Fixed ratio combinations of glucagon like peptide 1 receptor agonists with basal insulin: a systematic review and meta-analysis
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Basal insulin controls primarily fasting plasma glucose but causes hypoglycaemia and weight gain, whilst glucagon like peptide 1 receptor agonists induce weight loss without increasing risk for hypoglycaemia. We conducted a systematic review and meta-analysis of randomised controlled trials to investigate the efficacy and safety of fixed ratio combinations of basal insulin with glucagon like peptide 1 receptor agonists.
We searched Medline, Embase, and the Cochrane Library as well as conference abstracts up to December 2016. We assessed change in haemoglobin A1c, body weight, and incidence of hypoglycaemia and gastrointestinal adverse events.
We included eight studies with 5732 participants in the systematic review. Switch from basal insulin to fixed ratio combinations with a glucagon like peptide 1 receptor agonist was associated with 0.72% reduction in haemoglobin A1c [95% confidence interval –1.03 to –0.41; I 2 = 93%] and 2.35 kg reduction in body weight (95% confidence interval –3.52 to –1.19; I 2 = 93%), reducing also risk for hypoglycaemia [odds ratio 0.70; 95% confidence interval 0.57 to 0.86; I 2 = 85%] but increasing incidence of nausea (odds ratio 6.89; 95% confidence interval 3.73–12.74; I 2 = 79%). Similarly, switching patients from treatment with a glucagon like peptide 1 receptor agonist to a fixed ratio combination with basal insulin was associated with 0.94% reduction in haemoglobin A1c (95% confidence interval –1.11 to –0.77) and an increase in body weight by 2.89 kg (95% confidence interval 2.17–3.61).
Fixed ratio combinations of basal insulin with glucagon like peptide 1 receptor agonists improve glycaemic control whilst balancing out risk for hypoglycaemia and gastrointestinal side effects.
KeywordsBasal insulin Glucagon like peptide 1 receptor agonists Type 2 diabetes mellitus IdegLira LixiLan Systematic review
Compliance with Ethical Standards
Conflict of interest
P.L. was supported by a scholarship from Novo Nordisk for the completion of a Master’s degree in Diabetes Mellitus Care. A.L. has received travelling fees from Novo Nordisk. K. K. has received advisory board consulting fees or honoraria from Novo Nordisk, Astra Zeneca, and has lectured for Novo Nordisk, Sanofi, Boehringer Ingelheim, Astra Zeneca and Pharmaserve—Lilly. A.T. has received ad hoc clinical research support and speaker’s honoraria from Novo Nordisk and Sanofi. The remaining authors declare that they have no competing interests.
This article does not contain any studies with human participants or animals performed by any of the authors.
- 1.International Diabetes Federation Diabetes Atlas (7th edn). http://www.diabetesatlas.org/component/attachments/?task=download&id=116. Accessed 15 Mar 2017
- 2.S.C. Gough, B. Bode, V. Woo, H.W. Rodbard, S. Linjawi, P. Poulsen, L.H. Damgaard, J.B. Buse; N. N. Trial Investigators, Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2(11), 885–893 (2014)CrossRefPubMedGoogle Scholar
- 3.S.E. Inzucchi, R.M. Bergenstal, J.B. Buse, M. Diamant, E. Ferrannini, M. Nauck, A.L. Peters, A. Tsapas, R. Wender, D.R. Matthews, Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 58(3), 429–442 (2015)CrossRefPubMedGoogle Scholar
- 4.European Medicines Agency. Xultophy. Summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002647/WC500177657.pdf. Accessed 15 Mar 2017
- 5.European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Summary of opinion: Suliqua. http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/004243/WC500216058.pdf. Accessed 16 Mar 2017
- 6.Sanofi Aventis U.S. Sanofi receives FDA approval of SoliquaTM 100/33 for the treatment of adults with type 2 diabetes. http://www.news.sanofi.us/2016-11-21-Sanofi-Receives-FDA-Approval-of-Soliqua-100-33-for-the-Treatment-of-Adults-with-Type-2-Diabetes. Accessed 15 Mar 2017
- 7.Novo Nordisk. Novo Nordisk receives FDA Approval for Xultophy® 100/3.6 (insulin degludec and liraglutide injection). http://press.novonordisk-us.com/2016-11-21-Novo-Nordisk-Receives-FDA-Approval-for-Xultophy-100-3-6-insulin-degludec-and-liraglutide-injection. Accessed 15 Mar 2017
