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Once-Weekly GLP-1 Agonists: How Do They Differ from Exenatide and Liraglutide?

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Abstract

Incretin mimetics offer a new modality in diabetes treatment. This modality is based on the effects of the naturally occurring glucoregulatory gut hormone glucagon-like peptide-1 (GLP-1), which counteracts several pathophysiologic traits in type 2 diabetes. GLP-1 receptor agonists with extended half-lives entailing fewer injections and presumably an improved throughout-the-day glycemic control are in clinical development. This article summarizes the physiologic effects of GLP-1; the effects of the already marketed GLP-1 analogues for daily dosing, exenatide and liraglutide; and reviews the presently published data (with emphasis on clinical pharmacokinetics, efficacy, and safety) on GLP-1 agonists, which currently are in development and intended for once-weekly dosing: albiglutide/albugon, CJC-1131, CJC-1134-PC, exenatide once weekly, and taspoglutide.

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References

Papers of particular interest, published recently, have been highlighted as follows: • Of importance, •• Of major importance

  1. • Holst JJ: The physiology of glucagon-like peptide 1. Physiol Rev 2007, 87:1409–1439. This is an excellent review of the physiologic effects of GLP-1, which provide the basis for understanding the therapeutic use of GLP-1–based therapy.

  2. Deacon CF, Johnsen AH, Holst JJ: Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab 1995, 80:952–957.

    Article  CAS  PubMed  Google Scholar 

  3. Mentlein R: Dipeptidyl-peptidase IV (CD26)--role in the inactivation of regulatory peptides. Regul Pept 1999, 85:9–24.

    Article  CAS  PubMed  Google Scholar 

  4. Deacon CF, Nauck MA, Toft-Nielsen M, et al.: Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 1995, 44:1126–1131.

    Article  CAS  PubMed  Google Scholar 

  5. Fehmann HC, Göke R, Göke B: Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide. Endocr Rev 1995, 16:390–410.

    CAS  PubMed  Google Scholar 

  6. Egan JM, Bulotta A, Hui H, Perfetti R: GLP-1 receptor agonists are growth and differentiation factors for pancreatic islet beta cells. Diabetes Metab Res Rev 2003, 19:115–123.

    Article  CAS  PubMed  Google Scholar 

  7. Zhou J, Wang X, Pineyro MA, Egan JM: Glucagon-like peptide 1 and exendin-4 convert pancreatic AR42J cells into glucagon- and insulin-producing cells. Diabetes 1999, 48:2358–2366.

    Article  CAS  PubMed  Google Scholar 

  8. Buteau J, El-Assaad W, Rhodes CJ, et al.: Glucagon-like peptide-1 prevents beta cell glucolipotoxicity. Diabetologia 2004, 47:806–815.

    Article  CAS  PubMed  Google Scholar 

  9. Larsson H, Holst JJ, Ahrén B: Glucagon-like peptide-1 reduces hepatic glucose production indirectly through insulin and glucagon in humans. Acta Physiol Scand 1997, 160:413–422.

    Article  CAS  PubMed  Google Scholar 

  10. Flint A, Raben A, Astrup A, Holst JJ: Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 1998, 101:515–520.

    Article  CAS  PubMed  Google Scholar 

  11. Nikolaidis LA, Mankad S, Sokos GG, et al.: Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation 2004, 109:962–965.

    Article  CAS  PubMed  Google Scholar 

  12. Nikolaidis LA, Elahi D, Hentosz T, et al.: Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation 2004, 110:955–961.

    Article  CAS  PubMed  Google Scholar 

  13. Meier JJ, Gethmann A, Götze O, et al.: Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans. Diabetologia 2006, 49:452–458.

    Article  CAS  PubMed  Google Scholar 

  14. Nyström T, Gutniak MK, Zhang Q, et al.: Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab 2004, 287:E1209–E1215.

