The extra-pancreatic effects of GLP-1 receptor agonists: A focus on the cardiovascular, gastrointestinal and central nervous systems

Diabetes, Obesity and Metabolism

Volumn 16, Issue 8, 2014, Pages 673-688

  Seufert, J ^a   Gallwitz, B ^b  

^a UNIVERSITY OF FREIBURG   (Germany)

^b UNIVERSITY OF TÜBINGEN   (Germany)

Author keywords

Cardiovascular; Central nervous system; Exenatide; Gastrointestinal; GLP 1; Liraglutide; Lixisenatide; Receptor agonists

Indexed keywords

ADENOSINE TRIPHOSPHATE; ALANINE AMINOTRANSFERASE; ALBIGLUTIDE; ASPARTATE AMINOTRANSFERASE; C REACTIVE PROTEIN; CYCLIC AMP; ENDOTHELIAL NITRIC OXIDE SYNTHASE; EXENDIN 4; GLUCAGON LIKE PEPTIDE 1 RECEPTOR; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; GLUCOSE; GUANINE NUCLEOTIDE EXCHANGE FACTOR; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; LIRAGLUTIDE; LIXISENATIDE; LOW DENSITY LIPOPROTEIN CHOLESTEROL; METFORMIN; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE KINASE; OXIDIZED LOW DENSITY LIPOPROTEIN; PLASMINOGEN ACTIVATOR INHIBITOR 1; PROTEIN KINASE B; PROTEIN KINASE C; PROTEIN KINASE C ALPHA; TRIACYLGLYCEROL; VASCULAR CELL ADHESION MOLECULE 1; VERY LOW DENSITY LIPOPROTEIN; ANTIDIABETIC AGENT; GLUCAGON LIKE PEPTIDE 1; GLUCAGON RECEPTOR; GLUCAGON-LIKE PEPTIDE-1 RECEPTOR; INCRETIN; PEPTIDE; VENOM; ZP10A PEPTIDE;

ANTIINFLAMMATORY ACTIVITY; APOPTOSIS; ARTERIAL WALL THICKNESS; BLOOD BRAIN BARRIER; BLOOD GLUCOSE MONITORING; BODY WEIGHT; CARDIOVASCULAR DISEASE; CARDIOVASCULAR EFFECT; CARDIOVASCULAR RISK; CELL FUNCTION; CHOLESTEROL BLOOD LEVEL; DRUG EFFECT; ENDOPLASMIC RETICULUM STRESS; ENDOTHELIAL DYSFUNCTION; GLUCAGON RELEASE; GLUCOSE BLOOD LEVEL; GLUCOSE TRANSPORT; GLYCEMIC CONTROL; HEART FUNCTION; HEART INDEX; HEART PROTECTION; HEART RATE; HUMAN; KIDNEY FUNCTION; LIVER PROTECTION; META ANALYSIS; NEUROLOGIC DISEASE; NEUROPROTECTION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PROTEIN EXPRESSION; RANDOMIZED CONTROLLED TRIAL (TOPIC); RENAL PROTECTION; REVIEW; SIGNAL TRANSDUCTION; STOMACH EMPTYING; STOMACH PROTECTION; SURVIVAL; SYSTOLIC BLOOD PRESSURE; TREATMENT OUTCOME; UPREGULATION; WEIGHT CHANGE; WEIGHT REDUCTION; AGONISTS; ANALOGS AND DERIVATIVES; ANIMAL; COMPLICATION; DIABETES COMPLICATIONS; DIABETES MELLITUS, TYPE 2; DIABETIC CARDIOMYOPATHIES; DIABETIC NEUROPATHIES; EVIDENCE BASED MEDICINE; GASTROINTESTINAL DISEASES; OBESITY;

ANIMALS; DIABETES COMPLICATIONS; DIABETES MELLITUS, TYPE 2; DIABETIC CARDIOMYOPATHIES; DIABETIC NEUROPATHIES; EVIDENCE-BASED MEDICINE; GASTROINTESTINAL DISEASES; GLUCAGON-LIKE PEPTIDE 1; HUMANS; HYPOGLYCEMIC AGENTS; INCRETINS; OBESITY; PEPTIDES; RECEPTORS, GLUCAGON; VENOMS;

EID: 84904388473     PISSN: 14628902     EISSN: 14631326     Source Type: Journal    
DOI: 10.1111/dom.12251     Document Type: Review

References (160)

1. James WPT. Overweight and obesity (high body mass index). In: Ezzati M, ed. Comparative Quantification of Health Risks: Global and Regional Burden of Disease Attributable to Selected Major Risk Factors. Geneva: World Health Organization, 2004; 497-596.
2. Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia 2001; 44(Suppl. 2): S14-S21.
3. Donnelly R, Emslie-Smith AM, Gardner ID, Morris AD. Vascular complications of diabetes. BMJ 2000; 320: 1062-1066.
4. Nauck MA, Homberger E, Siegel EG et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab 1986; 63: 492-498.
5. Wick A, Newlin K. Incretin-based therapies: therapeutic rationale and pharmacological promise for type 2 diabetes. J Am Acad Nurse Pract 2009; 21: 623-630.
6. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev 2007; 87: 1409-1439.
7. 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: 1473-1486.
8. Panjwani N, Mulvihill EE, Longuet C et al. GLP-1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE(-/-) mice. Endocrinology 2013; 154: 127-139.
9. Mentlein R, Gallwitz B, Schmidt WE. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem 1993; 214: 829-835.
10. Madsbad S. Exenatide and liraglutide: different approaches to develop GLP-1 receptor agonists (incretin mimetics) - preclinical and clinical results. Best Pract Res Clin Endocrinol Metab 2009; 23: 463-477.
11. Stonehouse A, Walsh B, Cuddihy R. Exenatide once-weekly clinical development: safety and efficacy across a range of background therapies. Diabetes Technol Ther 2011; 13: 1063-1069.
12. 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: 207-220.
13. Bunck MC, Cornér A, Eliasson B et al. Effects of exenatide on measures of β-cell function after 3years in metformin-treated patients with type 2 diabetes. Diabetes Care 2011; 34: 2041-2047.
14. Fonseca V, Madsbad S, Falahati A, Zychma MJ, Plutzky J. Once-daily human GLP-1 analog liraglutide reduces systolic blood pressure - a meta-analysis of 6 clinical trials (Abstract 545-P). Diabetes 2009; 58(Suppl. 1): A146.
15. Vilsbøll T, Christensen M, Junker AE, Knop FK, Gluud LL. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ 2012; 344: d7771.
16. Klonoff D, 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 3years. Curr Med Res Opin 2008; 24: 275-286.
17. Gallwitz B, Guzman J, Dotta F et al. Exenatide twice daily versus glimepiride for prevention of glycaemic deterioration in patients with type 2 diabetes with metformin failure (EUREXA): an open-label, randomised controlled trial. Lancet 2012; 379: 2270-2278.
18. 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.
19. 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: 252-258.
20. 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: 2234-2243.
21. Nathanson D, Ullman B, Löfström 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: 926-935.
22. Noyan-Ashraf M, Sadi AM, Momen MA, Drucker DJ, Husain M. Administration of a glucagon-like peptide-1 receptor agonist prevents cardiac rupture and increases survival in mice undergoing myocardial infarction (Abstract 1004). Circulation 2007; 116(Suppl. 16): II_200.
23. Noyan-Ashraf MH, Momen MA, Ban K et al. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes 2009; 58: 975-983.
24. Noyan-Ashraf M, Billia F, Mukovozov IM et al. The glucagon-like peptide-1 receptor agonist liraglutide reduces inflammation and improves cardiac function in a mouse model of obesity (Abstract 19477). Circulation 2010; 122(Suppl. 21): A19477.
25. Timmers L, Henriques JP, de Kleijn DP et al. Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury. J Am Coll Cardiol 2009; 53: 501-510.
26. Younce C, Burmeister MA, Ayala JE. Exendin-4 (ex4) attenuates cardiomyocyte apoptosis by inhibiting oxidative stress-induced endoplasmic reticulum (ER) stress (Abstract 206-OR). Diabetes 2012; 61(Suppl. 1): A55.
27. Leonardini A, Laviola L, Orlando MR et al. Exendin-4 inhibits palmitate-induced apoptosis of human cardiac progenitor cells (Abstract 1111-P). Diabetes 2012; 61(Suppl. 1): A287.
28. Wohlfart P, Linz W, Hübschle T et al. Cardioprotective effects of lixisenatide in rat myocardial ischemia-reperfusion injury studies. J Transl Med 2013; 11: 84.
29. Bao W, Aravindhan K, Alsaid H et al. Albiglutide, a long lasting glucagon-like peptide-1 analog, protects the rat heart against ischemia/reperfusion injury: evidence for improving cardiac metabolic efficiency. PLoS One 2011; 6: e23570.
