The review will be performed according to the recommendations specified in the Cochrane Handbook for Intervention Reviews.38
The reporting of the review will follow the preferred reporting items for systematic reviews and meta-analyses statement.39
The analyses will be performed based on analyses of individual patient data from published randomised trials and summarised data presented in published trials or supplied by authors of included trials.
Criteria for considering studies for this review
Types of studies
The review will include randomised controlled trials, irrespective of blinding, publication status or language. The first period of any crossover trials will be included. Unpublished trials will be included if the methodology and data are accessible in written form.
Types of participants
Adult patients (at least 18 years of age) of both genders with T2DM will be included. Inclusion criteria should be reported in the included trials. Ideally, the diagnostic criteria for T2DM should be based on the criteria of the WHO, the American Diabetes Association and/or the European Association for the Study of Diabetes,37
but if necessary, trials will be included with the definition of T2DM used by the authors of the trial in question.
Types of interventions
The intervention comparisons will include BASs (cholestyramine, colestilan/colestimide, colestipol or colesevelam) versus placebo, oral antidiabetic drugs or insulin. Co-interventions with other antidiabetic agents will be accepted if administered to the intervention and control group.
Types of outcome measures
The following outcome measures will be assessed based on analyses of individual patient data from included trials or from published reports.
Secondary outcome measures
- Fasting plasma glucose
- LDL cholesterol, high-density lipoprotein (HDL) cholesterol, total cholesterol and triglycerides
- Body weight and BMI
- Adverse events (defined based on the international guidelines for good clinical practice as any untoward medical occurrence)
Search methods for identification of studies
The electronic searches will be performed in The Cochrane Library, MEDLINE and EMBASE using the following strategy:
- Cochrane Library (‘bile acid sequestrants’ OR ‘sequestrants’) AND ‘type 2 diabetes’
- Medline (1) exp type 2 diabetes, bile acid sequestrants; (2) sequestrants.mp [mp=title, original title, abstract, name of substance word, subject heading word and unique identifier]
- Embase (1) exp bile acid sequestrants/; (2) sequestrants.mp [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer and drug manufacturer's name]
Searching other resources
Manual searches including scanning of reference lists in relevant papers, specialist journals and conference proceedings will be performed. Additional trials will be sought through the WHO Trial Register,41
and through correspondence with experts.
Data collection and analysis
Three authors (MH, DPS and KHM) will independently extract data and resolve disagreements through discussion before analysis. In the case of unresolved matters, a third party (TV, LLG and/or FKK) will be involved. When necessary data are not included in the published trial reports, authors of included trials will be contacted for additional information. Also, principal investigators of the included randomised trials will be contacted to obtain validated data based on individual patients.
Selection of studies
Trials identified through the electronic and manual searches will be listed, and—using the criteria described above—trials will be selected for inclusion.
Data extraction and management
Standardised extraction forms will be used. The following data will be extracted from included trials:
- Patient characteristics: inclusion criteria, proportion of patients with T2DM, mean age, proportion of men, BMI, baseline HbA1c, baseline fasting plasma glucose, baseline total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and antidiabetic background treatment.
- Intervention characteristics: type, dose and duration of interventions applied.
- Trial characteristics: number of clinical sites, country of origin and funding.
Assessment of risk of bias in included studies
- Randomisation (selection bias): based on empirical evidence, the randomisation methods will be extracted as the primary measure of bias control.43 Methodological quality in the randomisation methods will be based on the allocation sequence generation (classed as adequate if based on computer-generated random numbers, a table of random numbers or similar) and allocation concealment (classed as adequate if randomisation was performed through a central independent unit, identically appearing coded drug containers, serially numbered opaque sealed envelopes or similar) and incomplete outcome data (whether all patients were accounted for).
- Blinding (performance and detection bias): we will extract data on whether single or double blinding was performed, the method of blinding (eg, use of placebo) and the persons who were blinded with regard to the interventions assessed (ie, patients, healthcare providers or other persons involved in the trial).
- Incomplete outcome data (attrition bias): the extent to which all patients lost to follow-up are accounted for will be evaluated as a measure of attrition bias.
- Outcome reporting (reporting bias): the extent to which clinically relevant outcome measures are reported and differences between trial protocols and subsequent reports will be evaluated as a marker of reporting bias.
- Other biases: sample size calculations and whether the planned sample size was achieved will be evaluated.
Measures of treatment effect
Dichotomous data will be analysed using risk differences (RD) and continuous data using weighted mean differences, both with 95% CIs. For dichotomous data, the number needed to treat will be calculated based on the RD as 1/RD.
Unit of analysis issues
For crossover trials, data from the first treatment period will be used. For trials in which more than one control group was assessed, the primary analysis will combine data from each control group. Subgroup analyses on control groups will also be performed. Each patient will be counted only once in the analysis.
Dealing with missing data
Intention-to-treat analyses including all patients randomised will be performed. In the case of patients with missing outcome data, carry forward of the last observed response will be used. Individual patient data will be sought from the original source or from the published trial reports where individual patient data are unavailable.
Assessment of heterogeneity
The intertrial heterogeneity will be expressed as I2 values.
Assessment of reporting biases
We will extract whether clinically relevant outcomes are reported and compare trial protocols with subsequent publications when available.
Analyses will be performed in RevMan44
and Stata V.12 (Stata Corp, Texas, USA). The primary meta-analyses will be performed using random effects models owing to an expected intertrial heterogeneity.
Sequential analyses will be performed to evaluate the robustness of the results after correction for potential errors associated with cumulative testing. The analyses will be performed using the results of the primary meta-analysis, model-based heterogeneity and an α-value of 5% and a power of 80%.
Subgroup analysis and investigation of heterogeneity
Subgroup analyses will be performed to analyse the influence of patient, intervention and trial characteristics and intertrial heterogeneity. The subgroup analyses will compare the different types of BASs. The test for subgroup differences will be calculated and the results will be presented as P and I2 values.
Fixed effect meta-analyses will be performed to evaluate the influence of small trials. Additional sensitivity analyses with exclusion of trials with unclear randomisation will also be performed.