The safety and efficacy of once-weekly glucagon-like peptide-1 receptor agonist semaglutide in patients with type 2 diabetes mellitus: a systemic review and meta-analysis
To investigate the safety and efficacy of once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide as monotherapy or add-on to other antihyperglycaemic agents (AHAs) in patients with type 2 diabetes mellitus (T2DM).
PubMed, Embase, Cochrane library and ClinicalTrials.gov were searched from the inception to January 18, 2018. Randomised controlled trials (RCTs) comparing semaglutide with placebo or other AHAs in T2DM patients were included in our meta-analysis. Risk ratio (RR) and mean difference (MD) with 95% confidence intervals (CI) were used to evaluate the outcomes.
A total of 11 studies with 9519 patients were included in our meta-analysis. The results revealed that compared with placebo or other AHAs, semaglutide had further reduced the level of haemoglobin A1c (HbA1c) [MD 1.03%, 95% CI (0.85%, 1.22%), p < 0.00001], self-measured plasma glucose (SMPG) [MD 1.19 mmol/L, 95% CI (0.84 mmol/L, 1.53 mmol/L), p < 0.00001], fasting plasma glucose (FPG) [MD 1.33 mmol/L, 95% CI (0.97 mmol/L, 1.69 mmol/L), p < 0.00001] and weight [MD 3.61 kg, 95% CI (3.05 kg, 4.17 kg), p < 0.00001] and significantly increased participants who achieved HbA1c < 7.0% [RR 2.26, 95% CI (1.89, 2.70), p < 0.00001] in T2DM patients. Semaglutide had a significant increase in the incidence of adverse events (AEs) [RR 1.06, 95% CI (1.02, 1.11), p < 0.0001] and an analogous incidence in serious adverse events (SAEs) [RR 0.94, 95% CI (0.86, 1.02), p = 0.11] and hypoglycaemic events (severe or blood glucose (BG)-confirmed symptomatic) [RR 0.93, 95% CI (0.74, 1.16), p = 0.50] compared with the control group.
This article revealed that semaglutide had a favourable efficacy and safety in treating T2DM patients. It maybe a superior choice for T2DM patients who have obesity or a poor adherence to daily AHAs.
KeywordsSafety Efficacy Semaglutide Type 2 diabetes mellitus Meta-analysis
G.L. and X.L. made contributions to have the idea for this study and design this study. G.L., X.W. and S.Q. contributed towards literature search, data extraction, data analysis, drafting and critical revision of the manuscript. X.L., Y.Z. and Y.L. made contributions to data interpretation, assess the quality of the studies, drafting and critical revision of the manuscript. All authors had reviewed the manuscript, approved the final draft and decided to submit it for publication.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
- 1.IDF, IDF diabetes atlas, 8th edn (2017). http://www.diabetesatlas.org/. Accessed 15 July 2018
- 2.WHO, World Health Organization Global Report on Diabetes (2016). http://apps.who.int/iris/bitstream/10665/204871/1/9789241565257_eng.pdf?ua=1. Accessed 15 July 2018
- 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 hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 38(1), 140–149 (2015)CrossRefGoogle Scholar
- 8.H.W. Rodbard, L. Blonde, S.S. Braithwaite, E.M. Brett, R.H. Cobin, Y. Handelsman, R. Hellman, P.S. Jellinger, L.G. Jovanovic, P. Levy, J.I. Mechanick, F. Zangeneh, American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr. Pract. 13(Suppl 1), 1–68 (2007)CrossRefGoogle Scholar
- 16.J. Lau, P. Bloch, L. Schaffer, I. Pettersson, J. Spetzler, J. Kofoed, K. Madsen, L.B. Knudsen, J. McGuire, D.B. Steensgaard, H.M. Strauss, D.X. Gram, S.M. Knudsen, F.S. Nielsen, P. Thygesen, S. Reedtz-Runge, T. Kruse, Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J. Med. Chem. 58(18), 7370–7380 (2015)CrossRefGoogle Scholar
- 17.C. Sorli, S.I. Harashima, G.M. Tsoukas, J. Unger, J.D. Karsbøl, T. Hansen, S.C. Bain, Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 5(4), 251–260 (2017)CrossRefGoogle Scholar
- 18.B. Ahrén, L. Masmiquel, H. Kumar, M. Sargin, J.D. Karsbøl, S.H. Jacobsen, F. Chow, Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial. Lancet Diabetes Endocrinol. 5(5), 341–354 (2017)CrossRefGoogle Scholar
- 19.R.E. Pratley, V.R. Aroda, I. Lingvay, J. Lüdemann, C. Andreassen, A. Navarria, A. Viljoen, SUSTAIN 7 investigators, Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet. Diabetes Endocrinol. 6(4), 275–286 (2018)CrossRefGoogle Scholar
- 21.A. Liberati, D.G. Altman, J. Tetzlaff, C. Mulrow, P.C. Gøtzsche, 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 healthcare interventions: explanation and elaboration. BMJ 339, b2700 (2009)CrossRefGoogle Scholar
- 22.J. P. T. Higgins, S. Green (eds.), Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. http://handbook.cochrane.org (2011). Accessed 27 July 2018
