Cardiovascular safety and benefits of GLP-1 receptor agonists

Expert Opinion on Drug Safety

Volumn 16, Issue 3, 2017, Pages 351-363

  Dalsgaard, Niels B ^a   Brønden, Andreas ^a   Vilsbøll, Tina ^a,b   Knop, Filip K ^a,b,c  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

^b UNIVERSITY OF COPENHAGEN   (Denmark)

^c Capital Region   (Denmark)

Author keywords

Cardiovascular safety; glucagon like peptide 1 (GLP 1) receptor agonists (GLP 1RAs); type 2 diabetes

Indexed keywords

ALBIGLUTIDE; DULAGLUTIDE; EXENDIN 4; GLUCAGON LIKE PEPTIDE 1; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; ITCA 650; LIRAGLUTIDE; LIXISENATIDE; SEMAGLUTIDE; UNCLASSIFIED DRUG; ANTIDIABETIC AGENT; GLUCAGON LIKE PEPTIDE; GLUCAGON LIKE PEPTIDE 1 RECEPTOR;

CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CONTROLLED CLINICAL TRIAL (TOPIC); DIABETIC PATIENT; DIARRHEA; DRUG SAFETY; GLYCEMIC CONTROL; HIGH RISK PATIENT; HUMAN; HYPOGLYCEMIA; INJECTION SITE REACTION; META ANALYSIS (TOPIC); NAUSEA; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PANCREAS CANCER; PANCREATITIS; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); RETINOPATHY; REVIEW; RISK BENEFIT ANALYSIS; RISK REDUCTION; SYSTEMATIC REVIEW; THYROID TUMOR; VOMITING; AGONISTS; CARDIOVASCULAR DISEASES; DIABETES MELLITUS, TYPE 2; RISK FACTOR;

CARDIOVASCULAR DISEASES; DIABETES MELLITUS, TYPE 2; GLUCAGON-LIKE PEPTIDE-1 RECEPTOR; GLUCAGON-LIKE PEPTIDES; HUMANS; HYPOGLYCEMIC AGENTS; LIRAGLUTIDE; RISK FACTORS;

EID: 85013308968     PISSN: 14740338     EISSN: 1744764X     Source Type: Journal    
DOI: 10.1080/14740338.2017.1281246     Document Type: Review

References (100)

