Treatment with GLP-1 Receptor Agonists

Living reference work entry
Part of the Endocrinology book series (ENDOCR)

Abstract

The GLP-1 RAs have become popular because of their efficacy and durability in relation to glycemic control and their low risk of hypoglycemia in combination with weight loss in most patients. GLP-1 RAs mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases satiety, and slows gastric emptying. Notably, the insulinotropic and glucagonostatic effects are glucose dependent, and therefore the risk of hypoglycemia is very low during treatment with a GLP-1 RA. The effect on gastric emptying is primarily observed with the short-acting GLP-1 RAs, since significant tachyphylaxis for this effect develops after few days’ treatment with the long-acting GLP-1 RAs. The postprandial glucose control mediated by the short-acting GLP-1 RA seems to be primarily explained through the delaying effect on gastric emptying rather than the effect on insulin and glucagon secretion. In addition, GLP-1 RAs reduce blood pressure during chronic treatment, increase pulse rate, and reduce postprandial triglyceride concentrations. Studies have suggested that GLP-1 receptor agonists might have neuroprotective effects.

The most common adverse events are nausea and other gastrointestinal discomfort. The drawbacks of the GLP-1 RAs include the subcutaneous administration, the gastrointestinal side effects, and the cost.

Several GLP-1 RAs are now licensed for the treatment of type 2 diabetes. However, the intra-class difference raises challenges in relation to individual treatment. In the present chapter, the individual GLP-1 RAs will be presented followed by a head-to-head comparison of GLP-1 RAs. Thereafter, the adverse events and the cardiovascular effects of GLP-1 RAs including the cardiovascular endpoint trials with GLP-1 RAs will be discussed. The efficacy and safety of fixed combination of basal insulin and a GLP-1 RA will be reviewed. The use of GLP-1 RAs in the treatment of patients with type 1 diabetes or in treatment of obesity will also be examined.

Keywords

GLP-1RA Type 2 diabetes Type 1 diabetes Obesity, fixed combination Head-to-head comparison Adverse events Cardiovascular effects 

Reference

  1. Agerso H, Jensen LB, Elbrond B, Rolan P, Zdravkovic M. The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia. 2002;45:195–202.PubMedCrossRefGoogle Scholar
  2. Ahren B, Hirsch IB, Pieber TR, et al. Efficacy and safety of Liraglutide added to capped insulin treatment in subjects with type 1 diabetes: the ADJUNCT TWO randomized trial. Diabetes Care. 2016;39:1693–701.PubMedCrossRefGoogle Scholar
  3. Ahren B, Masmiquel L, Kumar H, et al. 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. 2017;5:341–54.PubMedCrossRefGoogle Scholar
  4. Aroda VR, Rosenstock J, Wysham C, et al. 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. 2016;39:1972–80.PubMedCrossRefGoogle Scholar
  5. Aroda VR, Bain SC, Cariou B, et al. 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. 2017;5:355–66.PubMedCrossRefGoogle Scholar
  6. Asmar A, Simonsen L, Asmar M, et al. Renal extraction and acute effects of glucagon-like peptide-1 on central and renal hemodynamics in healthy men. Am J Physiol Endocrinol Metab. 2015;308:E641–9.PubMedCrossRefGoogle Scholar
  7. Astrup A, Rossner S, Van GL, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009;374:1606–16.PubMedCrossRefGoogle Scholar
  8. Astrup A, Carraro R, Finer N, et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond). 2012;36:843–54.CrossRefGoogle Scholar
  9. Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390:1664.PubMedCrossRefGoogle Scholar
  10. Balena R, Hensley IE, Miller S, Barnett AH. Combination therapy with GLP-1 receptor agonists and basal insulin: a systematic review of the literature. Diabetes Obes Metab. 2013;15:485–502.PubMedCrossRefGoogle Scholar
