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Safety and Tolerability of Glucagon-Like Peptide-1 Receptor Agonists Utilizing Data from the Exenatide Clinical Trial Development Program

  • Hui Peng
  • Laura L. Want
  • Vanita R. ArodaEmail author
Pharmacologic Treatment of Type 2 Diabetes (HE Lebovitz and G Bahtiyar, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Pharmacologic Treatment of Type 2 Diabetes

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated benefits for patients with type 2 diabetes including A1C reduction and weight loss with minimal risk of hypoglycemia. This article provides an evidence-based update of safety and tolerability considerations for the clinical use of GLP-1RAs as a class, with a specific detailed review of data from the exenatide clinical trial development program, which has the longest history and availability of safety and tolerability data as the first-approved GLP-1RA. Specific areas covered include comparative risk of hypoglycemia, as well as pancreatic, thyroid, and cardiovascular safety data; clinical guidance regarding current safety and tolerability data is also reviewed.

Keywords

GLP-1 receptor agonists Incretin Exenatide Safety Pancreatitis Cardiovascular 

Notes

Acknowledgments

The authors wish to acknowledge Róisín O’Connor and Amanda Sheldon of inScience Communications, Springer Healthcare, for medical writing assistance, which was funded by AstraZeneca.

Compliance with Ethical Standards

Conflict of Interest

Hui Peng declares that he has no conflict of interest.

Laura L. Want has been involved in clinical research trials for AstraZeneca, Sanofi, NovoNordisk, Hanmi, Halozyme, Calibra, and Janssen.

Vanita R. Aroda has served as a consultant for Janssen, Novo Nordisk, and Sanofi-Aventis on behalf of Medstar Health Research Institute. She has been involved in clinical research trials for AstraZeneca/Bristol-Myers Squibb/Amylin, Boehringer-Ingelheim, Eisai, GI Dynamics, Halozyme, Hanmi, Intarcia, Janssen, Novo Nordisk, Sanofi-Aventis, and Takeda. She is an employee of MedStar Health Research Institute.

Human and Animal Rights and Informed Consent

This review article does not contain any new studies with human or animal subjects performed by any of the authors.