30. Lønborg J, Vejlstrup N, Kelbæk H et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J 2012; 33: 1491-1499.
31. Bernink FJ, Timmers L, Diamant M et al. Effect of additional treatment with exenatide in patients with an acute myocardial infarction: the EXAMI study. Int J Cardiol 2013; 167: 289-290.
32. Gaspari T, Liu H, Welungoda I et al. A GLP-1 receptor agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE-/- mouse model. Diabetes Vasc Dis Res 2011; 8: 117-124.
33. Shiraki A, Oyama J, Komoda H et al. The glucagon-like peptide 1 analog liraglutide reduces TNF-α-induced oxidative stress and inflammation in endothelial cells. Atherosclerosis 2012; 221: 375-382.
34. Simpson RW, Gaspari T, Welungoda I, Widdop RE, Knudsen LB, Dear AE. The GLP-1 receptor agonist liraglutide attenuates atherosclerotic lesion development and potentially enhances plaque stability in an ApoE-/- mouse model (Abstract 1896-P). Diabetes 2012; 61(Suppl. 1): A486.
35. Erdogdu Ö, Eriksson L, Nyström T, Sjöholm Å, Zhang Q. Exendin-4 restores glucolipotoxicity-induced gene expression in human coronary artery endothelial cells. Biochem Biophys Res Commun 2012; 419: 790-795.
36. Han WN, Hölscher C, Yuan L et al. Liraglutide protects against amyloid-β protein-induced impairment of spatial learning and memory in rats. Neurobiol Aging 2013; 34: 576-588.
37. Forst T, Michelson G, Ratter F et al. Addition of liraglutide in patients with type 2 diabetes well controlled on metformin monotherapy improves several markers of vascular function. Diabet Med 2012; 29: 1115-1118.
38. Rizzo M, Maria Patti A, Di Bartolo V, Vincenza Giglio R, Montalto G, Rizvi AA. Effect of liraglutide on carotid intima-media thickness in patients with type-2 diabetes: a 4-month prospective study (Abstract 418-P). Diabetes 2012; 61(Suppl. 1): A109.
39. Irace C, De Luca S, Shehaj E et al. Exenatide improves endothelial function assessed by flow mediated dilation technique in subjects with type 2 diabetes: results from an observational research. Diab Vasc Dis Res 2013; 10: 72-77.
40. Fonseca V, DeVries JH, Bain SC. Liraglutide improves the profile of lipid and cardiovascular risk biomarkers from baseline. In: IDF 2011 21th World Congress Abstract Book. Dubai: IDF, 2011; 442-443 (Poster 1355).
41. Matsumoto Y, Yagi K, Kobayashi J et al. GLP-1 analog improved BNP through improvement in myocardial diastolic dysfunction presentation (Abstract 1066-P). Diabetes 2012; 61(Suppl. 1): A274.
42. 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.
43. Marso SP, Poulter NR, Nissen SE et al. Liraglutide effect and action in diabetes: evaluation of cardiovascular outcome and results (LEADER) trial design and methods. Diabetologia 2013; 56(Suppl. 1): S1-S566.
44. 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.
45. ClinicalTrials.gov. 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 (NCT01144338). Available from URL: http://clinicaltrials.gov/ct2/show/NCT01144338. Accessed 13 September 2013.
46. Jelsing J, Vrang N, Hansen G, Raun K, Tang-Christensen M, Knudsen LB. Liraglutide: short lived effect on gastric emptying - long lasting effects on body-weight. Diabetes Obes Metab 2012; 14: 531-538.
47. Horowitz M, Flint A, Jones KL et al. Effect of the once-daily human GLP-1 analogue liraglutide on appetite, energy intake, energy expenditure and gastric emptying in type 2 diabetes. Diabetes Res Clin Pract 2012; 97: 258-266.
48. Flint A, Kapitza C, Hindsberger C, Zdravkovic M. The once-daily human glucagon-like peptide-1 (GLP-1) analog liraglutide improves postprandial glucose levels in type 2 diabetes patients. Adv Ther 2011; 28: 213-226.
49. 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: 1240-1250.
50. Lorenz M, Pfeiffer C, Steinsträßer A et al. Effects of lixisenatide once daily on gastric emptying in type 2 diabetes - relationship to postprandial glycemia. Regul Pept 2013; 185C: 1-8.
