GLP-1 receptor agonists: A clinical perspective on cardiovascular effects

Diabetes and Vascular Disease Research

Volumn 9, Issue 2, 2012, Pages 95-108

  Mundil, Dhanwantee ^a,b   Cameron Vendrig, Alison ^a,b   Husain, Mansoor ^a,b  

^a UNIVERSITY OF TORONTO   (Canada)

^b UNIVERSITY HEALTH NETWORK   (Canada)

Author keywords

Cardiovascular disease; Clinical perspective GLP 1 receptor agonists; Type 2 diabetes

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; BIPHASIC INSULIN; EXENDIN 4; FATTY ACID; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; HEMOGLOBIN A1C; HIGH DENSITY LIPOPROTEIN; INSULIN GLARGINE; LIRAGLUTIDE; LIXISENATIDE; LOW DENSITY LIPOPROTEIN; METFORMIN; PIOGLITAZONE; SITAGLIPTIN; SULFONYLUREA; TASPOGLUTIDE; TRIACYLGLYCEROL;

ADD ON THERAPY; ANTIDIABETIC ACTIVITY; BODY WEIGHT; CARDIOVASCULAR EFFECT; CARDIOVASCULAR RISK; CHOLESTEROL BLOOD LEVEL; DIASTOLIC BLOOD PRESSURE; DIET THERAPY; DRUG ABSORPTION; DRUG DEGRADATION; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG PROTEIN BINDING; GASTROINTESTINAL SYMPTOM; GLOMERULUS FILTRATION; GLYCEMIC CONTROL; HEART ARRHYTHMIA; HEART FAILURE; HEART INFARCTION; HEART RATE; HUMAN; HYPERGLYCEMIA; HYPERLIPIDEMIA; HYPERTENSION; INSULIN LIKE ACTIVITY; INSULIN RELEASE; KINESIOTHERAPY; MAXIMUM PLASMA CONCENTRATION; MONOTHERAPY; NON INSULIN DEPENDENT DIABETES MELLITUS; QT INTERVAL; REVIEW; STROKE; SUSTAINED DRUG RELEASE; SYSTOLIC BLOOD PRESSURE; TIME TO MAXIMUM PLASMA CONCENTRATION; WEIGHT GAIN;

ANIMALS; BIOLOGICAL MARKERS; BLOOD GLUCOSE; CARDIOVASCULAR DISEASES; DIABETES MELLITUS, TYPE 2; DRUG DESIGN; EVIDENCE-BASED MEDICINE; GLUCAGON-LIKE PEPTIDE 1; HEMOGLOBIN A, GLYCOSYLATED; HUMANS; HYPOGLYCEMIC AGENTS; PEPTIDES; RECEPTORS, GLUCAGON; RISK ASSESSMENT; RISK FACTORS; TIME FACTORS; TREATMENT OUTCOME; VENOMS;

EID: 84861018492     PISSN: 14791641     EISSN: 17528984     Source Type: Journal    
DOI: 10.1177/1479164112441526     Document Type: Review

References (100)

