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Journal Article•DOI•

Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: A systematic review and mixed-treatment comparison analysis

Zin Zin Htike1, Zin Zin Htike2, Francesco Zaccardi2, Francesco Zaccardi1, Dimitris Papamargaritis2, Dimitris Papamargaritis1, David R. Webb2, David R. Webb1, Kamlesh Khunti2, Kamlesh Khunti1, Melanie J. Davies1, Melanie J. Davies2 •
University Hospitals of Leicester NHS Trust1, University of Leicester2
01 Apr 2017-Diabetes, Obesity and Metabolism (WILEY)-Vol. 19, Iss: 4, pp 524-536
TL;DR: To compare efficacy and safety of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) in people with type 2 diabetes, a large number of subjects were randomly assigned to receive either a GLP or a non‐GLP agonist treatment.
Abstract: Aims To compare efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in people with type 2 diabetes. Materials and methods We electronically searched, up to June 3, 2016, published randomized clinical trials lasting between 24 and 32 weeks that compared a GLP-1RA (albiglutide, dulaglutide, twice-daily exenatide and once-weekly exenatide, liraglutide, lixisenatide, semaglutide and taspoglutide) with placebo or another GLP-1RA. Data on cardiometabolic and safety outcomes were analysed using a mixed-treatment comparison meta-analysis. Results A total of 34 trials (14 464 participants) met the inclusion criteria; no published data for semaglutide were available. Compared with placebo, all GLP-1RAs reduced glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels (reductions ranged from −0.55% and −0.73 mmol/L, respectively, for lixisenatide to −1.21% and −1.97 mmol/L, respectively, for dulaglutide). There were no differences within short-acting (twice-daily exenatide and lixisenatide) or long-acting (albiglutide, dulaglutide, once-weekly exenatide, liraglutide and taspoglutide) groups. Compared with twice-daily exenatide, dulaglutide treatment was associated with the greatest HbA1c and FPG reduction (0.51% and 1.04 mmol/L, respectively), followed by liraglutide (0.45% and 0.93 mmol/L, respectively) and once-weekly exenatide (0.38% and 0.85 mmol/L, respectively); similar reductions were found when these 3 agents were compared with lixisenatide. Compared with placebo, all GLP-1RAs except albiglutide reduced weight and increased the risk of hypoglycaemia and gastrointestinal side effects, and all agents except dulaglutide and taspoglutide reduced systolic blood pressure. When all GLP-1RAs were compared with each other, no clinically meaningful differences were observed in weight loss, blood pressure reduction or hypoglycaemia risk. Albiglutide had the lowest risk of nausea and diarrhoea and once-weekly exenatide the lowest risk of vomiting. Conclusions The RCTs in the present analysis show that all GLP-1RAs improve glycaemic control, reduce body weight and increase the risk of adverse gastrointestinal symptoms compared with placebo. Although there were no differences when short-acting agents were compared with each other or when long-acting agents were compared with each other, dulaglutide, liraglutide and once-weekly exenatide were superior to twice-daily exenatide and lixisenatide at lowering HbA1c and FPG levels. There were no differences in hypoglycaemia between these 3 agents, whilst once-weekly exenatide had the lowest risk of vomiting. These results, along with patient's preferences and individualized targets, should be considered when selecting a GLP-1RA.

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  • Coquilles bivalves sont composées de deux pièces qu'on nomme valves ou battans.
  • Le bord des ruisseaux et des rivières , sur les arbustes et les plantes.
  • Coquille cylindrique , iaunâtre , très* brillante ; ouverture ovale et blanche.
  • Testa compressa , alba , iimbilicata ; apertura circinnata ; labio amplo reiiexo.
  • Sar le tronc des arbres et parmi les roclieis.
  • Coquille concave à ses deux faces ; tours de spire presque ronds ; ouverture ovale.