51. Linnebjerg H, Park S, Kothare PA et al. Effect of exenatide on gastric emptying and relationship to postprandial glycemia in type 2 diabetes. Regul Pept 2008; 151: 123-129.
52. Buse JB, Henry RR, Han J et al. Effects of exenatide (exendin-4) on glycemic control over 30weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004; 27: 2628-2635.
53. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005; 28: 1092-1100.
54. Kendall DM, Riddle MC, Rosenstock J et al. Effects of exenatide (exendin-4) on glycemic control over 30weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 2005; 28: 1083-1091.
55. Buse JB, Nauck MA, 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: 117-124.
56. Scott LJ. Lixisenatide: a review of its use in patients with type 2 diabetes mellitus. BioDrugs 2013; 27: 509-523.
57. Wysham CH, Blevins T, Arakaki A, et al. Efficacy and Safety of Dulaglutide Versus Placebo and Exenatide in Type 2 Diabetes (AWARD-1). Presented at ADA 2013; abstract 66-OR. Available from URL: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=795037e5-ca6e-44a8-8b54-cfb1400cd733&cKey=c59c6fdc-969b-478f-8995-1197e735f91f&mKey=89918d6d-3018-4ea9-9d4f-711f98a7ae5d. Accessed on 13 September 2013.
58. Umpierrez GE, Manghi F, Povedano ST, Shurzinske L, Pechtner V. Efficacy and Safety of Dulaglutide vs. Metformin in Type 2 Diabetes (AWARD-3). Presented at ADA 2013; abstract 69-OR. Available from URL: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=795037e5-caz6e-44a8-8b54-cfb1400cd733&cKey=06bd0397-4d33-4883-ab74-b61cc9632c88&mKey=89918d6d-3018-4ea9-9d4f-711f98a7ae5d. Accessed on 13 September 2013.
59. Pratley R, Barnett A, Feinglos MN, et al. Efficacy and Safety of Once-Weekly (QW) Albiglutide vs Once-daily (QD) Liraglutide in Type 2 Diabetes (T2D) Inadequately Controlled on Oral Agents: Harmony 7 Trial. Presented at ADA 201; abstract 945-P. Available from URL: http://www.abstractsonline.comPlan/ViewAbstract.aspx?sKey=761b96ad-5b5d-4d0c-80d2-a7cb9c3b63fa&cKey=84f095e6-2c91-40e6-9744-4cf4920d9cb2&mKey={0F70410F-8DF3-49F5-A63D-3165359F5371}. Accessed 13 September 2013.
60. Ahren B, Stewart M, Cirkel D, Yang F, Perry C, Johnson S. HARMONY 3: 104 Week (Wk) Efficacy of Albiglutide (Albi) Compared to Sitagliptin (Sita) and Glimepiride (SU) in Patients (pts) With Type 2 Diabetes Mellitus (T2DM) on Metformin (Met). Presented at ADA 2013; abstract 52-LB. Available from URL: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=0687e7c8-c97d-442b-92ec-ae505e051854&cKey=536ec2d4-682a-49ce-80c1-bebcccae0900&mKey=89918d6d-3018-4ea9-9d4f-711f98a7ae5d. Accessed on 13 September 2013.
61. Pratley R, Stewart M, Cirkel D, Ye J, Perry C, Carr MC. HARMONY 4: 52-Wk Efficacy of Albiglutide (Albi). Insulin Glargine (Glar) in Patients (pts) With T2DM. Presented at ADA 2013; abstract 54-LB. Available from URL: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=0687e7c8-c97d-442b-92ec-ae505e051854&cKey=7fda08fd-2fbc-41fa-8cff-7a5152a22488&mKey=89918d6d-3018-4ea9-9d4f-711f98a7ae5d. Accessed on 13 September 2013.
62. Reusch J, Stewart M, Perkins C, et al. HARMONY 1 Week 52 Results: Albiglutide vs. Placebo in Patients With Type 2 Diabetes Mellitus not Controlled on Pioglitazone ± Metformin. Presented at ADA 2013; abstract 57-LB. Available from URL: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=0687e7c8-c97d-442b-92ec-ae505e051854&cKey=37d3bc28-d232-4cf4-969b-1f061e2de0de&mKey=89918d6d-3018-4ea9-9d4f-711f98a7ae5d. Accessed on 13 September 2013.
