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Advances in Therapy

, Volume 30, Issue 2, pp 81–101 | Cite as

Mechanisms and Clinical Efficacy of Lixisenatide for the Management of Type 2 Diabetes

  • Michael HorowitzEmail author
  • Christopher K. Rayner
  • Karen L. Jones
Open Access
Review

Abstract

Introduction

“Incretin-based” therapies, such as the glucagon-like peptide-1 (GLP-1) receptor agonists, represent a major advance in type 2 diabetes mellitus (T2DM) treatment. GLP-1 receptor agonists differ substantially in their duration of action, frequency of administration and clinical profile.

Methods

This article reviews the mechanisms of action and clinical evidence for GLP-1 receptor targeting and discusses differences between GLP-1 therapies, focusing particularly on clinical data for the GLP-1 receptor agonist, lixisenatide.

Results

GLP-1 therapies target islet cell “defects” of insufficient insulin and excessive glucagon secretion in T2DM, in a glucose-dependent manner, with minimal risk of hypoglycemia. Different GLP-1 therapies exert differential effects on fasting and postprandial glycemia (both being major determinants of glycemic control). They also slow gastric emptying to different extents, probably accounting for different effects to reduce postprandial glycemia. The GetGoal phase 3 studies in T2DM have confirmed the efficacy of once-daily lixisenatide in reducing plasma glucose and glycated hemoglobin (HbA1c), with a pronounced lowering of postprandial plasma glucose (PPG), as monotherapy and as add-on to oral antidiabetic drugs and to basal insulin. Lixisenatide’s ability to diminish PPG is probably partly mediated by its marked ability to delay gastric emptying. Lixisenatide is generally well tolerated, with possibly better gastrointestinal tolerability and lower risk of hypoglycemia than exenatide immediate release. Lixisenatide is associated with a beneficial effect on weight, with either no change or a decrease in body weight when administered as add-on therapy to basal insulin in overweight patients with T2DM.

Conclusions

Lixisenatide improves glycemic control, by primarily affecting PPG, while preventing weight gain or reducing body weight with a low risk of hypoglycemia in T2DM. Lixisenatide is likely to represent a significant advance in the management of T2DM, perhaps particularly in those patients with relatively faster gastric emptying and lower levels of HbA1c, including those receiving basal insulin.

Keywords

Exenatide Gastric emptying Glucagon-like peptide-1 receptor agonists Hypoglycemia Incretin therapies Liraglutide Lixisenatide Pharmacokinetics Postprandial plasma glucose Type 2 diabetes mellitus 

