Non-glycaemic effects mediated via GLP-1 receptor agonists and the potential for exploiting these for therapeutic benefit: Focus on liraglutide

Diabetes, Obesity and Metabolism

Volumn 14, Issue SUPPL. 2, 2012, Pages 41-49

  Vilsboll T ^a   Garber, A J ^b  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

^b BAYLOR COLLEGE OF MEDICINE   (United States)

Author keywords

Extra pancreatic; GLP 1; Liraglutide; cell

Indexed keywords

EXENDIN 4; GLIMEPIRIDE; GLUCAGON LIKE PEPTIDE 1; GLUCAGON LIKE PEPTIDE 1 RECEPTOR; LIRAGLUTIDE; ROSIGLITAZONE;

CARDIOVASCULAR RISK; DRUG EFFECT; FOOD INTAKE; GLYCEMIC CONTROL; HEART INFARCTION; HEART PROTECTION; HUMAN; NEUROPROTECTION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PROTEIN EXPRESSION; REVIEW; WEIGHT REDUCTION;

EID: 84858132726     PISSN: 14628902     EISSN: 14631326     Source Type: Journal    
DOI: 10.1111/j.1463-1326.2012.01579.x     Document Type: Review

References (100)

1. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev 2007; 87: 1409-1439.
2. Vilsbøll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced post-prandial concentrations of intact biologically active glucagon-like peptide-1 in type 1 and type 2 diabetic patients. Diabetes 2001; 50: 609-613.
3. Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide-1 [7-36 amide] in type 2 (non-insulin dependent) diabetic patients. Diabetologia 1993; 36: 741-744.
4. Vilsbøll T, Agersø H, Krarup T, Holst JJ. Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects. J Clin Endocrinol Metab 2003; 88: 220-224.
5. Steensgaard DB, Thomsen JK, Olsen HB, Knudsen LB. The molecular basis for the delayed absorption of the once daily human GLP-1 analogue, liraglutide. Diabetes 2008; 57(Suppl. 1): A164.
6. Goldstein BJ, Feinglos MN, Lunceford JK et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care 2007; 30: 1979-1987.
7. Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care 2007; 30: 890-895.
8. DeFronzo RA, Hissa MN, Garber AJ et al. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care 2009; 32: 1649-1655.
9. Marre M, Shaw J, Brändle M, LEAD-1 SU study group 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.
10. 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: 84-90.
11. 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: 473-481.
12. Zinman B, Gerich J, Buse JB, LEAD-4 Study Investigators 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.
13. Russell-Jones D, Vaag A, Schmitz O, Liraglutide Effect and Action in Diabetes 5 (LEAD-5) met+SU Study Group 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.
14. Buse JB, Rosenstock J, Sesti G et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009; 374: 39-47.
15. 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: 1447-1456.
16. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005; 28: 1092-1100.
17. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD. Exenatide-113 Clinical Study Group. 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.
18. 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.
19. 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.
20. Vilsbøll T, Knop FK, Christensen M, Gluud LL. Weight-lowering efficacy of glucagon-like peptide-1 receptor agonists: a meta-analysis. Diabetes 2011; 60(Suppl. 1): A315.
21. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Available from URL: Accessed 5 October 2011.
22. US Department of Health and Human Services. Weight-control Information Network: Do you know the risks of being overweight? Available from URL: Accessed 5 October 2011.
23. Blonde L, Montanya E. Comparison of liraglutide versus other incretin-related anti-hyperglycaemic agents. Diabetes Obes Metab 2012; 14(Suppl. 2): 20-32.
24. Garber AJ. Liraglutide in oral antidiabetic drug combination therapy. Diabetes Obes Metab 2012; 14(Suppl. 2): 13-19.