References

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

  1. 1.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364–79.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38:140–9.CrossRefPubMedGoogle Scholar
  4. 4.
    American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2015;38 Suppl 1:S1–93.Google Scholar
  5. 5.
    BYETTA [package insert]. Wilmington, DE, AstraZeneca Pharmaceuticals LP, 2015Google Scholar
  6. 6.
    BYDUREON [package insert]. Wilmington, DE, AstraZeneca Pharmaceuticals LP, 2015Google Scholar
  7. 7.
    Victoza [package insert]. Bagsvaerd, Denmark, Novo Nordisk A/S, 2015Google Scholar
  8. 8.
    TANZEUM [package insert]. Research Triangle Park, NC, GlaxoSmithKline, 2015Google Scholar
  9. 9.
    TRULICITY [package insert]. Indianapolis, IN, Eli Lilly and Company, 2015Google Scholar
  10. 10.
    Gallwitz B. Preclinical and clinical data on extraglycemic effects of GLP-1 receptor agonists. Rev Diabet Stud. 2009;6:247–59.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Aroda VR, Ratner R. The safety and tolerability of GLP-1 receptor agonists in the treatment of type 2 diabetes: a review. Diabetes Metab Res Rev. 2011;27:528–42.CrossRefPubMedGoogle Scholar
  12. 12.
    Buse JB, Henry RR, Han J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27:2628–35.CrossRefPubMedGoogle Scholar
  13. 13.
    DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28:1092–100.CrossRefPubMedGoogle Scholar
  14. 14.
    Kendall DM, Riddle MC, Rosenstock J, et al. 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. 2005;28:1083–91.CrossRefPubMedGoogle Scholar
  15. 15.
    Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005;143:559–69.CrossRefPubMedGoogle Scholar
  16. 16.
    Zinman B, Hoogwerf BJ, Duran Garcia S, et al. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2007;146:477–85.CrossRefPubMedGoogle Scholar
  17. 17.
    Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther. 2007;29:2333–48.CrossRefPubMedGoogle Scholar
  18. 18.
    Nauck MA, Duran S, Kim D, et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia. 2007;50:259–67.CrossRefPubMedGoogle Scholar
  19. 19.
    Moretto TJ, Milton DR, Ridge TD, et al. Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2008;30:1448–60.CrossRefPubMedGoogle Scholar
  20. 20.
    Bunck MC, Diamant M, Corner A, et al. One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial. Diabetes Care. 2009;32:762–8.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Davies MJ, Donnelly R, Barnett AH, Jones S, Nicolay C, Kilcoyne A. Exenatide compared with long-acting insulin to achieve glycaemic control with minimal weight gain in patients with type 2 diabetes: results of the Helping Evaluate Exenatide in patients with diabetes compared with Long-Acting insulin (HEELA) study. Diabetes Obes Metab. 2009;11:1153–62.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Apovian CM, Bergenstal RM, Cuddihy RM, et al. Effects of exenatide combined with lifestyle modification in patients with type 2 diabetes. Am J Med. 2010;123(468):e469–17.Google Scholar
  23. 23.
    DeFronzo RA, Triplitt C, Qu Y, Lewis MS, Maggs D, Glass LC. Effects of exenatide plus rosiglitazone on beta-cell function and insulin sensitivity in subjects with type 2 diabetes on metformin. Diabetes Care. 2010;33:951–7.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Riddle M, Ahmann A, Basu A, Aroda V, Ratner R. Metformin+exenatide+basal insulin vs metformin+placebo+basal insulin: reaching A1c <6.5% without weight-gain or serious hypoglycemia (abstract). Diabetes. 2010;59(Suppl 1A):LB6.Google Scholar
  25. 25.
    Gallwitz B, Bohmer M, Segiet T, et al. Exenatide twice daily versus premixed insulin aspart 70/30 in metformin-treated patients with type 2 diabetes: a randomized 26-week study on glycemic control and hypoglycemia. Diabetes Care. 2011;34:604–6.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Buse JB, Bergenstal RM, Glass LC, et al. Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2011;154:103–12.CrossRefPubMedGoogle Scholar
  27. 27.
    Kadowaki T, Namba M, Imaoka T, et al. Improved glycemic control and reduced bodyweight with Exenatide: a double-blind, randomized, phase 3 study in Japanese patients with suboptimally controlled type 2 diabetes over 24 weeks. J Diabetes Invest. 2011;2:210–7.CrossRefGoogle Scholar
  28. 28.
    Diamant M, Nauck MA, Shaginian R, et al. Glucagon-like peptide 1 receptor agonist or bolus insulin with optimized basal insulin in type 2 diabetes. Diabetes Care. 2014;37:2763–73.CrossRefPubMedGoogle Scholar
  29. 29.
    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.CrossRefPubMedGoogle Scholar
  30. 30.
