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Clinical pharmacology of glucagon-like peptide-1 receptor agonists

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Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are an important asset in the armamentarium for the treatment of type 2 diabetes mellitus (type 2 DM). Incretin failure is a critical etiopathogenetic feature of type 2 DM, which, if reversed, results in improved glycaemic control. GLP-1 RAs are injectable peptides that resemble the structure and function of endogenous incretin GLP-1, but as they are not deactivated by the dipeptidyl peptidase-4 (DPP-4), their half-life is prolonged compared with native GLP-1. Based on their ability to activate GLP-1 receptor, GLP-1 RAs are classified as short-acting (exenatide twice-daily and lixisenatide once-daily), and long-acting (liraglutide once-daily and the once-weekly formulations of exenatide extended-release, dulaglutide, and albiglutide). Semaglutide, another long-acting, once-weekly GLP-1 RA, was recently approved by the FDA and EMA. Although all of these agents potently reduce haemoglobin A1C (HbA1c), there are unique features and fundamental differences among them related to fasting and postprandial hyperglycaemia reduction, weight loss potency, cardiovascular protection efficacy, and adverse events profile. It is imperative that current evidence be integrated and applied in the context of an individualised patient-centred approach. This should include not only glucose management but also targeting as many as possible of the pathophysiologic mechanisms responsible for type 2 DM development and progression.

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References

  1. American Diabetes Association Classification and diagnosis of diabetes: standards of medical care in diabetes-2018. Diabetes Care 41: S13-S27

  2. Organization WH. Global report on diabetes: World Health Organization; 2016

    Google Scholar 

  3. Guariguata L, Whiting D, Hambleton I, Beagley J, Linnenkamp U, Shaw J (2014) Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 103:137–149

    Article  PubMed  CAS  Google Scholar 

  4. Fowler MJ (2008) Microvascular and macrovascular complications of diabetes. Clin diabetes 26:77–82

    Article  Google Scholar 

  5. Forouhi NG, Wareham NJ (2014) Epidemiology of diabetes. Medicine (Abingdon) 42:698–702

    Google Scholar 

  6. Halban PA, Polonsky KS, Bowden DW et al (2014) β-Cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. J Clin Endocrinol Metab 99:1983–1992

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Kahn SE, Cooper ME, Del Prato S (2014) Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet 383:1068–1083

    Article  PubMed  CAS  Google Scholar 

  8. DeFronzo RA (1988) The triumvirate: β-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes 37:667–687

    Article  PubMed  CAS  Google Scholar 

  9. DeFronzo RA (2004) Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 88:787–835

    Article  PubMed  CAS  Google Scholar 

  10. Sparks JD, Sparks CE, Adeli K (2012) Selective hepatic insulin resistance, VLDL overproduction, and hypertriglyceridemia. Arterioscler Thromb Vasc Biol 32:2104–2112

    Article  PubMed  CAS  Google Scholar 

  11. DeFronzo RA (2009) From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58:773–795

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. DeFronzo RA, Triplitt CL, Abdul-Ghani M, Cersosimo E (2014) Novel agents for the treatment of type 2 diabetes. Diabetes Spectr 27:100–112

    Article  PubMed  PubMed Central  Google Scholar 

  13. Meier JJ, Nauck MA (2010) Is the diminished incretin effect in type 2 diabetes just an epi-phenomenon of impaired β-cell function? Diabetes 59:1117–1125

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Holst JJ, Knop FK, Vilsbøll T, Krarup T, Madsbad S (2011) Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes. Diabetes Care 34:S251–S257

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Lovshin JA, Drucker DJ (2009) Incretin-based therapies for type 2 diabetes mellitus. Nat Rev Endocrinol 5:262–269

    Article  PubMed  CAS  Google Scholar 

  16. La Barre J (1932) Sur les possibilités d'un traitement du diabète par I'incrétine. Bull Acad R Med Belg 12:620–634

    Google Scholar 

  17. Freeman JS (2010) A physiologic and pharmacological basis for implementation of incretin hormones in the treatment of type 2 diabetes mellitus. Mayo Clin Proc 85:S5–S14