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Accepted Article
Efficacy and Safety of Glucagon-like peptide-1 receptor agonists
in type 2 diabetes
Systematic review and mixed-treatment comparison analysis
GLP-1RAs treatments in diabetes
Zin Z Htike
, MBBS
Francesco Zaccardi
, MD
Dimitris Papamargaritis, PhD
David R Webb, PhD
Kamlesh Khunti, PhD
Melanie J Davies, MD
Diabetes Research Centre, University of Leicester, Leicester, UK
Leicester Diabetes Centre, Leicester General Hospital, University Hospitals of Leicester NHS
Trust
Corresponding Author and reprint requests
Dr Zin Zin Htike
Leicester Diabetes Centre, Leicester General Hospital, Leicester, UK
Phone: +44 0116 258 8602 – Fax: +44 0116 258 4499
Email: zzhtike@gmail.com
ABSTRACT
Aims
To compare efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in
subjects with type 2 diabetes
Materials and Methods
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1111/dom.12849
This article is protected by copyright. All rights reserved.
Accepted Article
We electronically searched, up to June 3
rd
, 2016, published randomised clinical trials lasting
between 24 and 32 weeks and comparing a GLP-1RA (albiglutide, dulaglutide, twice-daily
(EBID) and once-weekly exenatide, liraglutide, lixisenatide, semaglutide, and taspoglutide)
with placebo or another GLP-1RA. Data on cardiometabolic and safety outcomes were
analysed using a mixed-treatment comparison meta-analysis
Results
34 trials (14464 participants) met the inclusion criteria; no published data for semaglutide
were available. Compared to placebo, all GLP-1RAs reduced HbA1c and fasting plasma
glucose (FPG) (from -0.55% and -0.73mmol/L for lixisenatide to -1.21% and -1.97mmol/L
for dulaglutide). There were no differences within short-acting (EBID and lixisenatide) or
long-acting (albiglutide, dulaglutide, once-weekly exenatide, liraglutide, and taspoglutide)
groups. Compared to EBID, dulaglutide treatment was associated with the greatest HbA1c
and FPG reduction (0.51% and 1.04mmol/L), followed by liraglutide (0.45%, 0.93mmol/L)
and once-weekly exenatide (0.38% and 0.85mmol/L); similar reductions were found when
these three agents were compared to lixisenatide. Compared to placebo, all GLP-1RAs except
albiglutide reduced weight and increased the risk of hypoglycaemia and gastrointestinal (GI)
side effects and all agents except dulaglutide and taspoglutide reduced systolic blood pressure.
When all GLP-1RAs were compared against each other, no clinically meaningful differences
were observed in weight loss, blood pressure reduction or hypoglycaemia risk. Albiglutide
had the lowest risk of nausea and diarrhoea and once-weekly exenatide the lowest risk of
vomiting.
Conclusions
This article is protected by copyright. All rights reserved.
Accepted Article
RCTs demonstrate that all GLP-1RAs improve glycaemic control, reduce body weight, and
increase the risk of adverse gastrointestinal symptoms vs placebo. Although there are no
differences when short-acting agents are compared against each-other or when long-acting
agents are compared against each-other, dulaglutide, liraglutide, and once-weekly exenatide
are superior to EBID and lixisenatide at lowering HbA1c and FPG. There are no differences
in hypoglycaemia between these three agents whilst once-weekly exenatide has a lowest risk
of vomiting. These results, along with patient’s preferences and individualised targets, should
be considered in selecting a GLP-1RA.
This article is protected by copyright. All rights reserved.
Accepted Article
Introduction
Type 2 diabetes (T2DM) is a chronic metabolic disorder characterised by complex
pathophysiology of progressive beta cell dysfunction and a varying degree of insulin
resistance. As the condition progresses, achieving and maintaining glycaemic control
becomes a challenge despite the availability and use of a number of classes of glucose
lowering therapies[1]. Current guidelines recommend a patient-centred approach when
choosing appropriate glucose lowering treatments, with a primary goal of achieving
individualised glycaemic target whilst minimising adverse effects, particularly weight gain
and hypoglycaemia [2].
Glucagon like peptide-1 receptor agonists (GLP-1RAs) are a class of therapeutic agent,
which provide significant improvement in HbA1c with an added benefit of promoting weight
loss and low risk of hypoglycaemia [3-6]. GLP-1 is a gut hormone produced by the small
intestine in response to oral ingestion of glucose, which promotes a glucoregulatory effect by
increasing insulin and suppressing glucagon secretion [7]. It also facilitates weight loss by
delaying gastric emptying and acting centrally on the satiety centre to reduce the food intake
[7]. Manipulating the molecular structure of GLP-1 alters its pharmacological properties and
produces biological effects that can be exploited clinically. GLP-1RAs are increasingly
classified by duration of action into long-acting (albiglutide, dulaglutide, once-weekly
exenatide, liraglutide, semaglutide, and taspoglutide) and short-acting (twice-daily exenatide
(EBID) and lixisenatide) agents [8].
To date, EBID, lixisenatide, liraglutide, albiglutide, dulaglutide, and once-weekly exenatide
are licensed by the US Food and Drug Administration (FDA) to be used in the management
of T2DM. The clinical trials and development of taspoglutide were discontinued in 2010 and
therefore it is not available in clinical practice while semaglutide in a once-weekly
subcutaneous formulation is in phase III clinical trials.
This article is protected by copyright. All rights reserved.
Accepted Article
The American Diabetes Association (ADA)/European Association for the study of Diabetes
(EASD) guidelines recommend the use of GLP-1RAs as an adjunctive therapy to lifestyle
modification and metformin [9]. However, there are no specific recommendations on which
GLP-1RA to choose in clinical practice possibly due to limited availability of head to head
studies comparing the efficacy and safety of GLP-1RAs [10]. When direct comparisons are
limited, mixed-treatment comparison analysis (also known as network meta-analysis) is
regarded as the methodology of choice to compare several treatments [11, 12]. Using this
approach and available data, we therefore aimed to compare the clinical profiles of GLP-
1RAs.
This article is protected by copyright. All rights reserved.
Citations
More filters
Journal Article•DOI•
Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

