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Benefits and Harms of Once-Weekly Glucagon-like Peptide-1 Receptor Agonist Treatments: A Systematic Review and Network Meta-analysisComparative Clinical Profiles of Once-Weekly GLP-1RAs

Francesco Zaccardi, MD; Zin Zin Htike, MD; David R. Webb, PhD; Kamlesh Khunti, PhD; and Melanie J. Davies, MD
[+] Article, Author, and Disclosure Information

This article was published at www.annals.org on 8 December 2015.


From the Diabetes Research Centre, University of Leicester, Leicester, United Kingdom.

Disclaimer: The views expressed are those of the authors and do not necessarily reflect those of the United Kingdom's National Health Service, National Institute for Health Research, or Department of Health.

Acknowledgment: The authors thank the National Institute for Health Research, Collaboration for Leadership in Applied Health Research and Care—East Midlands and Diet, Lifestyle & Physical Activity Biomedical Research Unit, based at the University Hospitals of Leicester and Loughborough University, United Kingdom, for their support of this work. They also thank Sarah Sutton (University of Leicester, United Kingdom) for her assistance with the literature search and Dimitris Mavridis (University of Ioannina, Greece) for his valuable suggestions.

Grant Support: From Sanofi Aventis to the University of Leicester.

Disclosures: Dr. Khunti reports having acted as a consultant, speaker, and advisory board member for AstraZeneca, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme, Janssen Pharmaceuticals, and Boehringer Ingelheim; grants from AstraZeneca, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, Merck Sharp & Dohme, and Roche. Dr. Davies reports having acted as a consultant, an advisory board member, and speaker for Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca, and Janssen Pharmaceuticals and as a speaker for the Mitsubishi Tanabe Pharma Corporation, as well as grants in support of investigator and investigator-initiated trials from Novo Nordisk, Sanofi-Aventis, and Lilly, outside the submitted work. Authors not named here have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-1432.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.

Reproducible Research Statement:Study protocol: Available as Supplement 1. Statistical code and data set: Available from Dr. Zaccardi (e-mail, fz43@le.ac.uk).

Requests for Single Reprints: Francesco Zaccardi, MD, Diabetes Research Centre, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, United Kingdom; e-mail, fz43@le.ac.uk.

Current Author Addresses: Drs. Zaccardi, Htike, Webb, Khunti, and Davies: Diabetes Research Centre, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, United Kingdom.

Author Contributions: Conception and design: F. Zaccardi, Z.Z. Htike, D.R. Webb, M.J. Davies.

Analysis and interpretation of the data: F. Zaccardi, D.R. Webb.

Drafting of the article: F. Zaccardi, Z.Z. Htike, D.R. Webb, M.J. Davies.

Critical revision of the article for important intellectual content: F. Zaccardi, Z.Z. Htike, D.R. Webb, M.J. Davies.

Final approval of the article: F. Zaccardi, Z.Z. Htike, D.R. Webb, K. Khunti, M.J. Davies.

Statistical expertise: F. Zaccardi.

Obtaining of funding: D.R. Webb.

Collection and assembly of data: F. Zaccardi, Z.Z. Htike, K. Khunti.


Ann Intern Med. 2016;164(2):102-113. doi:10.7326/M15-1432
Text Size: A A A

Background: Once-weekly glucagon-like peptide-1 receptor agonists (GLP-1RAs) are new drugs for the treatment of type 2 diabetes.

Purpose: To summarize evidence for the cardiometabolic efficacy and adverse effects of once-weekly GLP-1RAs in adults with type 2 diabetes.

Data Sources: Electronic databases (PubMed, Web of Science, Cochrane Central Register of Controlled Trials, U.S. Food and Drug Administration, European Medicines Agency, ClinicalTrials.gov) and congress abstracts from inception through 26 September 2015.

Study Selection: Randomized, controlled trials (≥24 weeks of follow-up) studying albiglutide, dulaglutide, once-weekly exenatide, semaglutide, and taspoglutide and reporting a cardiometabolic (primary outcome, hemoglobin A1c [HbA1c]) or safety outcome.

Data Extraction: Extraction was done in duplicate, and risk of bias was assessed. No language restriction was applied.

Data Synthesis: 34 trials (21 126 participants) were included. Compared with placebo, all once-weekly GLP-1RAs reduced HbA1c and fasting plasma glucose; taspoglutide, 20 mg, once-weekly exenatide, and dulaglutide, 1.5 mg, reduced body weight. Among once-weekly GLP-1RAs, the greatest differences were found between dulaglutide, 1.5 mg, and taspoglutide, 10 mg, for HbA1c (–0.4% [95% CI, –0.7% to –0.2%]), once-weekly exenatide and albiglutide for fasting plasma glucose (–0.7 mmol/L [CI, –1.1 to –0.2 mmol/L]; –12.6 mg/dL [CI, –19.8 to –3.6 mg/dL]), and taspoglutide, 20 mg, and dulaglutide, 0.75 mg, for body weight (–1.5 kg [CI, –2.2 to –0.8]). Clinically marginal or no differences were found for blood pressure, blood lipid levels, and C-reactive protein levels. Once-weekly exenatide increased heart rate compared with albiglutide and dulaglutide (1.4 to 3.2 beats/min). Among once-weekly GLP-1RAs, the risk for hypoglycemia was similar, whereas taspoglutide, 20 mg, had the greatest risk for nausea (odds ratios, 1.9 to 5.9).