    Article  PubMed  PubMed Central  Google Scholar 

  18. Drucker DJ (2006) The biology of incretin hormones. Cell Metab 3:153–165

    Article  PubMed  CAS  Google Scholar 

  19. Garber AJ (2011) Long-acting glucagon-like peptide 1 receptor agonists. Diabetes Care 34:S279–S284

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W (1993) Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 91:301–307

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Kjems LL, Holst JJ, Vølund A, Madsbad S (2003) The influence of GLP-1 on glucose-stimulated insulin secretion: effects on β-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 52:380–386

    Article  PubMed  CAS  Google Scholar 

  22. Højberg P, Vilsbøll T, Rabøl R et al (2009) 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 52:199–207

    Article  PubMed  CAS  Google Scholar 

  23. Toft-Nielsen M-B, Damholt MB, Madsbad S et al (2001) Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab 86:3717–3723

    Article  PubMed  CAS  Google Scholar 

  24. Baggio LL, Drucker DJ (2007) Biology of incretins: GLP-1 and GIP. Gastroenterology 132:2131–2157

    Article  PubMed  CAS  Google Scholar 

  25. Brubaker PL (2006) The glucagon-like peptides. Ann N Y Acad Sci 1070:10–26

    Article  PubMed  CAS  Google Scholar 

  26. Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ (2011) Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia 54:10–18

    Article  PubMed  CAS  Google Scholar 

  27. Rask E, Olsson T, Söderberg S, Johnson O, Seckl J, Holst JJ et al (2001) Impaired incretin response after a mixed meal is associated with insulin resistance in nondiabetic men. Diabetes Care 24:1640–1645

    Article  PubMed  CAS  Google Scholar 

  28. Reimann F, Gribble FM (2002) Glucose-sensing in glucagon-like peptide-1-secreting cells. Diabetes 51:2757–2763

    Article  PubMed  CAS  Google Scholar 

  29. Vilsbøll T, Krarup T, Deacon CF, Madsbad S, Holst JJ (2001) Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 50:609–613

    Article  PubMed  Google Scholar 

  30. Ørskov C, Wettergren A, Holst JJ (1993) Biological effects and metabolic rates of glucagonlike peptide-1 7–36 amide and glucagonlike peptide-1 7–37 in healthy subjects are indistinguishable. Diabetes 42:658–661

    Article  PubMed  Google Scholar 

  31. Ørskov C, Rabenhøj L, Wettergren A, Kofod H, Holst JJ (1994) Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans. Diabetes 43:535–539

    Article  PubMed  Google Scholar 

  32. Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ (1995) 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 44:1126–1131

    Article  PubMed  CAS  Google Scholar 

  33. Mentlein R, Gallwitz B, Schmidt WE (1993) Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1 (7–36) amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem 214:829–835

    Article  PubMed  CAS  Google Scholar 

  34. Samson SL, Garber AJ (2016) A plethora of GLP-1 agonists: decisions about what to use and when. Curr Diab Rep 16:120

    Article  PubMed  CAS  Google Scholar 

  35. Drucker DJ (2007) Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes: preclinical biology and mechanisms of action. Diabetes Care 30:1335–1343

    Article  PubMed  CAS  Google Scholar 

  36. Aroda VR, Henry RR, Han J et al (2012) Efficacy of GLP-1 receptor agonists and DPP-4 inhibitors: meta-analysis and systematic review. Clin Ther 34:1247–1258 e1222

    Article  PubMed  CAS  Google Scholar 

  37. Eng J, Kleinman W, Singh L, Singh G, Raufman J-P (1992) 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 267:7402–7405

    PubMed  CAS  Google Scholar 

  38. Madsbad S (2016) Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists. Diabetes Obes Metab 18:317–332

    Article  PubMed  CAS  Google Scholar 

  39. Novo Nordisk receives FDA Approval of OZEMPIC® (semaglutide) injection for the treatment of adults with type 2 diabetes, 2017. Available from: http://press.novonordisk-us.com/2017-12-5-Novo-Nordisk-Receives-FDA-Approval-of-OZEMPIC-R-semaglutide-Injection-For-the-Treatment-of-Adults-with-Type-2-Diabetes

  40. EMA, 2018 Summary of the European public assessment report (EPAR) for Ozempic. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=/pages/medicines/human/medicines/004174/human_med_002211.jsp&mid=WC0b01ac058001d124