[...]

Melanie J. Davies1, David A. D'Alessio2, Judith E. Fradkin3, Walter N. Kernan4, Chantal Mathieu5, Geltrude Mingrone6, Peter Rossing7, Apostolos Tsapas, Deborah J. Wexler8, John B. Buse9 •
University of Leicester1, Duke University2, National Institutes of Health3, Yale University4, Katholieke Universiteit Leuven5, The Catholic University of America6, Steno Diabetes Center7, Harvard University8, University of North Carolina at Chapel Hill9
01 Dec 2018-Diabetes Care
TL;DR: A panel to update the prior position statements on the management of type 2 diabetes in adults includes additional focus on lifestyle management and diabetes self-management education and support and efforts targeting weight loss.
Abstract: The American Diabetes Association and the European Association for the Study of Diabetes have briefly updated their 2018 recommendations on management of hyperglycemia, based on important research findings from large cardiovascular outcomes trials published in 2019. Important changes include: 1) the decision to treat high-risk individuals with a glucagon-like peptide 1 (GLP-1) receptor agonist or sodium-glucose cotransporter 2 (SGLT2) inhibitor to reduce major adverse cardiovascular events (MACE), hospitalization for heart failure (hHF), cardiovascular death, or chronic kidney disease (CKD) progression should be considered independently of baseline HbA1c or individualized HbA1c target; 2) GLP-1 receptor agonists can also be considered in patients with type 2 diabetes without established cardiovascular disease (CVD) but with the presence of specific indicators of high risk; and 3) SGLT2 inhibitors are recommended in patients with type 2 diabetes and heart failure, particularly those with heart failure with reduced ejection fraction, to reduce hHF, MACE, and CVD death, as well as in patients with type 2 diabetes with CKD (estimated glomerular filtration rate 30 to ≤60 mL min-1 [1.73 m]-2 or urinary albumin-to-creatinine ratio >30 mg/g, particularly >300 mg/g) to prevent the progression of CKD, hHF, MACE, and cardiovascular death.

2,592 citations

Cites background from "Efficacy and safety of glucagon-lik..."

  • ...All GLP-1 receptor agonists reduce weight (110); the reduction ranges from about 1....

    [...]

  • ...GLP-1 receptor agonists have high glucose-lowering efficacy, but with variation within the drug class (110,111)....

    [...]

Journal Article•DOI•
Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

[...]