  11. Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation. 2008;117:2340–50.PubMedCrossRefGoogle Scholar
  12. Barrington P, Chien JY, Showalter HD, et al. A 5-week study of the pharmacokinetics and pharmacodynamics of LY2189265, a novel, long-acting glucagon-like peptide-1 analogue, in patients with type 2 diabetes. Diabetes Obes Metab. 2011;13:426–33.PubMedCrossRefGoogle Scholar
  13. Bettge K, Kahle M, Abd El Aziz MS, Meier JJ, Nauck MA. Occurrence of nausea, vomiting and diarrhoea reported as adverse events in clinical trials studying glucagon-like peptide-1 receptor agonists: a systematic analysis of published clinical trials. Diabetes Obes Metab. 2017;19:336–47.PubMedCrossRefGoogle Scholar
  14. Bjerre KL, Madsen LW, Andersen S, et al. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010;151:1473–86.CrossRefGoogle Scholar
  15. Blackman A, Foster GD, Zammit G, et al. Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnea: the SCALE Sleep Apnea randomized clinical trial. Int J Obes (Lond). 2016;40:1310–9.CrossRefGoogle Scholar
  16. Blair HA, Keating GM. Albiglutide: a review of its use in patients with type 2 diabetes mellitus. Drugs. 2015;75:651–63.PubMedCrossRefGoogle Scholar
  17. Blevins T, Pullman J, Malloy J, et al. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011;96:1301–10.PubMedCrossRefGoogle Scholar
  18. Bolli GB, Munteanu M, Dotsenko S, et al. Efficacy and safety of lixisenatide once daily vs. placebo in people with type 2 diabetes insufficiently controlled on metformin (GetGoal-F1). Diabet Med. 2014;31:176–84.PubMedCrossRefGoogle Scholar
  19. Brunton S, Davidson JA. Exenatide once weekly: a review of pharmacology and treatment considerations in type 2 diabetes. Clin Ther. 2016;38:582–94.PubMedCrossRefGoogle Scholar
  20. Bunck MC, Corner A, Eliasson B, et al. Effects of exenatide on measures of beta-cell function after 3 years in metformin-treated patients with type 2 diabetes. Diabetes Care. 2011;34:2041–7.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 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
  22. Buse JB, Drucker DJ, Taylor KL, et al. DURATION-1: exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks. Diabetes Care. 2010a;33:1255–61.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Buse JB, Sesti G, Schmidt WE, et al. Switching to once-daily liraglutide from twice-daily exenatide further improves glycemic control in patients with type 2 diabetes using oral agents. Diabetes Care. 2010b;33:1300–3.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Buse JB, Garber A, Rosenstock J, et al. Liraglutide treatment is associated with a low frequency and magnitude of antibody formation with no apparent impact on glycemic response or increased frequency of adverse events: results from the Liraglutide Effect and Action in Diabetes (LEAD) trials. J Clin Endocrinol Metab. 2011;96:1695–702.PubMedCrossRefGoogle Scholar
  25. Buse JB, Nauck M, Forst T, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet. 2013;381:117–24.PubMedCrossRefGoogle Scholar
  26. Buse JB, Vilsboll T, Thurman J, et al. Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira). Diabetes Care. 2014;37:2926–33.PubMedCrossRefGoogle Scholar
  27. Calsolaro V, Edison P. Novel GLP-1 (Glucagon-like Peptide-1) analogues and insulin in the treatment for Alzheimer’s disease and other neurodegenerative diseases. CNS Drugs. 2015;29:1023–39.PubMedCrossRefGoogle Scholar
  28. Cefalu WT, Buse JB, Del PS, et al. Beyond metformin: safety considerations in the decision-making process for selecting a second medication for type 2 diabetes management: reflections from a diabetes care editors’ expert forum. Diabetes Care. 2014;37:2647–59.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Cervera A, Wajcberg E, Sriwijitkamol A, et al. Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes. Am J Physiol Endocrinol Metab. 2008;294:E846–52.PubMedCrossRefGoogle Scholar
