Which drugs should be used to treat diabetes in cirrhotic patients?

Transcription

1 Which drugs should be used to treat diabetes in cirrhotic patients? Frankfurt am Main September 2015 Jörg Bojunga Medizinische Klinik I Johann Wolfgang Goethe-Universität Frankfurt am Main

2 Significance of the clinical problem Barriers to optimal treatment Diabetes is a common comorbidity in LCI - prevalence 37%, 5x higher than in non-lci Most antidiabetic drugs are not approved in LCI Treatment targets may differ from diabetics without LCI adverse events may be more common

3 Why treating diabetes? intervention epidemiology Diabetes Care 32 (7):1327, 2009

4 ADVANCE follow up 2014 no benefits with respect to mortality or vascular events N Engl J Med 2014;epub

5 HbA1c the lower the better? Risk factors for increased mortality: -Weight gain -hypoglycemia Lancet 2010; 375:

6 What is the A1c-target of diabetes therapy? LCI: 7.5%-8% Diabetes Care 2015;38(Suppl. 1):S1 S2 DOI: /dc15-S001

7 Diabetes how to treat? Diabetes Care 2015;38(Suppl. 1):S1 S2 DOI: /dc15-S001

8 Hypoglycemic risk DPP-IV-inhibitors vs. sulfonylureas Curr Med Res Opin 2012; 28:

9 Insulinregimen and risk of hypoglycemia 4T-study BOT vs. SIT vs. CT N Engl J Med 2009;361:1736

10 Pharmacokinetic (PK) and toxicological considerations Almost no PK studies have been published regarding metformin, sulfonylureas, thiazolidinediones and α-glucosidase inhibitors in patients with hepatic impairment (HI) only mild changes in PK of glinides, dipeptidyl peptidase-4 inhibitors and sodium glucose cotransporters type 2 inhibitors were observed in dedicated PK studies in patients with various degrees of HI, presumably without major clinical relevance large clinical experience is lacking Expert Opin Drug Metab Toxicol Jun;10(6):839-57

11 Inkretins and liver disease Only mild changes in pharmacokinetic characteristics of DPP-4 inhibitors were observed in patients with different degrees of hepatic impairment (HI) GLP-1 receptor agonists have a renal excretion or intravascular degradation rather than liver metabolism specific pharmacokinetic data in patients with HI are 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. Clin Pharmacokinet Sep;53(9):773-85

12 Diabetes and liver cirrhosis how to treat? General approach Define individual treatment target (HbA1c usually 7.5-8%) Most OAD are not approved in cirrhosis Avoid hypoglycemic substances (SU, sa Insulin) Define severity of liver disease (Child-Pugh) Calculate relevance of co-morbidity (renal impairment, alcohol abuse) and risk of progression or decompensation of liver disease Primary goal: avoid symptomatic diabetes (hypoglycemia, dehydration, further cognitive impairment)

13 Diabetes and cancer risk BMJ 2014;350:(Published 2 January 2015)

14 Metformin, cirrhosis and diabetes J Clin Endocrinol Metab 96: , 2011

15 Metformin, cirrhosis and diabetes Hepatology May 2014 epub

16 Metformin in CKD really a contraindiaction? JAMA. 2014;312(24):

17 Exenatide hepatic steatosis Ding Hepatology 43: , 2006

18 0 Liraglutide 1,8mg Placebo - n=52-33% T2DM - 52% F3/F4 patients with regression of fibrosis EASL 2015

19 SGLT2-inhibitors Bojunga, Arzneimitteltherapie 2015

20 ALT U/l pre treatment week 12 EASL 2015

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22 Diabetes and liver cirrhosis how to treat? Practical approach Child A cirrhosis: although not approved, most OAD can be used safely Metformin: drug of choice, if no severe CKD (GFR <30ml/min) or alcoholism DPPIV-inhibitors can be used safely, no CYP3A4 metabolism of vildagliptin GLP-1 analogs: no adjustment for exenatide, dulaglutide, liraglutide in HI, for dula and lira also not in CKD Insulin: if used prefer simple regimens, e.g. BOT Child B and C cirrhosis: Metformin in specialized centers, GLP-1-RA,simple insulin regimens Personal view, drugs not approved, off-label use

23 Which drugs should be used to treat diabetes in cirrhotic patients? Frankfurt am Main September 2015 Jörg Bojunga Medizinische Klinik I Johann Wolfgang Goethe-Universität Frankfurt am Main

24 CYP3A4- interactions Substance Pioglitazon Glimepirid Metformin SGLT2 Sitagliptin Interaction CYP450:2C8, 3A4 CYP450: 2C9 CYP450: no CYP450: no CYP450: 2C8, 3A4 Saxagliptin CYP450: 3A4/5 Vildagliptin Exenatide CYP450: no CYP450: nd Inhibitors: Azole, Clarithromycin, Ritonavir Inductors: Rifampicin, Carbamazepin

25 SGLT2-inhibitors Nat Rev Drug Discov Jul;9(7):551-9

26 Metformin use and HCC risk Scandinavian Journal of Gastroenterology. 2013; 48: 78 87

27 Hypoglycemia and risk of dementia N Engl J Med 2013;369:540-8.

28 AT-1 antagonists and NASH Hirose Hepatology 2007;45:1375

29 Posttransplantations-Diabetes ein klinisches Problem? Marchetti, Liver Transplantation, Vol 11, No 6, 2005

30 Posttransplantations-Diabetes ein klinisches Problem? Baid et al., Transplantation Vol. 72, No. 6, 2001

31 Posttransplantations-Diabetes ein klinisches Problem? Bodziak Transplant International22 (2009) 519

32 Posttransplantations-Diabetes gibt es Prädiktoren? Veldt et al. American Journal of Transplantation 2012 Epub ahead of print

33 HbA1c the lower the better? Diabet. Med. 30, e170 e177 (2013)