  41. Sorli C, S-i H, Tsoukas GM et al (2017) 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 5:251–260

    Article  PubMed  CAS  Google Scholar 

  42. DeFronzo RA (2017) Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor. Diabetes Obes Metab 19:1353–1362

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  43. Bunck MC, Corner A, Eliasson B et al (2011) Effects of exenatide on measures of beta-cell function after 3 years in metformin-treated patients with type 2 diabetes. Diabetes Care 34:2041–2047

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Chang AM, Jakobsen G, Sturis J et al (2003) The GLP-1 derivative NN2211 restores beta-cell sensitivity to glucose in type 2 diabetic patients after a single dose. Diabetes 52:1786–1791

    Article  PubMed  CAS  Google Scholar 

  45. Vilsbøll T (2009) The effects of glucagon-like peptide-1 on the beta cell. Diabetes Obes Metab 11:11–18

    Article  PubMed  CAS  Google Scholar 

  46. Sandoval DA, D'Alessio DA (2015) Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol Rev 95:513–548

    Article  PubMed  CAS  Google Scholar 

  47. Nauck MA, Heimesaat MM, Behle K et al (2002) Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab 87:1239–1246

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  49. van Bloemendaal L, IJzerman RG, Ten Kulve JS et al (2014) GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans. Diabetes 63:4186–4196

    Article  PubMed  CAS  Google Scholar 

  50. Marathe CS, Rayner CK, Jones KL, Horowitz M (2011) Effects of GLP-1 and incretin-based therapies on gastrointestinal motor function. Exp Diabetes Res 2011:279530

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Chilton R, Wyatt J, Nandish S, Oliveros R, Lujan M (2011) Cardiovascular comorbidities of type 2 diabetes mellitus: defining the potential of glucagonlike peptide–1-based therapies. Am J Med 124:S35–S53

    Article  PubMed  CAS  Google Scholar 

  52. Mayo KE, Miller LJ, Bataille D et al (2003) International Union of Pharmacology. XXXV. The glucagon receptor family. Pharmacol Rev 55:167–194

    Article  PubMed  CAS  Google Scholar 

  53. Kreymann B, Ghatei M, Williams G, Bloom S (1987) Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet 2:1300–1304

    Article  PubMed  CAS  Google Scholar 

  54. Alarcon C, Wicksteed B, Rhodes C (2006) Exendin 4 controls insulin production in rat islet beta cells predominantly by potentiation of glucose-stimulated proinsulin biosynthesis at the translational level. Diabetologia 49:2920–2929

    Article  PubMed  CAS  Google Scholar 

  55. Yabe D, Seino Y (2011) Two incretin hormones GLP-1 and GIP: comparison of their actions in insulin secretion and β cell preservation. Prog Biophys Mol Biol 107:248–256

    Article  PubMed  CAS  Google Scholar 

  56. Fehmann HC, Habener JF (1991) Functional receptors for the insulinotropic hormone glucagon-like peptide-I (7–37) on a somatostatin secreting cell line. FEBS Lett 279:335–340

    Article  PubMed  CAS  Google Scholar 

  57. Triplitt C, Solis-Herrera C (2015) GLP-1 receptor agonists: practical considerations for clinical practice. Diabetes Educ 41:32S–46S

    Article  PubMed  Google Scholar 

  58. Drucker DJ (2016) The cardiovascular biology of glucagon-like peptide-1. Cell Metab 24:15–30

    Article  PubMed  CAS  Google Scholar 

  59. Muskiet MHA, Smits MM, Morsink LM, Diamant M (2014) The gut-renal axis: do incretin-based agents confer renoprotection in diabetes? Nat Rev Nephrol 10:88–103

    Article  PubMed  CAS  Google Scholar 

  60. Dalsgaard NB, Vilsbøll T, Knop FK (2018) Effects of glucagon-like peptide-1 (GLP-1) receptor agonists on cardiovascular risk factors: a narrative review of head-to-head comparisons. Diabetes Obes Metab 20:508–519

    Article  PubMed  CAS  Google Scholar 

  61. Marso SP, Daniels GH, Brown-Frandsen K et al (2016) Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 375:311–322

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Marso SP, Bain SC, Consoli A et al (2016) Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 375:1834–1844