    Article  PubMed  Google Scholar 

  15. Carraro-Lacroix LR, Malnic G, Girardi ACC: Regulation of Na+/H+ exchanger NHE3 by glucagon-like peptide 1 receptor agonist exendin-4 in renal proximal tubule cells. Am J Physiol Renal Physiol 2009, 297:F1647–F1655.

    Article  CAS  PubMed  Google Scholar 

  16. Li Y, Perry T, Kindy MS, et al.: GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc Natl Acad Sci U S A 2009, 106:1285–1290.

    Article  CAS  PubMed  Google Scholar 

  17. During MJ, Cao L, Zuzga DS, et al.: Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med 2003, 9:1173–1179.

    Article  CAS  PubMed  Google Scholar 

  18. Eng J, Kleinman WA, Singh L, et al.: Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 1992, 267:7402–7405.

    CAS  PubMed  Google Scholar 

  19. Thorens B, Porret A, Bühler L, et al.: Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor. Diabetes 1993, 42:1678–1682.

    Article  CAS  PubMed  Google Scholar 

  20. European Medicines Agency: EPARs for authorised medicinal products for human use. Byetta: Scientific Discussion (6). Available at http://www.ema.europa.eu/humandocs/Humans/EPAR/byetta/byetta.htm. Accessed February 2010.

  21. Simonsen L, Holst JJ, Deacon CF: Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs. Diabetologia 2006, 49:706–712.

    Article  CAS  PubMed  Google Scholar 

  22. Bosi E, Lucotti P, Setola E, et al.: Incretin-based therapies in type 2 diabetes: a review of clinical results. Diabetes Res Clin Pract 2008, 82(Suppl 2):S102–S107.

    Article  CAS  PubMed  Google Scholar 

  23. Heine RJ, Van Gaal LF, Johns D, et al.: Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med 2005, 143:559–569.

    CAS  PubMed  Google Scholar 

  24. Nauck MA, Duran S, Kim D, et al.: A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia 2007, 50:259–267.

    Article  CAS  PubMed  Google Scholar 

  25. Madsbad S, Krarup T, Deacon CF, Holst JJ: Glucagon-like peptide receptor agonists and dipeptidyl peptidase-4 inhibitors in the treatment of diabetes: a review of clinical trials. Curr Opin Clin Nutr Metab Care 2008, 11:491–499.

    Article  CAS  PubMed  Google Scholar 

  26. Klonoff DC, Buse JB, Nielsen LL, et al.: Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin 2008, 24:275–286.

    CAS  PubMed  Google Scholar 

  27. Okerson T, Yan P, Stonehouse A, Brodows R: Effects of Exenatide on Systolic Blood Pressure in Subjects With Type 2 Diabetes. Am J Hypertens 2009 Dec 17 [Epub ahead of print].

  28. Elbrønd 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.

    Article  PubMed  Google Scholar 

  29. Garber A, Henry R, Ratner R, et al.: Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 2009, 373:473–481.

    Article  CAS  PubMed  Google Scholar 

  30. Nauck M, Frid A, Hermansen K, et al.: Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009, 32:84–90.

    Article  CAS  PubMed  Google Scholar 

  31. Marre M, Shaw J, Brändle M, et al.: Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Diabet Med 2009, 26:268–278.

    Article  CAS  PubMed  Google Scholar 

  32. Zinman B, Gerich J, Buse JB, et al.: Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care 2009, 32:1224–1230.

    Article  CAS  PubMed  Google Scholar 

  33. 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.

    Article  CAS  PubMed  Google Scholar 

  34. Amori RE, Lau J, Pittas AG: Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA 2007, 298:194–206.

    Article  CAS  PubMed  Google Scholar 

  35. European Medicines Agency: EPARs for authorised medicinal products for human use. Victoza: Public assessment report (6). Available from: http://www.ema.europa.eu/humandocs/Humans/EPAR/victoza/victoza.htm. Accessed February 2010.

  36. Blonde L, Russell-Jones D: The safety and efficacy of liraglutide with or without oral antidiabetic drug therapy in type 2 diabetes: an overview of the LEAD 1-5 studies. Diabetes Obes Metab 2009, 11(Suppl 3):26–34.