  30. Chen WR, Hu SY, Chen YD, et al. Effects of liraglutide on left ventricular function in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Am Heart J. 2015;170:845–54.PubMedCrossRefGoogle Scholar
  31. Conway B, Miller RG, Costacou T, et al. Temporal patterns in overweight and obesity in type 1 diabetes. Diabet Med. 2010;27:398–404.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Danne T, Biester T, Kapitzke K, et al. Liraglutide in an adolescent population with obesity: a randomized, double-blind, placebo-controlled 5-week trial to assess safety, tolerability, and pharmacokinetics of Liraglutide in adolescents aged 12–17 years. J Pediatr. 2017;181:146–53.PubMedCrossRefGoogle Scholar
  33. Davies MJ, Bergenstal R, Bode B, et al. Efficacy of Liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA. 2015;314:687–99.PubMedCrossRefGoogle Scholar
  34. Day JW, Gelfanov V, Smiley D, et al. Optimization of co-agonism at GLP-1 and glucagon receptors to safely maximize weight reduction in DIO-rodents. Biopolymers. 2012;98:443–50.PubMedCrossRefGoogle Scholar
  35. De SA, Salem V, Long CJ, et al. The gut hormones PYY 3-36 and GLP-1 7-36 amide reduce food intake and modulate brain activity in appetite centers in humans. Cell Metab. 2011;14:700–6.CrossRefGoogle Scholar
  36. Deacon CF, Knudsen LB, Madsen K, Wiberg FC, Jacobsen O, Holst JJ. Dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1 which have extended metabolic stability and improved biological activity. Diabetologia. 1998;41:271–8.PubMedCrossRefGoogle Scholar
  37. DeFronzo RA. Banting lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773–95.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Dejgaard TF, Frandsen CS, Holst JJ, Madsbad S. Liraglutide for treating type 1 diabetes. Expert Opin Biol Ther. 2016a;16:579–90.PubMedCrossRefGoogle Scholar
  39. Dejgaard TF, Frandsen CS, Hansen TS, et al. Efficacy and safety of liraglutide for overweight adult patients with type 1 diabetes and insufficient glycaemic control (Lira-1): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2016b;4:221–32.PubMedCrossRefGoogle Scholar
  40. Dejgaard TF, Johansen NB, Frandsen CS, et al. Effects of liraglutide on cardiovascular risk factors in patients with type 1 diabetes. Diabetes Obes Metab. 2017;19:734–8.PubMedCrossRefGoogle Scholar
  41. Diamant M, Van GL, Guerci B, et al. Exenatide once weekly versus insulin glargine for type 2 diabetes (DURATION-3): 3-year results of an open-label randomised trial. Lancet Diabetes Endocrinol. 2014;2:464–73.PubMedCrossRefGoogle Scholar
  42. Dong JZ, Shen Y, Zhang J, Tsomaia N, Mierke DF, Taylor JE. Discovery and characterization of taspoglutide, a novel analogue of human glucagon-like peptide-1, engineered for sustained therapeutic activity in type 2 diabetes. Diabetes Obes Metab. 2011;13:19–25.PubMedCrossRefGoogle Scholar
  43. Drucker DJ. The cardiovascular biology of glucagon-like Peptide-1. Cell Metab. 2016;24:15–30.PubMedCrossRefGoogle Scholar
  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;372:1240–50.PubMedCrossRefGoogle Scholar
  45. Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet. 2014;384:1349–57.PubMedCrossRefGoogle Scholar
  46. Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs – FDA and EMA assessment. N Engl J Med. 2014;370:794–7.PubMedCrossRefGoogle Scholar
  47. Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet. 2014;384:2228–34.PubMedCrossRefGoogle Scholar
  48. Fonseca VA, Alvarado-Ruiz R, Raccah D, Boka G, Miossec P, Gerich JE. 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;35:1225–31.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Frandsen CS, Dejgaard TF, Holst JJ, Andersen HU, Thorsteinsson B, Madsbad S. Twelve-week treatment with Liraglutide as add-on to insulin in normal-weight patients with poorly controlled type 1 diabetes: a randomized, placebo-controlled, double-blind parallel study. Diabetes Care. 2015;38:2250–7.PubMedCrossRefGoogle Scholar