63. Home P, Stewart M, Yang F, Perry C, Carr MC. 52-Week Efficacy of Albiglutide vs Placebo and vs Pioglitazone in Triple Therapy (Background Metformin and Glimepiride) in People With Type 2 Diabetes: HARMONY5 Study. Presented at ADA 2013; abstract 58-LB. Available from URL: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=0687e7c8-c97d-442b-92ec-ae505e051854&cKey=d0f7798c-ce40-4cce-8c6d-5ef628044c84&mKey=89918d6d-3018-4ea9-9d4f-711f98a7ae5d. Accessed 13 September 2013.
64. 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: 1606-1616.
65. Astrup A, Carraro R, Finer N et al. Safety, tolerability and sustained weight loss over 2years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond) 2012; 36: 843-854.
66. Elkind-Hirsch K, Marrioneaux O, Bhushan M, Vernor D, Bhushan R. Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 2008; 93: 2670-2678.
67. Rosenstock J, Klaff LJ, Schwartz S et al. Effects of exenatide and lifestyle modification on body weight and glucose tolerance in obese subjects with and without pre-diabetes. Diabetes Care 2010; 33: 1173-1175.
68. Kelly AS, Metzig AM, Rudser KD et al. Exenatide as a weight-loss therapy in extreme pediatric obesity: a randomized, controlled pilot study. Obesity 2012; 20: 364-370.
69. Perry T, Haughey NJ, Mattson MP, Egan JM, Greig NH. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J Pharmacol Exp Ther 2002; 302: 881-888.
70. Perry T, Lahiri DK, Sambamurti K et al. Glucagon-like peptide-1 decreases endogenous amyloid-β peptide (Aβ) levels and protects hippocampal neurons from death induced by Aβ and iron J. Neurosci Res 2003; 72: 603-612.
71. Han L, Yu Y, Sun X, Wang B. Exendin-4 directly improves endothelial dysfunction in isolated aortas from obese rats through the cAMP or AMPK-eNOS pathways. Diabetes Res Clin Pract 2012; 97: 453-460.
72. Huang HJ, Chen YH, Liang KC et al. Exendin-4 protected against cognitive dysfunction in hyperglycemic mice receiving an intrahippocampal lipopolysaccharide injection. PLoS One 2012; 7: e39656.
73. Hamilton A, Patterson S, Porter D, Gault VA, Holscher C. Novel GLP-1 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain. J Neurosci Res 2011; 89: 481-489.
74. McClean PL, Parthsarathy V, Faivre E, Hölscher C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. J Neurosci 2011; 31: 6587-6594.
75. Kim S, Moon M, Park S. Exendin-4 protects dopaminergic neurons by inhibition of microglial activation and matrix metalloproteinase-3 expression in an animal model of Parkinson's disease. J Endocrinol 2009; 202: 431-439.
76. Li Y, Perry T, Kindy MS et al. GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc Natl Acad Sci U S A 2009; 106: 1285-1289.
77. Okouchi M, Okayama N, Shigeki G et al. GLP-1 analogs represent a novel treatment strategy for diabetic encephalopathy (Abstract 569-P). Diabetes 2012; 61(Suppl. 1): A145.
78. Himeno T, Kamiya H, Naruse K et al. Beneficial effects of exendin-4 on experimental polyneuropathy in diabetic mice. Diabetes 2011; 60: 2397-2406.
79. Liu WJ, Jin HY, Lee KA, Xie SH, Baek HS, Park TS. Neuroprotective effect of the glucagon-like peptide-1 receptor agonist, synthetic exendin-4, in streptozotocin-induced diabetic rats. Br J Pharmacol 2011; 164: 1410-1420.
80. Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A. Exenatide and the treatment of patients with Parkinson's disease. J Clin Invest 2013; 123: 2730-2736.
81. Davidson JA, Brett J, Falahati A, Scott D. Mild renal impairment has no effect on the efficacy and safety of liraglutide. Endocr Pract 2010; 6: 1-31.
82. Armstrong M, Falahati A, Houlihan DD et al. Effects of two years of liraglutide treatment on fatty liver disease in patients with type 2 diabetes: analysis of the Liraglutide Effect and Action in Diabetes-2 extension trial. Gut 2010; 59: A1-A2.
83. Armstrong MJ, Houlihan DD, Rowe IA et al. Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program. Aliment Pharmacol Ther 2013; 37: 234-242.
84. ClinicalTrials.gov. Liraglutide Efficacy and Action in Non-alcoholic Steatohepatitis (LEAN) (NCT01237119). Available from URL: http://clinicaltrials.gov/show/NCT01237119. Accessed on 13 September 2013.
