Influence of hepatic impairment on pharmacokinetics of the human GLP-1 analogue, liraglutide

British Journal of Clinical Pharmacology

Volumn 70, Issue 6, 2010, Pages 807-814

  Flint, Anne ^a   Nazzal, Khalil ^b   Jagielski, Pawel ^c   Hindsberger, Charlotte ^a   Zdravkovic, Milan ^a  

^a NOVO NORDISK A S   (Denmark)

^b MEDICAL UNIVERSITY OF WARSAW   (Poland)

^c PRA Early Development Services   (Poland)

Author keywords

DPP IV; Exenatide; Glucagon like peptide 1; Incretin; Liver disease; Once daily; Type 2 diabetes mellitus

Indexed keywords

ALBUMIN; BILIRUBIN; GLUCOSE; LIRAGLUTIDE;

ADULT; AGED; AREA UNDER THE CURVE; ARTICLE; ASCITES; BIOEQUIVALENCE; BLOOD SAMPLING; BRONCHITIS; CLINICAL ARTICLE; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DIABETIC PATIENT; DISEASE SEVERITY; DRUG BLOOD LEVEL; DRUG EXPOSURE; DRUG INDICATION; DRUG INDUCED HEADACHE; DRUG SAFETY; DRUG TOLERABILITY; ENZYME LINKED IMMUNOSORBENT ASSAY; FEMALE; FOLLOW UP; GLUCOSE BLOOD LEVEL; HEPATIC ENCEPHALOPATHY; HUMAN; HYPOGLYCEMIA; LABORATORY TEST; LIVER BLOOD FLOW; LIVER DYSFUNCTION; LIVER FUNCTION; MALE; MAXIMUM PLASMA CONCENTRATION; NAUSEA; NON INSULIN DEPENDENT DIABETES MELLITUS; OPEN STUDY; PARTIAL THROMBOPLASTIN TIME; PRIORITY JOURNAL; SINGLE DRUG DOSE; THIGH; TIME TO MAXIMUM PLASMA CONCENTRATION;

ADOLESCENT; ADULT; AGED; DIABETES MELLITUS, TYPE 2; FEMALE; GLUCAGON-LIKE PEPTIDE 1; HALF-LIFE; HUMANS; HYPOGLYCEMIC AGENTS; LIVER DISEASES; MALE; MIDDLE AGED; SERUM ALBUMIN; SEVERITY OF ILLNESS INDEX; YOUNG ADULT;

EID: 78049354214     PISSN: 03065251     EISSN: 13652125     Source Type: Journal    
DOI: 10.1111/j.1365-2125.2010.03762.x     Document Type: Article

References (39)