  50. Frandsen CS, Dejgaard TF, Madsbad S. Non-insulin drugs to treat hyperglycaemia in type 1 diabetes mellitus. Lancet Diabetes Endocrinol. 2016;4:766–80.PubMedCrossRefGoogle Scholar
  51. Frandsen CS, Dejgaard TF, Andersen HU, et al. Liraglutide as adjunct to insulin treatment in type 1 diabetes does not interfere with glycaemic recovery or gastric emptying rate during hypoglycaemia: a randomized, placebo-controlled, double-blind, parallel-group study. Diabetes Obes Metab. 2017;19:773–82.PubMedCrossRefGoogle Scholar
  52. Frias JP, Guja C, Hardy E, et al. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016;4:1004–16.PubMedCrossRefGoogle Scholar
  53. Frias JP, Bastyr EJ III, Vignati L, et al. The sustained effects of a dual GIP/GLP-1 receptor agonist, NNC0090-2746, in patients with type 2 diabetes. Cell Metab. 2017;26:343–52.PubMedCrossRefGoogle Scholar
  54. Gallwitz B, Ropeter T, Morys-Wortmann C, Mentlein R, Siegel EG, Schmidt WE. GLP-1-analogues resistant to degradation by dipeptidyl-peptidase IV in vitro. Regul Pept. 2000;86:103–11.PubMedCrossRefGoogle Scholar
  55. Gallwitz B, Vaag A, Falahati A, Madsbad S. Adding liraglutide to oral antidiabetic drug therapy: onset of treatment effects over time. Int J Clin Pract. 2010;64:267–76.PubMedCrossRefGoogle Scholar
  56. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the american association of clinical endocrinologists and american college of endocrinology on the comprehensive type 2 diabetes management algorithm – 2016 executive summary. Endocr Pract. 2016;22:84–113.PubMedCrossRefGoogle Scholar
  57. Glaesner W, Vick AM, Millican R, et al. Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY2189265, an Fc fusion protein. Diabetes Metab Res Rev. 2010;26:287–96.PubMedCrossRefGoogle Scholar
  58. Gough SC, Bode B, Woo V, et al. 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. 2014;2:885–93.PubMedCrossRefGoogle Scholar
  59. Gough SC, Bode BW, Woo VC, et al. 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. 2015;17:965–73.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Guh DP, Zhang W, Bansback N, Amarsi Z, Birmingham CL, Anis AH. The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health. 2009;9:88.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Haahr H, Heise T. A review of the pharmacological properties of insulin degludec and their clinical relevance. Clin Pharmacokinet. 2014;53:787–800.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Halbirk M, Norrelund H, Moller N, et al. Cardiovascular and metabolic effects of 48-h glucagon-like peptide-1 infusion in compensated chronic patients with heart failure. Am J Physiol Heart Circ Physiol. 2010;298:H1096–102.PubMedCrossRefGoogle Scholar
  63. Harder H, Nielsen L, Tu DT, Astrup A. The effect of liraglutide, a long-acting glucagon-like peptide 1 derivative, on glycemic control, body composition, and 24-h energy expenditure in patients with type 2 diabetes. Diabetes Care. 2004;27:1915–21.PubMedCrossRefGoogle Scholar
  64. Harkavyi A, Abuirmeileh A, Lever R, Kingsbury AE, Biggs CS, Whitton PS. Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson’s disease. J Neuroinflammation. 2008;5:19.PubMedPubMedCentralCrossRefGoogle Scholar
  65. Hegedus L, Moses AC, Zdravkovic M, Le TT, Daniels GH. GLP-1 and calcitonin concentration in humans: lack of evidence of calcitonin release from sequential screening in over 5000 subjects with type 2 diabetes or nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide. J Clin Endocrinol Metab. 2011;96:853–60.PubMedCrossRefGoogle Scholar
  66. Henry RR, Rosenstock J, Logan DK, Alessi TR, Luskey K, Baron MA. Randomized trial of continuous subcutaneous delivery of exenatide by ITCA 650 versus twice-daily exenatide injections in metformin-treated type 2 diabetes. Diabetes Care. 2013a;36:2559–65.PubMedPubMedCentralCrossRefGoogle Scholar