85. Bulchandani D, Nachnani JS, Eaton C, Hamburg M. Association of exenatide with liver enzymes in patients with type 2 diabetes. Endocrinologist 2009; 19: 114-115.
86. Cuthbertson DJ, Irwin A, Gardner CJ et al. Improved glycaemia correlates with liver fat reduction in obese, type 2 diabetes, patients given glucagon-like peptide-1 (GLP-1) receptor agonists. PLoS One 2012; 7: e50117.
87. Sathyanarayana P, Jogi M, Muthupillai R, Krishnamurthy R, Samson SL, Bajaj M. Effects of combined exenatide and pioglitazone therapy on hepatic fat content in type 2 diabetes. Obesity (Silver Spring) 2011; 19: 2310-2315.
88. Faurschou A, Knop FK, Thyssen JP, Zachariae C, Skov L, Vilsbøll T. Improvement in psoriasis after treatment with the glucagon-like peptide-1 receptor agonist liraglutide. Acta Diabetol 2014; 51: 147-150.
89. Hogan AE, Tobin AM, Ahern T et al. Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis. Diabetologia 2011; 54: 2745-2754.
90. Ahern T, Tobin AM, Corrigan M et al. Glucagon-like peptide-1 analogue therapy for psoriasis patients with obesity and type 2 diabetes: a prospective cohort study. J Eur Acad Dermatol Venereol 2013; 27: 1440-1443.
91. Buysschaert M, Tennstedt D, Preumont V. Improvement of psoriasis during exenatide treatment in a patient with diabetes. Diabetes Metab 2012; 8: 86-88.
92. He L, Wong CK, Cheung K et al. Anti-inflammatory effects of exendin-4 on human peripheral lymphocytes in patients with type 1/2 diabetes (Abstract 75-LB). Diabetes 2012; 61(Suppl. 1): 437.
93. Turner RC, Millns H, Neil HA et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ 1998; 316: 823-828.
94. Emerging Risk Factors Collaboration, Seshasai SR, Kaptoge S et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011; 364: 829-841.
95. ADVANCE Collaborative Group, Patel A, MacMahon S et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358: 2560-2572.
96. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group, Gerstein HC, Miller ME et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545-2559.
97. Nikolaidis LA, Mankad S, Sokos GG et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation 2004; 109: 962-965.
98. Simo R, Guerci B, Schernthaner G et al. Long-term administration of exenatide and changes in body weight and markers of cardiovascular risk: a comparative study with glimepiride (Abstract 781). Diabetologia 2012; 55(Suppl. 1): S332.
99. Buse J, Rosenstock J, Sesti G, for the LEAD 6 Study Group 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.
100. Chhabra N. Endothelial dysfunction - a predictor of atherosclerosis. Internet J Med Updat 2009; 4: 33-41.
101. Kelly AS, Bergenstal RM, Gonzalez-Campoy JM, Katz H, Bank AJ. Effects of exenatide vs. metformin on endothelial function in obese patients with pre-diabetes: a randomized trial. Cardiovasc Diabetol 2012; 11: 64.
102. 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: 1196-1200.
103. Linnebjerg H, Seger M, Kothare PA, Hunt T, Wolka AM, Mitchell MI. A thorough QT study to evaluate the effects of single dose exenatide 10μg on cardiac repolarization in healthy subjects. Int J Clin Pharmacol Ther 2011; 49: 594-604.
104. Darpö 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: 979-989.
105. Chatterjee DJ, Khutoryansky N, Zdravkovic M, Sprenger CR, Litwin JS. 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; 11: 1353-1362.
106. Ussher JR, Drucker DJ. Cardiovascular biology of the incretin system. Endocr Rev 2012; 33: 187-215.
107. Lønborg J, Kelbæk H, Vejlstrup N et al. Exenatide reduces final infarct size in patients with ST-segment-elevation myocardial infarction and short-duration of ischemia. Circ Cardiovasc Interv 2012; 5: 288-295.
108. ClinicalTrials.gov. Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010 (Lixisenatide) (ELIXA) (NCT01147250). 2013. Available from URL: http://clinicaltrials.gov/show/NCT01147250. Accessed 13 September 2013.
109. ORIGIN Trial Investigators, Gerstein HC, Bosch J. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012; 367: 319-328.
