Potential side effects to GLP-1 agonists: Understanding their safety and tolerability

Expert Opinion on Drug Safety

Volumn 14, Issue 2, 2015, Pages 207-218

  Consoli, Agostino ^a   Formoso, Gloria ^a  

^a UNIVERSITY OF CHIETI   (Italy)

Author keywords

Cancer risk; GLP 1 receptor agonists; Incretin based therapy; Side effects

Indexed keywords

EXENDIN 4; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; INCRETIN; LIRAGLUTIDE; LIXISENATIDE; GLUCAGON LIKE PEPTIDE 1; GLUCAGON RECEPTOR; GLUCAGON-LIKE PEPTIDE-1 RECEPTOR; PEPTIDE; VENOM; ZP10A PEPTIDE;

CANCER RISK; CONSTIPATION; DIARRHEA; DRUG SAFETY; DRUG TOLERABILITY; GASTROINTESTINAL SYMPTOM; HEART RATE; HUMAN; INJECTION SITE REACTION; NAUSEA; NEOPLASM; NONHUMAN; PANCREAS CANCER; PANCREATITIS; POSTMARKETING SURVEILLANCE; REVIEW; THYROID CANCER; VOMITING; AGONISTS; ANALOGS AND DERIVATIVES; ANIMAL;

ANIMALS; GLUCAGON-LIKE PEPTIDE 1; HUMANS; PEPTIDES; RECEPTORS, GLUCAGON; VENOMS;

EID: 84921340542     PISSN: 14740338     EISSN: 1744764X     Source Type: Journal    
DOI: 10.1517/14740338.2015.987122     Document Type: Review

References (111)

