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Efficacy and safety of long-acting glucagon-like peptide-1 receptor agonists compared with exenatide twice daily and sitagliptin in type 2 diabetes mellitus: a systematic review and meta-analysis |
Pinelli NR, Hurren KM |
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CRD summary The review concluded that liraglutide and exenatide once weekly resulted in greater improvement in haemoglobin 1C and fasting plasma glucose than exenatide twice daily and sitagliptin. Due to the limited evidence base and potential for publication bias, the authors’ conclusions should be considered tentative. Authors' objectives To compare the efficacy and safety of maximum dose long-acting glucogon-like peptide-1 receptor agonists with exenatide twice daily and dipeptidyll-peptidase-IV (sitagliptin) in patients with type 2 diabetes. Searching PubMed, EMBASE and The Cochrane Library were searched from inception to December 2010 for relevant studies published in English; search terms were reported. Abstracts from the American Diabetes Association Scientific Sessions in 2009 and 2010 and the reference lists of retrieved studies were searched for additional studies. Study selection Randomised controlled trials (RCTs) of non-pregnant adults with type 2 diabetes mellitus that compared the efficacy and safety of maximum dose long-acting GLP-1 receptor agonists (liraglutide, exenatide once weekly, albiglutide or lixisenatide) with exenatide twice daily, sitagliptin or saxagliptin were eligible for inclusion. Studies were required to include the measurement of haemoglobin A1C as an outcome. Studies with duration less than 24 weeks, that assessed the experimental long-acting GLP-1 receptor agonists taspoglutide, post-hoc analyses and extension studies were excluded. In the included studies, mean age ranged from 52 to 57 years and the proportion of participants of white ethnicity ranged from 32 to 92%, where reported. Approximately half of participants were men. Diabetes duration ranged from six to eight years and body mass index ranged from 32 to 35kg/m2, where reported. In the intervention groups, three trials used exenatide 2mg per week plus oral agents or metformin and two trials used liraglutide 1.8mg per day plus metformin and/or sulphonylurea. In the control groups, three trials used exenatide 10ug twice daily plus metformin and/or sulphonylurea and two trials used metformin plus sitagliptin 100mg per day. The primary outcome was haemoglobin A1C (mean change from baseline). Secondary outcomes included proportion of participants that achieved haemoglobin A1C below 7%, mean change in fasting plasma glucose, postprandial glucose (PPG), mean change in body weight, lipids and blood pressure and adverse events. Two reviewers independently selected studies for the review. Discrepancies were resolved by consensus. Assessment of study quality Studies were assessed for quality; criteria included description of sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting and other sources of bias. Two reviewers assessed the included studies for quality. Data extraction Data were extracted on the outcomes; odds ratios (ORs) for dichotomous data and mean differences (MDs) for continuous data, with 95% confidence intervals (CIs), were calculated. Two reviewers independently extracted data for the review. Methods of synthesis Where possible, meta-analyses were undertaken using a DerSimonian and Laird random-effects model. Summary effect odds ratios and weighted mean differences (WMDs) with 95% confidence intervals were estimated. Synthesis of postprandial glucose, lipids, blood pressure and adverse events were described in narrative format. Heterogeneity was assessed with Ι² and publication bias by inspection of funnel plots. Sensitivity analyses were planned to determine the effects on the outcomes of excluding open label studies, but were not undertaken because few studies were blinded. Results of the review Five RCTs (1,777 participants) were included in the review. Sequence generation and allocation concealment were described in two of the five studies, incomplete data and selective outcome reporting was present in two and four of the five studies respectively, and only one study was double blinded. All studies were sponsored by pharmaceutical companies. Duration of follow up ranged from 24 to 30 weeks. Primary outcomes: Long-acting GLP-1 receptor agonists were associated with a significant reduction in haemoglobin A1C, both when compared to exenatide twice daily (WMD -0.47%, 95% CI -0.69 to -0.25; Ι²=4.3%; three studies) and sitagliptin (WMD -0.60%, 95% CI -0.75 to -0.45; Ι²=0%; two studies). long-acting GLP-1 receptor agonists were also associated with a significantly larger percentage of patients reaching the target haemoglobin A1C less than 7%, both when compared to exenatide twice daily (OR 2.14, 95% CI 1.38 to 3.34; Ι²=64%; three studies) and sitagliptin (OR 3.84, 95% CI 2.78 to 5.31; Ι²=9.5%; two studies). Secondary