    Article  CAS  PubMed  Google Scholar 

  37. Russell-Jones D, Vaag A, Schmitz O, et al.: 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 2009, 52:2046–2055.

    Article  CAS  PubMed  Google Scholar 

  38. Thibaudeau K, Robitaille M, Wen S, Paradis V: CJC-1134-PC: An Exendin-4 Conjugate with Extended Pharmacodynamic Profiles in Rodents [abstract 434-P]. Presented at the 66th Scientific Sessions of the American Diabetes Association. Washington, D.C.; June 9–13, 2006.

  39. Wang M, Kipnes M, Matheson S, Wen S: Safety and Pharmacodynamics of CJC-1134-PC, a Novel GLP-1 Receptor Agonist, in Patients with Type 2 Diabetes Mellitus: A Randomized, Placebo-Controlled, Double-Blind, Dose-Escalation Study [abstract 0498-P]. Presented at the 67th Scientific Sessions of the American Diabetes Association. Chicago, IL; June 21–25, 2007.

  40. Wang M, Matheson S, Picard J, Pezzullo J: PC-DAC™: Exendin-4 (CJC-1134-PC) Significantly Reduces HbA1c and Body Weight as an Adjunct Therapy to Metformin: Two Randomized, Double-Blind, Placebo-Controlled, 12 Week, Phase II Studies in Patients with Type 2 Diabetes Mellitus [abstract 553-P]. Presented at the 69th Scientific Sessions of the American Diabetes Association. New Orleans, LA; June 5–9, 2009.

  41. Léger R, Thibaudeau K, Robitaille M, et al. : Identification of CJC-1131-albumin bioconjugate as a stable and bioactive GLP-1(7–36) analog. Bioorg Med Chem Lett 2004, 14:4395–4398.

    Article  PubMed  Google Scholar 

  42. Kim J, Baggio LL, Bridon DP, et al. : Development and characterization of a glucagon-like peptide 1-albumin conjugate: the ability to activate the glucagon-like peptide 1 receptor in vivo. Diabetes 2003, 52:751–759.

    Article  CAS  PubMed  Google Scholar 

  43. Baggio LL, Huang Q, Cao X, Drucker DJ: An albumin-exendin-4 conjugate engages central and peripheral circuits regulating murine energy and glucose homeostasis. Gastroenterology 2008, 134:1137–1147.

    Article  CAS  PubMed  Google Scholar 

  44. Baggio LL, Huang Q, Brown TJ, Drucker DJ: A recombinant human glucagon-like peptide (GLP)-1-albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis. Diabetes 2004, 53:2492–2500.

    Article  CAS  PubMed  Google Scholar 

  45. Bush MA, Matthews JE, De Boever EH, et al.: Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in healthy subjects. Diabetes Obes Metab 2009, 11:498–505.

    Article  CAS  PubMed  Google Scholar 

  46. Rosenstock J, Reusch J, Bush M, et al.: Potential of albiglutide, a long-acting GLP-1 receptor agonist, in type 2 diabetes: a randomized controlled trial exploring weekly, biweekly, and monthly dosing. Diabetes Care 2009, 32:1880–1886.

    Article  CAS  PubMed  Google Scholar 

  47. Matthews JE, Stewart MW, De Boever EH, et al.: Pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in patients with type 2 diabetes. J Clin Endocrinol Metab 2008, 93:4810–4817.

    Article  CAS  PubMed  Google Scholar 

  48. Seino Y, Nakajima H, Miyahara H, et al.: Safety, tolerability, pharmacokinetics and pharmacodynamics of albiglutide, a long-acting GLP-1-receptor agonist, in Japanese subjects with type 2 diabetes mellitus. Curr Med Res Opin 2009, 25:3049–3057.

    Article  CAS  PubMed  Google Scholar 

  49. Woon C, Taylor J, Dong J, Shen Y: BIM 51077, A Stable Glucagon-Like Peptide-1 (GLP-1) Analogue With Preserved Gluco-Incretin Property in Vitro [abstract P1-359]. Presented at the Program of the Endocrine Society's 83 rd Annual Meeting. Denver, CO; June 19–23, 2001.

