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Effect of Bile Acid Sequestrants on Glycaemic Control: Protocol for a Systematic Review with Meta-Analysis of Randomised Controlled Trials

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Effect of Bile Acid Sequestrants on Glycaemic Control: Protocol for a Systematic Review with Meta-Analysis of Randomised Controlled Trials BMJ Open: first published as 10.1136/bmjopen-2012-001803 on 12 November 2012. Downloaded from Open Access Protocol Effect of bile acid sequestrants on glycaemic control: protocol for a systematic review with meta-analysis of randomised controlled trials Morten Hansen, David Peick Sonne, Kristian Hallundbæk Mikkelsen, Lise Lotte Gluud, Tina Vilsbøll, Filip Krag Knop To cite: Hansen M, ABSTRACT ARTICLE SUMMARY Sonne DP, Mikkelsen KHæk, Introduction: In addition to the lipid-lowering effect of et al . Effect of bile acid bile acid sequestrants (BASs), they also lower blood sequestrants on glycaemic Article focus glucose and, therefore, could be beneficial in the control: protocol for ▪ Impact of bile acid sequestrants (BASs) on gly- a systematic review with treatment of patients with type 2 diabetes mellitus caemic control (HbA1c), effects on fasting meta-analysis of randomised (T2DM). Three oral BASs are approved by the US Food plasma glucose, body weight (and body mass controlled trials. BMJ Open and Drug Administration (FDA) for the treatment of index, BMI), lipids and adverse events in patients 2012;2:e001803. hypercholesterolaemia: colestipol, cholestyramine and with type 2 diabetes mellitus (T2DM). doi:10.1136/bmjopen-2012- colesevelam. The BAS colestimide/colestilan is used in 001803 Japan. Colesevelam was recently approved by the FDA Key messages for the treatment of T2DM. We plan to provide a ▪ A systematic review with meta-analysis on the ▸ Prepublication history and systematic review with meta-analysis of the glucose- glucose-lowering effect of BASs is lacking, but at additional material for this lowering effect of BASs with the aim to evaluate their the same time needed to evaluate the potential paper are available online. To potential as glucose-lowering agents in patients with of BASs as glucose-lowering agents in patients view these files please visit T2DM. with T2DM. There is an unmet need for effective, the journal online Methods and analysis: In accordance with the individualised and safe treatment, as only a small (http://dx.doi.org/10.1136/ preferred reporting items for systematic reviews and fraction of the patients with type 2 diabetes bmjopen-2012-001803). reach the treatment goals. meta-analyses statement, a systematic review with http://bmjopen.bmj.com/ Received 11 July 2012 meta-analysis of randomised clinical trials of BASs (vs Strengths and limitations of this study Accepted 2 October 2012 placebo, oral antidiabetes drugs or insulin), reporting ▪ A clear strength is the knowledge and experi- measures of glycaemic control in adult patients with ence, within our group—on how to conduct a This final article is available T2DM, will be performed. Change in glycated systematic review and meta-analysis. A possible for use under the terms of haemoglobin constitutes the primary endpoint, and the Creative Commons weakness may be the quality of the trials we secondary endpoints include changes in fasting plasma identify. Attribution Non-Commercial glucose, low-density lipoprotein cholesterol, high- 2.0 Licence; see density lipoprotein cholesterol, total cholesterol, http://bmjopen.bmj.com triglycerides, body weight and body mass index and INTRODUCTION on September 25, 2021 by guest. Protected copyright. adverse events. Electronic searches will be performed Description of the condition in The Cochrane Library, MEDLINE and EMBASE, along Type 2 diabetes mellitus (T2DM) is a severe with manual searches in the reference lists of relevant metabolic disease characterised by relative papers. The analyses will be performed based on fi individual patient data and summarised data. The insulin de ciency, including defective insulin primary meta-analysis will be performed using random secretion and insulin resistance, inappropri- effects models owing to expected intertrial ate glucagon secretion and impaired incretin heterogeneity. Dichotomous data will be analysed effect resulting in fasting and postprandial using risk difference and continuous data using hyperglycaemia.12T2DM is associated with weighted mean differences, both with 95% CIs. overweight and dyslipidaemia and increases Ethics and dissemination: The study will evaluate long-term risk of microvascular and macro- Diabetes Research Division, the potential of BASs as glucose-lowering agents and 3 Department of Internal vascular disease. possibly contribute to the clinical management of Medicine, Gentofte Hospital, University of Copenhagen, patients with T2DM. Description of the intervention Results: The study will be disseminated by