  67. Henry RR, Logan D, Alessi T, Baron MA. A randomized, open-label, multicenter, 4-week study to evaluate the tolerability and pharmacokinetics of ITCA 650 in patients with type 2 diabetes. Clin Ther. 2013b;35:634–45.PubMedCrossRefGoogle Scholar
  68. Henry RR, Rosenstock J, Logan D, Alessi T, Luskey K, Baron MA. Continuous subcutaneous delivery of exenatide via ITCA 650 leads to sustained glycemic control and weight loss for 48 weeks in metformin-treated subjects with type 2 diabetes. J Diabetes Complicat. 2014;28:393–8.PubMedCrossRefGoogle Scholar
  69. Hermansen K, Baekdal TA, During M, et al. Liraglutide suppresses postprandial triglyceride and apolipoprotein B48 elevations after a fat-rich meal in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, cross-over trial. Diabetes Obes Metab. 2013;15:1040–8.PubMedCrossRefGoogle Scholar
  70. Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly Exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377:1228–39.PubMedCrossRefGoogle Scholar
  71. Holst JJ, Knop FK, Vilsboll T, Krarup T, Madsbad S. Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes. Diabetes Care. 2011;34(Suppl 2):S251–7.PubMedPubMedCentralCrossRefGoogle Scholar
  72. Iepsen EW, Lundgren J, Dirksen C, et al. Treatment with a GLP-1 receptor agonist diminishes the decrease in free plasma leptin during maintenance of weight loss. Int J Obes (Lond). 2015;39:834–41.CrossRefGoogle Scholar
  73. Inzucchi SE, Bergenstal RM, Buse JB, et al. 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. 2015;58:429–42.PubMedCrossRefGoogle Scholar
  74. 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;14:531–8.PubMedCrossRefGoogle Scholar
  75. Jendle J, Grunberger G, Blevins T, Giorgino F, Hietpas RT, Botros FT. Efficacy and safety of dulaglutide in the treatment of type 2 diabetes: a comprehensive review of the dulaglutide clinical data focusing on the AWARD phase 3 clinical trial program. Diabetes Metab Res Rev. 2016;32:776–90.PubMedCrossRefGoogle Scholar
  76. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol. 2014;63:2985–3023.PubMedCrossRefGoogle Scholar
  77. Ji L, Onishi Y, Ahn CW, et al. Efficacy and safety of exenatide once-weekly vs exenatide twice-daily in Asian patients with type 2 diabetes mellitus. J Diabetes Investig. 2013;4:53–61.PubMedCrossRefGoogle Scholar
  78. Jorsal A, Kistorp C, Holmager P, et al. Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)-a multicentre, double-blind, randomised, placebo-controlled trial. Eur J Heart Fail. 2017;19:69–77.PubMedCrossRefGoogle Scholar
  79. Kapitza C, Forst T, Coester HV, Poitiers F, Ruus P, Hincelin-Mery A. Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin. Diabetes Obes Metab. 2013;15:642–9.PubMedPubMedCentralCrossRefGoogle Scholar
  80. Kapitza C, Nosek L, Jensen L, Hartvig H, Jensen CB, Flint A. Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel. J Clin Pharmacol. 2015;55:497–504.PubMedPubMedCentralCrossRefGoogle Scholar
  81. Kielgast U, Holst JJ, Madsbad S. Treatment of type 1 diabetic patients with glucagon-like peptide-1 (GLP-1) and GLP-1R agonists. Curr Diabetes Rev. 2009;5:266–75.PubMedCrossRefGoogle Scholar
  82. Kielgast U, Holst JJ, Madsbad S. Antidiabetic actions of endogenous and exogenous GLP-1 in type 1 diabetic patients with and without residual beta-cell function. Diabetes. 2011;60:1599–607.PubMedPubMedCentralCrossRefGoogle Scholar
  83. Knudsen LB, Nielsen PF, Huusfeldt PO, et al. Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem. 2000;43:1664–9.PubMedCrossRefGoogle Scholar
  84. Kolterman OG, Kim DD, Shen L, et al. Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am J Health Syst Pharm. 2005;62:173–81.PubMedGoogle Scholar
