The present study protocol is reported in accordance with the reporting guidance provided in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement [22] [Additional file 1]. This protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (registration ID: CRD42020168032).
Eligibility criteria
Both published and unpublished studies including a weight maintenance intervention will be analysed. Studies will be included irrespective of the country where they have been carried out, year of publication and the language of the report. Studies may be both randomised and non-randomised, and blinding is not required given that it is not always possible in behavioural interventions. The use of the findings from this review to develop a novel intervention and design a randomised controlled trial justify the inclusion of non-randomised studies [23]. Studies meeting the following criteria will be deemed eligible for analysis (PICO structure):
Population
Participants will be adults (age ≥ 18 years), with a clinical diagnosis of T2DM or pre-diabetes according to the criteria of the World Health Organisation [24] or equivalent international standards [25]. When it is unclear whether a diagnosis was conducted, the study authors will be contacted to obtain the information. Further, studies where participants display impaired fasting glucose or non-diabetic hyperglycaemia will also be included. Participants will additionally have had to achieve weight loss within 24 months prior to the start of the weight maintenance intervention or have been instructed to maintain their weight as a preventative measure. No restriction will be placed on the amount of weight loss achieved during a weight loss programme given differential targets and success rates across studies [26]. Participants may have been recruited from the general community, hospital, clinical care centre or other health services. Exclusion criteria include individuals with overweight or obesity who do not have a diagnosis of pre-diabetes or T2DM, individuals with type 1 diabetes mellitus, and individuals with conditions requiring antipsychotic drugs.
Intervention
Behaviour change and lifestyle interventions (e.g. with a focus on promoting physical activity and healthier eating habits) will be included, along with pharmacological treatments (e.g. lipase inhibitors such as orlistat) and nutrition therapies targeting the modification of nutrient or whole-food intake (as defined by the American Diabetes Association; [27]). Pharmacological treatments must be approved as a weight loss drug by a regulatory agency (e.g. European Medicines Agency or UK Medical Medicines & Healthcare products Regulatory Agency), and food supplements to complement the normal diet must adhere to the definition provided by the Food and Drug Administration on food supplements (see: https://www.fda.gov/food/information-consumers-using-dietary-supplements/questions-and-answers-dietary-supplements). Both stand-alone and combined interventions will be included, and any delivery approach for the non-pharmacological interventions will be accepted (e.g. face-to-face, online, as part of an education programme). Papers will be excluded if the intervention focuses solely on weight loss or the weight loss component is not clearly distinguished from the weight maintenance phase. Further, studies that use Ephedra as a supplement will be excluded as it is banned in both the European Union and by the Food and Drug Administration, as well as those using Chinese traditional medicine or Ayurvedic medicine where there are no details of active ingredients/herbs utilised.
Control/Comparator
Single-cohort studies will be accepted, as well as studies where the comparator is no intervention, standard or minimal care, waitlist, or the use of a placebo. When the details of the information are unclear, authors will be contacted to provide further information.
Outcomes
Primary outcomes will be those most important to patients receiving the interventions. These are weight maintenance, glycaemic control (as indicated by one or more of the following: HbA1c, fasting plasma glucose, insulin sensitivity/resistance), and adverse effects. As there is no current consensus on a definition for weight maintenance, we will focus on weight difference between baseline and at least one post-intervention measurement. Adverse effects will be the physical and/or psychological side effects that may emerge from the intervention (e.g. disordered eating behaviour).
Secondary outcomes will include cardiovascular risk factors (e.g. total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triacylglycerol, diastolic blood pressure, systolic blood pressure), psychological wellbeing (including health related quality of life), change to glucose medication and waist circumference. Quantitative (both continuous and categorical) outcomes will be considered.
Should amendments be necessary, these shall be documented, reported, and fully justified.
Information sources and search strategy
A systematic search of research conducted up to the date of search initiation will be carried out. This includes searching the following databases (no restriction on publication status):
- MEDLINE and PreMEDLINE (OvidSP) (1950 to date)
- EMBASE Classic + EMBASE (OvidSP) (1974 to date)
- PsycINFO (OvidSP) (1806 to date)
- CENTRAL (The Cochrane Library)
- ISI Web of Science: Science Citation Index Expanded (SCIEXPANDED) (1900 to date)
- ISI Web of Science: Conference Proceedings Citation Index-Science (1990 to date).