1. Stumvoll M, Goldstein BJ, van Haeften TW., Type 2 diabetes:principles of pathogenesis and therapy. Lancet. 2005;365(9467):1333–1346.
2. McGuire DK. Diabetes and the cardiovascular system, in Braunwald’s heart disease:a textbook of cardiovascular medicine. Philadelphia, PA:Saunders, Elsevier; 2014. 1365–1390.
3. Chilton R, Wyatt J, Nandish S, et al. Cardiovascular comorbidities of type 2 diabetes mellitus:defining the potential of glucagonlike peptide-1-based therapies. Am J Med. 2011;124(1 Suppl):S35–53.
4. Sandoval DA, D’Alessio DA. Physiology of proglucagon peptides:role of glucagon and GLP-1 in health and disease. Physiol Rev. 2015;95(2):513–548.
5. Drucker DJ. The cardiovascular biology of glucagon-like peptide-1. Cell Metab. 2016;24(1):15–30.•• A comprehensive review of native GLP-1 physiology and its effects in the cardiovascular system.
6. Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, et al. Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes:meta-analysis of randomised controlled trials. BMJ. 2011;343:d4169.
7. FDA. Guidance for Industry Diabetes Mellitus — evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 2008 Available from:http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf
8. Wei Y, Mojsov S. Tissue-specific expression of the human receptor for glucagon-like peptide-I:brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS Lett. 1995;358(3):219–224.
9. 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):1280–1290.• An interesting paper concerning the localization of the GLP-1 receptor.
10. Korner M, Stockli M, Waser B, et al. GLP-1 receptor expression in human tumors and human normal tissues:potential for in vivo targeting. J Nucl Med. 2007;48(5):736–743.
11. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8(12):728–742.
12. 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(10):4473–4488.
13. 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 Endocrinol Metab. 2004;287(6):E1209–15.
14. Pyke C, Knudsen LB. The glucagon-like peptide-1 receptor–or not? Endocrinology. 2013;154(1):4–8.
15. 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(8):962–965.
16. Sokos GG, Nikolaidis LA, Mankad S, et al. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail. 2006;12(9):694–699.
17. 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 receptor-dependent and -independent pathways. Circulation. 2008;117(18):2340–2350.
18. Meier JJ, Gethmann A, Gotze O, et al. Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans. Diabetologia. 2006;49(3):452–458.
19. Read PA, Hoole SP, White PA, et al. A pilot study to assess whether glucagon-like peptide-1 protects the heart from ischemic dysfunction and attenuates stunning after coronary balloon occlusion in humans. Circ Cardiovasc Interv. 2011;4(3):266–272.
20. Ceriello A, Novials A, Canivell S, et al. Simultaneous GLP-1 and insulin administration acutely enhances their vasodilatory, antiinflammatory, and antioxidant action in type 2 diabetes. Diabetes Care. 2014;37(7):1938–1943.
21. Sivertsen J, Rosenmeier J, Holst JJ, et al. The effect of glucagon-like peptide 1 on cardiovascular risk. Nat Rev Cardiol. 2012;9(4):209–222.
22. Skov J, Holst JJ, Gotze JP, et al. Glucagon-like peptide-1:effect on pro-atrial natriuretic peptide in healthy males. Endocr Connect. 2014;3(1):11–16.
23. Lovshin JA, Barnie A, DeAlmeida A, et al. Liraglutide promotes natriuresis but does not increase circulating levels of atrial natriuretic peptide in hypertensive subjects with type 2 diabetes. Diabetes Care. 2015;38(1):132–139.
24. Jensen MT, Marott JL, Allin KH, et al. Resting heart rate is associated with cardiovascular and all-cause mortality after adjusting for inflammatory markers:the Copenhagen City heart study. Eur J Prev Cardiol. 2012;19(1):102–108.
25. Nakatani Y, Kawabe A, Matsumura M, et al. Effects of GLP-1 receptor agonists on heart rate and the autonomic nervous system using holter electrocardiography and power spectrum analysis of heart rate variability. Diabetes Care. 2016;39(2):e22–3.
26. 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(7):1263–1273.
27. Smits MM, Tonneijck L, Muskiet MH, et al. Heart rate acceleration with GLP-1 receptor agonists in type 2 diabetes patients:an acute and 12-week randomised, double-blind, placebo-controlled trial. Eur J Endocrinol. 2017;176(1):77–86.
28. 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. 2016;40(1):117–124.
29. Lund A, Knop FK, Vilsboll T. Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes:differences and similarities. Eur J Intern Med. 2014;25(5):407–414.
30. Tomlinson B, Hu M, Zhang Y, et al. An overview of new GLP-1 receptor agonists for type 2 diabetes. Expert Opin Investig Drugs. 2016;25(2):145–158.