1. Garber AJ. Novel GLP-1 receptor agonists for diabetes. Expert Opin Investig Drugs 2011;21(1):45-57
2. Russell-Jones D, Gough S. Recent advances in incretin-based therapies. Clin Endocrinol (Oxf) 2012;77(4):489-99
3. Forst T, Pfutzner A. Pharmacological profile, efficacy and safety of lixisenatide in type 2 diabetes mellitus. Expert Opin Pharmacother 2013;14(16):2281-96
4. Scott LJ. Exenatide extended-release: a review of its use in type 2 diabetes mellitus. Drugs 2012;72(12):1679-707
5. 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(4):1280-90
6. Richards P, Parker HE, Adriaenssens AE, et al. Identification and characterization of GLP-1 receptor-expressing cells using a new transgenic mouse model. Diabetes 2014;63(4):1224-33
7. 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(2):288-95
8. Lonborg J, Vejlstrup N, Kelbaek H, et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J 2012;33(12):1491-9
9. Drucker DJ, Goldfine AB. Cardiovascular safety and diabetes drug development. Lancet 2011;377(9770):977-9
10. Monami M, Cremasco F, Lamanna C, et al. Glucagon-like peptide-1 receptor agonists and cardiovascular events: a meta-analysis of randomized clinical trials. Exp Diabetes Res 2011;2011:215764
11. Seufert J, Gallwitz B. The extrapancreatic effects of GLP-1 receptor agonists: a focus on the cardiovascular, gastrointestinal and central nervous systems. Diabetes Obes Metab 2014;16(8):673-88
12. Bomba M, Ciavardelli D, Silvestri E, et al. Exenatide promotes cognitive enhancement and positive brain metabolic changes in PS1-KI mice but has no effects in 3xTg-AD animals. Cell Death Dis 2013;4:e612
13. Holscher C. The incretin hormones glucagonlike peptide 1 and glucose-dependent insulinotropic polypeptide are neuroprotective in mouse models of Alzheimer's disease. Alzheimers Dement 2014;10(1 Suppl):S47-54
14. 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 2013;36(3):498-504
15. Drucker DJ, Sherman SI, Bergenstal RM, Buse JB. The safety of incretin-based therapies-review of the scientific evidence. J Clin Endocrinol Metab 2011;96(7):2027-31
16. Labuzek K, Kozlowski M, Szkudlapski D, et al. Incretin-based therapies in the treatment of type 2 diabetes - more than meets the eye? Eur J Intern Med 2013;24(3):207-12
17. Nauck MA. A critical analysis of the clinical use of incretin-based therapies: the benefits by far outweigh the potential risks. Diabetes Care 2013;36(7):2126-32
18. Jelsing J, Vrang N, Hansen G, et al. Liraglutide: short-lived effect on gastric emptying - long lasting effects on body weight. Diabetes Obes Metab 2012;14(6):531-8
19. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev 2007;87(4):1409-39
20. Ruttimann EB, Arnold M, Hillebrand JJ, et al. Intrameal hepatic portal and intraperitoneal infusions of glucagon-like peptide-1 reduce spontaneous meal size in the rat via different mechanisms. Endocrinology 2009;150(3):1174-81
21. Wettergren A, Wojdemann M, Holst JJ. Glucagon-like peptide-1 inhibits gastropancreatic function by inhibiting central parasympathetic outflow. Am J Physiol 1998;275(5 Pt 1):G984-92
22. 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(9739):431-9
23. Buse JB, Henry RR, Han J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylureatreated patients with type 2 diabetes. Diabetes Care 2004;27(11):2628-35
24. DeFronzo RA, Ratner RE, Han J, et al. 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(5):1092-100
25. 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(5):1083-91
26. 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 2010;33(6):1300-3
27. Astrup A, Rossner S, Van Gaal L, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet 2009;374(9701):1606-16
28. Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformintreated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet 2014;384(9951):1349-57
29. 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(9683):39-47
30. 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(9645):1240-50
31. 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 2012;381(9861):117-24
32. 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(6):1255-61
33. Wysham C, Bergenstal R, Malloy J, et al. DURATION-2: efficacy and safety of switching from maximum daily sitagliptin or pioglitazone to once-weekly exenatide. Diabet Med 2011;28(6):705-14
34. 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(9733):2234-43
35. 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(5):1301-10
36. Fonseca VA, Alvarado-Ruiz R, Raccah D, et al. Efficacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy: a randomized, double-blind, placebocontrolled trial in patients with type 2 diabetes (GetGoal-Mono). Diabetes Care 2012;35(6):1225-31
37. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2012;8(12):728-42
38. Seino Y, Nakajima H, Miyahara H, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of albiglutide, a longacting GLP-1-receptor agonist, in Japanese subjects with type 2 diabetes mellitus. Curr Med Res Opin 2009;25(12):3049-57
39. Kaku K, Rasmussen MF, Clauson P, Seino Y. Improved glycaemic control with minimal hypoglycaemia and no weight change with the once-daily human glucagon-like peptide-1 analogue liraglutide as add-on to sulphonylurea in Japanese patients with type 2 diabetes. Diabetes Obes Metab 2010;12(4):341-7
40. Sun F, Yu K, Yang Z, et al. Impact of GLP-1 receptor agonists on major gastrointestinal disorders for type 2 diabetes mellitus: a mixed treatment comparison meta-analysis. Exp Diabetes Res 2013;2012:230624
41. Jeong KH, Yoo BK. The efficacy and safety of liraglutide. Int J Clin Pharm 2011;33(5):740-9