  85. Kumarathurai P, Anholm C, Nielsen OW, et al. Effects of the glucagon-like peptide-1 receptor agonist liraglutide on systolic function in patients with coronary artery disease and type 2 diabetes: a randomized double-blind placebo-controlled crossover study. Cardiovasc Diabetol. 2016;15:105.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Kumarathurai P, Anholm C, Larsen BS, et al. Effects of Liraglutide on heart rate and heart rate variability: a randomized, double-blind, placebo-controlled crossover study. Diabetes Care. 2017a;40:117–24.PubMedCrossRefGoogle Scholar
  87. Kumarathurai P, Anholm C, Fabricius-Bjerre A, et al. Effects of the glucagon-like peptide-1 receptor agonist liraglutide on 24-h ambulatory blood pressure in patients with type 2 diabetes and stable coronary artery disease: a randomized, double-blind, placebo-controlled, crossover study. J Hypertens. 2017b;35:1070–8.PubMedCrossRefGoogle Scholar
  88. Lau J, Bloch P, Schaffer L, et al. Discovery of the once-weekly glucagon-like Peptide-1 (GLP-1) analogue Semaglutide. J Med Chem. 2015;58:7370–80.PubMedCrossRefGoogle Scholar
  89. le Roux CW, Astrup A, Fujioka K, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet. 2017;389:1399–409.PubMedCrossRefGoogle Scholar
  90. Lepore JJ, Olson E, Demopoulos L, et al. Effects of the novel long-acting GLP-1 agonist, Albiglutide, on cardiac function, cardiac metabolism, and exercise capacity in patients with chronic heart failure and reduced ejection fraction. JACC Heart Fail. 2016;4:559–66.PubMedCrossRefGoogle Scholar
  91. Lingvay I, Perez MF, Garcia-Hernandez P, et al. 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. 2016;315:898–907.PubMedCrossRefGoogle Scholar
  92. Linjawi S, Bode BW, Chaykin LB, et al. 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. 2017;8:101–7.PubMedCrossRefGoogle Scholar
  93. Lonborg J, Kelbaek H, Vejlstrup N, et al. Exenatide reduces final infarct size in patients with ST-segment-elevation myocardial infarction and short-duration of ischemia. Circ Cardiovasc Interv. 2012;5:288–95.PubMedCrossRefGoogle Scholar
  94. Madsbad S. Prevalence of residual B cell function and its metabolic consequences in type 1 (insulin-dependent) diabetes. Diabetologia. 1983;24:141–7.PubMedGoogle Scholar
  95. 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;23:463–77.PubMedCrossRefGoogle Scholar
  96. Madsbad S. The role of glucagon-like peptide-1 impairment in obesity and potential therapeutic implications. Diabetes Obes Metab. 2014;16:9–21.PubMedCrossRefGoogle Scholar
  97. Madsbad S. Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists. Diabetes Obes Metab. 2016;18:317–32.PubMedCrossRefGoogle Scholar
  98. Madsbad S, Kielgast U, Asmar M, Deacon CF, Torekov SS, Holst JJ. An overview of once-weekly glucagon-like peptide-1 receptor agonists – available efficacy and safety data and perspectives for the future. Diabetes Obes Metab. 2011;13:394–407.PubMedCrossRefGoogle Scholar
  99. Mann KV, Raskin P. Exenatide extended-release: a once weekly treatment for patients with type 2 diabetes. Diabetes Metab Syndr Obes. 2014;7:229–39.PubMedPubMedCentralGoogle Scholar
  100. Mann JFE, Orsted DD, Brown-Frandsen K, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med. 2017;377:839–48.PubMedCrossRefGoogle Scholar
  101. Margulies KB, Hernandez AF, Redfield MM, et al. Effects of Liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. JAMA. 2016;316:500–8.PubMedPubMedCentralCrossRefGoogle Scholar
  102. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016a;375:311–22.PubMedPubMedCentralCrossRefGoogle Scholar
  103. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016b;375:1834.PubMedCrossRefGoogle Scholar
  104. Mathieu C, Zinman B, Hemmingsson JU, et al. Efficacy and safety of Liraglutide added to insulin treatment in type 1 diabetes: the ADJUNCT ONE treat-to-target randomized trial. Diabetes Care. 2016;39:1702–10.PubMedCrossRefGoogle Scholar
