Computer generated transcript

Warning!
The following transcript was generated automatically from the content and has not been checked or corrected manually.

Dr Amreen Dinani Updates in Metabolic Dysfunction-Associated Steatohepatitis ManagementObjectives Implement evidence-based strategies for long-term management of MASH • Design patient-centered lifestyle and dietary modifications, providing tailored advice for sustainable health improvements. • Apply the latest pharmacological treatments as per current guidelines, including timing and dosage considerations for optimal patient outcomesMASLD is a Global Epidemic Allen A et al. JHep 2023. Younossi ZM, et al. Hepatology 2023More than 100 million Americans will have MASLD by 2030 THAT’S MORE THAN THE POPULATION OF CALIFORNIA, TEXAS, NEW YORK and NORTH CAROLINA COMBINED Estes, et al. Hepatology 2018Case • 38F with Class 2 obesity ( BMI 34kg/m ), preDM who you see in clinic for MASLD. She would like to discuss what she can do to improve her underlying liver disease. She is not interested in medications and believes she can do this on her own. • Dietary history reveals that she east most of her meals outside including breakfast. She has to be at work early so picks up breakfast. She drinks a diet ginger ale with lunch. She east dinner at 6pm, has been trying to eat at home. She finds herself hungry at night, snacks on a couple of cookies or chips. Occasionally has fruit. • She has a gym membership, that she doesn’t use. She would like to start walking. No arthritis of the joints.What Lifestyle Recommendations Can You Suggest? 1. Meal planning and planning ahead for meals 2. Start walking 3. Eliminate diet drinks 4. Cut back on number of meals she eats outside 5. Set realistic weight loss goalsLifestyle Changes are the Backbone of Treatment for MASLD Weight loss (hypocaloric diet) and exercise AASLD guidelines: • Patients with NAFLD who are overweight or obese should be prescribed a diet that leads to a caloric deficit. When possible, diets with limited carbohydrates and saturated fat and enriched with high fiber and unsaturated fats (e.g., Mediterranean diet) should be encouraged due to their additional cardiovascular benefits. Rinella M, et al. Hepatology. 2023 EASL guidelines: • In adults with MASLD, dietary and behavioural therapy-induced weight loss should be recommended to improve liver injury, as assessed histologically or non-invasively (strong recommendation, strong consensus). • In adults with MASLD and overweight, dietary and behavioural therapy-induced weight loss should aim at a sustained reduction of ≥5% to reduce liver fat, 7-10% to improve liver inflammation, and ≥10% to improve fibrosis (strong recommendation, strong consensus). EASL-EASD-EASO. J Hepatology 2024Summary of Lifestyle Recommendations in MASLD Spectrum Westerndiet Westerndiet 7-10% weight reduction by Mediterranean diet energy deficit of 500-700 • High fibre Hypocaloric or kcal/day though either diet • High fish • Low fat • High vegetables isocaloric- • Low carb • Low cholesterol Mediterranean diet • Mediterranean • Low sugar Aerobic or resistance exercise Dietary composition modifications Drinks • Reduced fructose • Coffee >2-3 cups/daily • Mediterranean diet • No alcohol in cirrhosisImplications of Weight Loss on Biomarkers of MASLD Systematic review and meta-analysis: 22 studies, 2588 participants, 15 studies BWLP Weight loss improves Weight loss improves ALT hepatic steatosis Weight loss improves NAS score Koutoukidis et al. JAMA Internal Medicine. 20197% weight loss leads to NASH resolution • 293 pts with histology proven NASH recommended lifestyle changes over 52 weeks • Intervention: low-fat hypocaloric diet (750 kcal/d deficit), 200 mins exercise/wk • Liver biopsies baseline and Wk 52 • Post-hoc analysis: • Weight loss of 7-10% associated with lower rate of NASH resolution in those with unfavourable risk factors- female, T2DM, BMI >35 • > 10% weight loss resulted in higher rates of NASH resolution irrespective of presence of ‘unfavourable’ risk factors Vilar-Gomez, et al. Gastroenterology. 