- International trial registers (World Health Organisation International Clinical Trials Registry portal and ClinicalStudyResults.org).
We will additionally conduct hand searches of reference lists and relevant systematic reviews, and we will review the grey literature (e.g. conference papers/conference proceedings, theses, dissertations, studies published in non-indexed journals) via OpenGrey. Personal letters and e-mails will be sent to the corresponding authors of papers in the field of weight management in T2DM. The authors will be asked for information regarding unpublished or ongoing studies.
Search terms identified for each of the following relevant categories: population (“type 2 diabetes” or “diabetes mellitus” or “diabetes mellitus type 2” or “pre-diabetes” or “prediabetes” or “hyperglycaemia”), intervention (“weight maintenance” or “maintained weight” or “weight maintenence” AND “behav*” or “lifestyle*” or “online” or “computer” or “web” or “pharma*” or “food repla*” or “*supple*”), and outcome (“weight” or “body mass index” or “BMI” or “glycaemic* control” or “cardiovascular*” or “psych*”). Boolean searches will be carried out with terms combining categories and variations of the terms (via truncation). Medical Subject Headings (MeSH) keywords and Emtree keywords will be used. The draft search strategy for MEDLINE is presented in an additional file [Additional file 2].
Screening and data extraction
The search will be managed using the Rayyan (http://rayyan.qcri.org) software app (28). Results will be imported into Rayyan, which automatically detects duplicates. Duplicates will also be detected through the manual data screening process. We will seek information regarding the outlined PICOs.
Two reviewers will independently screen all titles and abstracts identified by the search strategy based on the inclusion criteria. Articles that appear to meet the inclusion criteria will be extracted and reviewed in full by two authors. Inconsistencies will be discussed, and if unresolved another member of the team will be brought in to make the final decision. Studies deemed irrelevant will be excluded, and reason will be provided. Authors of unpublished studies will be contacted.
Semi-automated screening
Search results will additionally be uploaded to AbstrackR, a citation screening programme functioning on an algorithmic framework that predicts the likelihood citations are relevant for further inspection [29]. Screening will be initiated by two reviewers until the programme indicates it is ready to make predictions. Citations extracted through this approach will be compared and cross-checked against the output of the manual screening and selection process. Precision, false negative rate, number of relevant citations missed, and researcher time saved will be examined to determine the usefulness of AbstrackR.
Data extraction
Two reviewers will independently extract the data of the included studies using a standardised data extraction form shown in an additional file [Additional file 3]. This includes the following:
- Publication details (authors, title, date of publication, country of origin, funding source, corresponding author contact details).
- Study characteristics (setting, study design, number of patients randomised to each group).
- Participant characteristics (demographics, clinical characteristics)
- Intervention and comparator characteristics. These will be prespecified for each type of intervention. We will also extract information from all included studies on the following factors: mode of delivery (verbal, written, computer, phone app), place of delivery, who delivered the intervention, duration of the intervention, number of sessions, format (individual or group).
- Outcomes (as detailed in the previous section). We will record the number of participants assessed for each outcome, the mean values and standard deviations (if available) or medians and interquartile ranges for continuous data and any reported summary statistics (e.g. effect estimates, CIs, standard errors, ranges).
Inconsistencies in data extraction will be discussed and recorded. If needed, a third author will be included in the discussion to reach a final decision. When data is missing or inadequately described, three attempts will be made to request the information from the corresponding author.
Data synthesis
A narrative synthesis of all included primary studies will be conducted. We will provide information on patient populations studied, the interventions evaluated, and any comparators used, how the studies have described and measured patient-important outcomes, and a brief summary of results in relation to weight maintenance, glucose control and adverse effects from the intervention. This will provide initial insight on study heterogeneity.