- 8.A. Liberati, D.G. Altman, J. Tetzlaff, C. Mulrow, P.C. Gotzsche, J.P. Ioannidis, M. Clarke, P.J. Devereaux, J. Kleijnen, D. Moher, The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann. Intern. Med. 151(4), W65–W94 (2009)CrossRefPubMedGoogle Scholar
- 9.C. Lefebvre E. Manheimer J. Glanville Chapter 6: searching for studies. in Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, ed. By The Cochrane Collaboration (The Cochrane Collaboration, 2011)Google Scholar
- 10.Scottish Intercollegiate Guidelines Network. Search filters. http://www.sign.ac.uk/methodology/filters.html. Accessed 15 Mar 2017
- 11.J.P. Higgins, D.G. Altman, P.C. Gotzsche, P. Juni, D. Moher, A.D. Oxman, J. Savovic, K.F. Schulz, L. Weeks, J.A. Sterne; Cochrane Bias Methods Group, Cochrane Statistical Methods Group, The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343, d5928 (2011)CrossRefPubMedPubMedCentralGoogle Scholar
- 14.V.R. Aroda, J. Rosenstock, C. Wysham, J. Unger, D. Bellido, G. Gonzalez-Galvez, A. Takami, H. Guo, E. Niemoeller, E. Souhami, R.M. Bergenstal, L. LixiLan; Trial Investigators, Efficacy and safety of LixiLan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide in type 2 diabetes inadequately controlled on basal insulin and metformin: the LixiLan-L randomized trial. Diabetes Care 39(11), 1972–1980 (2016)CrossRefPubMedGoogle Scholar
- 16.S.C. Gough, B.W. Bode, V.C. Woo, H.W. Rodbard, S. Linjawi, M. Zacho, P.D. Reiter, J.B. Buse, One-year efficacy and safety of a fixed combination of insulin degludec and liraglutide in patients with type 2 diabetes: results of a 26-week extension to a 26-week main trial. Diabetes Obes. Metab. 17(10), 965–973 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
- 17.I. Lingvay, F.P. Manghi, P. Garcia-Hernandez, P. Norwood, L. Lehmann, M.J. Tarp-Johansen, J.B. Buse; Dual V Investigators, Effect of insulin glargine up-titration vs insulin degludec/liraglutide on glycated hemoglobin levels in patients with uncontrolled type 2 diabetes: the DUAL V randomized clinical trial. JAMA 315(9), 898–907 (2016)CrossRefPubMedGoogle Scholar
- 18.S. Linjawi, B.W. Bode, L.B. Chaykin, J.P. Courreges, Y. Handelsman, L.M. Lehmann, A. Mishra, R.W. Simpson, The efficacy of IDegLira (insulin degludec/liraglutide combination) in adults with type 2 diabetes inadequately controlled with a GLP-1 receptor agonist and oral therapy: DUAL III randomized clinical trial. Diabetes Ther. 8(1), 101–114 (2017)CrossRefPubMedGoogle Scholar
- 19.H.W. Rodbard, B.W. Bode, S.B. Harris, L. Rose, L. Lehmann, H. Jarlov, J. Thurman; Dual Action of Liraglutide and insulin degludec (DUAL) IV trial investigators, Safety and efficacy of insulin degludec/liraglutide (IDegLira) added to sulphonylurea alone or to sulphonylurea and metformin in insulin-naive people with type 2 diabetes: the DUAL IV trial. Diabet. Med. 34(2), 189–196 (2017)CrossRefPubMedGoogle Scholar
- 20.J. Rosenstock, M. Diamant, V.R. Aroda, L. Silvestre, E. Souhami, T. Zhou, R. Perfetti, V. Fonseca; LixiLan PoC Study Group, Efficacy and safety of LixiLan, a titratable fixed-ratio combination of lixisenatide and insulin glargine, versus insulin glargine in type 2 diabetes inadequately controlled on metformin monotherapy: the LixiLan Proof-of-Concept randomized trial. Diabetes Care 39(9), 1579–1586 (2016)CrossRefPubMedGoogle Scholar
- 21.J. Rosenstock, R. Aronson, G. Grunberger, M. Hanefeld, P. Piatti, P. Serusclat, X. Cheng, T. Zhou, E. Niemoeller, E. Souhami, M. Davies; LixiLan-O Trial Investigators, Benefits of LixiLan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide, versus insulin glargine and lixisenatide monocomponents in type 2 diabetes inadequately controlled on oral agents: the LixiLan-O randomized trial. Diabetes Care 39(11), 2026–2035 (2016)CrossRefPubMedGoogle Scholar
- 23.M.J. Davies, D. Glah, B. Chubb, G. Konidaris, P. McEwan, Cost effectiveness of IDegLira vs. alternative basal insulin intensification therapies in patients with type 2 diabetes mellitus uncontrolled on basal insulin in a UK setting. Pharmacoeconomics 34(9), 953–966 (2016)CrossRefPubMedGoogle Scholar
- 24.Institute for Quality and Efficiency in Health Care (IQWiG). Insulin degludec/liraglutide—benefit assessment according to 35a Social Code Book V. https://www.iqwig.de/download/A15-15_Insulin-degludec_liraglutide_Extract-of-dossier-assessment.pdf. Accessed 15 Mar 2017
- 26.T Kunt, FJ Snoek Barriers to insulin initiation and intensification and how to overcome them. Int. J. Clin. Pract. 63(164), 6–10 (2009)Google Scholar