2015 How Does Weight Loss Improve MASLD? Improvement in liver enzymes (AST/ALT and GGT levels) Improvement in metabolic parameters (fasting glucose and insulin sensitivity) Improved intrahepatic triacylglycerol co1centrations (assessed by PDFF-MRS) Improvement in steatohepatitis with 7 % total body weight Improvement in liver fibrosis with10 % total body weight 1. Lazo M, et al. Diabetes Care 2010; 2. Harrison SA, et al. Hepatology 2009; 3. Eckard C, et al. Therap Adv Gastroenterol. 2013; 4. Promrat K, et al. Hepatology 2010; 5. Musso G, et al. Diabetologia 2012Diet and MASLD Mozaffarian D. Circulation. 2016.Ultra Processed Foods and Drinks Major source of added sugar, high energy dense foods and low nutritional value Ultra processed Unprocessed/minimally processedHow Do You Recognize an Ultra Processed Food? • List and list of ingredients that you do not use in your kitchen • High Fructose Corn Syrup • Cosmetic Additives- flavours, colouring • Hydrogenated OilsUltra Processed Foods is Associated with the Development of MASLD Grinshpan LS et al. J Hep Reports. 2024Red Meat and Processed Food is Associated with MASLD Selber-Sagi S et al. Jhep 2018; Alvaras- da- Silva M et al. EJCN 2024Consumption of Saturated Fat Increased Liver Fat 38 overweight patients Luukkonen PK et al. Diabetes Care. 2018Fructose Consumption is Associated with MASLD in Children 271 obese children with MASLD with liver biopsies Association between Fructose Consumption and Uric Acid and NAS >5 Odds Ratio ( 95% CI) p Fructose, g/day 1.612 (1.25,1.86) 0.001 Uric Acid mg/dl 2.488 (1.87,2.83) 0.001 WC, cm 1.842 (1.11,1.95) 0.03 HOMA-IR 3.21 (1.9, 5.72) 0.024 Triglycerides, mg/dl 1.208 (1.1,1.58) 0.048 Mosca Aet al. JHep 2017.Soft Drinks is Associated with HCC and Liver Related Mortality 98,786 postmenopausal women, 50-79 yrs enrolled in Women Health Initiative, 1993-1998, followed for > 20yrs Zhao L et al. JAMA. 2023 Sugary Diets Are Associated with MASLD • Fructose consumption is a risk factor for NAFLD • Consumption of fructose in patients with NAFLD 2- to 3-fold higher than controls. Increased fructose consumption is associated with fibrosis severity in patients with NAFLD (p <0.05) • Older adults, fructose consumption is associated with increased hepatic inflammation and hepatocellular ballooning. Fructose contained in fruits is not associated with NAFLD, so fruit consumption should not be restricted. Ouyang X et al. Journal of Hepatology, 2008; Abdelmalek MK et al. Hepatology. 2010; Kimura TR et al. et al. J Hepatol. 2018 Nutrition 2019 Low Free Sugar Diet in NAFLD Open-label, 8-week randomized clinical trial of adolescent boys histological diagnosed NAFLD randomized 1:1 to an intervention (Low Sugar Diet) group or usual diet group P< 0.001 )30 ( 25 n25 21 t20 20 Adjusted mean difference r 17 at Wk 8: t15 F -6.23 (95% CI: -9.45 to - t10 3.02) p H 5 n e 0 M Usual Diet (n= 20) Low SugarDiet(n= 20) Wk 0 Wk 8 * Quantified by MRI-PDFF Schwimmer JB,et al. JAMA.2019A Human and Planetary Health Plate Estimate deaths prevented among adults by a global adoption of this diet ≈ 20% of global deaths= ≈ 11 million adult deaths/year EAT-Lancet Commission on Healthy Diets From Sustainable Food Systems 2019Improved Diet Quality Is Associated with Liver Fat Reduction • Framingham Heart Study, n= 1521 • 6 year follow up • Semi-quantitative 126-item Harvard food frequency questionnaire- MD diet score • Liver fat by CT Alsoinsubjectswithgenetic risk for MASLD Ma J et al. Gastroenterology. 2018Age-Standardized Intake of Dietary Factors Among Adults Aged 25yrs or Older at the Global and regional Level in 2017 Daily intake of ALL unhealthy foods exceeds the optimal level GBD, Lancet, 2019Food Insecurity is Associated with MASLD and Liver Related Mortality Food Insecurity Affordability of energy-dense, high-fat foods and overall decline in dietary quality MASLD AdvancedFibrosis Golovaty I et al. J Nutr. 2019 Kardashian A, et al. Hepatology 2022.Exercise Can Independently Improve Hepatic Steatosis and ALT • Meta-analysis of RCT • Twenty RCTs with 1073 NAFLD patients Liver fat ALT AST Katsogoni C et al. Metabolism. 