  105. McClean PL, Parthsarathy V, Faivre E, Holscher C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J Neurosci. 2011;31:6587–94.PubMedCrossRefGoogle Scholar
  106. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8:728–42.PubMedCrossRefGoogle Scholar
  107. Meier JJ, Nauck MA. Incretin-based therapies: where will we be 50 years from now? Diabetologia. 2015;58:1745–50.PubMedCrossRefGoogle Scholar
  108. Meier JJ, Gallwitz B, Salmen S, et al. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes. J Clin Endocrinol Metab. 2003;88:2719–25.PubMedCrossRefGoogle Scholar
  109. Meier JJ, Nauck MA, Kranz D, et al. Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes. 2004;53:654–62.PubMedCrossRefGoogle Scholar
  110. Meier JJ, Rosenstock J, Hincelin-Mery A, et al. Contrasting effects of Lixisenatide and Liraglutide on postprandial glycemic control, gastric emptying, and safety parameters in patients with type 2 diabetes on optimized insulin glargine with or without metformin: a randomized, open-label trial. Diabetes Care. 2015;38:1263–73.PubMedCrossRefGoogle Scholar
  111. Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741–4.PubMedCrossRefGoogle Scholar
  112. Nauck MA, Petrie JR, Sesti G, et al. A phase 2, randomized, dose-finding study of the novel once-weekly human GLP-1 analog, Semaglutide, compared with placebo and open-label Liraglutide in patients with type 2 diabetes. Diabetes Care. 2016a;39:231–41.PubMedCrossRefGoogle Scholar
  113. Nauck M, Rizzo M, Johnson A, Bosch-Traberg H, Madsen J, Cariou B. Once-daily Liraglutide versus Lixisenatide as add-on to metformin in type 2 diabetes: a 26-week randomized controlled clinical trial. Diabetes Care. 2016b;39:1501–9.PubMedCrossRefGoogle Scholar
  114. 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;109:962–5.PubMedCrossRefGoogle Scholar
  115. Ostergaard L, Frandsen CS, Madsbad S. Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus: a review. Expert Rev Clin Pharmacol. 2016;9:241–65.PubMedCrossRefGoogle Scholar
  116. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247–57.PubMedCrossRefGoogle Scholar
  117. Pinget M, Goldenberg R, Niemoeller E, Muehlen-Bartmer I, Guo H, Aronson R. Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P). Diabetes Obes Metab. 2013;15:1000–7.PubMedCrossRefGoogle Scholar
  118. Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of Liraglutide in weight management. N Engl J Med. 2015;373:11–22.PubMedCrossRefGoogle Scholar
  119. Polonsky WH, Fisher L, Hessler D, Bruhn D, Best JH. Patient perspectives on once-weekly medications for diabetes. Diabetes Obes Metab. 2011;13:144–9.PubMedCrossRefGoogle Scholar
  120. Polster M, Zanutto E, McDonald S, Conner C, Hammer M. A comparison of preferences for two GLP-1 products – liraglutide and exenatide – for the treatment of type 2 diabetes. J Med Econ. 2010;13:655–61.PubMedCrossRefGoogle Scholar
  121. Pratley RE, Nauck MA, Barnett AH, et al. Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study. Lancet Diabetes Endocrinol. 2014;2:289–97.PubMedCrossRefGoogle Scholar
  122. Pujadas G, Drucker DJ. Vascular biology of glucagon receptor superfamily peptides: mechanistic and clinical relevance. Endocr Rev. 2016;37:554–83.PubMedCrossRefGoogle Scholar
  123. Pyke C, Heller RS, Kirk RK, et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology. 2014;155:1280–90.PubMedCrossRefGoogle Scholar
  124. Ratner RE, Rosenstock J, Boka G. 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;27:1024–32.PubMedPubMedCentralCrossRefGoogle Scholar
  125. Riddle MC, Aronson R, Home P, et al. Adding once-daily lixisenatide for type 2 diabetes inadequately controlled by established basal insulin: a 24-week, randomized, placebo-controlled comparison (GetGoal-L). Diabetes Care. 2013;36:2489–96.PubMedPubMedCentralCrossRefGoogle Scholar
  126. Robinson LE, Holt TA, Rees K, Randeva HS, O’Hare JP. Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis. BMJ Open. 2013;3:e001986.PubMedPubMedCentralCrossRefGoogle Scholar