peer- Hellerup, Denmark In recent years, it has become clear that bile review publication and conference presentation. acids are not only simple fat solubilisers, but Correspondence to Protocol registration: PROSPERO Filip K Knop; filipknop@ CRD42012002552. also signalling molecules that play an import- dadlnet.dk ant role in lipid, glucose and energy Hansen M, Sonne DP, Mikkelsen KHæk, et al. BMJ Open 2012;2:e001803. doi:10.1136/bmjopen-2012-001803 1 BMJ Open: first published as 10.1136/bmjopen-2012-001803 on 12 November 2012. Downloaded from Effect of bile acid sequestrants on glycaemic control – metabolism.4 6 In line with this, clinical studies have treatment, as only a small fraction of the patients reach shown that bile acid sequestrants (BASs) in addition to the treatment goals.36 37 To our knowledge, a systematic – their well-established lipid-lowering effects7 9 can lower review with meta-analysis on the glucose-lowering effect blood glucose and, therefore, could be potentially bene- of BASs is lacking, but at the same time it is needed to – ficial in the treatment of patients with T2DM.10 12 BASs, evaluate the potential of BASs as glucose-lowering agents also known as resins, are large, non-absorbable, polymer in patients with T2DM. 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 OBJECTIVES result is increased bile acid (and cholesterol) synthesis The primary objective of the present protocol is to evalu- with upregulation of the low-density lipoprotein (LDL) ate the impact of BASs on glycaemic control (HbA1c), receptors. Four oral BASs are available for the treatment and secondary objectives include effects on fasting of LDL-hypercholesterolaemia: colestipol, cholestyra- plasma glucose, body weight (and body mass index mine, colestilan/colestimide (in Japan) and coleseve- (BMI)) and lipids and adverse events associated with the lam. In 2008, colesevelam was approved by the US Food use of BASs in patients with T2DM. and Drug Administration—based on three large pivotal 10–12— studies for the treatment of hyperglycaemia in METHODS T2DM. The review will be performed according to the recom- mendations specified in the Cochrane Handbook for How the intervention might work Intervention Reviews.38 The reporting of the review will The mechanism(s) by which BASs exert their glucose- follow the preferred reporting items for systematic lowering action is not completely understood. Data from reviews and meta-analyses statement.39 The analyses will in vitro and in vivo animal and human studies have sug- be performed based on analyses of individual patient gested different mechanisms including enhanced data from published randomised trials and summarised glucose-stimulated release of the incretin hormone 14–18 data presented in published trials or supplied by authors glucagon-like peptide-1 (GLP-1) and activation of of included trials. the nuclear Farnesoid X receptor, which is implicated in lipid and glucose metabolism.619It has been speculated Criteria for considering studies for this review that increased GLP-1 secretion induced by BASs may be Types of studies dependent on increased concentration of bile acids in The review will include randomised controlled trials, the lumen of the gut and subsequent bile acid-mediated irrespective of blinding, publication status or language. activation of the seven-transmembrane receptor TGR5 The first period of any crossover trials will be included. http://bmjopen.bmj.com/ present in GLP-1-secreting enteroendocrine L cells,20 21 Unpublished trials will be included if the methodology thereby explaining their glucose-lowering effect.22 The and data are accessible in written form. glucose-lowering actions of GLP-1 are mediated by glucose-stimulated insulin secretion, inhibition of gluca- gon secretion and a suppressive effect on appetite and Types of participants food intake.23 Also, although studies are conflicting,24 25 Adult patients (at least 18 years of age) of both genders it is believed that the disturbed glucose homeostasis in with T2DM will be included. Inclusion criteria should be diabetes is associated with changes in bile acid pool size reported in the included trials. Ideally, the diagnostic and composition.61326 criteria for T2DM should be based on the criteria of the on September 25, 2021 by guest. Protected copyright. WHO, the American Diabetes Association and/or the 37 40 Why is it important to do this review? European Association for the Study of Diabetes, but fi T2DM affects more than 300 million people worldwide, if necessary, trials will be included with the de nition of according to the WHO.27 High level of glycated haemo- T2DM used by the authors of the trial in question. globin (HbA1c) is an established predictor of cardiovas- – cular disease in patients with T2DM.28 30 However, Types of interventions recent large clinical trials have shown that intensive The
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