1. Freeman H, Cox RD. Type-2 diabetes: a cocktail of genetic discovery. Hum Mol Genet 2006; 15: R202-9.
2. Naser KA, Gruber A, Thomson GA. The emerging pandemic of obesity and diabetes: are we doing enough to prevent a disaster? Int J Clin Pract 2006; 60: 1093-7.
3. Kasuga M. Insulin resistance and pancreatic beta cell failure. J Clin Invest 2006; 116: 1756-60.
4. Vilsbøll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 2001; 50: 609-13.
5. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132: 2131-57.
6. Larsson H, Holst JJ, Ahren B. Glucagon-like peptide-1 reduces hepatic glucose production indirectly through insulin and glucagon in humans. Acta Physiol Scand 1997; 160: 413-22.
7. Verdich C, Flint A, Gutzwiller JP, Naslund E, Beglinger C, Hellstrom PM, Long SJ, Morgan LM, Holst JJ, Astrup A. 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: 4382-9.
8. Haffner SM. Relationship of metabolic risk factors and development of cardiovascular disease and diabetes. Obesity (Silver Spring) 2006; 14: 121S-7S.
9. Muoio DM, Newgard CB. Obesity-related derangements in metabolic regulation. Annu Rev Biochem 2006; 75: 367-401.
10. Vilsbøll T. Liraglutide: a once-daily GLP-1 analogue for the treatment of type 2 diabetes mellitus. Expert Opin Investig Drugs 2007; 16: 231-7.
11. Nauck MA, Meier JJ, Creutzfeldt W. Incretins and their analogues as new antidiabetic agents. Drug News Perspect 2003; 16: 413-22.
12. Cohen A, Horton ES. Progress in the treatment of type 2 diabetes: new pharmacologic approaches to improve glycemic control. Curr Med Res Opin 2007; 23: 905-17.
13. Gallwitz B. Glucagon-like peptide-1 as a treatment option for type 2 diabetes and its role in restoring beta-cell mass. Diabetes Technol Ther 2005; 7: 651-7.
14. Wajchenberg BL. Beta-cell failure in diabetes and preservation by clinical treatment. Endocr Rev 2007; 28: 187-218.
15. Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Williams B, Holst JJ. Both subcutaneously and intravenously administered glucagon-like peptide 1 are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 1995; 44: 1126-31.
16. Agersø H, Jensen LB, Elbrond B, Rolan P, Zdravkovic M. The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia 2002; 45: 195-202.
17. Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR. 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: 1335-42.
18. Harder H, Nielsen L, Tu DT, Astrup A. 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: 1915-21.
19. Feinglos MN, Saad MF, Pi-Sunyer FX, An B, Santiago O, Liraglutide Dose-Response Study Group. 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: 1016-23.
20. Nauck MA, Hompesch M, Filipczak R, Le TD, Zdravkovic M, Gumprecht J, NN2211-1499 Study Group. Five weeks of treatment with the GLP-1 analogue liraglutide improves glycaemic control and lowers body weight in subjects with type 2 diabetes. Exp Clin Endocrinol Diabetes 2006; 114: 417-23.
21. Vilsbøll T, Zdravkovic M, Le-Thi T, Krarup T, Schmitz O, Courrèges JP, Verhoeven R, Bugánová I, Madsbad S. Liraglutide, a long-acting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care 2007; 30: 1608-10.
22. Degn KB, Juhl CB, Sturis J, Jakobsen G, Brock B, Chandramouli V, Rungby J, Landau BR, Schmitz O. One week's treatment with the long-acting GLP-1 derivative, liraglutide (NN2211), markedly improves 24-h glycaemia, alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes 2004; 53: 1187-94.
23. Juhl CB, Hollingdal M, Sturis J, Jakobsen G, Agersø H, Veldhuis J, Pørksen N, Schmitz O. Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes. Diabetes 2002; 51: 424-9.
24. Chang AM, Jakobsen G, Sturis J, Smith MJ, Bloem CJ, Galecki A, Halter JB. The GLP-1 derivative NN2211 restores beta-cell sensitivity to glucose in type 2 diabetic patients after a single dose. Diabetes 2003; 52: 1786-91.
25. Mari A, Degn K, Brock B, Rungby J, Ferrannini E, Schmitz O. Effects of the long-acting human GLP-1 analogue liraglutide on beta-cell function in normal living conditions. Diabetes Care 2007; 30: 2032-3.
26. Bregenholt S, Moldrup A, Blume N, Karlsen AE, Nissen Friedrichsen B, Tornhave D, Knudsen LB, Petersen JS. The long-acting glucagon-like peptide-1 analogue, liraglutide, inhibits beta-cell apoptosis in vitro. Biochem Biophys Res Commun 2005; 330: 577-84.
27. Piper Hanley K, Dijkstra I, Dunleavey L, Hanley NA. The long-acting GLP-1 analog, liraglutide, increases beta cell numbers during early human development. Diabetologia 2005; 48 (Suppl. 1): A151 (Abstract).
28. Hui H, Wang C, Xu J, Hui Z, Perfetti R. Liraglutide inhibits cell death in human isolated islets by regulating the expression of apoptosis-related genes. Diabetes 2006; 55 (Suppl. 1): A1993 (Abstract).
29. Sturis J, Gotfredsen CF, Rømer J, Rolin B, Ribel U, Brand CL, Wilken M, Wassermann K, Deacon CF, Carr RD, Knudsen LB. GLP-1 derivative liraglutide in rats with beta-cell deficiencies: influence of metabolic state on beta-cell mass dynamics. Br J Pharmacol 2003; 140: 123-32.
30. Rolin B, Larsen MO, Gotfredsen CF, Deacon CF, Carr RD, Wilken M, Knudsen LB. The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases beta-cell mass in diabetic mice. Am J Physiol Endocrinol Metab 2002; 283: E745-52.
31. Bjørnsdottir I, Olsen AK, Larsen U, Helleberg H, Vanggaard J, Oosterhuis B, Van Lier J, Zdravkovic M, Malm-Erjefält M. Metabolism and excretion of the once-daily human GLP-1 analogue liraglutide in human healthy subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase. Diabetologia 2008; 51 (Suppl. 1): S356 (Abstract).
32. Bell DS, Allbright E. The multifaceted associations of hepatobiliary disease and diabetes. Endocr Pract 2007; 13: 300-12.
33. FDA. Guidance for industry- pharmacokinetics in patients with impaired hepatic function-trial design, data analysis, and impact on dosing and labelling. 2010. Available at: (Accessed 19 August 2010).
34. EMA. Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function (CHMP/EWP/2339/02). 2005. Available at: (Accessed 19 August 2010).
35. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60: 646-9.
36. Jacobsen LV, Hindsberger C, Robson R, Zdrackovic M. Effect of renal impairment on the pharmacokinetics of the GLP-1 analogue liraglutide. Br J Clin Pharmacol 2009; 68: 898-905.
37. Skude G, Wadstein J. Amylase, hepatic enzymes and bilirubin in serum of chronic alcoholics. Acta Med Scand 1977; 201: 53-8.
38. Karoui S, Hamzaoui S, Sahli F, Matri S, Boubaker J, Filali A. [Mortality in cirrhosis: prevalence, causes, and predictive factors]. Tunis Med 2002; 80: 21-5.
39. Kapitza C, Zdravkovic M, Zijlstra E, Segel S, Heise T, Flint A. Effect of three different injection sites on the pharmacokinetics of the once-daily human GLP-1 analogue liraglutide. J Clin Pharmacol 2010; 0: 0091270010374474v1.