achieved HbA1c levels of 7 % on an average compared with 8.3 % among more than 25,000 patients from 67 US centres in the T1D exchange , and this was achieved without modern advances in therapy, such as insulin analogues and continuous glucose monitors. Therefore, we need to understand the effect, predictors and trends of early glycaemic control on complications risk in childhood and adults.
Our second aim is to look at which factors predict early HbA1c. These could be factors across the whole biopsychosocial model. For example, there may be social factors (deprivation, ethnic), psychological factors (teenage behaviour, fear of hypoglycaemia), physiological factors (glycation index) as well as wider cultural factors (the family, school, clinic setting, etc.).
By systematically reviewing evidence on effect of glycaemic control within first 2 years of T1D diagnosis and tracking with increasing diabetes duration, this will help identify predictors of early glycaemic control and understand future risk for complications in the paediatric population.
How this review compares with previous reviews in children and young adults
To our knowledge, this is the first review to robustly investigate evidence on the association of early glycaemic control in childhood-onset T1D with future complications risk. Furthermore, this is the first review to rigorously and systematically integrate quantitative (both intervention and observational) and qualitative evidence on this topic . Evidence synthesised this way is holistic and more reliable than syntheses of any one type of research in isolation.
Dissemination and updating plans
Results of the review will be disseminated through peer-reviewed publications, conference presentations and at meetings. The review will be updated if significant new evidence becomes available.
Diabetes Control and Complications Trial
Evidence for Policy and Practice Information
- HbA1c :
glycated haemoglobin A1c
National Diabetes Audit
National Institute for Health and Care Excellence
National Paediatric Diabetes Audit
International Prospective Register for systematic Reviews
randomised control trial
type 1 diabetes
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Our sincere thanks to the funders and the following from the University College London: Miss Heather Chester (HC) for her help with the literature search strategy and Mrs Linda Haines for her help and support throughout. The authors also thank the following collaborators for their comments and guidance on the project: Prof. David Dunger, Department of Paediatrics, University of Cambridge; Dr. Bob Young, consultant diabetologist and CMIO, Diabetes and Endocrinology, Salford Royal Foundation NHS Trust; clinical lead, National Diabetes Audit (NDA) and National Cardiovascular Intelligence Network (NCVIN), Dr. Alison Elderfield and project manager, National Paediatric Diabetes Audit Research and Policy Division; Royal College of Paediatrics and Child Health, Dr Justin Warner, consultant in Paediatric Endocrinology and Diabetes, honorary Senior Lecturer Cardiff University, and clinical lead for the National Paediatric Diabetes Audit; and Dr. Fiona Campbell, national clinical lead for the Children and Young People’s Diabetes Network and Peer Review Quality Assurance Programme, NHS England.
This project is funded by UCL IMPACT/Department of Health PhD Studentship 2014/15. This is an independent report commissioned and funded by the Policy Research Programme in the Department of Health. The views expressed are not necessarily those of the department.
No potential conflict of interest was reported by the authors.
VMP was the lead reviewer, created the study design and search strategy, searched electronic databases for literature and wrote the first draft of the protocol. RA conceptualised the project, was project lead, advised on the trajectories of the project, participated in the study design and helped revise the manuscript. DC double screened a proportion of titles/abstracts, participated in the study design and helped revise the manuscript. ARK participated in the design of the study and helped revise the manuscript. DTR participated in the design of the study and helped revise the manuscript. TS was overall project lead, advised on the trajectories of the project, participated in the study design and helped revise the manuscript. RV advised on the trajectories of the project, participated in the study design and helped revise the manuscript. JE advised on the trajectories of the project, participated in the study design and helped revise the manuscript. All authors contributed to the study design, critical revision of the manuscript and approved the final version.
Electronic database search strategy.