25. UK Prospective Diabetes Study Group. UK prospective diabetes study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease. Diabetes 1995; 44: 1249-1258.
26. Bulotta A, Hui H, Anastasi E et al. Cultured pancreatic ductal cells undergo cell cycle re-distribution and β-cell-like differentiation in response to glucagon-like peptide-1. J Mol Endocrinol 2002; 29: 347-363.
27. Farilla L, Hui H, Bertolotto C et al. Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology 2002; 143: 4397-4408.
28. Sturis J, Gotfredsen CF, Rømer J et al. GLP-1 derivative liraglutide in rats with β-cell deficiencies: influence of metabolic state on β-cell mass dynamics. Br J Pharmacol 2003; 140: 123-132.
29. Bock T, Pakkenberg B, Buschard K. The endocrine pancreas in non-diabetic rats after short-term and long-term treatment with the long-acting GLP-1 derivative NN2211. APMIS 2003; 111: 1117-1124.
30. Nielsen LL, Young AA, Parkes DG. Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes. Regul Pept 2004; 117: 77-88.
31. Tsunekawa S, Yamamoto N, Tsukamoto K et al. Protection of pancreatic ß-cells by exendin-4 may involve the reduction of endoplasmic reticulum stress; in vivo and in vitro studies. J Endocrinol 2007; 193: 65-74.
32. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group study. Lancet 2002; 359: 824-830.
33. Chang AM, Jakobsen G, Sturis J et al. The GLP-1 derivative NN2211 restores β-cell sensitivity to glucose in type 2 diabetic patients after a single dose. Diabetes 2003; 52: 1786-1791.
34. Bunck MC, Diamant M, Cornér A et al. One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial. Diabetes Care 2009; 32: 762-768.
35. Bunck MC, Cornér A, Eliasson B et al. Effects of exenatide on measures of β-cell function after 3 years in metformin-treated patients with type 2 diabetes. Diabetes Care 2011; 34: 2041-2047.
36. Stagnitti MN. The prevalence of obesity and other chronic health conditions among diabetic adults in the U.S. community population, 2001. Panel Survey-Household Component, 2001. Available from URL: Accessed 5 October 2011.
37. Jacobs MJ, Kleisli T, Pio JR et al. Prevalence and control of dyslipidemia among persons with diabetes in the United States. Diabetes Res Clin Pract 2005; 70: 263-269.
38. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003; 348: 383-393.
39. Nyström 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: E1209-1215.
40. Nyström T, Gonon AT, Sjöholm A, Pernow J. Glucagon-like peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism. Regul Pept 2005; 125: 173-177.
41. 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.
42. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail 2006; 12: 694-699.
43. Noyan-Ashraf MH, Momen MA, Ban K et al. GLP-1 R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes 2009; 58: 975-983.
44. Sonne DP, Engstrøm T, Treiman M. Protective effects of GLP-1 analogues exendin-4 and GLP-1(9-36) amide against ischemia-reperfusion injury in rat heart. Regul Pept 2008; 146: 243-249.
45. 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.
46. Lønborg J, Vejlstrup N, Kelbæk H et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J 2011; DOI: 10.1093/eurheartj/ehr309.
47. Plutzky J, Poulter NR, Falahati A, Toft AD, Davidson MH. Plasminogen activator inhibitor-1 is reduced by the once-daily human glucagon-like peptide-1 analog liraglutide when used in the treatment of type 2 diabetes. Circulation 2009; 120: S397.
48. Plutzky J, Garber AJ, Falahati A, Toft AD, Poulter NR. The once-daily human GLP-1 analogue, liraglutide, significantly reduces markers of cardiovascular risk in type 2 diabetes: a meta-analysis of six clinical trials. Eur Heart J 2009; 30(Suppl. 1): 917.