    Article  PubMed  CAS  Google Scholar 

  63. Pfeffer MA, Claggett B, Diaz R et al (2015) Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 373:2247–2257

    Article  PubMed  CAS  Google Scholar 

  64. Holman RR, Bethel MA, Mentz RJ et al (2017) Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 377:1228–1239

    Article  PubMed  CAS  Google Scholar 

  65. Bethel MA, Patel RA, Merrill P et al (2018) Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol 6:105–113

    Article  PubMed  Google Scholar 

  66. American Diabetes Association Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2018. Diabetes Care 41: S73-S85

  67. Montvida O, Klein K, Kumar S, Khunti K, Paul SK (2017) Addition of or switch to insulin therapy in people treated with glucagon- like peptide-1 receptor agonists: a real-world study in 66 583 patients. Diabetes Obes Metab 19:108–117

    Article  PubMed  CAS  Google Scholar 

  68. Maiorino MI, Chiodini P, Bellastella G, Capuano A, Esposito K, Giugliano D (2017) Insulin and glucagon-like peptide 1 receptor agonist combination therapy in type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Care 40:614–624

    Article  PubMed  Google Scholar 

  69. Abd El Aziz MS, Kahle M, Meier JJ, Nauck MA (2017) A meta-analysis comparing clinical effects of short- or long-acting GLP-1 receptor agonists versus insulin treatment from head-to-head studies in type 2 diabetic patients. Diabetes Obes Metab 19:216–227

    Article  PubMed  CAS  Google Scholar 

  70. Abdul-Ghani M, Mujahid O, Mujahid A, DeFronzo RA, Zirie M, Jayyousi A (2017) Efficacy of exenatide plus pioglitazone versus basal/bolus insulin in T2DM patients with very high HbA1c. J Clin Endocrinol Metab 102:2162–2170

    Article  PubMed  Google Scholar 

  71. Miñambres I, Pérez A (2017) Is there a justification for classifying GLP-1 receptor agonists as basal and prandial? Diabetol Metab Syndr 9:6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Monami M, Dicembrini I, Nreu B, Andreozzi F, Sesti G, Mannucci E (2017) Predictors of response to glucagon-like peptide-1 receptor agonists: a meta-analysis and systematic review of randomized controlled trials. Acta Diabetol 54:1101–1114

    Article  PubMed  CAS  Google Scholar 

  73. Dhir G, Cusi K (2017) Glucagon like peptide-1 receptor agonists for the management of obesity and non-alcoholic fatty liver disease: a novel therapeutic option. J Investig Med 66:7–10

  74. Armstrong MJ, Gaunt P, Aithal GP et al (2016) Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387:679–690

    Article  PubMed  CAS  Google Scholar 

  75. Janzen KM, Steuber TD, Nisly SA (2016) GLP-1 agonists in type 1 diabetes mellitus. Ann Pharmacother 50:656–665

    Article  PubMed  Google Scholar 

  76. Furman BL (2012) The development of Byetta (exenatide) from the venom of the Gila monster as an anti-diabetic agent. Toxicon 59:464–471

    Article  PubMed  CAS  Google Scholar 

  77. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD (2004) Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27:2628–2635

    Article  PubMed  CAS  Google Scholar 

  78. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD (2005) Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 28:1092–1100

    Article  PubMed  CAS  Google Scholar 

  79. Kendall DM, Riddle MC, Rosenstock J et al (2005) Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 28:1083–1091

    Article  PubMed  CAS  Google Scholar 

  80. Nauck MA (2011) Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications. Am J Med 124:S3–S18

    Article  PubMed  CAS  Google Scholar 

  81. Aroda VR, DeYoung MB (2011) Clinical implications of exenatide as a twice-daily or once-weekly therapy for type 2 diabetes. Postgrad Med 123:228–238

    Article  PubMed  Google Scholar 

  82. Drucker DJ, Buse JB, Taylor K et al (2008) Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 372:1240–1250

    Article  PubMed  CAS  Google Scholar 

  83. Frías JP, Guja C, Hardy E et al (2016) 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 4:1004–1016

    Article  PubMed  Google Scholar 

  84. Xultophy full prescribing information. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208583s000lbl.pdf

  85. Gough SCL, Jain R, Woo VC (2016) Insulin degludec/liraglutide (IDegLira) for the treatment of type 2 diabetes. Expert Rev Endocrinol Metab 11:7–19

