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Treatment with GLP-1 Receptor Agonists

  • Reference work entry
  • First Online:
Diabetes Epidemiology, Genetics, Pathogenesis, Diagnosis, Prevention, and Treatment

Part of the book series: Endocrinology ((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.

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Reference

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Blair HA, Keating GM. Albiglutide: a review of its use in patients with type 2 diabetes mellitus. Drugs. 2015;75:651–63.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Brunton S, Davidson JA. Exenatide once weekly: a review of pharmacology and treatment considerations in type 2 diabetes. Clin Ther. 2016;38:582–94.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Conway B, Miller RG, Costacou T, et al. Temporal patterns in overweight and obesity in type 1 diabetes. Diabet Med. 2010;27:398–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dejgaard TF, Frandsen CS, Holst JJ, Madsbad S. Liraglutide for treating type 1 diabetes. Expert Opin Biol Ther. 2016a;16:579–90.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Drucker DJ. The cardiovascular biology of glucagon-like Peptide-1. Cell Metab. 2016;24:15–30.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Frandsen CS, Dejgaard TF, Madsbad S. Non-insulin drugs to treat hyperglycaemia in type 1 diabetes mellitus. Lancet Diabetes Endocrinol. 2016;4:766–80.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • Haahr H, Heise T. A review of the pharmacological properties of insulin degludec and their clinical relevance. Clin Pharmacokinet. 2014;53:787–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Madsbad S. Prevalence of residual B cell function and its metabolic consequences in type 1 (insulin-dependent) diabetes. Diabetologia. 1983;24:141–7.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Madsbad S. The role of glucagon-like peptide-1 impairment in obesity and potential therapeutic implications. Diabetes Obes Metab. 2014;16:9–21.

    Article  CAS  PubMed  Google Scholar 

  • Madsbad S. Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists. Diabetes Obes Metab. 2016;18:317–32.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8:728–42.

    Article  CAS  PubMed  Google Scholar 

  • Meier JJ, Nauck MA. Incretin-based therapies: where will we be 50 years from now? Diabetologia. 2015;58:1745–50.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Pujadas G, Drucker DJ. Vascular biology of glucagon receptor superfamily peptides: mechanistic and clinical relevance. Endocr Rev. 2016;37:554–83.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Young MA, Wald JA, Matthews JE, et al. Clinical pharmacology of albiglutide, a GLP-1 receptor agonist. Postgrad Med. 2014;126:84–97.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark

    Sten Madsbad

  2. The NNF Center for Basic Metabolic Research and the Department of Medical Sciences, Panum Instituttet, University of Copenhagen, Copenhagen, Denmark

    Sten Madsbad & Jens J. Holst

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  1. Sten Madsbad
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  2. Jens J. Holst
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Correspondence to Sten Madsbad .

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Editors and Affiliations

  1. Division of Endocrinology, Diabetes and Metabolism, University and Hospital Trust of Verona, Verona, Italy

    Enzo Bonora

  2. Diabetes Division, Diabetes Research Unit, University of Texas Health Science Center, San Antonio, TX, USA

    Ralph A. DeFronzo

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Madsbad, S., Holst, J.J. (2018). Treatment with GLP-1 Receptor Agonists. In: Bonora, E., DeFronzo, R. (eds) Diabetes Epidemiology, Genetics, Pathogenesis, Diagnosis, Prevention, and Treatment . Endocrinology. Springer, Cham. https://doi.org/10.1007/978-3-319-45015-5_20

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