Melanie J. Davies1, Melanie J. Davies2, David A. D'Alessio3, Judith E. Fradkin4, Walter N. Kernan5, Chantal Mathieu6, Geltrude Mingrone7, Geltrude Mingrone8, Peter Rossing9, Peter Rossing10, Apostolos Tsapas, Deborah J. Wexler11, John B. Buse12 •
Leicester General Hospital1, University of Leicester2, Duke University3, National Institutes of Health4, Yale University5, Katholieke Universiteit Leuven6, The Catholic University of America7, King's College London8, Steno Diabetes Center9, University of Copenhagen10, Harvard University11, University of North Carolina at Chapel Hill12
01 Feb 2020-Diabetologia
TL;DR: A panel to update the prior position statements on the management of type 2 diabetes in adults includes additional focus on lifestyle management and diabetes self-management education and support and efforts targeting weight loss.
Abstract: The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the prior position statements, published in 2012 and 2015, on the management of type 2 diabetes in adults. A systematic evaluation of the literature since 2014 informed new recommendations. These include additional focus on lifestyle management and diabetes self-management education and support. For those with obesity, efforts targeting weight loss, including lifestyle, medication and surgical interventions, are recommended. With regards to medication management, for patients with clinical cardiovascular disease, a sodium–glucose cotransporter-2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) receptor agonist with proven cardiovascular benefit is recommended. For patients with chronic kidney disease or clinical heart failure and atherosclerotic cardiovascular disease, an SGLT2 inhibitor with proven benefit is recommended. GLP-1 receptor agonists are generally recommended as the first injectable medication.

1,192 citations

Journal Article•DOI•
Heart Disease and Stroke Statistics—2023 Update: A Report From the American Heart Association

[...]

21 Feb 2023-Circulation
TL;DR: The 2023 Statistical Update as mentioned in this paper provides the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health.
Abstract: Background: The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). Methods: The American Heart Association, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2023 Statistical Update is the product of a full year’s worth of effort in 2022 by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. The American Heart Association strives to further understand and help heal health problems inflicted by structural racism, a public health crisis that can significantly damage physical and mental health and perpetuate disparities in access to health care, education, income, housing, and several other factors vital to healthy lives. This year’s edition includes additional COVID-19 (coronavirus disease 2019) publications, as well as data on the monitoring and benefits of cardiovascular health in the population, with an enhanced focus on health equity across several key domains. Results: Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. Conclusions: The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

300 citations

Journal Article•DOI•
Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea: The PIONEER 3 Randomized Clinical Trial.

[...]

Julio Rosenstock, Dale Allison, Andreas L. Birkenfeld1, Thalia Marie Blicher2, Srikanth Deenadayalan2, Jacob Bonde Jacobsen2, Pierre Serusclat, Rafael Violante3, Hirotaka Watada4, Melanie J. Davies5 •
Dresden University of Technology1, Novo Nordisk2, Mexican Social Security Institute3, Juntendo University4, University of Leicester5
16 Apr 2019-JAMA
TL;DR: Semaglutide, 7 and 14 mg/d, compared with sitagliptin, significantly reduced HbA1c over 26 weeks, but there was no significant benefit with the 3-mg/d dosage.
Abstract: Importance Phase 3 trials have not compared oral semaglutide, a glucagon-like peptide 1 receptor agonist, with other classes of glucose-lowering therapy. Objective To compare efficacy and assess long-term adverse event profiles of once-daily oral semaglutide vs sitagliptin, 100 mg added on to metformin with or without sulfonylurea, in patients with type 2 diabetes. Design, Setting, and Participants Randomized, double-blind, double-dummy, parallel-group, phase 3a trial conducted at 206 sites in 14 countries over 78 weeks from February 2016 to March 2018. Of 2463 patients screened, 1864 adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea were randomized. Interventions Patients were randomized to receive once-daily oral semaglutide, 3 mg (n = 466), 7 mg (n = 466), or 14 mg (n = 465), or sitagliptin, 100 mg (n = 467). Semaglutide was initiated at 3 mg/d and escalated every 4 weeks, first to 7 mg/d then to 14 mg/d, until the randomized dosage was achieved. Main Outcomes and Measures The primary end point was change in glycated hemoglobin (HbA1c), and the key secondary end point was change in body weight, both from baseline to week 26. Both were assessed at weeks 52 and 78 as additional secondary end points. End points were tested for noninferiority with respect to HbA1c(noninferiority margin, 0.3%) prior to testing for superiority of HbA1cand body weight. Results Among 1864 patients randomized (mean age, 58 [SD, 10] years; mean baseline HbA1c, 8.3% [SD, 0.9%]; mean body mass index, 32.5 [SD, 6.4]; n=879 [47.2%] women), 1758 (94.3%) completed the trial and 298 prematurely discontinued treatment (16.7% for semaglutide, 3 mg/d; 15.0% for semaglutide, 7 mg/d; 19.1% for semaglutide, 14 mg/d; and 13.1% for sitagliptin). Semaglutide, 7 and 14 mg/d, compared with sitagliptin, significantly reduced HbA1c(differences, –0.3% [95% CI, –0.4% to –0.1%] and –0.5% [95% CI, –0.6% to –0.4%], respectively;P Conclusions and Relevance Among adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea, oral semaglutide, 7 mg/d and 14 mg/d, compared with sitagliptin, resulted in significantly greater reductions in HbA1cover 26 weeks, but there was no significant benefit with the 3-mg/d dosage. Further research is needed to assess effectiveness in a clinical setting. Trial Registration ClinicalTrials.gov Identifier:NCT02607865

