Skip to main content
SpringerLink
Log in

Pharmacokinetics in Patients with Chronic Liver Disease and Hepatic Safety of Incretin-Based Therapies for the Management of Type 2 Diabetes Mellitus

  • Review Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

An Erratum to this article was published on 22 October 2014

Abstract

Patients with type 2 diabetes mellitus have an increased risk of chronic liver disease (CLD) such as non-alcoholic fatty liver disease and steatohepatitis, and about one-third of cirrhotic patients have diabetes. However, the use of several antidiabetic agents, such as metformin and sulphonylureas, may be a concern in case of hepatic impairment (HI). New glucose-lowering agents targeting the incretin system are increasingly used for the management of type 2 diabetes. Incretin-based therapies comprise oral inhibitors of dipeptidyl peptidase-4 (DPP-4) (gliptins) or injectable glucagon-like peptide-1 (GLP-1) receptor agonists. This narrative review summarises the available data regarding the use of both incretin-based therapies in patients with HI. In contrast to old glucose-lowering agents, they were evaluated in specifically designed acute pharmacokinetic studies in patients with various degrees of HI and their hepatic safety was carefully analysed in large clinical trials. Only mild changes in pharmacokinetic characteristics of DPP-4 inhibitors were observed in patients with different degrees of HI, presumably without major clinical relevance. GLP-1 receptor agonists have a renal excretion rather than liver metabolism. Specific pharmacokinetic data in patients with HI are only available for liraglutide. No significant changes in liver enzymes were reported with DPP-4 inhibitors or GLP-1 receptor agonists, alone or in combination with various other glucose-lowering agents, in clinical trials up to 2 years in length. On the contrary, preliminary data suggested that incretin-based therapies may be beneficial in patients with CLD, more particularly in the presence of non-alcoholic fatty liver disease. Nevertheless, caution should be recommended, especially in patients with advanced cirrhosis, because of a lack of clinical experience with incretin-based therapies in these vulnerable patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Picardi A, D’Avola D, Gentilucci UV, et al. Diabetes in chronic liver disease: from old concepts to new evidence. Diabetes Metab Res Rev. 2006;22(4):274–83.

  2. Loria P, Lonardo A, Anania F. Liver and diabetes. A vicious circle. Hepatol Res. 2013;43(1):51–64.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Byrne CD. Dorothy Hodgkin Lecture 2012: non-alcoholic fatty liver disease, insulin resistance and ectopic fat: a new problem in diabetes management. Diabet Med. 2012;29(9):1098–107.

    Article  PubMed  CAS  Google Scholar 

  4. Hsieh PS, Hsieh YJ. Impact of liver diseases on the development of type 2 diabetes mellitus. World J Gastroenterol. 2011;17(48):5240–5.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Garcia-Compean D, Jaquez-Quintana JO, Maldonado-Garza H. Hepatogenous diabetes. Current views of an ancient problem. Ann Hepatol. 2009;8(1):13–20.

  6. Petrides AS, DeFronzo RA. Glucose and insulin metabolism in cirrhosis. J Hepatol. 1989;8(1):107–14.

    Article  PubMed  CAS  Google Scholar 

  7. Petrides AS, Vogt C, Schulze-Berge D, et al. Pathogenesis of glucose intolerance and diabetes mellitus in cirrhosis. Hepatology. 1994;19(3):616–27.

    Article  PubMed  CAS  Google Scholar 

  8. Mazza A, Fruci B, Garinis GA, et al. The role of metformin in the management of NAFLD. Exp Diabetes Res. 2012;2012:716404.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Fruci B, Giuliano S, Mazza A, et al. Nonalcoholic fatty liver: a possible new target for type 2 diabetes prevention and treatment. Int J Mol Sci. 2013;14(11):22933–66.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Scheen AJ. Pharmacokinetic and toxicological considerations for the treatment of diabetes in patients with liver disease. Expert Opin Drug Metab Toxicol. 2014;10(6):839–57.