42. Kapitza C, Forst T, Coester HV, et al. 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(7):642-9
43. Shyangdan DS, Royle P, Clar C, et al. Glucagon-like peptide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev 2011(10):CD006423
44. Pratley RE, Nauck M, Bailey T, et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trial. Lancet 2010;375(9724):1447-56
45. Pratley R, Nauck M, Bailey T, et al. One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel-group, open-label trial. Int J Clin Pract 2011;65(4):397-407
46. Evans M, McEwan P, O'Shea R, George L. A retrospective, case-note survey of type 2 diabetes patients prescribed incretin-based therapies in clinical practice. Diabetes Ther 2013;4(1):27-40
47. Taylor K, Gurney K, Han J, et al. Exenatide once weekly treatment maintained improvements in glycemic control and weight loss over 2 years. BMC Endocr Disord 2011;11:9
48. Russell S. Incretin-based therapies for type 2 diabetes mellitus: a review of direct comparisons of efficacy, safety and patient satisfaction. Int J Clin Pharm 2013;35(2):159-72
49. 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 2013;36(10):2945-51
50. Davies MJ, Kela R, Khunti K. Liraglutide - overview of the preclinical and clinical data and its role in the treatment of type 2 diabetes. Diabetes Obes Metab 2011;13(3):207-20
51. 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(2):252-8
52. Robinson LE, Holt TA, Rees K, et al. Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis. BMJ Open 2013;3:1
53. 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
54. Barragan JM, Rodriguez RE, Eng J, Blazquez E. Interactions of exendin-(9-39) with the effects of glucagon-like peptide-1-(7-36) amide and of exendin-4 on arterial blood pressure and heart rate in rats. Regul Pept 1996;67(1):63-8
55. Barragan JM, Eng J, Rodriguez R, Blazquez E. Neural contribution to the effect of glucagon-like peptide-1-(7-36) amide on arterial blood pressure in rats. Am J Physiol 1999;277(5 Pt 1):E784-91
56. Valensi P, Chiheb S, Fysekidis M. Insulin- and glucagon-like peptide-1-induced changes in heart rate and vagosympathetic activity: why they matter. Diabetologia 2013;56(6):1196-200
57. Nathanson D, Ullman B, Lofstrom U, et al. Effects of intravenous exenatide in type 2 diabetic patients with congestive heart failure: a double-blind, randomised controlled clinical trial of efficacy and safety. Diabetologia 2012;55(4):926-35
58. Linnebjerg H, Seger M, Kothare PA, et al. A thorough QT study to evaluate the effects of singledose exenatide 10 mug on cardiac repolarization in healthy subjects. Int J Clin Pharmacol Ther 2011;49(10):594-604
59. 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 2012;75(4):979-89
60. Chatterjee DJ, Khutoryansky N, Zdravkovic M, et al. Absence of QTc prolongation in a thorough QT study with subcutaneous liraglutide, a once-daily human GLP-1 analog for treatment of type 2 diabetes. J Clin Pharmacol 2009;49(11):1353-62
61. 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(4):1473-86
62. Madsen LW, Knauf JA, Gotfredsen C, et al. GLP-1 receptor agonists and the thyroid: C-cell effects in mice are mediated via the GLP-1 receptor and not associated with RET activation. Endocrinology 2012;153(3):1538-47
63. FDA. Endocrinologic and Metabolic Drugs Advisory Committee. Liraglutie injection. April 2 2009. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/Committees%20MeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisory Committee/UCM151129.pdf [Last accessed date 3 February 2014]
64. European Medical Agency (EMA). Assessment report for Byetta. 2012. Available from: http://www.ema.europa.eu/docs/en-GB/document-library/EPAR---Assessment-Report---Variation/human/000698/WC500128211.pdf [Last accessed 12 February 2014]
65. Waser B, Beetschen K, Pellegata NS, Reubi JC. Incretin receptors in non-neoplastic and neoplastic thyroid C cells in rodents and humans: relevance for incretin-based diabetes therapy. Neuroendocrinology 2011;94(4):291-301
66. Gier B, Butler PC, Lai CK, et al. Glucagon like peptide-1 receptor expression in the human thyroid gland. J Clin Endocrinol Metab 2011;97(1):121-31
67. European Medicines Agency. Assessment report for Bydureon. 2012. Available from: http://www.ema.europa.eu/docs/en-GB/document-library/EPAR---Public-assessment-report/human/002020/WC500108239.pdf [Last accessed 3 February 2014]
68. European Medicines Agency. Assesment report for Victoza. 2009. Available from: http://www.ema.europa.eu/docs/en-GB/document-library/EPAR---Public-assessment-report/human/001026/WC500050016.pdf [Last accessed 3 February 2014]
69. Hegedus L, Moses AC, Zdravkovic M, et al. 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(3):853-60
70. European Medicines Agency. Assessment report for Lixisenatide. 2012. Available from: http://www.ema.europa.eu/docs/en-GB/document-library/EPAR---Public-assessment-report/human/002445/WC500140449.pdf [Last accessed 11 February 2014]
71. Elashoff M, Matveyenko AV, Gier B, et al. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology 2011;141(1):150-6
72. Koehler JA, Baggio LL, Lamont BJ, et al. Glucagon-like peptide-1 receptor activation modulates pancreatitisassociated gene expression but does not modify the susceptibility to experimental pancreatitis in mice. Diabetes 2009;58(9):2148-61
73. Nyborg NC, Molck AM, Madsen LW, Knudsen LB. The human GLP-1 analog liraglutide and the pancreas: evidence for the absence of structural pancreatic changes in three species. Diabetes 2012;61(5):1243-9
74. Malhotra R, Singh L, Eng J, Raufman JP. Exendin-4, a new peptide from Heloderma suspectum venom, potentiates cholecystokinin-induced amylase release from rat pancreatic acini. Regul Pept 1992;41(2):149-56