1. International Diabetes Federation. IDF diabetes atlas, http://www.diabetesatlas.org (accessed November 2011).
2. Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339: 229-234. (Pubitemid 28350165)
3. Scheidt-Nave C, Barrett-Connor E and Wingard DL. Resting electrocardiographic abnormalities suggestive of asymptomatic ischemic heart disease associated with noninsulin- dependent diabetes mellitus in a defined population. Circulation 1990; 81: 899-906. (Pubitemid 20090387)
4. Grundy SM, Benjamin IJ, Burke GL, et al. Diabetes and cardiovasculardisease: a statement for healthcare professionals from the American Heart Association. Circulation 1999;100: 1134-1146. (Pubitemid 29416243)
5. Howard BV and Magee MF. Diabetes and cardiovascular disease. Curr Atheroscler Rep 2000; 2: 476-481.
6. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003; 348: 383-393. (Pubitemid 36159355)
7. Selvin E, Marinopoulos S, Berkenblit G, et al.Meta-analysis: Glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004; 141: 421-431.
8. Uwaifo GI and Ratner RE Differential effects of oral hypoglycemic agents on glucose control and cardiovascular risk. Am J Cardiol 2007; 99: 51B-67B.
9. Drucker DJ, Sherman SI, Gorelick FS, et al. Incretin-based therapies for the treatment of type 2 diabetes: Evaluation ofthe risks and benefits. Diabetes Care 2010; 33: 428-433.
10. Campbell RK. Clarifying the role of incretin-based therapies in the treatment of type 2 diabetes mellitus. Clin Ther 2011;33: 511-527.
11. Safety alerts for human medical products - Byetta (exenatide) October 2007, http://www.fda.gov/Safety/MedWatch/SafetyInformation/ SafetyAlertsforHumanMedicalProducts/ucm150839.htm (2007, accessed November 2011).
12. Human medicines - Byetta (Exenatide), http://www.ema.europa.eu/ema/index. jsp?curl=pages/medicines/human/medicines/000698/human-med-000682.jsp&mid= WC0b01ac058001d124 (accessed November 2011).
13. Byetta safety update for healthcare professionals, http://www.fda.gov/ Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ DrugSafetyInformationforHeathcareProfessionals/ucm190406.htm (accessed November 2011).
14. FDA News Release - FDA approves new treatment for type2diabetes, http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2010/ucm198638.htm (accessed November 2011).
15. Human medicines - Victoza (liraglutide), http://www.ema.europa.eu/ema/ index.jsp?curl=pages/medicines/human/medicines/001026/human-med-001137. jsp&mid=WC0b01ac058001d124 (accessedNovember 2011).
16. European Medicines Agency - Summary of opinion (initialauthorisation) Bydureon exenatide, http://www.ema.europa.eu/docs/en-GB/document-library/ Summary-of-opinion-Initial-authorisation/human/002020/WC500105273.pdf (accessed November 2011).
17. Eng J, Kleinman WA, Singh L, et al. Isolation and characterizationof exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 1992; 267: 7402-7405.
18. Raufman JP, Jensen RT, Sutliff VE, et al. Actions of Gila monster venom on dispersed acini from guinea pig pancreas. Am J Physiol 1982; 242: G470-G474. (Pubitemid 12099993)
19. Thorens B, Porret A, Buhler L, et al. Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin- (9-39) an antagonist of the receptor. Diabetes 1993; 42: 1678-1682. (Pubitemid 23318127)
20. Simonsen L, Holst JJ, Deacon CF. Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerularfiltration in anaesthetised pigs. Diabetologia 2006; 49: 706-712. (Pubitemid 43357544)
21. Tracy MA, Ward KL, Firouzabadian L, et al. Factors affecting the degradation rate of poly (lactide-co-glycolide) microspheres in vivo and in vitro. Biomaterials 1999; 20:1057-1062. (Pubitemid 29229474)
22. Aroda VR and DeYoung MB. Clinical implications ofexenatide as a twice-daily or once-weekly therapy for type 2 diabetes. Postgrad Med 2011; 123: 228-238.
23. 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: 1664-1669. (Pubitemid 30304999)
24. Madsen K, Knudsen LB, Agersoe H, et al. Structure-activity and protraction relationship of long-acting glucagon-like peptide-1 derivatives: Importance of fatty acid length, polarity, and bulkiness. J Med Chem 2007; 50: 6126-6132.
25. Steensgaard DB, Thomsen JK, Olsen HB, et al. The molecular basis for the delayed absorption of the once-daily humanGLP-1 analogue, liraglutide. Diabetes 2008; 57 (Suppl. 1): A164 (Abstract).