  127. Rodbard HW, Bode BW, Harris SB, et al. 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. 2017;34:189–96.PubMedCrossRefGoogle Scholar
  128. Rosenstock J, Raccah D, Koranyi L, et al. Efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin: a 24-week, randomized, open-label, active-controlled study (GetGoal-X). Diabetes Care. 2013a;36:2945–51.PubMedPubMedCentralCrossRefGoogle Scholar
  129. Rosenstock J, Balas B, Charbonnel B, et al. The fate of taspoglutide, a weekly GLP-1 receptor agonist, versus twice-daily exenatide for type 2 diabetes: the T-emerge 2 trial. Diabetes Care. 2013b;36:498–504.PubMedPubMedCentralCrossRefGoogle Scholar
  130. Rosenstock J, Hanefeld M, Shamanna P, et al. Beneficial effects of once-daily lixisenatide on overall and postprandial glycemic levels without significant excess of hypoglycemia in type 2 diabetes inadequately controlled on a sulfonylurea with or without metformin (GetGoal-S). J Diabetes Complicat. 2014a;28:386–92.PubMedCrossRefGoogle Scholar
  131. Rosenstock J, Fonseca VA, Gross JL, et al. Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care. 2014b;37:2317–25.PubMedCrossRefGoogle Scholar
  132. Rosenstock J, Diamant M, Aroda VR, et al. 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. 2016a;39:1579–86.PubMedPubMedCentralCrossRefGoogle Scholar
  133. Rosenstock J, Aronson R, Grunberger G, et al. 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. 2016b;39:2026–35.PubMedCrossRefGoogle Scholar
  134. Secher A, Jelsing J, Baquero AF, et al. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Invest. 2014;124:4473–88.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 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;14:910–7.PubMedPubMedCentralCrossRefGoogle Scholar
  136. Smits MM, Muskiet MH, Tonneijck L, et al. Exenatide acutely increases heart rate in parallel with augmented sympathetic nervous system activation in healthy overweight males. Br J Clin Pharmacol. 2016;81:613–20.PubMedPubMedCentralCrossRefGoogle Scholar
  137. Sorli C, Harashima SI, Tsoukas GM, et al. 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. 2017;5:251–60.PubMedCrossRefGoogle Scholar
  138. Tan TM, Salem V, Troke RC, et al. Combination of peptide YY3-36 with GLP-1(7-36) amide causes an increase in first-phase insulin secretion after IV glucose. J Clin Endocrinol Metab. 2014;99:E2317–24.PubMedPubMedCentralCrossRefGoogle Scholar
  139. Teramoto S, Miyamoto N, Yatomi K, et al. Exendin-4, a glucagon-like peptide-1 receptor agonist, provides neuroprotection in mice transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2011;31:1696–705.PubMedPubMedCentralCrossRefGoogle Scholar
  140. Vora J, Christensen T, Rana A, Bain SC. Insulin degludec versus insulin glargine in type 1 and type 2 diabetes mellitus: a meta-analysis of endpoints in phase 3a trials. Diabetes Ther. 2014;5:435–46.PubMedPubMedCentralCrossRefGoogle Scholar
  141. Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond). 2015;39:187.CrossRefGoogle Scholar
  142. Weissman PN, Carr MC, Ye J, et al. HARMONY 4: randomised clinical trial comparing once-weekly albiglutide and insulin glargine in patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea. Diabetologia. 2014;57:2475–84.PubMedCrossRefGoogle Scholar
  143. Young MA, Wald JA, Matthews JE, et al. Clinical pharmacology of albiglutide, a GLP-1 receptor agonist. Postgrad Med. 2014;126:84–97.PubMedCrossRefGoogle Scholar
  144. 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;359:824–30.PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of EndocrinologyHvidovre Hospital, University of CopenhagenCopenhagenDenmark
  2. 2.The NNF Center for Basic Metabolic Research and the Department of Medical Sciences, Panum InstituttetUniversity of CopenhagenCopenhagenDenmark

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