To assess the effects and adverse events of bile acid sequestrants in patients with type 2 diabetes.

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, 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, drug manufacturer 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 World Health Organization Trial Register http://apps.who.int/trialsearch/ and through correspondence with experts.

The review will include randomised controlled trials, irrespective of blinding, publication status, or language. The first period of cross over trials will be included. Unpublished trials will be included if the methodology and data are accessible in written form.

Type 2 diabetes mellitus (T2DM) is a severe metabolic disease characterised by relative insulin deficiency, including defect insulin secretion, insulin resistance, inappropriate glucagon secretion and impaired incretin effect resulting in fasting and postprandial hyperglycaemia. T2DM is also associated with overweight and dyslipidaemia and carries long-term risk of micro and macrovascular disease.

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 (ADA) or the European Association for the Study of Diabetes (EASD), but if necessary, trials will be included with the authors’ definition of T2DM.

The intervention comparisons will include all types of bile acid sequestrants (colestyramine, colestimide, colestipol, colestilan and colesevelam) versus placebo.

Co-interventions with other anti-diabetic agents will be accepted if administered to the intervention and control group.

Primary outcomes

HbA1c

Secondary outcomes

Fasting plasma glucose (FPG).

LDL-cholesterol.

HDL-cholesterol.

Total-cholesterol.

Triglycerides, Body mass index (BMI).

Adverse events: Adverse events will be defined based on the international guidelines for good clinical practice as any untoward medical occurrence.

Data collection and analysis:

Two authors (MH and DPS) will independently extract data and resolve disagreements through discussion before analysis. In case of unresolved matters, a third party will be involved. When the 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 included trials will be selected using the criteria described above. Excluded trials will be listed with the reason for exclusion. All authors will participate in the selection or trials 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 FPG, baseline total-cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and background treatment with antidiabetic agents.

• Intervention characteristics: type, dose, and duration of interventions applied.

• Trial characteristics: number of clinical sites, country of origin and funding.

Randomisation (selection bias): Based on empirical evidence, the randomisation methods will be extracted as the primary measure of bias control. 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 (e.g. use of placebo) and the persons who were blinded with regard to the interventions assessed (i.e. patients, health care 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 (WMD), both with 95% confidence intervals (CI). For dichotomous data, the number needed to treat (NNT) will be calculated based on the RD as 1/RD.

Unit of analysis issues:

For cross-over 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. For 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 I-squared values.

Assessment of reporting biases:

We will extract whether clinically relevant outcomes are reported and compare trial protocols with subsequent publications when available.

Data Analysis:

Analyses will be performed in RevMan (RevMan version 5) and STATA (Stata version 11). The primary meta-analyses will be performed using random effects models due to an expected intertrial heterogeneity.

Sequential analysis:

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 alpha 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 intertrial heterogeneity. The subgroup analyses will compare the different types of BASs. The test for subgroup differences will be calculated and the results presented as P and I-squared values.

Sensitivity analysis:

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.

A paper for publication describing the systematic review and meta-analysis will be drafted.

Morten Hansen

Diabetes Research Division

Department of Medicine

Gentofte Hospital

Niels Andersens Vej 65

2900 Hellerup

Denmark

mortenhansen.privat@gmail.com

Diabetes Research Division

Dr Morten Hansen, Diabetes Research Division
Dr David P. Sonne, Diabetes Research Division
Dr Lise Lotte Gluud, Department of Medicine, Gentofte Hospital
Dr Tina Vilsbøll, Diabetes Research Division
Dr Filip K. Knop, Diabetes Research Division

02 July 2012

31 December 2012

The work has not received funding.

None known

The protocol has not yet been published

English

Denmark

Subject indexing assigned by CRD

Allylamine; Bile Acids and Salts; Fluorobenzenes; Humans; Hypoglycemic Agents; Pyrimidines; Sulfonamides

27 June 2012

27 June 2012