References

  1. 1.
    Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364–1379.PubMedCrossRefGoogle Scholar
  2. 2.
    Hermansen K, Mortensen LS. Bodyweight changes associated with antihyperglycaemic agents in type 2 diabetes mellitus. Drug Saf. 2007;30:1127–1142.PubMedCrossRefGoogle Scholar
  3. 3.
    McIntyre N, Holdsworth CD, Turner DS. New interpretation of oral glucose tolerance. Lancet. 1964;2:20–21.PubMedCrossRefGoogle Scholar
  4. 4.
    Elrick H, Stimmler L, Hlad CJ, Jr., Arai Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964;24:1076–1082.PubMedCrossRefGoogle Scholar
  5. 5.
    Perley MJ, Kipnis DM. Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects. J Clin Invest. 1967;46:1954–1962.PubMedCrossRefGoogle Scholar
  6. 6.
    Dupre J, Ross SA, Watson D, Brown JC. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab. 1973;37:826–828.PubMedCrossRefGoogle Scholar
  7. 7.
    Schmidt WE, Siegel EG, Creutzfeldt W. Glucagon-like peptide-1 but not glucagon-like peptide-2 stimulates insulin release from isolated rat pancreatic islets. Diabetologia. 1985;28:704–707.PubMedCrossRefGoogle Scholar
  8. 8.
    Deacon CF, Nauck MA, Meier J, Hucking K, Holst JJ. Degradation of endogenous and exogenous gastric inhibitory polypeptide in healthy and in type 2 diabetic subjects as revealed using a new assay for the intact peptide. J Clin Endocrinol Metab. 2000;85:3575–3581.PubMedCrossRefGoogle Scholar
  9. 9.
    Hansen L, Deacon CF, Orskov C, Holst JJ. Glucagon-like peptide-1-(7–36)amide is transformed to glucagon-like peptide-1-(9–36) amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology. 1999;140:5356–5363.PubMedCrossRefGoogle Scholar
  10. 10.
    Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29:46–52.PubMedCrossRefGoogle Scholar
  11. 11.
    Hojberg PV, Vilsboll T, Rabol R, et al. Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia. 2009;52:199–207.PubMedCrossRefGoogle Scholar
  12. 12.
    Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132:2131–2157.PubMedCrossRefGoogle Scholar
  13. 13.
    Nauck M, Marre M. Adding liraglutide to oral antidiabetic drug monotherapy: efficacy and weight benefits. Postgrad Med. 2009;121:5–15.PubMedCrossRefGoogle Scholar
  14. 14.
    Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8:728–742.PubMedCrossRefGoogle Scholar
  15. 15.
    Holst JJ, Vilsboll T. Combining GLP-1 receptor agonists with insulin: therapeutic rationales and clinical findings. Diabetes Obes Metab. 2013;15:3–14.PubMedCrossRefGoogle Scholar
  16. 16.
    Kjems LL, Holst JJ, Volund A, Madsbad S. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes. 2003;52:380–386.PubMedCrossRefGoogle Scholar
  17. 17.
    Ahren B, Holst JJ, Mari A. Characterization of GLP-1 effects on beta-cell function after meal ingestion in humans. Diabetes Care. 2003;26:2860–2864.PubMedCrossRefGoogle Scholar
  18. 18.
    Wu L, Olverling A, Huang Z, et al. GLP-1, exendin-4 and C-peptide regulate pancreatic islet microcirculation, insulin secretion and glucose tolerance in rats. Clin Sci (Lond). 2012;122:375–384.CrossRefGoogle Scholar
  19. 19.
    Wang Y, Kole HK, Montrose-Rafizadeh C, Perfetti R, Bernier M, Egan JM. Regulation of glucose transporters and hexose uptake in 3T3-L1 adipocytes: glucagon-like peptide-1 and insulin interactions. J Mol Endocrinol. 1997;19:241–248.PubMedCrossRefGoogle Scholar
  20. 20.
    Hunt JN, Smith JL, Jiang CL. Effect of meal volume and energy density on the gastric emptying of carbohydrates. Gastroenterology. 1985;89:1326–1330.PubMedGoogle Scholar
  21. 21.
    Brener W, Hendrix TR, McHugh PR. Regulation of the gastric emptying of glucose. Gastroenterology. 1983;85:76–82.PubMedGoogle Scholar
  22. 22.
    Horowitz M, Harding PE, Maddox AF, et al. Gastric and oesophageal emptying in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1989;32:151–159.PubMedCrossRefGoogle Scholar
  23. 23.
    Jones KL, Horowitz M, Carney BI, Wishart JM, Guha S, Green L. Gastric emptying in early noninsulin-dependent diabetes mellitus. J Nucl Med. 1996;37:1643–1648.PubMedGoogle Scholar
  24. 24.
    Gonlachanvit S, Hsu CW, Boden GH, et al. Effect of altering gastric emptying on postprandial plasma glucose concentrations following a physiologic meal in type-II diabetic patients. Dig Dis Sci. 2003;48:488–497.PubMedCrossRefGoogle Scholar
  25. 25.