Limitation: Data were unavailable for semaglutide, definitions of outcomes were heterogeneous, the last-observation-carried-forward imputation method was used in 73% of trials, and publication bias is possible.

Conclusion: Compared with other once-weekly GLP-1RAs, dulaglutide, 1.5 mg; once-weekly exenatide; and taspoglutide, 20 mg, showed a greater reduction of HbA1c, fasting plasma glucose, and body weight. Taspoglutide, 20 mg, had the highest risk for nausea; risk for hypoglycemia among once-weekly GLP-1RAs was similar.

Primary Funding Source: Sanofi Aventis (grant to the University of Leicester).

Figures

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Appendix Figure 1.

Summary of evidence search and selection.

For PubMed, the search was “Exenatide” OR “Taspoglutide” OR “Albiglutide” OR “Dulaglutide” OR “Semaglutide”; limits: Humans and Randomized Controlled Trial. The search strategy was specifically translated for other databases. RCT = randomized, controlled trial.

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Figure 1.

Network maps for cardiometabolic and safety outcomes.

Nodes represent the treatments being compared; their size is proportional to the number of participants. Edges represent the available direct comparisons between pairs of treatments, and their width is proportional to the number of trials comparing every pair. ALB = albiglutide; BASAL = basal insulin; dGLP1 = daily glucagon-like peptide-1 receptor agonists; DUL 0.75 = dulaglutide, 0.75 mg; DUL 1.5 = dulaglutide, 1.5 mg; EOW = exenatide once-weekly; GLIM = glimepiride; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MET = metformin; PIO = pioglitazone; PLA = placebo; RAPID = rapid insulin; SITA = sitagliptin; TAS 10 = taspoglutide, 10 mg; TAS 20 = taspoglutide, 20 mg.

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Appendix Figure 2.

Pairwise random-effects meta-analysis for the primary outcome (HbA1c).

Mean differences are reported for comparisons with at least 1 once-weekly GLP-1RA group. GLP-1RA = glucagon-like peptide-1 receptor agonist; HbA1c = hemoglobin A1c.

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Appendix Figure 3.

Differences versus placebo (dashed line) for cardiometabolic outcomes.

ALB = albiglutide; BASAL = basal insulin; dGLP1 = daily glucagon-like peptide-1 receptor agonists; DUL 0.75 = dulaglutide, 0.75 mg; DUL 1.5 = dulaglutide, 1.5 mg; EOW = exenatide once-weekly; FPG = fasting plasma glucose; GLIM = glimepiride; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MET = metformin; PIO = pioglitazone; PLA = placebo; RAPID = rapid insulin; SITA = sitagliptin; TAS 10 = taspoglutide, 10 mg; TAS 20 = taspoglutide, 20 mg.

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Figure 2.

Comparison of once-weekly glucagon-like peptide-1 receptor agonists for cardiometabolic outcomes.

Data are reported as mean differences (95% CIs) and indicate differences versus the reference drug (for example, compared with dulaglutide, 1.5 mg, albiglutide increases HbA1c by 0.40% [CI, 0.17% to 0.63%]). ALB = albiglutide; DUL 0.75 = dulaglutide, 0.75 mg; DUL 1.5 = dulaglutide, 1.5 mg; EOW = exenatide once-weekly; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; LDL = low-density lipoprotein; TAS 10 = taspoglutide, 10 mg; TAS 20 = taspoglutide, 20 mg.

* To convert values to mg/dL, divide by 0.0555.

† To convert values to mg/dL, divide by 0.0259.

‡ To convert values to mg/dL, divide by 0.0113.

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Appendix Figure 4.

Rank probabilities for the primary outcome (hemoglobin A1c).

GLP-1RA = glucagon-like peptide-1 receptor agonist.

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Appendix Figure 5.

Differences versus placebo (dashed line) for safety outcomes.

ALB = albiglutide; BASAL = basal insulin; dGLP1 = daily glucagon-like peptide-1 receptor agonists; DUL 0.75 = dulaglutide, 0.75 mg; DUL 1.5 = dulaglutide, 1.5 mg; EOW = exenatide once-weekly; GLIM = glimepiride; MET = metformin; PIO = pioglitazone; PLA = placebo; RAPID = rapid insulin; SITA = sitagliptin; TAS 10 = taspoglutide, 10 mg; TAS 20 = taspoglutide, 20 mg.

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Figure 3.

Comparison of once-weekly glucagon-like peptide-1 receptor agonists for safety outcomes.

Data are reported as odds ratios (95% CIs) and indicate differences versus the reference drug (for example, compared with dulaglutide, 1.5 mg, treatment with dulaglutide, 0.75 mg, is associated with an odds ratio for nausea of 0.56 [CI, 0.45 to 0.69]). ALB = albiglutide; DUL 0.75 = dulaglutide, 0.75 mg; DUL 1.5 = dulaglutide, 1.5 mg; EOW = exenatide once-weekly; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; LDL = low-density lipoprotein; TAS 10 = taspoglutide, 10 mg; TAS 20 = taspoglutide, 20 mg.

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