    Bergenstal RM, Wysham C, Macconell L, et al. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet. 2010;376:431–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Diamant M, Van Gaal L, Stranks S, et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet. 2010;375:2234–43.CrossRefPubMedGoogle Scholar
  32. 32.
    Russell-Jones D, Cuddihy RM, Hanefeld M, et al. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. Diabetes Care. 2012;35:252–8.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    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.CrossRefPubMedGoogle Scholar
  34. 34.
    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.CrossRefPubMedGoogle Scholar
  35. 35.
    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. 2010;33:1255–61.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Singh S, Chang HY, Richards TM, Weiner JP, Clark JM, Segal JB. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med. 2013;173:534–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Perfetti R, Zhou J, Doyle ME, Egan JM. Glucagon-like peptide-1 induces cell proliferation and pancreatic-duodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats. Endocrinology. 2000;141:4600–5.CrossRefPubMedGoogle Scholar
  38. 38.
    Campbell RK, Cobble ME, Reid TS, Shomali ME. Distinguishing among incretin-based therapies. Glucose-lowering effects of incretin-based therapies. J Fam Pract. 2010;59:S10–9.PubMedGoogle Scholar
  39. 39.
    Chelikani PK, Haver AC, Reidelberger RD. Ghrelin attenuates the inhibitory effects of glucagon-like peptide-1 and peptide YY(3-36) on food intake and gastric emptying in rats. Diabetes. 2006;55:3038–46.CrossRefPubMedGoogle Scholar
  40. 40.
    Gill A, Hoogwerf BJ, Burger J, et al. Effect of exenatide on heart rate and blood pressure in subjects with type 2 diabetes mellitus: a double-blind, placebo-controlled, randomized pilot study. Cardiovasc Diabetol. 2010;9:6.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    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.CrossRefPubMedGoogle Scholar
  42. 42.
    Darpo B, Sager P, MacConell L, et al. Exenatide at therapeutic and supratherapeutic concentrations does not prolong the QTc interval in healthy subjects. Br J Clin Pharmacol. 2013;75:979–89.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Linnebjerg H, Seger M, Kothare PA, Hunt T, Wolka AM, Mitchell MI. A thorough QT study to evaluate the effects of single dose exenatide 10 mug on cardiac repolarization in healthy subjects. Int J Clin Pharmacol Ther. 2011;49:594–604.CrossRefPubMedGoogle Scholar
  44. 44.
    MacConell L, Pencek R, Li Y, Maggs D, Porter L. Exenatide once weekly: sustained improvement in glycemic control and cardiometabolic measures through 3 years. Diabetes Metab Syndr Obes. 2013;6:31–41.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Taylor K, Gurney K, Han J, Pencek R, Walsh B, Trautmann M. Exenatide once weekly treatment maintained improvements in glycemic control and weight loss over 2 years. BMC Endocr Disord. 2011;11:9.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.•
    Alves C, Batel-Marques F, Macedo AF. A meta-analysis of serious adverse events reported with exenatide and liraglutide: acute pancreatitis and cancer. Diabetes Res Clin Pract. 2012;98:271–84. This study describes a large meta-analysis (25 studies), reporting that exenatide and liraglutide are not associated with an increased risk for thyroid cancer. CrossRefPubMedGoogle Scholar
  47. 47.
    Dore DD, Hussein M, Hoffman C, Pelletier EM, Smith DB, Seeger JD. A pooled analysis of exenatide use and risk of acute pancreatitis. Curr Med Res Opin. 2013;29:1577–86.CrossRefPubMedGoogle Scholar
  48. 48.•
    Grimm M, Han J, Weaver C, et al. Efficacy, safety, and tolerability of exenatide once weekly in patients with type 2 diabetes mellitus: an integrated analysis of the DURATION trials. Postgrad Med. 2013;125:47–57. This pooled analysis describes the overall efficacy (detailing improvements in A1C, fasting blood glucose, blood pressure, lipids, and weight) and safety and tolerability (including hypoglycemia, gastrointestinal events, and injection site reactions) findings of exenatide treatment in a large (n = 1379) and varied patient population. CrossRefPubMedGoogle Scholar
  49. 49.
    MacConell L, Brown C, Gurney K, Han J. Safety and tolerability of exenatide twice daily in patients with type 2 diabetes: integrated analysis of 5594 patients from 19 placebo-controlled and comparator-controlled clinical trials. Diabetes Metab Syndr Obes. 2012;5:29–41.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E. Glucagon-like peptide-1 receptor agonists and pancreatitis: a meta-analysis of randomized clinical trials. Diabetes Res Clin Pract. 2014;103:269–75.CrossRefPubMedGoogle Scholar