    Article  PubMed  CAS  Google Scholar 

  11. Khan R, Foster GR, Chowdhury TA. Managing diabetes in patients with chronic liver disease. Postgrad Med. 2012;124(4):130–7.

    Article  PubMed  Google Scholar 

  12. Tolman KG, Fonseca V, Dalpiaz A, et al. Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care. 2007;30(3):734–43.

    Article  PubMed  CAS  Google Scholar 

  13. Olaywi M, Bhatia T, Anand S, et al. Novel anti-diabetic agents in non-alcoholic fatty liver disease: a mini-review. Hepatobiliary Pancreat Dis Int. 2013;12(6):584–8.

    Article  PubMed  CAS  Google Scholar 

  14. Giorda CB, Nada E, Tartaglino B. Pharmacokinetics, safety, and efficacy of DPP-4 inhibitors and GLP-1 receptor agonists in patients with type 2 diabetes mellitus and renal or hepatic impairment. A systematic review of the literature. Endocrine. Epub 2014 Feb 8.

  15. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):1696–705.

    Article  PubMed  CAS  Google Scholar 

  16. Scheen AJ. A review of gliptins in 2011. Expert Opin Pharmacother. 2012;13(1):81–99.

    Article  PubMed  CAS  Google Scholar 

  17. Owens DR, Monnier L, Bolli GB. Differential effects of GLP-1 receptor agonists on components of dysglycaemia in individuals with type 2 diabetes mellitus. Diabetes Metab. 2013;39(6):485–96.

    Article  PubMed  CAS  Google Scholar 

  18. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8(12):728–42.

    Article  PubMed  CAS  Google Scholar 

  19. Blaslov K, Bulum T, Zibar K, et al. Incretin based therapies: a novel treatment approach for non-alcoholic fatty liver disease. World J Gastroenterol. 2014;20(23):7356–65.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol. 2008;64(12):1147–61.

    Article  PubMed  CAS  Google Scholar 

  21. Srivastava B, Alexander GJ. Renal failure in chronic liver disease and the hepatorenal syndrome. Br J Hosp Med (Lond). 2011;72(9):497–503.

    Article  Google Scholar 

  22. Scheen AJ. Pharmacokinetic considerations for the treatment of diabetes in patients with chronic kidney disease. Expert Opin Drug Metab Toxicol. 2013;9(5):529–50.

    Article  PubMed  CAS  Google Scholar 

  23. Scheen AJ. Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes Metab. 2010;12(8):648–58.

    Article  PubMed  CAS  Google Scholar 

  24. Golightly LK, Drayna CC, McDermott MT. Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors. Clin Pharmacokinet. 2012;51(8):501–14.

    Article  PubMed  CAS  Google Scholar 

  25. Vincent SH, Reed JR, Bergman AJ, et al. Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C]sitagliptin in humans. Drug Metab Dispos. 2007;35(4):533–8.

    Article  PubMed  CAS  Google Scholar 

  26. Migoya EM, Stevens CH, Bergman AJ, et al. Effect of moderate hepatic insufficiency on the pharmacokinetics of sitagliptin. Can J Clin Pharmacol 2009;16(1):e165–70.

  27. Arase Y, Kawamura Y, Seko Y, et al. Efficacy and safety in sitagliptin therapy for diabetes complicated by non-alcoholic fatty liver disease. Hepatol Res. 2013;43(11):1163–8.

    Article  PubMed  CAS  Google Scholar 

  28. Iwasaki T, Yoneda M, Inamori M, et al. Sitagliptin as a novel treatment agent for non-alcoholic fatty liver disease patients with type 2 diabetes mellitus. Hepatogastroenterology 2011;58 (112):2103–5.