31. EMA. Lyxumia (lixisenatide) Summary of Product Characteristics. [cited 2016]. Available from:http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002445/WC500140401.pdf
32. EMA. Byetta (exenatide) Summary of Product Characteristics. [cited 2016]. Available from:http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000698/WC500051845.pdf
33. EMA. Bydureon (exenatide) Summary of Product Characteristics. [cited 2016]. Available from:http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002020/WC500108241.pdf
34. EMA. Victoza (liraglutide) Summary of Product Characteristics. [cited 2016]. Available from:http://ec.europa.eu/health/documents/community-register/2016/20160526135038/anx_135038_en.pdf
35. EMA. Trulicity (dulaglutide) Summary of Product Characteristics. [cited 2016]. Available from:http://ec.europa.eu/health/documents/community-register/2014/20141121130063/anx_130063_en.pdf
36. EMA. Eperzan (albiglutide) Summary of Product Characteristics. [cited 2016]. Available from:http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002735/WC500165117.pdf
37. 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.
38. Umapathysivam MM, Lee MY, Jones KL, et al. Comparative effects of prolonged and intermittent stimulation of the glucagon-like peptide 1 receptor on gastric emptying and glycemia. Diabetes. 2014;63(2):785–790.
39. Kjems L., Peltz M., Fielding R., et al. Effects of renal impairment on the pharmacokinetics, safety, and tolerability of ITCA 650 ||ePoster #756. 2016 [cited 2016 Oct8]. Available from:http://www.easdvirtualmeeting.org/resources/effects-of-renal-impairment-on-the-pharmacokinetics-safety-and-tolerability-of-itca-650-cf91c45f-3a72-4790-a6fd-92325e157fbc
40. Jespersen MJ, Knop FK, Christensen M. GLP-1 agonists for type 2 diabetes:pharmacokinetic and toxicological considerations. Expert Opin Drug Metab Toxicol. 2013;9(1):17–29.
41. Linnebjerg H, Kothare PA, Park S, et al. Effect of renal impairment on the pharmacokinetics of exenatide. Br J Clin Pharmacol. 2007;64(3):317–327.
42. 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(2):173–181.
43. Copley K, McCowen K, Hiles R, et al. Investigation of exenatide elimination and its in vivo and in vitro degradation. Curr Drug Metab. 2006;7(4):367–374.
44. Christensen M, Knop FK, Vilsboll T, et al. Lixisenatide for type 2 diabetes mellitus. Expert Opin Investig Drugs. 2011;20(4):549–557.
45. Fineman M, Flanagan S, Taylor K, et al. Pharmacokinetics and pharmacodynamics of exenatide extended-release after single and multiple dosing. Clin Pharmacokinet. 2011;50(1):65–74.
46. 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(8):1398–1404.
47. 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(2):195–202.
48. Geiser JS, Heathman MA, Cui X, et al. Clinical pharmacokinetics of dulaglutide in patients with type 2 diabetes:analyses of data from clinical trials. Clin Pharmacokinet. 2016;55(5):625–634.
49. 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(4):287–296.
50. Matthews JE, Stewart MW, De Boever EH, et al. Pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in patients with type 2 diabetes. J Clin Endocrinol Metab. 2008;93(12):4810–4817.
51. Young MA, Wald JA, Matthews JE, et al. Effect of renal impairment on the pharmacokinetics, efficacy, and safety of albiglutide. Postgrad Med. 2014;126(3):35–46.
52. 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(18):7370–7380.
53. Kapitza C, Nosek L, Jensen L, et al. 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(5):497–504.
54. Henry RR, Rosenstock J, Logan D, et al. 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 Complications. 2014;28(3):393–398.
55. Scott LJ. Lixisenatide:a review of its use in patients with type 2 diabetes mellitus. BioDrugs. 2013;27(5):509–523.
56. 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. 2016;39(2):231–241.
57. Sun F, Chai S, Yu K, et al. Gastrointestinal adverse events of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes:a systematic review and network meta-analysis. Diabetes Technol Ther. 2015;17(1):35–42.
58. 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. 2012;2012:230624.
59. Zaccardi F, Htike ZZ, Webb DR, et al. Benefits and harms of once-weekly glucagon-like peptide-1 receptor agonist treatments:a systematic review and network meta-analysis. Ann Intern Med. 2016;164(2):102–113.
60. Elashoff M, Matveyenko AV, Gier B, et al. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011;141(1):150–156.
61. 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):794–797.