- 24.K. Kaku, Y. Yamada, H. Watada, A. Abiko, T. Nishida, J. Zacho, A. Kiyosue, Safety and efficacy of once-weekly semaglutide vs additional oral antidiabetic drugs in Japanese people with inadequately controlled type 2 diabetes: a randomized trial. Diabetes Obes. Metab. 20(5), 1202–1212 (2018)CrossRefGoogle Scholar
- 25.M. Davies, T.R. Pieber, M.L. Hartoft-Nielsen, O.K.H. Hansen, S. Jabbour, J. Rosenstock, Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA 318(15), 1460–1470 (2017)CrossRefGoogle Scholar
- 26.A.J. Ahmann, M. Capehorn, G. Charpentier, F. Dotta, E. Henkel, I. Lingvay, A.G. Holst, M.P. Annett, V.R. Aroda, Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized clinical trial. Diabetes Care 41(2), 258–266 (2018)CrossRefGoogle Scholar
- 27.V.R. Aroda, S.C. Bain, B. Cariou, M. Piletič, L. Rose, M. Axelsen, E. Rowe, J.H. DeVries, Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. Lancet Diabetes Endocrinol. 5(5), 355–366 (2017)CrossRefGoogle Scholar
- 29.S.P. Marso, S.C. Bain, A. Consoli, F.G. Eliaschewitz, E. Jódar, L.A. Leiter, I. Lingvay, J. Rosenstock, J. Seufert, M.L. Warren, V. Woo, O. Hansen, A.G. Holst, J. Pettersson, T. Vilsbøll, SUSTAIN-6 investigators, semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 375(19), 1834–1844 (2016)CrossRefGoogle Scholar
- 31.D.M. Nathan, J.B. Buse, M.B. Davidson, E. Ferrannini, R.R. Holman, R. Sherwin, B. Zinman, American Diabetes Association, European Association for Study of Diabetes, Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 32(1), 193–203 (2009)CrossRefGoogle Scholar
- 32.American Diabetes Association, Standards of medical care in diabetes–2010. Diabetes Care 33(Suppl 1), S11–S61 (2010)Google Scholar
- 33.I.M. Stratton, A.I. Adler, H.A. Neil, D.R. Matthews, S.E. Manley, C.A. Cull, D. Hadden, R.C. Turner, R.R. Holman, Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321(7258), 405–412 (2000)CrossRefGoogle Scholar
- 34.D. Russell-Jones, A. Vaag, O. Schmitz, B.K. Sethi, N. Lalic, S. Antic, M. Zdravkovic, G.M. Ravn, R. Simó, Liraglutide effect and action in diabetes 5 (LEAD-5) met + SU Study Group, liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met + SU): a randomised controlled trial. Diabetologia 52(10), 2046–2055 (2009)CrossRefGoogle Scholar
- 37.B. Zinman, C. Wanner, J.M. Lachin, D. Fitchett, E. Bluhmki, S. Hantel, M. Mattheus, T. Devins, O.E. Johansen, H.J. Woerle, U.C. Broedl, S.E. Inzucchi, EMPA-REG OUTCOME Investigators, empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373(22), 2117–2128 (2015)CrossRefGoogle Scholar
- 38.S.P. Marso, G.H. Daniels, K. Brown-Frandsen, P. Kristensen, J.F. Mann, M.A. Nauck, S.E. Nissen, S. Pocock, N.R. Poulter, L.S. Ravn, W.M. Steinberg, M. Stockner, B. Zinman, R.M. Bergenstal, J.B. Buse, LEADER Steering Committee, LEADER Trial Investigators, Liraglutide and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 375(4), 311–322 (2016)CrossRefGoogle Scholar
- 41.P. Poirier, T.D. Giles, G.A. Bray, Y. Hong, J.S. Stern, F.X. Pi-Sunyer, R.H. Eckel, American Heart Association, Obesity Committee of the Council on Nutrition, Physical activity, and metabolism, obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 113(6), 898–918 (2006)CrossRefGoogle Scholar
- 49.The Diabetes Control and Complications Trial Research Group, Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch. Ophthalmol. 116(7), 874–886 (1998)Google Scholar
- 51.M. Witkowski, L. Wilkinson, N. Webb, A. Weids, D. Glah, H. Vrazic, A systematic literature review and network meta-analysis comparing once-weekly semaglutide with other GLP-1 receptor agonists in patients with type 2 diabetes previously receiving 1-2 oral anti-diabetic drugs. Diabetes Ther. 9(3), 1149–1167 (2018)CrossRefGoogle Scholar
- 52.M. Witkowski, L. Wilkinson, N. Webb, A. Weids, D. Glah, H. Vrazic, A systematic literature review and network meta-analysis comparing once-weekly semaglutide with other GLP-1 receptor agonists in patients with type 2 diabetes previously receiving basal insulin. Diabetes Ther. 9(3), 1233–1251 (2018)CrossRefGoogle Scholar
- 53.R. Sharma, L. Wilkinson, H. Vrazic, E. Popoff, S. Lopes, S. Kanters, E. Druyts, Comparative efficacy of once-weekly semaglutide and SGLT-2 inhibitors in type 2 diabetic patients inadequately controlled with metformin monotherapy: a systematic literature review and network meta-analysis. Curr. Med. Res. Opin. 29, 1–9 (2018)Google Scholar
- 55.P. Andreadis, T. Karagiannis, K. Malandris, I. Avgerinos, A. Liakos, A. Manolopoulos, E. Bekiari, D. R. Matthews, A. Tsapas, Semaglutide for type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Obes. Metab. (2018). https://doi.org/10.1111/dom.13361. [Epub ahead of print]CrossRefGoogle Scholar