110. Goldberg RB, Kendall DM, Deeg MA et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005; 28: 1547-1554.
111. Goldstein BJ, Weissman PN, Wooddell MJ, Waterhouse BR, Cobitz AR. Reductions in biomarkers of cardiovascular risk in type 2 diabetes with rosiglitazone added to metformin compared with dose escalation of metformin: an EMPIRE trial sub-study. Curr Med Res Opin 2006; 22: 1715-1723.
112. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356: 2457-2471. Erratum in N Engl J Med 2007; 357: 100.
113. White WBW, Cannon CP, Heller SR et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013; 369: 1327-1335.
114. 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: 1317-1326.
115. Cobble ME, Frederich R. Saxagliptin for the treatment of type 2 diabetes mellitus: assessing cardiovascular data. Cardiovasc Diabetol 2012; 11: 6.
116. White WB, Pratley R, Fleck P et al. Cardiovascular safety of the dipeptidyl peptidase-4 inhibitor alogliptin in type 2 diabetes mellitus. Diabetes Obes Metab 2013; 15: 668-673.
117. Kanoski SE, Rupprecht LE, Fortin SM, De Jonghe BC, Hayes MR. The role of nausea in food intake and body weight suppression by peripheral GLP-1 receptor agonists, exendin-4 and liraglutide. Neuropharmacology 2012; 62: 1916-1927.
118. Lean ME, Carraro R, Finer N et al. Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults. Int J Obes (Lond) 2014; 38: 689-697.
119. Niswender K, Pi-Sunyer X, Buse J et al. Weight change with liraglutide and comparator therapies: an analysis of seven phase 3 trials from the liraglutide diabetes development programme. Diabetes Obes Metab 2013; 15: 42-54.
120. Eli Lilly and Company Limited. Summary of Product Characteristics: Byetta 5 micrograms solution for injection, Prefilled Pen. Byetta 10 Micrograms Solution for Injection, Prefilled Pen. 2012. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000698/WC500051845.pdf. Accessed 13 September 2013.
121. Kastin AJ, Akerstrom V. Entry of exendin-4 into brain is rapid but may be limited at high doses. Int J Obes Relat Metab Disord 2003; 27: 313-318.
122. Punjabi M, Arnold M, Geary N, Langhans W, Pacheco-López G. Peripheral glucagon-like peptide-1 (GLP-1) and satiation. Physiol Behav 2011; 105: 71-76.
123. Hunter K, Hölscher C. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci 2012; 23: 13-33.
124. Kanoski SE, Fortin SM, Arnold M, Grill HJ, Hayes MR. Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, liraglutide and exendin-4. Endocrinology 2011; 152: 3103-3112.
125. IDF. Diabetes Atlas 2nd Edition, 2003. Available from URL: http://www.idf.org/sites/default/files/IDF_Diabetes_Atlas_2ndEd.pdf. Accessed 3 June 2013.
126. Davies M. The reality of glycaemic control in insulin treated diabetes: defining the clinical challenges. Int J Obes 2004; 28(Suppl. 2): S14-S22.
127. Bogers RP, Bemelmans WJ, Hoogenveen RT et al. Association of overweight with increased risk of coronary heart disease partly independent of blood pressure and cholesterol levels: a meta-analysis of 21 cohort studies including more than 300 000 persons. Arch Intern Med 2007; 167: 1720-1728.
128. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2012; 8: 728-742.
129. Irie F, Fitzpatrick AL, Lopez OL et al. Enhanced risk for Alzheimer disease in persons with type 2 diabetes and APOE epsilon4: the Cardiovascular Health Study Cognition Study. Arch Neurol 2008; 65: 89-93.
130. Driver JA, Smith A, Buring JE, Gaziano JM, Kurth T, Logroscino G. Prospective cohort study of type 2 diabetes and the risk of Parkinson's disease. Diabetes Care 2008; 31: 2003-2005.
131. Hölscher C, Li L. New roles for insulin-like hormones in neuronal signalling and protection: new hopes for novel treatments of Alzheimer's disease? Neurobiol Aging 2010; 31: 1495-1502.
132. Egefjord L, Gejl M, Møller A et al. Effects of liraglutide on neurodegeneration, blood flow and cognition in Alzheimer's disease - protocol for a controlled, randomized double-blinded trial. Dan Med J 2012; 59: A4519.
133. ClinicalTrials.gov. Identifying Potential Effects of Liraglutide on Degenerative Changes (NCT01469351). Available from URL: http://clinicaltrials.gov/show/NCT01469351. Accessed on 13 September 2013.