    Article  PubMed  CAS  Google Scholar 

  86. Russell-Jones D (2009) Molecular, pharmacological and clinical aspects of liraglutide, a once-daily human GLP-1 analogue. Mol Cell Endocrinol 297:137–140

    Article  PubMed  CAS  Google Scholar 

  87. Buse JB, Rosenstock J, Sesti G et al (2009) 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 374:39–47

    Article  PubMed  CAS  Google Scholar 

  88. Buse JB, Nauck M, Forst T et al (2013) Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet 381:117–124

    Article  PubMed  CAS  Google Scholar 

  89. Davies MJ, Bergenstal R, Bode B et al (2015) Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. Jama 314:687–699

    Article  PubMed  CAS  Google Scholar 

  90. Pi-Sunyer X, Astrup A, Fujioka K et al (2015) A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med 373:11–22

    Article  PubMed  CAS  Google Scholar 

  91. le Roux CW, Astrup A, Fujioka K et al (2017) 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 389:1399–1409

    Article  PubMed  CAS  Google Scholar 

  92. Buse JB, Vilsbøll T, Thurman J et al (2014) Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira). Diabetes Care 37:2926–2933

    Article  PubMed  CAS  Google Scholar 

  93. Linjawi S, Bode BW, Chaykin LB et al (2017) The efficacy of IDegLira (insulin Degludec/Liraglutide combination) in adults with type 2 diabetes inadequately controlled with a GLP-1 receptor agonist and oral therapy: DUAL III randomized clinical trial. Diabetes Ther 8:101–114

    Article  PubMed  CAS  Google Scholar 

  94. Rodbard H, Bode B, Harris S et al (2017) Safety and efficacy of insulin degludec/liraglutide (IDegLira) added to sulphonylurea alone or to sulphonylurea and metformin in insulin- naïve people with type 2 diabetes: the DUAL IV trial. Diabet Med 34:189–196

    Article  PubMed  CAS  Google Scholar 

  95. Mann JFE, Ørsted DD, Brown-Frandsen K et al (2017) Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med 377:839–848

    Article  PubMed  CAS  Google Scholar 

  96. Brønden A, Knop FK, Christensen MB (2017) Clinical pharmacokinetics and pharmacodynamics of albiglutide. Clin Pharmacokinet 56:719–731

    Article  PubMed  CAS  Google Scholar 

  97. Pratley RE, Nauck MA, Barnett AH et al (2014) 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 2:289–297

    Article  PubMed  CAS  Google Scholar 

  98. Rosenstock J, Reusch J, Bush M, Yang F, Stewart M, Group AS (2009) Potential of albiglutide, a long-acting GLP-1 receptor agonist, in type 2 diabetes. Diabetes Care 32:1880–1886

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. TANZEUM (albiglutide) discontinuation—Q&A (2017) Available from: https://www.tanzeum.com/pdfs/consumer-faq.pdf

  100. Anderson JE, Thieu VT, Boye KS, Hietpas RT, Garcia-Perez L-E (2016) Dulaglutide in the treatment of adult type 2 diabetes: a perspective for primary care providers. Postgrad Med 128:810–821

    Article  PubMed  Google Scholar 

  101. Jendle J, Grunberger G, Blevins T, Giorgino F, Hietpas RT, Botros FT (2016) 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 32:776–790

    Article  PubMed  CAS  Google Scholar 

  102. Glaesner W, Mark Vick A, Millican R et al (2010) Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY2189265, an Fc fusion protein. Diabetes Metab Res Rev 26:287–296

    Article  PubMed  CAS  Google Scholar 

  103. Umpierrez G, Povedano ST, Manghi FP, Shurzinske L, Pechtner V (2014) Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care 37:2168–2176

    Article  PubMed  CAS  Google Scholar 

  104. Nauck M, Weinstock RS, Umpierrez GE, Guerci B, Skrivanek Z, Milicevic Z (2014) Efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5). Diabetes Care 37:2149–2158

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Dungan KM, Povedano ST, Forst T et al (2014) 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 384:1349–1357