75. Fehmann HC, Goke B, Weber V, et al. Interaction of glucagon-like peptide-1 (7-36)amide and cholecystokinin-8 in the endocrine and exocrine rat pancreas. Pancreas 1990;5(3):361-5
76. Zhou J, Montrose-Rafizadeh C, Janczewski AM, et al. Glucagon-like peptide-1 does not mediate amylase release from AR42J cells. J Cell Physiol 1999;181(3):470-8
77. Tatarkiewicz K, Smith PA, Sablan EJ, et al. Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents. Am J Physiol Endocrinol Metab 2010;299(6):E1076-86
78. Nachnani JS, Bulchandani DG, Nookala A, et al. Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas. Diabetologia 2009;53(1):153-9
79. Denker PS, Dimarco PE. Exenatide (exendin-4)-induced pancreatitis: a case report. Diabetes Care 2006;29(2):471
80. FDA safety alert on Byetta. 2007. Available from: http://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety AlertsforHumanMedicalProducts/ucm150839.htm [Last accessed 14 February 2014]
81. Singh S, Chang HY, Richards TM, et al. 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(7):534-9
82. Dore DD, Seeger JD, Arnold Chan K. 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(4):1019-27
83. 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(11):2349-54
84. Endocrine and Metabolic Drug Advisor Commettee. Liraglutide (Injection) for Treatment of Patients with type 2 Diabetes NDA 22-34 Briefing Document. 2009
85. Funch D, Gydesen H, Tornoe K, et al. A prospective, claims-based assessment of the risk of pancreatitis and pancreatic cancer with liraglutide compared to other antidiabetic drugs. Diabetes Obes Metab 2013;16(3):273-5
86. Monami M, Dicembrini I, Nardini C, et al. Glucagon-like peptide-1 receptor agonists and pancreatitis: a meta-analysis of randomized clinical trials. Diabetes Res Clin Pract 2014;103(2):269-75
87. Giorda CB, Picariello R, Nada E, et al. Incretin therapies and risk of hospital admission for acute pancreatitis in an unselected population of European patients with type 2 diabetes: a case-control study. Lancet Diabetes Endocrinol 2014;2(2):111-15
88. European Medicines Agency. Assessment report for GLP-1 based therapies. July 25 2013. Available from: http://www.emaeuropa.eu/docs/en-GB/document-library/Report/2013/08/WC500147026.pdf [Last accessed date 11 February 2014]
89. 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.
90. Pancreatic cancer associated with Exenatide (Byetta). Arzneimittelkommission der Deutschen ärzteschaft (Drug Commission of the German Medical Association). "Aus der UAWDatenbank": Pankreaskarzinome im Zusammenhang mit Exenatid (Byetta®). Dtsch Arztebl 2011.108:A-1080
91. Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010;467(7319):1114-17
92. Monami M, Dicembrini I, Martelli D, Mannucci E. Safety of dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized clinical trials. Curr Med Res Opin 2011;27(Suppl 3):57-64
93. Nauck MA, Friedrich N. Do GLP-1-based therapies increase cancer risk? Diabetes Care 2013;36(Suppl 2):S245-52
94. Butler AE, Campbell-Thompson M, Gurlo T, et al. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes 2013;62(7):2595-604
95. Bonner-Weir S, In't Veld PA, Weir GC. Reanalysis of study of pancreatic effects of incretin therapy: methodological deficiencies. Diabetes Obes Metab 2014;16(7):661-6
96. Madsbad S. Treatment of type 2 diabetes with incretin-based therapies. Lancet 2009;373(9662):438-9
97. Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs - FDA and EMA assessment. N Engl J Med 2014;370(9):794-7
98. Kahn SE. Incretin therapy and islet pathology: a time for caution. Diabetes 2013;62(7):2178-80
99. Montilla S, Marchesini G, Sammarco A, et al. Drug utilization, safety, and effectiveness of exenatide, sitagliptin, and vildagliptin for type 2 diabetes in the real world: Data from the Italian AIFA Anti-diabetics Monitoring Registry. Nutr Metab Cardiovasc Dis 2014. [Epub ahead of print]
100. Ahren B, Leguizamo Dimas A, Miossec P, et al. Efficacy and safety of lixisenatide once-daily morning or evening injections in type 2 diabetes inadequately controlled on metformin (GetGoal-M). Diabetes Care 2013;36(9):2543-50
101. Pinget M, Goldenberg R, Niemoeller E, et al. Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P). Diabetes Obes Metab 2013;15(11):1000-7
102. 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(9):2489-96
103. Riddle MC, Forst T, Aronson R, et al. Adding once-daily lixisenatide for type 2 diabetes inadequately controlled with newly initiated and continuously titrated basal insulin glargine: a 24-week, randomized, placebo-controlled study (GetGoal-Duo 1). Diabetes Care 2013;36(9):2497-503
104. 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 2013;31(2):176-84
105. Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 2009;373(9662):473-81
106. Marre M, Shaw J, Brandle M, et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med 2009;26(3):268-78
107. Nauck M, Frid A, Hermansen K, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009;32(1):84-90
108. Zinman B, Gerich J, Buse JB, et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care 2009;32(7):1224-30
109. Russell-Jones D, Vaag A, Schmitz O, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia 2009;52(10):2046-55
110. Jespersen MJ, Knop FK, Christensen M. GLP-1 agonists for type 2 diabetes: pharmacokinetic and toxicological considerations. Expert Opin Drug Metab Toxicol 2012;9(1):17-29
111. Meier JJ, Nauck MA. Risk of pancreatitis in patients treated with incretin-based therapies. Diabetologia 2014;57(7):1320-4