  51. 51.
    Norris SL, Lee N, Thakurta S, Chan BK. Exenatide efficacy and safety: a systematic review. Diabet Med. 2009;26:837–46.CrossRefPubMedGoogle Scholar
  52. 52.•
    Ratner R, Han J, Nicewarner D, Yushmanova I, Hoogwerf BJ, Shen L. Cardiovascular safety of exenatide BID: an integrated analysis from controlled clinical trials in participants with type 2 diabetes. Cardiovasc Diabetol 2011;10:22. This large, pooled, post hoc analysis (~4000 patients from 12 clinical studies) reports that exenatide does not increase the risk of major adverse cardiovascular events compared with comparator treatment (placebo or insulin).Google Scholar
  53. 53.
    Ridge T, Moretto T, Macconell L, et al. Comparison of safety and tolerability with continuous (exenatide once weekly) or intermittent (exenatide twice daily) GLP-1 receptor agonism in patients with type 2 diabetes. Diabetes Obes Metab. 2012;26:1463–326.Google Scholar
  54. 54.
    Fineman MS, Mace KF, Diamant M, et al. Clinical relevance of anti-exenatide antibodies: safety, efficacy and cross-reactivity with long-term treatment. Diabetes Obes Metab. 2012;14:546–54.CrossRefPubMedGoogle Scholar
  55. 55.
    Hegedus L, Moses AC, Zdravkovic M, Le Thi T, 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.CrossRefPubMedGoogle Scholar
  56. 56.
    Li L, Shen J, Bala MM, et al. Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies. BMJ. 2014;348:g2366.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Nikfar S, Abdollahi M, Salari P. The efficacy and tolerability of exenatide in comparison to placebo; a systematic review and meta-analysis of randomized clinical trials. J Pharm Pharm Sci. 2012;15:1–30.PubMedGoogle Scholar
  58. 58.
    Dore DD, Bloomgren GL, Wenten M, et al. A cohort study of acute pancreatitis in relation to exenatide use. Diabetes Obes Metab. 2011;13:559–66.CrossRefPubMedGoogle Scholar
  59. 59.
    Dore DD, Seeger JD, Arnold CK. Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide. Curr Med Res Opin. 2009;25:1019–27.CrossRefPubMedGoogle Scholar
  60. 60.
    Garg R, Chen W, Pendergrass M. Acute pancreatitis in type 2 diabetes treated with exenatide or sitagliptin: a retrospective observational pharmacy claims analysis. Diabetes Care. 2010;33:2349–54.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Romley JA, Goldman DP, Solomon M, McFadden D, Peters AL. Exenatide therapy and the risk of pancreatitis and pancreatic cancer in a privately insured population. Diabetes Technol Ther. 2012;14:904–11.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Wenten M, Gaebler JA, Hussein M, et al. Relative risk of acute pancreatitis in initiators of exenatide twice daily compared with other anti-diabetic medication: a follow-up study. Diabet Med. 2012;29:1412–8.CrossRefPubMedGoogle Scholar
  63. 63.
    Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007;298:194–206.CrossRefPubMedGoogle Scholar
  64. 64.
    Fakhoury WK, Lereun C, Wright D. A meta-analysis of placebo-controlled clinical trials assessing the efficacy and safety of incretin-based medications in patients with type 2 diabetes. Pharmacology. 2010;86:44–57.CrossRefPubMedGoogle Scholar
  65. 65.
    Tang-Christensen M, Vrang N, Larsen PJ. Glucagon-like peptide containing pathways in the regulation of feeding behaviour. Int J Obes Relat Metab Disord. 2001;25 Suppl 5:S42–7.CrossRefPubMedGoogle Scholar
  66. 66.
    Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24:275–86.CrossRefPubMedGoogle Scholar
  67. 67.
    Moghissi E, Ismail-Beigi F, Devine RC. Hypoglycemia: minimizing its impact in type 2 diabetes. Endocr Pract. 2013;19:526–35.CrossRefPubMedGoogle Scholar
  68. 68.
    Huxley R, Ansary-Moghaddam A, Berrington de Gonzalez A, Barzi F, Woodward M. Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer. 2005;92:2076–83.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Stolzenberg-Solomon RZ, Graubard BI, Chari S, et al. Insulin, glucose, insulin resistance, and pancreatic cancer in male smokers. JAMA. 2005;294:2872–8.CrossRefPubMedGoogle Scholar
  70. 70.
    Denker PS, Dimarco PE. Exenatide (exendin-4)-induced pancreatitis: a case report. Diabetes Care. 2006;29:471.CrossRefPubMedGoogle Scholar
  71. 71.
    Tripathy NR, Basha S, Jain R, Shetty S, Ramachandran A. Exenatide and acute pancreatitis. J Assoc Physicians India. 2008;56:987–8.PubMedGoogle Scholar
  72. 72.
    Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011;141:150–6.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Waser B, Blank A, Karamitopoulou E, Perren A, Reubi JC. Glucagon-like-peptide-1 receptor expression in normal and diseased human thyroid and pancreas. Mod Pathol. 2015;28:391–402.CrossRefPubMedGoogle Scholar