49. Nicholl SM, Roztocil E, Davies MG. Plasminogen activator system and vascular disease. Curr Vasc Pharmacol 2006; 4: 101-116.
50. Blonde L, Klein EJ, Han J et al. Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. Diabetes Obes Metab 2006; 8: 436-447.
51. 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.
52. Drucker DJ, Buse JB, Taylor K, DURATION-1 Study Group 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.
53. Bergenstal RM, Wysham C, Macconell L, DURATION-2 Study Group et al. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet 2010; 376: 431-439.
54. 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 375: 2234-2243.
55. Boardman MK, Hanefeld M, Kumar A et al. DURATION-4: improvements in glucose control and cardiovascular risk factors in patients with type 2 diabetes treated with exenatide once weekly, metformin, pioglitazone, or sitagliptin (Abstract 779). Diabetologia 2011; 54(Suppl. 1): S315.
56. Blevins T, Pullman J, Malloy J et al. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab 2011; 96: 1301-1310.
57. Buse JB, Nauck MA, Forst T et al. Efficacy and safety of exenatide once weekly versus liraglutide in subjects with type 2 diabetes (DURATION-6): a randomised, open-label study (Abstract A75). Diabetologia 2011; 54(Suppl. 1): S38.
58. Gutzwiller JP, Tschopp S, Bock A et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab 2004; 89: 3055-3061.
59. Gallwitz B, Vaag A, Falahati A, Madsbad S. Adding liraglutide to oral antidiabetic drug therapy: onset of treatment effects over time. Int J Clin Pract 2010; 64: 267-276.
60. 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: 219-224.
61. Gutzwiller JP, Hruz P, Huber AR et al. Glucagon-like peptide-1 is involved in sodium and water homeostasis in humans. Digestion 2006; 73: 142-150.
62. Chagnac A, Herman M, Zingerman B et al. Obesity-induced glomerular hyperfiltration: its involvement in the pathogenesis of tubular sodium reabsorption. Nephrol Dial Transplant 2008; 23: 3946-3952.
63. Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease: an update. Hypertension 2001; 37: 1053-1059.
64. Larsen PJ, Fledelius C, Knudsen LB, Tang-Christensen M. Systemic administration of the long-acting GLP-1 derivative NN2211 induces lasting and reversible weight loss in both normal and obese rats. Diabetes 2001; 50: 2530-2539.
65. Retnakaran R, Cull CA, Thorne KI, Adler AI, Holman RR, Study Group UKPDS. Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74. Diabetes 2006; 55: 1832-1839.
66. Linnebjerg H, Kothare PA, Park S et al. Effect of renal impairment on the pharmacokinetics of exenatide. Br J Clin Pharmacol 2007; 64: 317-327.
67. ®) UK SPC. Available from URL: Accessed 13 September 2011.
68. 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.
69. ® (liraglutide) European SPC. Available from URL: Accessed 5 October 2011.
70. ® (liraglutide) US SPC. Available from URL: Accessed 5 October 2011.
71. Feldt-Rasmussen B, Available from URL: Accessed 7 November 2011.
72. Navarro M, Rodriquez de Fonseca F, Alvarez E et al. Colocalization of glucagon-like peptide-1 (GLP-1) receptors, glucose transporter GLUT-2, and glucokinase mRNAs in rat hypothalamic cells: evidence for a role of GLP-1 receptor agonists as an inhibitory signal for food and water intake. J Neurochem 1996; 67: 1982-1991.
73. 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.
74. Perry TA, Greig N. A new Alzheimer's disease interventive strategy: GLP-1. Curr Drug Targets 2004; 5: 565-571.
75. Hayes MR, Leichner TM, Zhao S et al. Intracellular signals mediating the food intake-suppressive effects of hindbrain glucagon-like peptide-1 receptor activation. Cell Metab 2011; 13: 320-330.
76. Raun K, von Voss P, Knudsen LB. Liraglutide, a once-daily human glucagon-like peptide-1 analog, minimizes food intake in severely obese minipigs. Obesity (Silver Spring) 2007; 15: 1710-1716.