134. ClinicalTrials.gov. A Clinical Trial of Exendin-4 for the Treatment of Alzheimer's Disease (NCT01255163). Available from URL: http: //clinicaltrials.gov/ct2/show/NCT01255163. Accessed on 13 September 2013.
135. Retnakaran R, Cull CA, Thorne KI, Adler AI, Holman RR. UKPDS Study Group. Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74. Diabetes 2006; 55: 1832-1839.
136. Weise WJ, Sivanandy MS, Block CA, Comi RJ. Exenatide-Associated Ischemic Renal Failure. Diabetes Care 2009; 32: e22-e23.
137. Gallwitz B, Rosenstock J, Rauch T et al. 2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial. Lancet 2012; 380: 475-483.
138. Eli Lilly and Company Limited. Summary of Product Characteristics: Bydureon 2 mg powder and solvent for prolonged-release suspension for injection. 2012. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002020/WC500108241.pdf. Accessed 13 September 2013.
139. Novo Nordisk Limited. Summary of Product Characteristics: Victoza 6 mg/ml Solution for Injection in Pre-filled Pen. 2012. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001026/WC500050017.pdf. Accessed 13 September 2013.
140. López-Ruiz A, del Peso-Gilsanz C, Meoro-Avilés A et al. Acute renal failure when exenatide is co-administered with diuretics and angiotensin II blockers. Pharm World Sci 2010; 32: 559-561.
141. Weise J, Sivanandy MS, Block CA, Comi RJ. Exenatide-associated ischemic renal failure. Diabetes Care 2009; 32: e22-e23.
142. Kaakeh Y, Kanjee S, Boone K, Sutton J. Liraglutide-induced acute kidney injury. Pharmacotherapy 2012; 32: e7-e11.
143. Nandakoban H, Furlong TJ, Flack JR. Acute tubulointerestitial nephritis following treatment with exenatide. Diabet Med 2013; 30: 123-125.
144. Liraglutide Treatment to Patients With Severe Renal Insufficiency. Available from URL: http://clinicaltrials.gov/show/NCT01394341. Accessed on 13 September 2013.
145. Cheng J, Kuai D, Zhang L, Yang X, Qiu B. Psoriasis increased the risk of diabetes: a meta-analysis. Arch Dermatol Res 2012; 304: 119-125.
146. Drucker D, Rosen CF. Glucagon-like peptide-1 (GLP-1) receptor agonists, obesity and psoriasis: diabetes meets dermatology. Diabetologia 2011; 54: 2741-2744.
147. 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: 2595-2604.
148. Kahn SE. Incretin therapy and islet pathology - a time for caution. Diabetes 2013; 62: 2178-2180.
149. EMA Statement Investigation into GLP-1-based Diabetes Therapies Concluded. Available from URL: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/07/news_detail_001856.jsp&mid=WC0b01ac058004d5c1. Accessed on 13 September 2013.
150. Williams AJ, Thrower SL, Sequeiros IM et al. Pancreatic volume is reduced in adult patients with recently diagnosed type 1 diabetes. J Clin Endocrinol Metab 2012; 97: E2109-E2113.
151. Williams AJ, Chau W, Callaway MP, Dayan CM. Magnetic resonance imaging: a reliable method for measuring pancreatic volume in type 1 diabetes. Diabet Med 2007; 24: 35-40.
152. NIDDK-NCI Workshop on Pancreatitis-Diabetes-Pancreatic Cancer. Available from URL: http: //www2.niddk.nih.gov/News/Calendar/PDPC2013.htm. Accessed on 13 September 2013.
153. Gaglia JL, Guimaraes AR, Harisinghani M et al. Noninvasive imaging of pancreatic islet inflammation in type 1A diabetes patients. J Clin Invest 2011; 121: 442-445.
154. FDA Drug Safety Communication: FDA Investigating Reports of Possible Increased Risk of Pancreatitis and Pre-cancerous Findings of the Pancreas From Incretin Mimetic Drugs for Type 2 Diabetes. Available from URL: http: //www.fda.gov/Drugs/DrugSafety/ucm343187.htm. Accessed on 13 September 2013.
155. 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.
156. Engel SS, Round E, Golm GT, Kaufman KD, Goldstein BJ. Safety and tolerability of sitagliptin in type 2 diabetes: pooled analysis of 25 clinical studies. Diabetes Ther 2013; 4: 119-145.
157. 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: 271-284.
158. Dore DD, Seegerac JD, Chanac KA. 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: 1019-1027.
159. Garg E, 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: 2349-2354.
160. 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: 1412-1418.