  29. Itou M, Kawaguchi T, Taniguchi E, et al. Dipeptidyl Peptidase IV inhibitor improves insulin resistance and steatosis in a refractory nonalcoholic fatty liver disease patient: a case report. Case Rep Gastroenterol. 2012;6(2):538–44.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Fukuhara T, Hyogo H, Ochi H, et al. Efficacy and safety of sitagliptin for the treatment of nonalcoholic fatty liver disease with type 2 diabetes mellitus. Hepatogastroenterology. 2014;61(130):323–8.

  31. Yilmaz Y, Yonal O, Deyneli O, et al. Effects of sitagliptin in diabetic patients with nonalcoholic steatohepatitis. Acta Gastroenterol Belg. 2012;75(2):240–4.

    PubMed  Google Scholar 

  32. Arase Y, Suzuki F, Kobayashi M, et al. Efficacy and safety in sitagliptin therapy for diabetes complicated by chronic liver disease caused by hepatitis C virus. Hepatol Res. 2011;41(6):524–9.

    Article  PubMed  CAS  Google Scholar 

  33. Iwasaki T, Tomeno W, Yoneda M, et al. Non-alcoholic fatty liver disease adversely affects the glycemic control afforded by sitagliptin. Hepatogastroenterology. 2012;59(117):1522–5.

  34. Gooßen K, Gräber S. Longer term safety of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus: systematic review and meta-analysis. Diabetes Obes Metab. 2012;14(12):1061–72.

    PubMed  Google Scholar 

  35. Toyoda-Akui M, Yokomori H, Kaneko F, et al. A case of drug-induced hepatic injury associated with sitagliptin. Intern Med. 2011;50(9):1015–20.

    Article  PubMed  CAS  Google Scholar 

  36. Gross BN, Cross LB, Foard J, et al. Elevated hepatic enzymes potentially associated with sitagliptin. Ann Pharmacother. 2010;44(2):394–5.

    Article  PubMed  Google Scholar 

  37. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354(7):731–9.

    Article  PubMed  CAS  Google Scholar 

  38. He YL. Clinical pharmacokinetics and pharmacodynamics of vildagliptin. Clin Pharmacokinet. 2012;51(3):147–62.

    Article  PubMed  CAS  Google Scholar 

  39. He YL, Sabo R, Campestrini J, et al. The influence of hepatic impairment on the pharmacokinetics of the dipeptidyl peptidase IV (DPP-4) inhibitor vildagliptin. Eur J Clin Pharmacol. 2007;63(7):677–86.

    Article  PubMed  CAS  Google Scholar 

  40. Ligueros-Saylan M, Foley JE, Schweizer A, et al. An assessment of adverse effects of vildagliptin versus comparators on the liver, the pancreas, the immune system, the skin and in patients with impaired renal function from a large pooled database of phase II and III clinical trials. Diabetes Obes Metab. 2010;12(6):495–509.

    Article  PubMed  CAS  Google Scholar 

  41. Schweizer A, Dejager S, Foley JE, et al. Assessing the general safety and tolerability of vildagliptin: value of pooled analyses from a large safety database versus evaluation of individual studies. Vasc Health Risk Manag. 2011;7:49–57.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Patel C, Castaneda L, Frevert U, et al. Single-dose pharmacokinetics and safety of saxagliptin in subjects with hepatic impairment compared with healthy subjects [abstract no. 537-P]. Diabetes 2008 57 Suppl 1:A160.

  43. Boulton DW, Li L, Frevert EU, et al. Influence of renal or hepatic impairment on the pharmacokinetics of saxagliptin. Clin Pharmacokinet. 2011;50(4):253–65.

    Article  PubMed  CAS  Google Scholar 

  44. Ali S, Fonseca V. Saxagliptin overview: special focus on safety and adverse effects. Expert Opin Drug Saf. 2013;12(1):103–9.

    Article  PubMed  CAS  Google Scholar 

  45. 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(14):1317–26.

    Article  PubMed  CAS  Google Scholar 

  46. Scheen AJ. Linagliptin for the treatment of type 2 diabetes (pharmacokinetic evaluation). Expert Opin Drug Metab Toxicol. 2011;7(12):1561–76.

