NAFLD - therapeutic intervention. CP Day Institute of Cellular Medicine Newcastle University UK

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1 NAFLD - therapeutic intervention CP Day Institute of Cellular Medicine Newcastle University UK

2 Therapy for NAFLD Why worry about NAFLD? Management strategy - who to treat? Therapies directed at features of the associated Metabolic Syndrome with potential liver effects Liver directed therapies

3 NAFLD is important It is very common It can progress to advanced liver disease with associated morbidity/mortality It may contribute to the development of insulin resistance/t2dm/mets and cardiovascular disease in obesity

4 Prevalence of NAFLD Normal Obesity Met S'drome Hyperten Diabetes

5 Steatosis Natural history of NAFLD (~ 8-13yrs) HCC 12-40% NASH and/or F1-F2 fibrosis 14% 5-10% 8% Advanced (F3) fibrosis Ratzui 2002 Harrison 2003 Fassio 2004 Adams 2005 Sanyal 2006 Ekstedt % 7% Liver Death/ OLTx 25-50% (Child s A) 25% 0-50% Cirrhosis

6 NAFLD independently associated with CVD in T2DM AND retinopathy/nephropathy Day, Targher et al Diabetologia 2008 Targher, Day et al Diabetes Care 2007

7 Need to know who (what) you are treating WHO TO TREAT? Overview Efficacy of interventions Psychoeducation Psychopharmacotherapy Behaviour modification Algorithm QA Conclusions

8 Who to treat? DEPENDS ON DISEASE STAGE Simple steatosis Treat the metabolic syndrome components No liver follow-up required NASH + advanced fibrosis Treat the metabolic syndrome components Liver follow-up (varices( & HCC surveillance) Tailor therapy for metabolic syndrome components Consider therapy directed at the liver

9 Therapeutic Targets Insulin FoxO1 Day Gastroenterology 2006

10 Therapies directed at feature of the associated Metabolic Syndrome with potential liver effects Weight reduction therapies Insulin sensitizers Lipid-lowering agents Anti-hypertensives

11 Weight reduction therapies (Harrison & Day, Gut 2007) Sound theoretical basis ( IR,( Insulin, Glu, FFA) Lots of uncontrolled evidence of benefit of diet + exercise on steatosis but improvement in inflammation/fibrosis seems to require drastic weight loss Surgery Gastric banding, Roux-en en-y Y diversion all beneficial for steatosis and? N/I and fibrosis ( duration of f/up)

12 Dietary fat content and NAFLD 10 non-diabetic obese women Two-week week cross-over over design Weight-maintenance diets Low-Fat, 16% High-Fat, 56% Pre-study Fat intake, 36% Liver fat assessed by proton spectroscopy No changes in total body fat, subcutaneous fat and intra-abdominal abdominal fat (MRI) Westerbacka, JCEM 2005

13 Treatment of diabetes & NAFLD Insulin sensitisers rational choice Mechanism is via liver/muscle steatosis Metformin drug-of of-choice for obese type 2 DM ( mortality)( Insulin may improve steatosis mortality) PDS Lancet 1998 Juurinen 2007 But may increase fibrosis (via CTGF/ Foxo1) Paradis et al 2001, Adachi et al 2007

14 Liver fat pre- and post 7 mo insulin therapy Juurinen et al 2007

15 Insulin sensitisers (1) metformin Sound theoretical basis Lipogenesis, fat oxidation Zhou 2001 steatosis/alt in ob/ob mouse Lin 2000 Contradictory pilot data Marchesini 2001, Tiikkainen 2004, Nair 2004 In largest RCT vs vit E or diet, metformin Greater in ALT (p<0.0001) steatosis/necrosis/fibrosis (p<0.012) Bugianesi 2005

16 Metformin Trial - Histology 100 Pre Post Pre Post Pre Post P=0.012 Grade 4 Grade P=0.004 P=0.012 Grade 2 Grade 1 Absent 10 0 Steatosis Necro Inflammation Fibrosis Bugianesi 2005

17 Insulin sensitisers (2) glitazones Sound theoretical basis - PPARγ agonists Anti-steatotic Maeda 2001, Mayerson 2002 Anti-inflammatory inflammatory Jiang 1998, Xu 2003 Anti-fibrotic Galli 2002 PPARγ mutations NASH Savage 2003 Three randomised, placebo-controlled controlled trials Belfort 2006, Aithal 2008, Ratziu 2008 NIH pioglitazone vs vit E RCT (n=200+, 2 yr f/up biopsy) reporting May 2009