26. Agerso H, Jensen LB, Elbrond B, et al. The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211,a new long-acting GLP-1 derivative, in healthy men.Diabetologia 2002; 45: 195-202. (Pubitemid 34208381)
27. Elbrond B, Jakobsen G, Larsen S, et al. Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose of NN2211, a long-acting glucagon-like peptide 1 derivative, in healthy male subjects. Diabetes Care 2002; 25: 1398-1404. (Pubitemid 41071152)
28. Malm-Erjefalt M, Bjornsdottir I, Vanggaard J, et al. Metabolism and excretion of the once-daily human glucagon- like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase. Drug Metab Dispos 2010; 38:1944-1953.
29. Bjornsdottir I, Olsen A, Larsen U, et al. Metabolism and excretion of the once-daily human GLP-1 analogue liraglutide in healthy subject and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase. Diabetologia 2008; 51 (Suppl. 1): S356 (Abstract).
30. Jacobsen LV, Hindsberger C, Robson R, et al. Effect of renal impairment on the pharmacokinetics of the GLP-1 analogue liraglutide. Br J Clin Pharmacol 2009; 68: 898-905.
31. Damholt B, Golor G, Wierich W, et al. An open-label, parallel group study investigating the effects of age and genderon the pharmacokinetics of the once-daily glucagon-like peptide-1 analogue liraglutide. J Clin Pharmacol 2006; 46: 635-641.
32. 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: 2628-2635. (Pubitemid 39441462)
33. DeFronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeksin metformin-treated patients with type 2 diabetes. Diabetes Care 2005; 28: 1092-1100. (Pubitemid 40616618)
34. 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: 1083-1091. (Pubitemid 40616617)
35. Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepaticbiomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin 2008; 24: 275-286. (Pubitemid 351160260)
36. Heine RJ, Van Gaal LF, Johns D, et al. Exenatide versusinsulin glargine in patients with suboptimally controlled type 2 diabetes: A randomized trial. Ann Intern Med 2005; 143:559-569.
37. Nauck MA, Duran S, Kim D, et al. A comparison of twicedaily exenatide and biphasic insulin aspart in patients withtype 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia2007; 50: 259-267.
38. 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): 1240-1250.
39. 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): 431-439.
40. 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): 2234-2243.
41. 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 Endocr Metab 2011; 96: 1301-1310.
42. Wintle M, Meloni A, DeYoung MB, et al. Effects of exenatide once weekly on glycaemic goals and selected cardiovascular risk factors in patients with type2 diabetes: A retrospective analysis of pooled clinical trial data. Diabetologia 2011;54 (Suppl. 1): S1-S542.
43. 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: 268-278.
44. Nauck M, Frid A, Hermansen KS, et al. Efficacy and safetycomparison 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: 84-90.
45. 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): 473-481.
46. 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: 1224-1230.
47. 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: 2046-2055.
48. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: A 26-weekrandomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009; 374 (9683): 39-47.
49. Eckel RH, Barouch WW and Ershow AG. Report of the National Heart, Lung, and Blood Institute-National Institute of Diabetes and Digestive and Kidney Diseases Working Group on the pathophysiology of obesity-associated cardiovascular disease. Circulation 2002; 105: 2923-2928.
50. Anonymous. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatmentand risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352 (9131): 837-853.
51. Kushner RF and Sujak M. Prevention of weight gain in adult patients with type 2 diabetes treated with pioglitazone. Obesity (Silver Spring) 2009; 17: 1017-1022.
52. Zinman B, Hoogwerf BJ, Duran Garcia S, et al. The effect ofadding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med 2007; 146: 477-485. (Pubitemid 351650556)
53. Bunck MC, Eliasson B, Corner A, et al. Exenatide treatment did not affect bone mineral density despite body weight reduction in patients with type 2 diabetes. Diabetes Obesity Metab 2011; 13: 374-377.
54. Varanasi A, Chaudhuri A, Dhindsa S, et al. Durability of effects of exenatide treatment on glycemic control, body weight, systolic blood pressure, C-reactive protein, and triglyceride concentrations. Endocr Pract 2011; 17: 192-200.