    Article  PubMed  CAS  Google Scholar 

  47. Graefe-Mody U, Rose P, Retlich S, et al. Pharmacokinetics of linagliptin in subjects with hepatic impairment. Br J Clin Pharmacol. 2012;74(1):75–85.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  48. Schernthaner G, Barnett AH, Emser A, et al. Safety and tolerability of linagliptin: a pooled analysis of data from randomized controlled trials in 3572 patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2012;14(5):470–8.

    Article  PubMed  CAS  Google Scholar 

  49. Kutoh E. Probable linagliptin-induced liver toxicity: a case report. Diabetes Metab. 2014;40(1):82–4.

    Article  PubMed  CAS  Google Scholar 

  50. Karim A, Fleck P, Dorsey D, et al. Single dose pharmacokinetics of alogliptin benzoate(SYR-322) in subjects with moderate hepatic impairment [abstract no. 107]. J Clin Pharmacol. 2007;47(9):1207.

  51. Food and Drug Administration, Center for Drug Evaluation and Research. Clinical Pharmacology and Biopharmaceutics Reviews: Application number: 022271Orig1s000 (Nesina, alogliptin). http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022271Orig1s000ClinPharmR.pdf. Accessed 10 Apr 2014.

  52. Scott LJ. Alogliptin: a review of its use in the management of type 2 diabetes mellitus. Drugs. 2010;70(15):2051–72.

    Article  PubMed  CAS  Google Scholar 

  53. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327–35.

    Article  PubMed  CAS  Google Scholar 

  54. Kajiwara A, Saruwatari J, Sakata M, et al. Risk factors for adverse symptoms during dipeptidyl peptidase-IV inhibitor therapy: a questionnaire-based study carried out by the Japan Pharmaceutical Association Drug Event Monitoring project in Kumamoto Prefecture. Drug Saf. 2013;36(10):981–7.

    Article  PubMed  CAS  Google Scholar 

  55. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2012;55(6):1577–96.

    Article  PubMed  CAS  Google Scholar 

  56. 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.

    Article  PubMed  CAS  Google Scholar 

  57. Flint A, Nazzal K, Jagielski P, et al. Influence of hepatic impairment on pharmacokinetics of the human GLP-1 analogue, liraglutide. Br J Clin Pharmacol. 2010;70(6):807–14.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  58. 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):367–74.

    Article  PubMed  CAS  Google Scholar 

  59. Fan H, Pan Q, Xu Y, et al. Exenatide improves type 2 diabetes concomitant with non-alcoholic fatty liver disease. Arq Bras Endocrinol Metabol. 2013;57(9):702–8.

    Article  PubMed  Google Scholar 

  60. 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(12):e50117.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  61. Shao N, Kuang HY, Hao M, et al. Effects of exenatide on obesity and NAFLD with elevated liver enzymes in patients with type 2 diabetes. Diabetes Metab Res Rev. Epub 2014 May 13. doi:10.1002/dmrr.2561.

  62. Kenny PR, Brady DE, Torres DM, et al. Exenatide in the treatment of diabetic patients with non-alcoholic steatohepatitis: a case series. Am J Gastroenterol. 2010;105(12):2707–9.

    Article  PubMed  Google Scholar 

  63. Xu F, Li Z, Zheng X, et al. SIRT1 mediates the effect of GLP-1 receptor agonist exenatide on ameliorating hepatic steatosis. Diabetes. Epub 2014 Jun 19. pii: DB_140263.

  64. Buse JB, Klonoff DC, Nielsen LL, et al. Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials. Clin Ther. 2007;29(1):139–53.

    Article  PubMed  CAS  Google Scholar 

  65. Malm-Erjefalt M, Bjornsdottir I, Vanggaard J, et al. Metabolism and excretion of the once-daily human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase. Drug Metab Dispos. 2010;38(11):1944–53.