18 Anti-fibrotic effect of glitazones Galli et al 2002

19 Ratziu et al Gastroenterology 2008 N=63 NASH 32% T2DM Rosiglitazone 8mg for 1 year Versus placebo: Improvement in fat %, Ins R and ALT No improvement in Necroinflammation or fibrosis Weight gain ~ 1.5 kg vs 1 kg loss

20 Rosiglitazone and CV risk: Nissen et al NEJM 2007 Doesn't seem to be a problem with Pioglitazone? OR: 0.82 Lincoff JAMA 2007

21 Belfort et al N Engl J Med patients with IGT/T2DM + bx-proven NASH 6 months Pio (45mg) + diet vs Placebo + diet

22 Aithal et al Gastroenterology 2008 N=61 NASH Non-diabetics 1 yr Pioglitazone 30mg Versus placebo: ALT, Glu, HbA1c, C-C peptide, γ-gt, ferritin hepatocellular injury, M-D D bodies and fibrosis NOT steatosis Weight vs -0.55kg

23 Pioglitazone needs to be lifelong? Lutchman Hepatology 2007

24 Lipid lowering agents Fibrates: good theory - PPARα agonists (anti NF-kB) NASH in MCD mouse model Ip 2003 & RCT of gemfibrozil (4/52) - LFTs 1 open trial of clofibrate (52/52) no benefit Basaranoglu 1998 Laurin 1996 Statins No rationale but appear to be safe

25 Anti-hypertensives RAS system Anti-fibrotic Animal models Hirose 2007 Humans Yokohama 2004 Insulin sensitising α blockers Anti-fibrotic May also progenitor cell proliferation Oben 2003

26 AIIR1B Olmersartan in MCD NASH Hirose et al 2007

27 Prazosin α-blockade injury and progenitors in MCDE NASH Oben et al 2003

28 Tested Liver-directed therapies Alcohol moderation NOT abstinence Antioxidants: Vitamin E: No benefit in RCT Harrison 2003 Betaine: ALT and histology Abdelmalek 2001 Probucol: ALT in small RCT Merat 2003 Iron depletion Facchini 2002, Riquelme 2004 Urso: No benefit in large RCT Lindor 2004 Urso + Vit E: encouraging pilot data Dufour 2006 OLTx successful but recurs Contos 2001

29 Ursodeoxycholic acid RCT 166 patients with NASH 2 years 13-15mg/Kg/d 15mg/Kg/d 107 got 2nd biopsy Biochemistry improved on drug AND placebo Steatosis improved on drug AND placebo NC in N/I or fibrosis Highlights importance of RCT evidence Lindor et al 2004

30 Urso + Vitamin E: 2 yrs Dufour et al 2006 Biochemistry Histology

31 Recurrence of NASH post OLTx Contos 2001

32 Untested liver-directed therapies Probiotics Li 2003 ER stress (chaperones) TUDCA, 4-phenylbutyrate Ozkan Science 2006 IKK inhibitors (eg. Sulphasalazine) Anti-inflammatory/anti inflammatory/anti-fibrotic fibrotic Oakley 2005 Insulin sensitising Yuan Science 2004 Improve NASH in experimental models Beraza 2008 blocker) Van Gaal 2005 Antifibrotic Teixeira-Clerc Nat Med 2006 Antisteatotic Gary-Bobo Hepatology 2007 Rimonabant (CB 1 blocker) Anti-fibrotics Tranilast (anti-tgf TGFβ) Uno Hepatology 2008

33 Rimonabant is anti-steatotic Gary-bobo et al Hepatology 2007

34 Tranilast (anti-tgf TGFβ) ) improves NASH Uno et al Hepatology 2008

35 Summary For patients with MS: tailored therapy Metformin/Pioglitazone for T2DM Statins/fibrates for dyslipidemia RAS/α-blockers for hypertension For those without MS: Best evidence for metformin/pioglitazone For the future: many promising agents awaiting RCTs

tage Percent Total & over Total & over Men Women Men Women

tage Percent Total & over Total & over Men Women Men Women Paul Angulo, MD, FACG, AGAF Professor of Medicine, Section Chief of Hepatology Division i i of Digestive i Diseases and Nutrition i University of Kentucky Medical Center Lexington, KY Paul Angulo, MD University