    Ma J, Pilichiewicz AN, Feinle-Bisset C, et al. Effects of variations in duodenal glucose load on glycaemic, insulin, and incretin responses in type 2 diabetes. Diabet Med. 2012;29:604–608.PubMedCrossRefGoogle Scholar
  26. 26.
    Deane AM, Nguyen NQ, Stevens JE, et al. Endogenous glucagon-like peptide-1 slows gastric emptying in healthy subjects, attenuating postprandial glycemia. J Clin Endocrinol Metab. 2010;95:215–221.PubMedCrossRefGoogle Scholar
  27. 27.
    Naslund E, Gutniak M, Skogar S, Rossner S, Hellstrom PM. Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying in obese men. Am J Clin Nutr. 1998;68:525–530.PubMedGoogle Scholar
  28. 28.
    Little TJ, Pilichiewicz AN, Russo A, et al. Effects of intravenous glucagon-like peptide-1 on gastric emptying and intragastric distribution in healthy subjects: relationships with postprandial glycemic and insulinemic responses. J Clin Endocrinol Metab. 2006;91:1916–1923.PubMedCrossRefGoogle Scholar
  29. 29.
    Willms B, Werner J, Holst JJ, Orskov C, Creutzfeldt W, Nauck MA. Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7–36) amide in type 2 (noninsulin-dependent) diabetic patients. J Clin Endocrinol Metab. 1996;81:327–332.PubMedCrossRefGoogle Scholar
  30. 30.
    Deane AM, Chapman MJ, Fraser RJ, et al. Effects of exogenous glucagon-like peptide-1 on gastric emptying and glucose absorption in the critically ill: relationship to glycemia. Crit Care Med. 2010;38:1261–1269.PubMedGoogle Scholar
  31. 31.
    Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol. 1997;273:E981–E988.PubMedGoogle Scholar
  32. 32.
    Meier JJ, Kemmeries G, Holst JJ, Nauck MA. Erythromycin antagonizes the deceleration of gastric emptying by glucagon-like peptide 1 and unmasks its insulinotropic effect in healthy subjects. Diabetes. 2005;54:2212–2218.PubMedCrossRefGoogle Scholar
  33. 33.
    Nauck MA, Kemmeries G, Holst JJ, Meier JJ. Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans. Diabetes. 2011;60:1561–1565.PubMedCrossRefGoogle Scholar
  34. 34.
    Flint A, Raben A, Ersboll AK, Holst JJ, Astrup A. The effect of physiological levels of glucagon-like peptide-1 on appetite, gastric emptying, energy and substrate metabolism in obesity. Int J Obes Relat Metab Disord. 2001;25:781–792.PubMedCrossRefGoogle Scholar
  35. 35.
    Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359:824–830.PubMedCrossRefGoogle Scholar
  36. 36.
    Gaddy DF, Riedel MJ, Pejawar-Gaddy S, Kieffer TJ, Robbins PD. In vivo expression of HGF/NK1 and GLP-1 from dsAAV vectors enhances pancreatic ss-cell proliferation and improves pathology in the db/db mouse model of diabetes. Diabetes. 2010;59:3108–3116.PubMedCrossRefGoogle Scholar
  37. 37.
    Cornu M, Yang JY, Jaccard E, Poussin C, Widmann C, Thorens B. Glucagon-like peptide-1 protects beta-cells against apoptosis by increasing the activity of an IGF-2/IGF-1 receptor autocrine loop. Diabetes. 2009;58:1816–1825.PubMedCrossRefGoogle Scholar
  38. 38.
    Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–165.PubMedCrossRefGoogle Scholar
  39. 39.
    Bray GM. Exenatide. Am J Health Syst Pharm. 2006;63:411–418.PubMedCrossRefGoogle Scholar
  40. 40.
    Malone J, Trautmann M, Wilhelm K, Taylor K, Kendall DM. Exenatide once weekly for the treatment of type 2 diabetes. Expert Opin Investig Drugs. 2009;18:359–367.PubMedCrossRefGoogle Scholar
  41. 41.
    Elbrond B, Jakobsen G, Larsen S, et al. Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose of NN2211, a long-acting glucagon-like peptide 1 derivative, in healthy male subjects. Diabetes Care. 2002;25:1398–1404.PubMedCrossRefGoogle Scholar
  42. 42.
    Flint A, Kapitza C, Hindsberger C, Zdravkovic M. The once-daily human glucagon-like peptide-1 (GLP-1) analog liraglutide improves postprandial glucose levels in type 2 diabetes patients. Adv Ther. 2011;28:213–226.PubMedCrossRefGoogle Scholar
  43. 43.
    Degn KB, Juhl CB, Sturis J, et al. One week’s treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes. 2004;53:1187–1194.PubMedCrossRefGoogle Scholar
  44. 44.
    Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008;372:1240–1250.PubMedCrossRefGoogle Scholar
  45. 45.
    DeYoung MB, MacConell L, Sarin V, Trautmann M, Herbert P. Encapsulation of exenatide in poly-(D,L-lactide-co-glycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes. Diabetes Technol Ther. 2011;13:1145–1154.PubMedCrossRefGoogle Scholar
  46. 46.
    Distiller L, Ruus P. Pharmacokinetics and pharmacodynamics of GLP-1 agonist AVE0010 in type 2 diabetes patients. Diabetes Care. 2008;57(Suppl. 1):Abstract A154.Google Scholar