55. Buysschaert M, Preumont V, Oriot PR, et al. One-year metabolic outcomes in patients with type 2 diabetes treated with exenatide in routine practice. Diabetes Metab 2010; 36:381-388.
56. Madsbad S, Schmitz O, Ranstam J, et al. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon- like peptide 1 analog liraglutide (NN2211): A 12-week, double-blind, randomized, controlled trial. Diabetes Care 2004; 27: 1335-1342. (Pubitemid 38679980)
57. Vilsboll T, Zdravkovic M, Le-Thi T, et al. Liraglutide, along-acting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patientswith type 2 diabetes. Diabetes Care 2007; 30: 1608-1610. (Pubitemid 46871185)
58. Harder H, Nielsen L, Tu DT, et al. 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; 27:1915-1921. (Pubitemid 38989232)
59. Feinglos MN, Saad MF, Pi-Sunyer FX, et al. Effects of liraglutide (NN2211), a long-acting GLP-1 analogue, on glycaemic control and bodyweight in subjects with type 2 diabetes. Diabet Med 2005; 22: 1016-1023. (Pubitemid 41025998)
60. Kaku K, Rasmussen MF, Clauson P, et al. 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 Obesity Metab 2010;12: 341-347.
61. Schmidt WE. Early clinical studies with liraglutide. IntJ Clin Pract Suppl 2010; 64: 12-20.
62. Jendle J, Nauck MA, Matthews DR, et al. Weight loss with liraglutide, a once-daily human glucagon-like peptide-1 analoguefor type 2 diabetes treatment as monotherapy or added to metformin, is primarily as a result of a reduction in fattissue. 2009; 11: 1163-1172.
63. Anonymous. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998; 317: 703-713.
64. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998; 351: 1755-1762. (Pubitemid 28269185)
65. Patel A, MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007; 370: 829-840. (Pubitemid 47362321)
66. Okerson T, Yan P, Stonehouse A, et al. Effects of exenatide on systolic blood pressure in subjects with type 2 diabetes. Am J Hypertens 2010; 23: 334-339.
67. 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.
68. Koska J, Schwartz EA, Mullin MP, et al. Improvement of postprandial endothelial function after a single dose of exenatide in individuals with impaired glucose tolerance and recent-onset type 2 diabetes. Diabetes Care 2010; 33: 1028-1030.
69. Nystrom T, Gutniak MK, Zhang Q, et al. Effects of glucagon- like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocr Metab 2004; 287: E1209-E1215. (Pubitemid 39491964)
70. Crajoinas RO, Oricchio FT, Pessoa TD, et al. Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1. Am J Physiol Renal Physiol 2011; 301: F355-F363.
71. Gutzwiller JP, Tschopp S, Bock A, et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and ininsulin-resistant obese men. J Clin Endocr Metab 2004; 89: 3055-3061. (Pubitemid 38766408)
72. Fonseca V, Falahati A, Zychma M, et al. A meta-analysis of six clinical trials demonstrates that the once-daily human GLP-1 analogue liraglutide reduces systolic blood pressure. Diabetologia 2009; 52 (Suppl. 1): S299.
73. Gallwitz B, Vaag A, Falahati A, et al. Adding liraglutide to oral antidiabetic drug therapy: onset of treatment effects over time. Int J Clin Pract 2010; 64: 267-276.
74. Griffioen Kj, Wan R, Okun E, et al. GLP-1 receptor stimulation depresses heart rate variability and inhibits neurotransmission to cardiac vagal neurons. Cardiovasc Res 2011; 89: 72-78. Epub ahead of print 24 August 2010.
75. Plutzky J, Garber A, Toft AD, et al. A meta-analysis demonstrates that liraglutide, a once-daily human GLP-1analogue significantly reduces lipids and other markers of cardiovascular risk in type 2 diabetes. Diabetologia 2009; 52 (Suppl. 1): S299.
76. Linnebjerg H, Seger M, Kothare PA, et al. A thorough QT study to evaluate the effects of singledose exenatide 10μg on cardiac repolarization in healthy subjects. Int J Clin Pharmacol Therapeut 2011; 49: 594-604.
77. 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: 1353-1362.
78. Best JH, Maggs D, Little W, et al. The risk of heart failure among patients receiving exenatide twice daily versus other glucose-lowering medications for diabetes: a matched retrospective analysis of the GE Healthcare EMR data.Diabetologia 2011; 54 (Suppl. 1): S1-S542.