    Article  PubMed  CAS  Google Scholar 

  106. Gerstein HC, Colhoun HM, Dagenais GR et al (2017) Design and baseline characteristics of participants in the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial of dulaglutide’s cardiovascular effects. Diabetes Obes Metab 20:42–49

    Article  PubMed  CAS  Google Scholar 

  107. Anderson SL, Trujillo JM (2016) Lixisenatide in type 2 diabetes: latest evidence and clinical usefulness. Ther Adv Chronic Dis 7:4–17

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Scott LJ (2017) Insulin glargine/lixisenatide: a review in type 2 diabetes. Drugs 77:1353–1362

    Article  PubMed  CAS  Google Scholar 

  109. Goldman J, Trujillo JM (2017) iGlarLixi: a fixed-ratio combination of insulin glargine 100 U/mL and lixisenatide for the treatment of type 2 diabetes. Ann Pharmacother 51:990–999

    Article  PubMed  CAS  Google Scholar 

  110. Fonseca VA, Alvarado-Ruiz R, Raccah D et al (2012) Efficacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy. Diabetes Care 35:1225–1231

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Rosenstock J, Raccah D, Korányi L et al (2013) Efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin. Diabetes Care 36:2945–2951

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Nauck M, Rizzo M, Johnson A, Bosch-Traberg H, Madsen J, Cariou B (2016) Once-daily liraglutide versus lixisenatide as add-on to metformin in type 2 diabetes: a 26-week randomized controlled clinical trial. Diabetes Care 39:1501–1509

    Article  PubMed  CAS  Google Scholar 

  113. Rosenstock J, Aronson R, Grunberger G et al (2016) Benefits of LixiLan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide, versus insulin glargine and lixisenatide monocomponents in type 2 diabetes inadequately controlled on oral agents: the LixiLan-O randomized trial. Diabetes Care 39:2026–2035

    Article  PubMed  CAS  Google Scholar 

  114. OZEMPIC (semaglutide) injection, for subcutaneous use (2017). Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf

  115. Lorenz M, Evers A, Wagner M (2013) Recent progress and future options in the development of GLP-1 receptor agonists for the treatment of diabesity. Bioorg Med Chem Lett 23:4011–4018

    Article  PubMed  CAS  Google Scholar 

  116. Lau J, Bloch P, Schäffer L et al (2015) Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J Med Chem 58:7370–7380

    Article  PubMed  CAS  Google Scholar 

  117. Gotfredsen CF, Mølck A-M, Thorup I et al (2014) The human GLP-1 analogs liraglutide and semaglutide: absence of histopathological effects on the pancreas in nonhuman primates. Diabetes 63:2486–2497

    Article  PubMed  Google Scholar 

  118. Mullard A (2015) Oral GLP1 analogue rounds phase II corner. Nat Rev Drug Discov 14:227

    Google Scholar 

  119. Ahmann A, Capehorn M, Charpentier G et al (2018) 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: 41:258–266

  120. Davies M, Pieber TR, Hartoft-Nielsen M-L, Hansen OKH, Jabbour S, Rosenstock J (2017) Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. Jama 318:1460–1470

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Prasad-Reddy L, Isaacs D (2015) A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond. Drugs Context 4:212283

    Article  PubMed  PubMed Central  Google Scholar 

  122. Monami M, Nreu B, Scatena A et al (2017) Safety issues with glucagon- like peptide-1 receptor agonists: pancreatitis, pancreatic cancer, and cholelithiasis. Data from randomised controlled trials. Diabetes Obes Metab 19:1233–1241

    Article  PubMed  CAS  Google Scholar 

  123. Azoulay L, Filion KB, Platt RW et al (2016) Incretin based drugs and the risk of pancreatic cancer: international multicentre cohort study. BMJ 352:i581

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Egan AG, Blind E, Dunder K et al (2014) Pancreatic safety of incretin-based drugs—FDA and EMA assessment. N Engl J Med 370:794–797

    Article  PubMed  CAS  Google Scholar 

  125. Haluzík M, Mráz M, Svačina Š (2014) Balancing benefits and risks in patients receiving incretin-based therapies: focus on cardiovascular and pancreatic side effects. Drug Saf 37:1003–1010

