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In addition to the lipid-lowering effect of bile acid sequestrants (BASs), they also lower blood glucose and, therefore, could be beneficial in the treatment of patients with type 2 diabetes mellitus (T2DM). Three oral BASs are approved by the US Food and Drug Administration (FDA) for the treatment of hypercholesterolaemia: colestipol, cholestyramine and colesevelam. The BAS colestimide/colestilan is used in Japan. Colesevelam was recently approved by the FDA for the treatment of T2DM. We plan to provide a systematic review with meta-analysis of the glucose-lowering effect of BASs with the aim to evaluate their potential as glucose-lowering agents in patients with T2DM.
In accordance with the preferred reporting items for systematic reviews and meta-analyses statement, a systematic review with meta-analysis of randomised clinical trials of BASs (vs placebo, oral antidiabetes drugs or insulin), reporting measures of glycaemic control in adult patients with T2DM, will be performed. Change in glycated haemoglobin constitutes the primary endpoint, and secondary endpoints include changes in fasting plasma glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, triglycerides, body weight and body mass index and adverse events. Electronic searches will be performed in The Cochrane Library, MEDLINE and EMBASE, along with manual searches in the reference lists of relevant papers. The analyses will be performed based on individual patient data and summarised data. The primary meta-analysis will be performed using random effects models owing to expected intertrial heterogeneity. Dichotomous data will be analysed using risk difference and continuous data using weighted mean differences, both with 95% CIs.
The study will evaluate the potential of BASs as glucose-lowering agents and possibly contribute to the clinical management of patients with T2DM.
The study will be disseminated by peer-review publication and conference presentation.
Type 2 diabetes mellitus (T2DM) is a severe metabolic disease characterised by relative insulin deficiency, including defective insulin secretion and insulin resistance, inappropriate glucagon secretion and impaired incretin effect resulting in fasting and postprandial hyperglycaemia.1 2 T2DM is associated with overweight and dyslipidaemia and increases long-term risk of microvascular and macrovascular disease.3
In recent years, it has become clear that bile acids are not only simple fat solubilisers, but also signalling molecules that play an important role in lipid, glucose and energy metabolism.4–6 In line with this, clinical studies have shown that bile acid sequestrants (BASs) in addition to their well-established lipid-lowering effects7–9 can lower blood glucose and, therefore, could be potentially beneficial in the treatment of patients with T2DM.10–12 BASs, also known as resins, are large, non-absorbable, polymer molecules that bind negatively charged bile salts in the intestine. This diverts bile acids from the enterohepatic cycle and increases their faecal excretion.13 The end result is increased bile acid (and cholesterol) synthesis with upregulation of the low-density lipoprotein (LDL) receptors. Four oral BASs are available for the treatment of LDL-hypercholesterolaemia: colestipol, cholestyramine, colestilan/colestimide (in Japan) and colesevelam. In 2008, colesevelam was approved by the US Food and Drug Administration—based on three large pivotal studies 10–12—for the treatment of hyperglycaemia in T2DM.
The mechanism(s) by which BASs exert their glucose-lowering action is not completely understood. Data from in vitro and in vivo animal and human studies have suggested different mechanisms including enhanced glucose-stimulated release of the incretin hormone glucagon-like peptide-1 (GLP-1)14–18 and activation of the nuclear Farnesoid X receptor, which is implicated in lipid and glucose metabolism.6 19 It has been speculated that increased GLP-1 secretion induced by BASs may be dependent on increased concentration of bile acids in the lumen of the gut and subsequent bile acid-mediated activation of the seven-transmembrane receptor TGR5 present in GLP-1-secreting enteroendocrine L cells,20 21 thereby explaining their glucose-lowering effect.22 The glucose-lowering actions of GLP-1 are mediated by glucose-stimulated insulin secretion, inhibition of glucagon secretion and a suppressive effect on appetite and food intake.23 Also, although studies are conflicting,24 25 it is believed that the disturbed glucose homeostasis in diabetes is associated with changes in bile acid pool size and composition.6 13 26
T2DM affects more than 300 million people worldwide, according to the WHO.27 High level of glycated haemoglobin (HbA1c) is an established predictor of cardiovascular disease in patients with T2DM.28–30 However, recent large clinical trials have shown that intensive treatment (resulting in HbA1c of ≤6.0%) in longstanding T2DM might be harmful,31–33 and, thus, individualised glycaemic control is pivotal in reducing morbidity and mortality of T2DM.34 35 Hyperlipidaemia is an important part of the pathophysiology of T2DM, and treatment with lipid-lowering drugs reduces cardiovascular mortality in T2DM.3 However, despite numerous glucose and lipid-lowering agents being used in the management of patients with T2DM, there is still an unmet need for effective, individualised and safe treatment, as only a small fraction of the patients reach the treatment goals.36 37 To our knowledge, a systematic review with meta-analysis on the glucose-lowering effect of BASs is lacking, but at the same time it is needed to evaluate the potential of BASs as glucose-lowering agents in patients with T2DM.
The primary objective of the present protocol is to evaluate the impact of BASs on glycaemic control (HbA1c), and secondary objectives include effects on fasting plasma glucose, body weight (and body mass index (BMI)) and lipids and adverse events associated with the use of BASs in patients with T2DM.
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.
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.
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 40 but if necessary, trials will be included with the definition of T2DM used by the authors of the trial in question.
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.
The following outcome measures will be assessed based on analyses of individual patient data from included trials or from published reports.
The electronic searches will be performed in The Cochrane Library, MEDLINE and EMBASE using the following strategy:
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.
Trials identified through the electronic and manual searches will be listed, and—using the criteria described above—trials will be selected for inclusion.
Standardised extraction forms will be used. The following data will be extracted from included trials:
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.
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.
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.
The intertrial heterogeneity will be expressed as I2 values.
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 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.
The study will evaluate the impact of BASs on glycaemic control (HbA1c) and also assess effects on fasting plasma glucose, body weight and lipids and adverse events associated with the use of BASs in patients with T2DM, and hence possibly contribute to the clinical management of patients with T2DM. MH will draft a paper describing the systematic review and the study will be disseminated by peer-reviewed publication and conference presentation.
Contributors: MH, TV, LLG and FKK participated in the conception and design of this protocol including search strategy development. MH, DPS and KHM participated in search strategy development and performed pilot searches. LLG provided statistical advice for the design. All authors drafted and critically reviewed the manuscript and approved the final version.
Funding: MH and FKK are supported by an unrestricted grant from the Novo Nordisk Foundation. This research did not otherwise receive specific grant from any funding agency in the public, commercial or not-for-profit sectors. No sponsor was involved in study design, and no sponsor will have authority in collection, management, analysis and interpretation of data. Writing of the report and the decision to submit the results for publication is strictly made by the authors.
Competing interests: None.
Provenance and peer review: Not commissioned; externally peer reviewed.