62. Chalmer T, Almdal TP, Vilsboll T, et al. Adverse drug reactions associated with the use of liraglutide in patients with type 2 diabetes–focus on pancreatitis and pancreas cancer. Expert Opin Drug Saf. 2015;14(1):171–180.
63. Tseng CH, Lee KY, Tseng FH. An updated review on cancer risk associated with incretin mimetics and enhancers. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2015;33(1):67–124.
64. 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):1473–1486.
65. Kang YM, Jung CH. Cardiovascular effects of glucagon-like peptide-1 receptor agonists. Endocrinol Metab (Seoul). 2016;31(2):258–274.
66. 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(8):1448–1460.
67. Sun F, Wu S, Guo S, et al. Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among patients with type 2 diabetes:a systematic review and network meta-analysis. Diabetes Res Clin Pract. 2015;110(1):26–37.
68. Simo R, Guerci B, Schernthaner G, et al. Long-term changes in cardiovascular risk markers during administration of exenatide twice daily or glimepiride:results from the European exenatide study. Cardiovasc Diabetol. 2015;14:116.
69. Sun F, Wu S, Wang J, et al. Effect of glucagon-like peptide-1 receptor agonists on lipid profiles among type 2 diabetes:a systematic review and network meta-analysis. Clin Ther. 2015;37(1):225–241. e8
70. 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.
71. Best JH, Hoogwerf BJ, Herman WH, et al. Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the 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(1):90–95.
72. Paul SK, Klein K, Maggs D, et al. The association of the treatment with glucagon-like peptide-1 receptor agonist exenatide or insulin with cardiovascular outcomes in patients with type 2 diabetes:a retrospective observational study. Cardiovasc Diabetol. 2015;14:10.
73. 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.
74. FLAT-SUGAR INVESTIGATORS. Glucose variability in a 26-week randomized comparison of mealtime treatment with rapid-acting insulin versus GLP-1 agonist in participants with type 2 diabetes at high cardiovascular risk. Diabetes Care. 2016;39(6):973–981.
75. 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(23):2247–2257.• The first completed cardiovascular safety trial ‘ELIXA’ showing lixisenatide to hold a neutral cardiovascular safety profile.
76. DeYoung MB, MacConell L, Sarin V, et al. Encapsulation of exenatide in poly-(D,L-lactide-co-glycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes. Diabetes Technol Ther. 2011;13(11):1145–1154.
77. Blonde L, Pencek R, MacConell L. Association among weight change, glycemic control, and markers of cardiovascular risk with exenatide once weekly:a pooled analysis of patients with type 2 diabetes. Cardiovasc Diabetol. 2015;14:12.
78. AstraZeneca. Exenatide study of cardiovascular event lowering trial (EXSCEL):a trial to evaluate cardiovascular outcomes after treatment with exenatide once weekly in patients with type 2 diabetes mellitus. 2010 [cited 2016 Oct25]. Available from:https://clinicaltrials.gov/ct2/show/NCT01144338?term=exenatide+once+weekly+EXSCEL&rank=1
79. Holman RR, Bethel MA, George J, et al. Rationale and design of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial. Am Heart J. 2016;174:103–110.
80. Plutzky J, Garber A, Falahati A, et al. Reductions in lipids and CV risk markers in patients with type 2 diabetes treated with liraglutide:a meta-analysis. Can J Diabetes. 2009;33(3):209–210.
81. Jorsal A, Wiggers H, Holmager P, et al. A protocol for a randomised, double-blind, placebo-controlled study of the effect of LIraglutide on left VEntricular function in chronic heart failure patients with and without type 2 diabetes (The LIVE Study). BMJ Open. 2014;4(5):e004885.
82. Brauser D, Liraglutide doesn’t lower LVEF in HF but does increase heart rate, says LIVE trial. Heartwire from medscape conference news. 2016 [cited 2016 Aug19]. Available from:http://www.medscape.com/viewarticle/863730
83. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–322.•• An important paper from the cardiovascular safety trial ‘LEADER’ showing liraglutide to reduce the incidence of cardiovascular death, compared to placebo.
84. Nauck M, Weinstock RS, Umpierrez GE, et al. Efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5). Diabetes Care. 2014;37(8):2149–2158.
85. Ferdinand KC, White WB, Calhoun DA, et al. Effects of the once-weekly glucagon-like peptide-1 receptor agonist dulaglutide on ambulatory blood pressure and heart rate in patients with type 2 diabetes mellitus. Hypertension. 2014;64(4):731–737.
86. Ferdinand KC, Botros FT, Atisso CM, et al. Cardiovascular safety for once-weekly dulaglutide in type 2 diabetes:a pre-specified meta-analysis of prospectively adjudicated cardiovascular events. Cardiovasc Diabetol. 2016;15:38.