  47. 47.
    Vilsboll T, Christensen M, Junker AE, Knop FK, Gluud LL. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ. 2012;344:d7771.PubMedCrossRefGoogle Scholar
  48. 48.
    Monami M, Marchionni N, Mannucci E. Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials. Eur J Endocrinol. 2009;160:909–917.PubMedCrossRefGoogle Scholar
  49. 49.
    Madsbad S. Exenatide and liraglutide: different approaches to develop GLP-1 receptor agonists (incretin mimetics) — preclinical and clinical results. Best Pract Res Clin Endocrinol Metab. 2009;23:463–477.PubMedCrossRefGoogle Scholar
  50. 50.
    Gallwitz B. Preclinical and clinical data on extraglycemic effects of GLP-1 receptor agonists. Rev Diabet Stud. 2009;6:247–259.PubMedCrossRefGoogle Scholar
  51. 51.
    Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374:39–47.PubMedCrossRefGoogle Scholar
  52. 52.
    Kapitza C, Coester H-V, Poitiers F, Heumann G, Ruus P, Hincelin-Méry A. Pharmacodynamic characteristics of lixisenatide (QD 2) versus liraglutide QD in patients with T2DM inadequately controlled with metformin. Poster presented at: 21st World Diabetes Congress, Dubai, UAE, December 8 2011. Abstract D-0740.Google Scholar
  53. 53.
    Buse JB, Bergenstal RM, Glass LC, et al. Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2011;154:103–112.PubMedGoogle Scholar
  54. 54.
    Fineman MS, Cirincione BB, Maggs D, Diamant M. GLP-1 based therapies: differential effects on fasting and postprandial glucose. Diabetes Obes Metab. 2012;14:675–688.PubMedCrossRefGoogle Scholar
  55. 55.
    Linnebjerg H, Park S, Kothare PA, et al. Effect of exenatide on gastric emptying and relationship to postprandial glycemia in type 2 diabetes. Regul Pept. 2008;151:123–129.PubMedCrossRefGoogle Scholar
  56. 56.
    Horowitz M, Dent J. Disordered gastric emptying: mechanical basis, assessment and treatment. Baillieres Clin Gastroenterol. 1991;5:371–407.PubMedCrossRefGoogle Scholar
  57. 57.
    Parkman HP, Hasler WL, Fisher RS. American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology. 2004;127:1592–1622.PubMedCrossRefGoogle Scholar
  58. 58.
    Szarka LA, Camilleri M, Vella A, et al. A stable isotope breath test with a standard meal for abnormal gastric emptying of solids in the clinic and in research. Clin Gastroenterol Hepatol. 2008;6:635–643, e1.PubMedCrossRefGoogle Scholar
  59. 59.
    Perri F, Pastore MR, Annese V. 13C-octanoic acid breath test for measuring gastric emptying of solids. Eur Rev Med Pharmacol Sci. 2005;9:3–8.PubMedGoogle Scholar
  60. 60.
    Jelsing J, Vrang N, Hansen G, Raun K, Tang-Christensen M, Knudsen LB. Liraglutide: short-lived effect on gastric emptying — long lasting effects on body weight. Diabetes Obes Metab. 2012;14:531–538.PubMedCrossRefGoogle Scholar
  61. 61.
    Barnett A. Lixisenatide: evidence for its potential use in the treatment of type 2 diabetes. Core Evidence. 2011;6:67–79.PubMedCrossRefGoogle Scholar
  62. 62.
    Seino Y, Min KW, Niemoeller E, Takami A. Randomized, double-blind, placebo-controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea (GetGoal-L-Asia). Diabetes Obes Metab. 2012;14:910–917.PubMedCrossRefGoogle Scholar
  63. 63.
    Zhang F, Tang X, Cao H, et al. Impaired secretion of total glucagon-like peptide-1 in people with impaired fasting glucose combined impaired glucose tolerance. Int J Med Sci. 2012;9:574–581.PubMedCrossRefGoogle Scholar
  64. 64.
    Yagi T, Nishi S, Hinata S, Murakami M, Yoshimi T. A population association study of four candidate genes (hexokinase II, glucagon-like peptide-1 receptor, fatty acid binding protein-2, and apolipoprotein C-II) with type 2 diabetes and impaired glucose tolerance in Japanese subjects. Diabet Med. 1996;13:902–907.PubMedCrossRefGoogle Scholar
  65. 65.
    Ratner RE, Rosenstock J, Boka G, Investigators DRIS. Dose-dependent effects of the once-daily GLP-1 receptor agonist lixisenatide in patients with type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled trial. Diabet Med. 2010;27:1024–1032.Google Scholar
  66. 66.
    Becker R, Stechl J, Kapitza C, Msihid J. Augmentation of 1st-phase insulin release with lixisenatide in non-diabetic subjects. Diabetes. 2012;61:A212–A344. Abstract 1149-P.CrossRefGoogle Scholar
  67. 67.