    Article  PubMed  CAS  Google Scholar 

  66. 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(2):234–42.

    Article  PubMed  CAS  Google Scholar 

  67. Ohki T, Isogawa A, Iwamoto M, et al. The effectiveness of liraglutide in nonalcoholic fatty liver disease patients with type 2 diabetes mellitus compared to sitagliptin and pioglitazone. ScientificWorldJournal. 2012;2012:496453.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Kahal H, Abouda G, Rigby AS, et al. Glucagon-like peptide-1 analogue, liraglutide, improves liver fibrosis markers in obese women with polycystic ovary syndrome and nonalcoholic fatty liver disease. Clin Endocrinol (Oxf). Epub 2013 Nov 21. doi:10.1111/cen.12369.

  69. D’Amico E. Efficacy of liraglutide in a patient with type 2 diabetes and cryptogenic cirrhosis. Acta Biomed. 2011;82(2):160–1.

    PubMed  Google Scholar 

  70. Eguchi Y, Kitajima Y, Hyogo H, et al. Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J). Hepatol Res. Epub 2014 May 4. doi:10.1111/hepr.12351.

  71. Kern E, VanWagner LB, Yang GY, et al. Liraglutide-induced autoimmune hepatitis. JAMA Intern Med. 2014;174(6):984–7.

    Article  PubMed  CAS  Google Scholar 

  72. Forst T, Pfutzner A. Pharmacological profile, efficacy and safety of lixisenatide in type 2 diabetes mellitus. Expert Opin Pharmacother. 2013;14(16):2281–96.

    Article  PubMed  CAS  Google Scholar 

  73. European Medicines Agency. Assessment report: Lyxumia (lixisenatide). http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Public_assessment_report/human/002445/WC500140449.pdf?. Accessed 10 Apr 2014.

  74. Balaban YH, Korkusuz P, Simsek H, et al. Dipeptidyl peptidase IV (DDP IV) in NASH patients. Ann Hepatol. 2007;6(4):242–50.

  75. Itou M, Kawaguchi T, Taniguchi E, et al. Dipeptidyl peptidase-4: a key player in chronic liver disease. World J Gastroenterol. 2013;19(15):2298–306.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  76. Armstrong MJ, Barton D, Gaunt P, et al. Liraglutide efficacy and action in non-alcoholic steatohepatitis (LEAN): study protocol for a phase II multicentre, double-blinded, randomised, controlled trial. BMJ Open. 2013;3(11):e003995.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Bernsmeier C, Meyer-Gerspach AC, Blaser LS, et al. Glucose-induced glucagon-like peptide 1 secretion is deficient in patients with non-alcoholic fatty liver disease. PLoS One. 2014;9(1):e87488.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Muscelli E, Mari A, Casolaro A, et al. Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients. Diabetes. 2008;57(5):1340–8.

    Article  PubMed  CAS  Google Scholar 

Download references

Funding and Conflict of Interest

No sources of funding were used to assist in the preparation of this manuscript. The author has no conflicts of interest that are directly relevant to the content of this manuscript.

A.J. Scheen has received lecture/advisor fees from AstraZeneca/BMS, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, NovoNordisk, Sanofi-Aventis and Takeda.

Author information

Authors and Affiliations

  1. Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, University of Liège, Liège, Belgium

    André J. Scheen

  2. Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM), CHU Sart Tilman (B35), University of Liège, 4000, Liège 1, Belgium

    André J. Scheen

Authors
  1. André J. Scheen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to André J. Scheen.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Scheen, A.J. Pharmacokinetics in Patients with Chronic Liver Disease and Hepatic Safety of Incretin-Based Therapies for the Management of Type 2 Diabetes Mellitus. Clin Pharmacokinet 53, 773–785 (2014). https://doi.org/10.1007/s40262-014-0157-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-014-0157-y

Keywords

Search

Navigation