  74. 74.
    Faillie JL, Azoulay L, Patenaude V, Hillaire-Buys D, Suissa S. Incretin based drugs and risk of acute pancreatitis in patients with type 2 diabetes: cohort study. BMJ. 2014;348:g2780.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.••
    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. This report describes the joint position of the regulatory bodies in the United States and Europe, summarizing a review of safety data on incretin-based drugs and pancreatic effects. CrossRefPubMedGoogle Scholar
  76. 76.
    Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–26.CrossRefPubMedGoogle Scholar
  77. 77.
    White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–35.CrossRefPubMedGoogle Scholar
  78. 78.
    European Medicines Agency. Assessment report: Eperzan. Procedure No. EMEA/H/C/002735/0000, 2014. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002735/WC500165119.pdf. Accessed 3 June 2015.
  79. 79.
    Bjerre Knudsen L, 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.CrossRefPubMedGoogle Scholar
  80. 80.
    Bulchandani D, Nachnani JS, Herndon B, et al. Effect of exendin (exenatide)–GLP 1 receptor agonist on the thyroid and parathyroid gland in a rat model. Eur J Pharmacol. 2012;691:292–6.CrossRefPubMedGoogle Scholar
  81. 81.
    Costante G, Durante C, Francis Z, Schlumberger M, Filetti S. Determination of calcitonin levels in C-cell disease: clinical interest and potential pitfalls. Nat Clin Pract Endocrinol Metab. 2009;5:35–44.CrossRefPubMedGoogle Scholar
  82. 82.
    Rosol TJ. On-target effects of GLP-1 receptor agonists on thyroid C-cells in rats and mice. Toxicol Pathol. 2013;41:303–9.CrossRefPubMedGoogle Scholar
  83. 83.
    Chilton R, Wyatt J, Nandish S, Oliveros R, Lujan M. Cardiovascular comorbidities of type 2 diabetes mellitus: defining the potential of glucagonlike peptide-1-based therapies. Am J Med. 2011;124:S35–53.CrossRefPubMedGoogle Scholar
  84. 84.
    US Food and Drug Administration. Guidance for industry. Diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes, 2008. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf. Accessed 3 June 2015
  85. 85.
    Blonde L, Klein EJ, Han J, et al. Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. Diabetes Obes Metab. 2006;8:436–47.CrossRefPubMedGoogle Scholar
  86. 86.
    Ratner RE, Maggs D, Nielsen LL, et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2006;8:419–28.CrossRefPubMedGoogle Scholar
  87. 87.
    Okerson T, Chilton RJ. The cardiovascular effects of GLP-1 receptor agonists. Cardiovasc Ther. 2012;30:e146–55.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Koska J, Sands M, Burciu C, et al. Exenatide protects against glucose and lipid-induced endothelial dysfunction: evidence for direct vasodilation effect of GLP-1 receptor agonists in humans. Diabetes. 2015;64:2624–35.CrossRefPubMedGoogle Scholar
  89. 89.
    US Food and Drug Administration. NDA: 21-919. BYETTA (exenatide), 2005. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/021919s000pharmr.pdf. Accessed 3 June 2015
  90. 90.
    Chilton RJ, MacConell LA, Han J, Marso SP. Characterization of heart rate increases with glucagon-like peptide-1 agonist therapy (abstract). Circulation. 2013;128:A16290.Google Scholar
  91. 91.
    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.CrossRefPubMedGoogle Scholar
  92. 92.
    Gutzwiller JP, Drewe J, Goke B, et al. Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol. 1999;276:R1541–4.PubMedGoogle Scholar
  93. 93.
    Naslund E, Gutniak M, Skogar S, Rossner S, Hellstrom PM. Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying in obese men. Am J Clin Nutr. 1998;68:525–30.PubMedGoogle Scholar
  94. 94.
    Painter NA, Morello CM, Singh RF, McBane SE. An evidence-based and practical approach to using Bydureon in patients with type 2 diabetes. J Am Board Fam Med. 2013;26:203–10.CrossRefPubMedGoogle Scholar
  95. 95.
    Reid TS. Practical use of glucagon-like peptide-1 receptor agonist therapy in primary care. Clin Diabetes. 2013;31:148–57.CrossRefGoogle Scholar
  96. 96.
    US Food and Drug Administration. Application number: 022200orig1s000. Clinical pharmacology and biopharmaceutics review(s), 2011. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022200Orig1s000PharmR.pdf. Accessed 3 June 2015

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.MedStar Health Research InstituteHyattsvilleUSA
  2. 2.MedStar Washington Hospital CenterWashingtonUSA
  3. 3.Georgetown University School of MedicineWashingtonUSA

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