87. Eli Lilly and Company. Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND). 2011 [cited 2016 Oct25]. Available from:https://clinicaltrials.gov/ct2/show/NCT01394952?term=REWIND+dulaglutide&rank=1
88. Nauck MA, Stewart MW, Perkins C, et al. Efficacy and safety of once-weekly GLP-1 receptor agonist albiglutide (HARMONY 2):52 week primary endpoint results from a randomised, placebo-controlled trial in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetologia. 2016;59(2):266–274.
89. Fisher M, Petrie MC, Ambery PD, et al. Cardiovascular safety of albiglutide in the Harmony programme:a meta-analysis. Lancet Diabetes Endocrinol. 2015;3(9):697–703.
90. GlaxoSmithKline. Effect of albiglutide, when added to standard blood glucose lowering therapies, on major cardiovascular events in subjects with type 2 diabetes mellitus. 2015 [cited 2016 Oct 25]. Available from:https://clinicaltrials.gov/ct2/show/NCT02465515?term=HARMONY+albiglutide&rank=1
91. Sorli C., Harashima S., Tsoukas G., et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in subjects with type 2 diabetes (SUSTAIN 1) ||ePoster #765. 2016 [cited 2016 Oct8]. Available from:http://www.easdvirtualmeeting.org/resources/efficacy-and-safety-of-once-weekly-semaglutide-monotherapy-versus-placebo-in-subjects-with-type-2-diabetes-sustain-1-8845729e-9b33-499b-8931-19bf410cd059
92. Ahren B., Masmiquel Comas L., Kumar H., et al. Efficacy and safety of once-weekly semaglutide vs sitagliptin as add-on to metformin and/or thiazolidinediones after 56 weeks in subjects with type 2 diabetes (SUSTAIN 2) ||ePoster #767. 2016 [cited 2016 Nov5]. Available from:http://www.easdvirtualmeeting.org/resources/efficacy-and-safety-of-once-weekly-semaglutide-vs-sitagliptin-as-add-on-to-metformin-and-or-thiazolidinediones-after-56-weeks-in-subjects-with-type-2-diabetes-sustain-2
93. Rodbard H., Lingvay I., Reed J., et al. Efficacy and safety of semaglutide once-weekly vs placebo as add-on to basal insulin alone or in combination with metformin in subjects with type 2 diabetes (SUSTAIN 5) ||ePoster #766. 2016 [cited 2016 Nov5]. Available from:http://www.easdvirtualmeeting.org/resources/efficacy-and-safety-of-semaglutide-once-weekly-vs-placebo-as-add-on-to-basal-insulin-alone-or-in-combination-with-metformin-in-subjects-with-type-2-diabetes-sustain-5-871c6042-fbff-48ef-aec0-e9b358e10195
94. DeVries J., Bain SC., Cariou B., et al. Efficacy and safety of once-weekly semaglutide vs once-daily insulin glargine in insulin-naïve subjects with type 2 diabetes (SUSTAIN 4) ||Abstract #148. [cited 2016 Nov5]. Available from:http://www.easdvirtualmeeting.org/resources/efficacy-and-safety-of-once-weekly-semaglutide-vs-once-daily-insulin-glargine-in-insulin-naive-subjects-with-type-2-diabetes-sustain-4
95. Ahmann A., Capehorn M., Charpentier G., et al. Efficacy and safety of once-weekly semaglutide vs exenatide ER after 56 weeks in subjects with type 2 diabetes (SUSTAIN 3). 2016 [cited 2016 Nov5]. Available from:http://www.easdvirtualmeeting.org/resources/efficacy-and-safety-of-once-weekly-semaglutide-vs-exenatide-er-after-56-weeks-in-subjects-with-type-2-diabetes-sustain-3
96. Hjerpsted J., Buhl Axelsen M., Brooks A., et al. Semaglutide improves postprandial glucose and lipid metabolism and delays first-hour gastric emptying in subjects with obesity ||ePoster #763. 2016 [cited 2016 Oct8]. Available from:http://www.easdvirtualmeeting.org/resources/semaglutide-improves-postprandial-glucose-and-lipid-metabolism-and-delays-first-hour-gastric-emptying-in-subjects-with-obesity-393914b1-6a6b-4fde-b35d-70ad4e09f944
97. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–1844.•• An important paper from the cardiovascular safety trial ‘SUSTAIN-6’ showing semaglutide to reduce the incidence of nonfatal stroke, compared to placebo.
98. Baron M., Buse J., Azeem R., et al. A randomised, double-blind, placebo-controlled, 39 week trial of ITCA 650 as add-on therapy in type 2 diabetes ||oral Presentation #112. 2016 [cited 2016 Oct8]. Available from:http://www.easdvirtualmeeting.org/resources/a-randomised-double-blind-placebo-controlled-39-week-trial-of-itca-650-as-add-on-therapy-in-type-2-diabetes
99. Intarcia Therapeutics Inc. Intarcia announces successful cardiovascular safety results in phase 3 FREEDOM-CVO trial for ITCA 650, an investigational therapy for type 2 diabetes. 2016 [cited 2016 Oct8]. Available from:http://www.prnewswire.com/news-releases/intarcia-announces-successful-cardiovascular-safety-results-in-phase-3-freedom-cvo-trial-for-itca-650-an-investigational-therapy-for-type-2-diabetes-300264245.html
100. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–2128.