  50. Wargent E, Nolan A, Shen Y, Dong J: Insulin secretagogue activity in vitro and in perfused pancreas of dipeptidase IV resistant GLP-1 analogs. Diabetologia 2000, 44(Suppl 1):Abstract 532.

  51. Culler M, Carlile L, Sullivan T, Taylor J: BIM-51077, A Novel Glucagon-Like Peptide-1 (GLP-1) Analog With Enhanced in Vivo Efficacy [abstract P1-360]. Presented at the Program of the Endocrine Society's 83 rd Annual Meeting. Denver, CO; June 19–23, 2001.

  52. Kapitza C, Heise T, Birman P, et al.: Pharmacokinetic and pharmacodynamic properties of taspoglutide, a once-weekly, human GLP-1 analogue, after single-dose administration in patients with type 2 diabetes. Diabet Med 2009, 26:1156–1164.

    Article  CAS  PubMed  Google Scholar 

  53. Nauck MA, Ratner RE, Kapitza C, et al.: Treatment with the human once-weekly glucagon-like peptide-1 analog taspoglutide in combination with metformin improves glycemic control and lowers body weight in patients with type 2 diabetes inadequately controlled with metformin alone: a double-blind placebo-controlled study. Diabetes Care 2009, 32:1237–1243.

    Article  CAS  PubMed  Google Scholar 

  54. Ratner R, Nauck M, Asnaghi V, Berria R: Safety and tolerability of high doses of the long acting, human GLP-1 analogue R1583 in diabetic subjects treated with metformin: a double-blind, placebo-controlled phase 2 study. Diabetes 2008, 57(Suppl 1):Abstract 10-O.

  55. Tracy MA, Ward KL, Firouzabadian L, et al.: Factors affecting the degradation rate of poly(lactide-co-glycolide) microspheres in vivo and in vitro. Biomaterials 1999, 20:1057–1062.

    Article  CAS  PubMed  Google Scholar 

  56. Verspohl EJ: Novel therapeutics for type 2 diabetes: incretin hormone mimetics (glucagon-like peptide-1 receptor agonists) and dipeptidyl peptidase-4 inhibitors. Pharmacol Ther 2009, 124:113–138.

    Article  CAS  PubMed  Google Scholar 

  57. Kim D, MacConell L, Zhuang D, et al.: Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes. Diabetes Care 2007, 30:1487–1493.

    Article  CAS  PubMed  Google Scholar 

  58. •• 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. This is presently the only published head-to-head comparison of short-acting versus long-acting GLP-1 analogues.

  59. Iwamoto K, Nasu R, Yamamura A, et al.: Safety, tolerability, pharmacokinetics, and pharmacodynamics of exenatide once weekly in Japanese patients with type 2 diabetes. Endocr J 2009, 56:951–962.

    Article  PubMed  Google Scholar 

  60. Gedulin BR, Smith P, Prickett KS, et al.: Dose-response for glycaemic and metabolic changes 28 days after single injection of long-acting release exenatide in diabetic fatty Zucker rats. Diabetologia 2005, 48:1380–1385.

    Article  CAS  PubMed  Google Scholar 

  61. Mazze R, Strock E, Morgan B, et al.: Diurnal glucose patterns of exenatide once weekly: a 1-year study using continuous glucose monitoring with ambulatory glucose profile analysis. Endocr Pract 2009, 15:326–334.

    Article  PubMed  Google Scholar 

  62. Best JH, Boye KS, Rubin RR, et al.: Improved treatment satisfaction and weight-related quality of life with exenatide once weekly or twice daily. Diabet Med 2009, 26):722–728.

    Google Scholar 

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Christensen, M., Knop, F.K. Once-Weekly GLP-1 Agonists: How Do They Differ from Exenatide and Liraglutide?. Curr Diab Rep 10, 124–132 (2010). https://doi.org/10.1007/s11892-010-0102-x

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