79. Best JH, Hoogwerf BJ, Herman WH, et al. Risk of cardiovascular disease events in patients with type 2 diabetes prescribedthe glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: A retrospective analysis of the LifeLink database. Diabetes Care 2011; 34: 90-95.
80. Ban K, Noyan-Ashraf MH, Hoefer J, et al. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptordependent and -independent pathways. Circulation 2008; 117: 2340-2350. (Pubitemid 351653542)
81. Ban K, Kim KH, Cho CK, et al. Glucagon-like peptide (GLP)-1 (9-36)amide-mediated cytoprotection is blocked by exendin (9-39) yet does not require the known GLP-1 receptor. Endocrinology 2010; 151: 1520-1531.
82. Noyan-Ashraf MH, Momen MA, Ban K, et al. GLP-1R agonist liraglutide activates cytoprotective pathways andimproves outcomes after experimental myocardial infarction in mice. Diabetes 2009; 58: 975-983.
83. Lonborg J, Vejlstrup N, Kelbaek H, et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J. Epub ahead of print. DOI: 10.1093/eurheartj/ehr309.
84. Ray JA, Boye KS, Yurgin N, et al. Exenatide versus insulin glargine in patients with type 2 diabetes in the UK: A model of long-term clinical and cost outcomes. Curr Med Res Opin 2007; 23: 609-622. (Pubitemid 46456909)
85. Sullivan SD, Alfonso-Cristancho R, Conner C, et al. Longterm outcomes in patients with type 2 diabetes receiving glimepiride combined with liraglutide or rosiglitazone. Cardiovasc Diabetol 2009; 8: 12.
86. Marso SP, Lindsey JB, Stolker JM, et al. Cardiovascular safety of liraglutide assessed in a patient-level pooled analysis of phase 2: 3 liraglutide clinical development studies. Diab Vasc Dis Res 2011; 8: 237-240.
87. Ratner R, Han J, Nicewarner D, et al. Cardiovascular safety of exenatide BID: An integrated analysis from controlled clinical trials in participants with type 2 diabetes. Cardiovasc Diabetol 2011; 10: 22.
88. Administration USFaD. Evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. In: Guidance for industry diabetes mellitus. Silver Spring, MD: FDA, 2008.
89. Liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results - a long term evaluation (LEADER)TM. http://www.clinicaltrials. gov/ct2/show/NCT01179048 (accessed December 2011).
90. Exenatide Study of Cardiovascular Event Lowering trial (EXSCEL): A trial to evaluate cardiovascular outcomes aftertreatment with exenatide once weekly in patients with type 2 diabetes mellitus. http://www.clinicaltrials.gov/ct2/show/ NCT01144338 (accessed December 2011).
91. Liraglutide and heart failure in type 2 diabetes. http://www. clinicaltrials.gov/ct2/show/NCT01425580 (accessedDecember 2011).
92. 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: 397-407.
93. Dong JZ, Shen Y, Zhang J, et al. Discovery and characterizationof taspoglutide, a novel analogue of human glucagonlike peptide-1, engineered for sustained therapeutic activity in type 2 diabetes. Diabetes Obesity Metab 2011; 13: 19-25.
94. Kapitza C, Heise T, Birman P, et al. Pharmacokinetic andpharmacodynamic properties of taspoglutide, a once-weekly, human GLP-1 analogue, after single-dose administration in patients with type 2 diabetes. Diabet Med 2009; 26: 1156-1164.
95. Nauck MA, Ratner RE, Kapitza C, et al. Treatment with the human once-weekly glucagon-like peptide-1 analog taspoglutide in combination with metformin improves glycemic control and lowers body weight in patients with type 2 diabetes inadequately controlled with metformin alone: A double-blind placebo-controlled study. Diabetes Care 2009; 32: 1237-1243.
96. Ratner R, Nauck M, Kapitza C, et al. Safety and tolerability of high doses of taspoglutide, a once-weekly human GLP-1 analogue, in diabetic patients treated with metformin: A randomized double-blind placebo-controlled study. Diabet Med 2010; 27: 556-562.
97. Roche announces amendment of the trial protocols for the taspoglutide Phase III programme, http://www.roche.com/investors/ir-update/inv-update-2010- 06-18b.htm (accessed December 2011).
98. Werner U, Haschke G, Herling AW, et al. Pharmacological profile of lixisenatide: A new GLP-1 receptor agonist for the treatment of type 2 diabetes. Regul Pept 2010; 164:58-64.
99. Ratner RE, Rosenstock J, Boka G; DRI6012 Study Investigators. 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 Med2010; 27: 1024-1032.
100. Evaluation of cardiovascular outcomes in patients with type 2 diabetes after acute coronary syndrome during treatment with AVE0010 (Lixisenatide) (Elixa), http://www.Clinicaltrials. govct2/show/NCT01147250 (accessed January 2012).