outcomes: Long-acting GLP-1 receptor agonists were associated with a significant reduction in fasting plasma glucose, both when compared to exenatide twice daily (OR -18.39mg/dL, 95% CI -24.67 to -12.10; Ι²=0%; three studies) and sitagliptin (OR -20.96mg/dL, 95% CI -27.88 to -14.04; Ι²=17.1; two studies). Compared to long-acting GLP-1 receptor agonists, exenatide twice daily was associated with significantly greater reductions in postprandial glucose after morning and evening meals (refer to publication for estimates). There was no evidence of significant differences in body weight between long-acting GLP-1 receptor agonists and exenatide twice daily, but long-acting GLP-1 receptor agonists were associated with a significant reduction in body weight when compared to sitagliptin (WMD -1.99kg, 95% CI -2.69 to -1.09; Ι²=58%; two studies). The findings related to lipids were mixed and were located in the publication. Long-acting GLP-1 receptor agonists were not associated with severe hypoglycaemia or pancreatitis. Compared with exenatide, long-acting GLP-1 receptor agonists were associated with a significant reduction in vomiting (OR 0.55, 95% CI 0.34 to 0.89; two studies), there was a trend favouring long-acting GLP-1 receptor agonists in reduction of nausea (OR 0.58, 95% CI 0.32 to 1.06; three studies) and no evidence of a significant difference between groups in the rates of diarrhoea (two studies). Compared with sitagliptin, long-acting GLP-1 receptor agonists were associated with increased rates of nausea (OR 4.70, 955 CI 1.81 TO 12.24; Ι²=76%), vomiting (OR 3.22, 95% CI 1.63 to 6.36; Ι²=7%) and diarrhoea (OR 2.32, 95% CI 1.42 to 3.81; Ι²=0%) in two studies. Authors' conclusions Liraglutide and exenatide once weekly resulted in greater improvement in haemoglobin A1C and fasting plasma glucose than other incretin based therapies. Compared to exenatide twice daily, they produced less effect on postprandial glucose, similar reduction in body weight and resulted in a favourable adverse event profile. CRD commentary The review addressed a clear research question, supported by appropriate inclusion criteria. A range of relevant sources were searched to identify studies and attempts were made to find unpublished studies, but only English language studies were eligible so publication bias could not be ruled out. Appropriate methods were used to select studies, make quality assessments and extract data, which minimised the chance of reviewer error and bias. The few included studies were not generally of good quality and most were open label, so the reliability of the findings was not clear. Funnel plots of the primary outcome were asymmetrical which suggested that publication bias could not be excluded, but funnel plot analysis was not considered appropriate with few studies. Synthesis of studies and assessment of heterogeneity were appropriate, but sensitivity analyses could not be undertaken because of the limited evidence base. Due to the limited evidence base and potential for publication bias, the authors’ conclusions should be considered tentative. Implications of the review for practice and research Practice: The authors did not state any implications for practice. Research: The authors stated that further clinical trials, some of which were ongoing, were required to determine whether long-acting GLP-1 receptor agonists were associated with reduced mortality and morbidity in patients with type 2 diabetes. Bibliographic details Pinelli NR, Hurren KM. Efficacy and safety of long-acting glucagon-like peptide-1 receptor agonists compared with exenatide twice daily and sitagliptin in type 2 diabetes mellitus: a systematic review and meta-analysis. Annals of Pharmacotherapy 2011; 45(7-8): 850-860 Indexing Status Subject indexing assigned by NLM MeSH Delayed-Action Preparations /administration & Diabetes Mellitus, Type 2 /blood /drug therapy; Dipeptidyl-Peptidase IV Inhibitors /administration & Female; Glucagon-Like Peptide 1 /administration & Glucagon-Like Peptide-1 Receptor; Hemoglobin A, Glycosylated /analysis; Humans; Hyperglycemia /prevention & Hypoglycemic Agents /administration & Incretins /administration & Liraglutide; Male; Middle Aged; Peptides /administration & Pyrazines /adverse effects /therapeutic use; Randomized Controlled Trials as Topic; Receptors, Glucagon /agonists; Sitagliptin Phosphate; Triazoles /adverse effects /therapeutic use; Venoms /administration & control; derivatives /therapeutic use; dosage /adverse effects /agonists /analogs & dosage /adverse effects /agonists /therapeutic use; dosage /adverse effects /therapeutic use; dosage /adverse effects /therapeutic use; dosage /adverse effects /therapeutic use; dosage /adverse effects /therapeutic use; dosage /adverse effects /therapeutic use AccessionNumber 12011004990 Date bibliographic record published 21/12/2011 Date abstract record published 22/08/2012 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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