77. Raun K, von Voss P, Gotfredsen CF, Golozoubova V, Rolin B, Knudsen LB. Liraglutide, a long-acting glucagon-like peptide-1 analog, reduces body weight and food intake in obese candy-fed rats, whereas a dipeptidyl peptidase-IV inhibitor, vildagliptin, does not. Diabetes 2007; 56: 8-15.
78. Verdich C, Flint A, Gutzwiller JP et al. A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake in humans. J Clin Endocrinol Metab 2001; 86: 4382-4389.
79. Bjerre Knudsen L, Tang-Christiansen M, Jelsing J, Vrang N, Raun K. Liraglutide: short lived effect on gastric emptying-long lasting effects on body-weight. Diabetes 2010; 59(Suppl. 1): 591-P.
80. Ribel U, Larsen MO, Rolin B et al. NN2211: a long-acting glucagon-like peptide-1 derivative with antidiabetic effects in glucose-intolerant pigs. Eur J Pharmacol 2002; 451: 217-225.
81. Vrang N, Jelsing J, Raun K, Knudsen LB. Liraglutide regulates key hypothalamic appetite-related signals in diet-induced obese rats (Abstract 159). Diabetologia 2010; 53(Suppl. 1): S72.
82. Jelsing J, Vrang N, Raun K, Knudsen LB. Liraglutide induced anorexia is not mediated by brainstem GLP-1 neurons. Diabetes 2011; 60(Suppl. 1): A297.
83. Vrang N, Jelsing J, Raun K, Knudsen LB. The effect of liraglutide on gastric emptying and bodyweight is not mediated by vagal afferents nor the area postrema (Abstract 587). Diabetologia 2011; 54(Suppl. 1): S241.
84. Young AA, Gedulin BR, Bhavsar S et al. Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta). Diabetes 1999; 48: 1026-1034.
85. Klonoff DC, Buse JB, Nielsen LL et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin 2008; 24: 275-286.
86. Pratley R, Nauck M, Bailey T, 1860-LIRA-DPP-4 Study Group 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.
87. Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 1998; 101: 515-520.
88. Flint A, Hindsberger C. The relationship between pharmacokinetics of the once-daily human GLP-1 analogue liraglutide and pharmacodynamic effects on glycemia, gastric emptying and energy intake. Diabetes 2010; 59(Suppl. 1): A420.
89. Jendle J, Nauck MA, Matthews DR et al. Weight loss with liraglutide, a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes treatment as monotherapy or added to metformin, is primarily as a result of a reduction in fat tissue. Diabetes Obes Metab 2009; 11: 1163-1172.
90. Russell-Jones D, Sesti G, Garber A et al. Liraglutide causes reductions in body weight both in patients with and without gastrointestinal side effects. Diabetes 2010; 59(Suppl. 1): A493.
91. Gough SCL. Liraglutide: from clinical trials to clinical practice. Diabetes Obes Metab 2012; 14(Suppl. 2): 33-40.
92. Giorda CB, Avogaro A, Maggini M et al. Incidence and risk factors for stroke in type 2 diabetic patients. Stroke 2007; 38: 1154.
93. 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.
94. 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.
95. Steen E, Terry BM, Rivera EJ et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease-is this type 3 diabetes? J Alzheimers Dis 2005; 7: 63-80.
96. Gao H, Wang X, Zhang Z et al. GLP-1 amplifies insulin signaling by up-regulation of IRbeta IRS-1 and Glut4 in 3T3-L1 adipocytes. Endocrine 2007; 32: 90-95.
97. 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.
98. McClean PL, Gault VA, Harriott P, Hölscher C. Glucagon-like peptide-1 analogues enhance synaptic plasticity in the brain: a link between diabetes and Alzheimer's disease. Eur J Pharmacol 2010; 630: 158-162.
99. 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.
100. US Department of Health and Human Services. Do you know the risks of being overweight? NIH Publication No. 07-4098; 2007. Available from URL: Accessed 20 February 2011.