202 citations

Journal Article•DOI•
PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes

[...]

Vanita R. Aroda1, Vanita R. Aroda2, Julio Rosenstock, Yasuo Terauchi3, Yuksel Altuntas4, Nebojsa Lalic5, Enrique C. Morales Villegas, Ole K. Jeppesen6, Erik Christiansen6, Christin L. Hertz6, Martin Haluzik •
MedStar Health1, Brigham and Women's Hospital2, Yokohama City University3, University of Health Sciences Antigua4, University of Belgrade5, Novo Nordisk6
01 Sep 2019-Diabetes Care
TL;DR: In patients with type 2 diabetes, oral semaglutide monotherapy demonstrated superior and clinically relevant improvements in HbA1c (all doses) and body weight loss (14 mg dose) versus placebo, with a safety profile consistent with other GLP-1 receptor agonists.
Abstract: OBJECTIVE This trial compared the efficacy and safety of the first oral glucagon-like peptide 1 (GLP-1) receptor agonist, oral semaglutide, as monotherapy with placebo in patients with type 2 diabetes managed by diet and exercise alone. Two estimands addressed two efficacy-related questions: a treatment policy estimand (regardless of trial product discontinuation or rescue medication use) and a trial product estimand (on trial product without rescue medication use) in all randomized patients. RESEARCH DESIGN AND METHODS This was a 26-week, phase 3a, randomized, double-blind, placebo-controlled, parallel-group trial conducted in 93 sites in nine countries. Adults with type 2 diabetes insufficiently controlled with diet and exercise were randomized (1:1:1:1) to once-daily oral semaglutide 3 mg, 7 mg, 14 mg, or placebo. The primary end point was change from baseline to week 26 in HbA1c. The confirmatory secondary end point was change from baseline to week 26 in body weight. RESULTS In the 703 patients randomized (mean age 55 years, 50.8% male, and mean baseline HbA1c 8.0% [64 mmol/mol]), oral semaglutide reduced HbA1c (placebo-adjusted treatment differences at week 26: treatment policy estimand, −0.6% [3 mg], −0.9% [7 mg], and −1.1% [14 mg]; trial product estimand, −0.7% [3 mg], −1.2% [7 mg], and −1.4% [14 mg]; P CONCLUSIONS In patients with type 2 diabetes, oral semaglutide monotherapy demonstrated superior and clinically relevant improvements in HbA1c (all doses) and body weight loss (14 mg dose) versus placebo, with a safety profile consistent with other GLP-1 receptor agonists.

192 citations

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Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement.