    Becker RH, Kapitza C, Stechl J, Ruus P, Msihid J. Restitution of glucose disposition with lixisenatide in T2DM subjects. Diabetes. 2012;61:A212–A344. Abstract 1081-P.CrossRefGoogle Scholar
  68. 68.
    Lorenz M, Pfeiffer C, Steinsträßer A, Ruus P. Effects of lixisenatide once daily on gastric emptying and relationship to postprandial glycemia in type 2 diabetes mellitus. Diabetes. 2012;61:A212–A344. Abstract 1085-P.CrossRefGoogle Scholar
  69. 69.
    Schvarcz E, Palmer M, Aman J, Horowitz M, Stridsberg M, Berne C. Physiological hyperglycemia slows gastric emptying in normal subjects and patients with insulin-dependent diabetes mellitus. Gastroenterology. 1997;113:60–66.PubMedCrossRefGoogle Scholar
  70. 70.
    Riddle M, Home P, Marre M, Niemoeller E, Ping L, Rosenstock J. Efficacy and safety of once-daily lixisenatide in type 2 diabetes insufficiently controlled with basal insulin ± metformin: GetGoal-L Study. Diabetes. 2012;61(Suppl. 1): A212–A344. Abstract 983-P.Google Scholar
  71. 71.
    Rosenstock J, Forst T, Aronson R, et al. Efficacy and safety of once-daily lixisenatide added on to titrated glargine plus oral agents in type 2 diabetes: GetGoal-Duo 1 Study. Presented at: 72nd Scientific Sessions of the American Diabetes Association, Philadelphia PA, 8–12 June 2012. Abstract 62-OR.Google Scholar
  72. 72.
    Ahrén B, Dimas L, Miossec P, Saubado S, Aronson R. Efficacy and safety of lixisenatide QD morning and evening injections vs placebo in T2DM inadequately controlled on metformin (GetGoal-M). Oral presentation at the 21st World Diabetes Congress, Dubai, UAE, December 8 2011. Abstract 0-0591.Google Scholar
  73. 73.
    Ratner R, Hanefield M, Shamanna P, et al. Efficacy and safety of lixisenatide once daily versus placebo in patients with T2DM insufficiently controlled on sulfonylurea + metformin (GetGoal-S). Poster presented at: 47th Annual Meeting of the European Association for the Study of Diabetes, September 12–16 2011, Lisbon, Portugal. Diabetologia. 2011;54(Suppl. 1):1–542. Abstract 785.Google Scholar
  74. 74.
    Pinget M, Goldenberg R, Niemoeller E, Muehlen-Bartmer I, Aronson R. Efficacy and safety of lixisenatide once daily versus placebo in patients with type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P). Diabetes. 2012;61(Suppl. 1):A212–A344. Abstract 1010-P.Google Scholar
  75. 75.
    Rosenstock J, Raccah D, Koranyi L, et al. Efficacy and safety of lixisenatide once daily versus exenatide twice daily in patients with T2DM insufficiently controlled on metformin (GetGoal-X). Poster presented at: 47th Annual Meeting of the European Association for the Study of Diabetes, September 12–16 2011, Lisbon, Portugal. Diabetologia. 2011;54(Suppl. 1):1–542. Abstract 786.Google Scholar
  76. 76.
    Bolli G, Munteanu M, Dotsenko S, Niemoeller E, Boka G, Hanefield M. Efficacy and safety of lixisenatide once-daily versus placebo in patients with T2DM insufficiently controlled on metformin (GetGoal-F1). Poster presented at: 47th Annual Meeting of the European Association for the Study of Diabetes, September 12–16 2011, Lisbon, Portugal. Diabetologia. 2011;54(Suppl. 1):1–542. Abstract 784.Google Scholar
  77. 77.
    Fonseca VA, Alvarado-Ruiz R, Raccah D, et al. Efficacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy: a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes (GetGoal-Mono). Diabetes Care. 2012;35:1225–1231.PubMedCrossRefGoogle Scholar
  78. 78.
    Raccah D, Miossec P, Esposito V, Niemoeller E, Cho M, Gerich JE. Efficacy and safety of lixisenatide in elderly (≥65 yr) and very elderly (≥75 yr) patients with type 2 diabetes: an analysis from the GetGoal phase 3 program. Diabetes. 2012;61:A212–A344. Abstract 972-P.CrossRefGoogle Scholar
  79. 79.
    Liu YH, Ruus P. Pharmacokinetics and safety of the GLP-1 agonist AVE0010 in patients with renal impairment. Diabetes. 2009;58(Suppl. 1):Abstract 557-P.Google Scholar

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© The Author(s) 2013

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Authors and Affiliations

  • Michael Horowitz
    • 1
    • 2
    Email author
  • Christopher K. Rayner
    • 1
    • 2
  • Karen L. Jones
    • 1
    • 2
  1. 1.Discipline of Medicine, Royal Adelaide HospitalUniversity of AdelaideAdelaideAustralia
  2. 2.NHMRC, Centre for Clinical Research Excellence in Nutritional Physiology Interventions and OutcomesUniversity of Adelaide/Royal Adelaide HospitalAdelaideAustralia

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