A more detailed quantitative summary of the data for each study included will be reported in a separate table. The table will show location where the study was conducted, population demographics, interventions and comparators, assessment time frame and outcomes (primary and secondary separately). An overall synthesis of the data extracted will be provided in the form of forest plots for each of the primary outcome variables. All results of both primary and secondary outcomes will be reported in a results table. Overall effect size on outcome change between baseline and follow-up assessments will be reported as weighed mean differences with 95% confidence intervals.
Meta-analyses will only be conducted if data from three or more studies were available. We will attempt to combine the results for studies that use similar interventions and report similar outcomes. However, there is likely to be heterogeneity in the types of participants, the intervention and its delivery. We will therefore be using random-effects meta-analysis models for our primary analysis to pool data across trials, where study weighing is based on in-study and between-study variances. However, fixed-effect meta-analysis models will also be explored. All meta-analyses will be carried out with the Comprehensive Meta-Analysis software [30]. Clinical heterogeneity between studies will be evaluated by identifying variability in participants, baseline data, interventions, and outcomes. The I2 statistic will be calculated to quantify and interpret statistical heterogeneity [31]. We will apply the following thresholds for the interpretation of the I2 statistic: 0% to 40%: might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: represents considerable heterogeneity [32].
Pooled risk ratios and 95% confidence intervals (CIs) will be calculated for dichotomous outcomes. Pooled mean differences and 95% CIs or standardised mean differences and 95% CI will be calculated for continuous outcomes when results are reported on the same scale (or can be converted to the same scale), or if results are reported on different scales, respectively. When available data does not enable statistical pooling, results will be reported in a narrative format.
Subgroup analyses
If there is enough data, subgroup analysis will be completed. We expect that some weight maintenance interventions may have been attached to the end of a weight-loss programme, while others might be stand-alone. Factors that contribute to weight regain is time lapse since weight loss intervention [33]. Hence, effectiveness of weight maintenance interventions may be differential if they were preceded by a weight loss intervention or not. We will also compare studies based on intervention type (e.g. diet vs combined behavioural), intervention delivery format (e.g. face to face vs online), and duration of intervention, given that these characteristics have previously been linked to effectiveness in weight loss interventions [34–36].
Missing data
If data is not available in the format required, we will first contact study authors or we will back-calculate the data if possible (e.g. standard deviation from standard errors or 95% CIs, mean and standard deviation from median and range, etc.). Reasons for missing data will be recorded (e.g. drop-outs, losses to follow-up and withdrawals).
Risk of bias in individual studies
The Cochrane Risk of Bias Version 2 tool [37] will be used for randomised controlled trials, while the ROBINS-I tool [38] for observational studies. Two independent reviewers will assess risk of bias using the relevant tool. The latest version of the Cochrane risk of bias tool (v2; [37]) assesses each study on the following 5 domains:
Domain 1: Risk of bias arising from the randomization process.
Domain 2: Risk of bias due to deviations from the intended interventions.
Domain 3: Risk of bias due to missing outcome data.
Domain 4: Risk of bias in measurement of the outcome.
Domain 5: Risk of bias in selection of the reported result.
Justification for decisions will be presented as supplementary material.
Additional analyses
A sensitivity analysis will be conducted including only studies classified as low risk of bias. Any studies that had imputed results will be removed from the pooled analysis. Fixed effects meta- analyses will also be conducted. Further, we expect to carry out at least one sensitivity analysis to ensure robustness of conclusions from pooled estimate against variation in the timing of outcome assessment by eligible studies. Further sensitivity analyses may be conducted if deemed necessary depending on the studies identified from the search.
If over 10 studies are identified, a funnel plot will be generated to assess further publication bias.
Confidence in cumulative evidence
The strength of the overall body of evidence for each outcome will be assessed using the GRADE system [39] (software: https://gradepro.org/), after generating a summary of findings table. Grading will be carried out by the team of reviewers. Grading will be based on risk of bias of individual studies, inconsistency (based on variation in point estimates, confidence intervals overlap, p-value of heterogeneity, I2 score, outcome of the subgroup analysis), indirectness (based on differences in interventions and patients, method of measurement of patient-important outcomes, and comparison of interventions), imprecision (based on Optimal Information Size, sample size, overlapping confidence intervals, and judgment on the importance of observed differences), and publication bias (based on funding sources, size of studies and the comprehensiveness of data search).