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TL;DR: The QUOROM Statement (QUality Of Reporting Of Meta-analyses) as mentioned in this paper was developed to address the suboptimal reporting of systematic reviews and meta-analysis of randomized controlled trials.
Abstract: Systematic reviews and meta-analyses have become increasingly important in health care. Clinicians read them to keep up to date with their field,1,2 and they are often used as a starting point for developing clinical practice guidelines. Granting agencies may require a systematic review to ensure there is justification for further research,3 and some health care journals are moving in this direction.4 As with all research, the value of a systematic review depends on what was done, what was found, and the clarity of reporting. As with other publications, the reporting quality of systematic reviews varies, limiting readers' ability to assess the strengths and weaknesses of those reviews. Several early studies evaluated the quality of review reports. In 1987, Mulrow examined 50 review articles published in 4 leading medical journals in 1985 and 1986 and found that none met all 8 explicit scientific criteria, such as a quality assessment of included studies.5 In 1987, Sacks and colleagues6 evaluated the adequacy of reporting of 83 meta-analyses on 23 characteristics in 6 domains. Reporting was generally poor; between 1 and 14 characteristics were adequately reported (mean = 7.7; standard deviation = 2.7). A 1996 update of this study found little improvement.7 In 1996, to address the suboptimal reporting of meta-analyses, an international group developed a guidance called the QUOROM Statement (QUality Of Reporting Of Meta-analyses), which focused on the reporting of meta-analyses of randomized controlled trials.8 In this article, we summarize a revision of these guidelines, renamed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses), which have been updated to address several conceptual and practical advances in the science of systematic reviews (Box 1). Box 1 Conceptual issues in the evolution from QUOROM to PRISMA

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"Efficacy and safety of glucagon-lik..." refers methods in this paper

  • ...Details of the search strategy are provided in Figure S1....

    [...]

  • ...1 | Data sources and searches The present study was performed according to a prespecified protocol and the PRISMA guidelines for the conducting and reporting of systematic reviews and meta-analyses (File S1).(11,13,14) We searched PubMed, ISI Web of Science and the Cochrane Library for randomized clinical trials (RCTs) published from inception to June 3, 2016 that compared a GLP-1RA with placebo or another GLP-1RA (twicedaily exenatide, lixisenatide, liraglutide, albiglutide, dulaglutide, onceweekly exenatide, semaglutide and taspoglutide) in adults with T2DM....

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TL;DR: The Cochrane Collaboration’s tool for assessing risk of bias aims to make the process clearer and more accurate.
Abstract: Flaws in the design, conduct, analysis, and reporting of randomised trials can cause the effect of an intervention to be underestimated or overestimated. The Cochrane Collaboration’s tool for assessing risk of bias aims to make the process clearer and more accurate

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Journal Article•DOI•
Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

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Steven P. Marso1, Gilbert H. Daniels2, Kirstine Brown-Frandsen3, Peter Lommer Kristensen3, Johannes F.E. Mann4, Michael A. Nauck5, Steven E. Nissen6, Stuart J. Pocock7, Neil R Poulter8, Lasse Steen Ravn3, William M. Steinberg9, Mette Stockner3, Bernard Zinman10, Richard M. Bergenstal, John B. Buse11 •
University of Texas Southwestern Medical Center1, Harvard University2, Novo Nordisk3, University of Erlangen-Nuremberg4, Ruhr University Bochum5, Cleveland Clinic6, University of London7, Imperial College London8, George Washington University9, University of Toronto10, University of North Carolina at Chapel Hill11
13 Jun 2016-The New England Journal of Medicine
TL;DR: In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, orNonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo.
Abstract: BackgroundThe cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. MethodsIn this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. ResultsA total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo ...

4,409 citations

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4,126 citations

"Efficacy and safety of glucagon-lik..." refers background in this paper

  • ...The American Diabetes Association (ADA)/European Association for the study of Diabetes (EASD) guidelines recommend the use of GLP-1RAs as an adjunctive therapy to lifestyle modification and metformin.(9) However, there are no specific recommendations about which GLP-1RA to choose in clinical practice, possibly because of the limited availability of head-to-head studies comparing the efficacy and safety of GLP-1RAs....

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Q1. What have the authors contributed in "Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes systematic review and mixed-treatment comparison analysis: " ?

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10. This article is protected by copyright. Compared to EBID, dulaglutide treatment was associated with the greatest HbA1c and FPG reduction ( 0. 51 % and 1. 04mmol/L ), followed by liraglutide ( 0. 45 %, 0. 93mmol/L ) and once-weekly exenatide ( 0. 38 % and 0. 85mmol/L ) ; similar reductions were found when these three agents were compared to lixisenatide. 

Compared to placebo, all GLP-1RAs reduced HbA1c and fasting plasma glucose (FPG) (from -0.55% and -0.73mmol/L for lixisenatide to -1.21% and -1.97mmol/L for dulaglutide).