    Article  PubMed  Google Scholar 

  126. Drucker DJ, Sherman SI, Bergenstal RM, Buse JB (2011) The safety of incretin-based therapies—review of the scientific evidence. J Clin Endocrinol Metab 96:2027–2031

    Article  PubMed  CAS  Google Scholar 

  127. Betônico CCR, Titan SMO, Correa-Giannella MLC, Nery M, Queiroz M (2016) Management of diabetes mellitus in individuals with chronic kidney disease: therapeutic perspectives and glycemic control. Clinics (Sao Paulo) 71:47–53

    Article  Google Scholar 

  128. Neumiller JJ, Alicic RZ, Tuttle KR (2017) Therapeutic considerations for antihyperglycemic agents in diabetic kidney disease. J Am Soc Nephrol 28:2263–2274

    Article  PubMed  PubMed Central  Google Scholar 

  129. Tsimichodimos V, Karanatsis N, Tzavela E, Elisaf M (2017) Antidiabetic drugs and the kidney. Curr Pharm Des 23:6310–6320

    Article  CAS  Google Scholar 

  130. Davies MJ, Bain SC, Atkin SL et al (2015) Efficacy and safety of liraglutide versus placebo as add-on to glucose-lowering therapy in patients with type 2 diabetes and moderate renal impairment (LIRA-RENAL): a randomized clinical trial. Diabetes Care 39:222–230

    PubMed  Google Scholar 

  131. Kei A, Liberopoulos E, Siamopoulos K, Elisaf M (2011) A patient with exenatide-associated acute-on-chronic renal failure requiring hemodialysis. Cardiovasc Continuum 2:14–16

    Google Scholar 

  132. Li L, Li S, Liu J et al (2016) Glucagon-like peptide-1 receptor agonists and heart failure in type 2 diabetes: systematic review and meta-analysis of randomized and observational studies. BMC Cardiovasc Disord 16:91

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Wang T, Wang F, Zhou J, Tang H, Giovenale S (2016) Adverse effects of incretin-based therapies on major cardiovascular and arrhythmia events: meta-analysis of randomized trials. Diabetes Metab Res Rev 32:843–857

    Article  PubMed  CAS  Google Scholar 

  134. Margulies KB, Hernandez AF, Redfield MM et al (2016) Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. Jama 316:500–508

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Buse JB, Garber A, Rosenstock J et al (2011) 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 96:1695–1702

    Article  PubMed  CAS  Google Scholar 

  136. Ratner R, Rosenstock J, Boka G (2010) 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 27:1024–1032

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine, School of Medicine, University of Ioannina, Stavrou Niarchou Str, 45110, Ioannina, Greece

    Dimitrios Sfairopoulos & Evangelos Liberopoulos

  2. First Department of Propaedeutic and Internal Medicine, Medical School, Laiko General Hospital, National and Kapodistrian University of Athens, 10559, Athens, Greece

    Stavros Liatis

  3. Department of Endocrinology, School of Medicine, University of Ioannina, 45110, Ioannina, Greece

    Stelios Tigas

Authors
  1. Dimitrios Sfairopoulos
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  2. Stavros Liatis
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  3. Stelios Tigas
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  4. Evangelos Liberopoulos
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Correspondence to Evangelos Liberopoulos.

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DS has no relevant conflict of interest to report. SL has received research support and/or consulting honoraria from Astra-Zeneca, Boehringer-Ingelheim, MSD, Novartis, Novo Nordisk, Sanofi-Aventis, Eli Lilly, and ELPEN. ST has received lecture honoraria or travel grants from, and/or has participated in advisory boards of, Astra-Zeneca, Boehringer-Ingelheim, Eli Lilly, ELPEN, Galenica, MSD, Novartis, Novo Nordisk, and Sanofi-Aventis. EL has participated in educational, research, and advisory activities sponsored by Astra-Zeneca, MSD, Eli Lilly, Bayer, Amgen, Sanofi-Aventis, Boehringer-Ingelheim, Novartis, Novo Nordisk, Servier, Galenica, ELPEN, and Valeant.

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Sfairopoulos, D., Liatis, S., Tigas, S. et al. Clinical pharmacology of glucagon-like peptide-1 receptor agonists. Hormones 17, 333–350 (2018). https://doi.org/10.1007/s42000-018-0038-0

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