2016Exercise T raining • NASHFit Trial, patients with MASH randomized to receive either moderate- Improves Serum intensity aerobic exercise training or Biomarkers in MASH standard clinical care for 20 weeks. • Mediterranean dietary counselling was provided to each group Stine J et al. Liver Int. 2023High Intensity 52 MASLD, 12 W follow up, TE Aerobic Exercise High intensity interval aerobic Moderate intensity continuous Improves Liver ResistancN= 19ining x 3/WK training 3/wk, 40 mins aerobic training 3/wk, 40 mins N=20 N= 13N= 19 Stiffness Oh S et al. J Hep Reports. 2021HowT oImplementEffectiveLifestyle InterventioninMASLDInternet Based Approach for Lifestyle Change in MASLD 716 pts with NAFLD (in-person vs. web based, 2 year period). Mean Age 52yrs, T2D 33% • Primary outcome: weight loss ≥10% • Secondary outcomes: change in liver enzymes, surrogate markers of steatosis and fibrosis Mazzotti A et al. J Hep. 2018Internet Based Approach for Lifestyle Change in MASLD INPERSONPROGRAM Weight losstarget-15% WEBBASED PROGRAM Weight loss target-20% Mazzotti A et al. J Hep. 2018Diabetes Prevention Program a Possibility to Achieve Weight Loss in MASLD? Evidence-based intervention targeted to individuals with pre- diabetes with the primary goal of weight loss & behavior change Diabetes Prevention Program reduce new cases of type 2 diabetes by 58% and 71% in age > 60yrs Modified DPP Lifestyle Program for NAFLD Core sessions Maintenance sessions (every week, total 16 weeks) ( every 2-4 weeks, total 10-12 sessions) Weigh-in performed at every session • Group setting 15-20 Make up sessions are available in person, email or telephone Weight loss participants • Lifestyle coach and MD goal of 7% • 1 year program Primary Endpoints Retention rates and other indicators of feasibility Secondary Endpoints Impact of DPP on NAFLD, hepatic steatosis and comorbidities Visit with Hepatology including blood work and Fibroscan Hershman M, et al. Obes Sci Practice. 2023 Table 2: Change in Parameters from Baseline to 6-month and 12-month follow-up visits Patient Baseline 6 month 12 month Baseline to Baseline to Characteristics N= 14 N=11 N=11 6 months 12 months mean, (range) mean, (range) mean, (range) p-value * p-value * Weight (kg) 97.2 (76.0-102.9) 92.7 (72.3-115) 94.6 (71.2 -125.6) 0.012 0.002 BMI 36.3 (27.8-49) 35.8 (28.2-44.8) 34.4 (26.8-44.3) 0.24 0.06 CAP (dB/m) 354 (244-400) 315 (219-393) 303 (240-399) 0.16 0.03 LS (kPa) 8.2 (4.1-17.5) 6.2 (4.3-8.6) 6.6 (3.6-8.9) 0.09 0.05 ALT 67 (15-172) • 79% retention rate at 12 months-96) 0.17 0.04 AST • A49 (18-179)f 12 month33 (20-70)cant weight28( 16-53)rved, 0.20 0.09 normalized ALTs and showed significant improvements from ALP 82 (50-120) baseline metabolic parameters-155) 0.85 0.944 GGT 52 (20-151) • Conside36 (19-79) pts with p34 (17-66) 0.27 0.12 • Limitations: pilot data, no QOL measures HgA1c 6.3 (5.2-11.4) 6.1 (5.4-7.3) 6.0 (5.5- 7.0) 0.30 0.34 HDL 51 (35-67) 54 (45-61) 60 (44-76) 0.74 0.01 LDL 115 (52-167) 117 (65-181) 125 (65-167) 0.86 0.04 TG 171 (88-365) 145 (94-234) 138 (102-221) 0.28 0.08 *Paired Sample T-test p-value Hershman M, et al. Obes Sci Practice. 2023SUSTAINABLE healthy behaviour approach versus Weight reduction approach Address modifiable risk factors Acknowledge Set Realistic any positive Weight Loss • Smoking change Goals • Alcohol Accountability Address stressors • Use technology to Reinforce learn track food and physical activity importance of sleep • Make it part of daily routine Physical Activity Work with patient towards adopting a healthy lifestyle • Encourage any movement • Work up to 150 • Dietician • Meal planning • mins/week • Work with Exercise • Apps Physiologist • Touch BaseChallenges to Maintaining Healthy Lifestyle - Examples of Interventions to Address Challenges Consider Cost • Cheaper to buy in a bag that individually • Fres> Frozen> Canned • Think seasonal Knowledge and Misconceptions • Educate your patients about food Physical Limitations • Focus on physical activity versus what type of activity • Encourage movement, 150 mins/week Toxic Environment • Avoid shopping in the centre of the grocery store • Temptations at checkout Socioeconomic Risk Factors • 12.5% US residents receive SNAP benefits • 40.2% of Coco Cola revue from food stamps • EducateSummary of Lifestyle Recommendations in MASLD Spectrum Westerndiet Westerndiet 7-10% weight reduction by Mediterranean diet energy deficit of 500-700 • High fibre Hypocaloric or kcal/day though either diet • High fish • Low fat • High vegetables isocaloric- • Low carb • Low cholesterol Mediterranean diet • Mediterranean • Low sugar Aerobic or resistance exercise Dietary composition modifications Drinks • Reduced fructose • Coffee >2-3 cups/daily • Mediterranean diet • No alcohol in cirrhosis Patient with T2DM and New Diagnosis of MASH 60F with Class 2 obesity (BMI 36), HTN, hyperlipidemia and a 15 year history of T2D and abnormal aminotransferase levels for many years. Statin was stopped due to elevated liver enzymes. Currently on amlodipine, enalapril, metformin, omeprazole. Recent evaluation has revealed the following: Laboratory Test Result Alb 4.0 g/dL ALP 112 U/L Noninvasive Testing: • FIB4 2.4 HCV & HBV: negative ALT 92 U/L • VCTE 16kPa ASMA, ANA: normal A1AT, iron profile: AST 80 U/L Liver Biopsy: normal TBil 0.6 mg/dL active steatohepatitis with extensive bridging fibrosis but plt 210 not cirrhosis HbA1c 7.6% TG 210 LDL 120Patient with T2DM and New Diagnosis of MASH You recommend lifestyle change and increased physical activity for weight loss and refer the patient to a dietician for support. In addition to the above recommendations, which of the following is the best next step in treating his MASH? 1. GLP1-RA 2. Resmiterom 3. Start Vitamin E 4. PioglitazonePatient with T2DM and New Diagnosis of MASH Which of the following agents has been shown to result in MASH resolution and improved cardiovascular risk? 1. Semaglutide 2. Empagliflozin 3. Pioglitazone 4. Vitamin E Initial evaluation • Screening for DM • Lipid risk levels (statins are safe and first line) Cusi K, Isaacs S, Barb D, et al. Endocrine Practice 2022; 28: 528-562. Multidisciplinary Approach to MASLD: AASLD Guidelines 2023 Primary Care/Endocrinology • Initial Risk Stratification • Management of medical co- morbidities with preferential effect on MASLD Cardiology/Lipid • Other endocrine driver Weight Management Management • Lifestyle changes Medical/Interventional Gastroenterology/Hepatology Comprehensive Liver/Fibrosis assessment MASLD Nutrition/Lifestyle Intervention Patient • Liver directed therapies • Assessment of Dietary habits • Identification of additional co- • Develop personalized dietary morbidities goals • HCC screening and Preventative • Identify barriers Health • Referral to behaviour intervention • Management of advanced fibrosis • Prescriptive follow up and Health Psychology • Clinical trial opportunities management planPharmacotherapy for MASLD • AASLD guidelines: • Drugs approved to treat associated FDA Liver Histologic Endpoints Likely to Predict Clinical Benefit comorbidities with potential benefit in NAFLD may be considered. NASH Resolution • Semaglutide can be considered for its Resolution of steatohepatitis (Ballooning = 0, Inflammation = 0/1) AND no worsening of liver approved indications (T2DM/obesity) in fibrosis patients with NASH, as it confers a cardiovascular benefit and improves NASH. Fibrosis Improvement • Pioglitazone improves NASH and can be Improvement ≥ 1 fibrosis stage AND no worsening considered for patients with NASH in the of steatohepatitis context of patients with T2DM. US FDA. Draft Guidance. Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Rinella M et al, Hepatology. 2023 Developing Drugs for Treatment Guidance for Industry. December 2018. st Resmetirom- 1 Pharmacological Therapy Approved for MASH Approved for patients with MASH and moderate to advanced fibrosis (F2-F3 fibrosis) Harrison SA et al. NEJM. 2024 The Thyroid Hormone Receptor-βeta Pathway: Role in Hepatic Lipid Metabolism ▪ THR-β agonists act on multiple hepatic FFA pathways by controlling : 1 Mitophagy Mitochondrial THR-β Lipid FFA ATP biogenesis droplet • De novo lipogenesis FAO THR-β DNL THR-β • Fatty acid oxidation TAG • Mitochondrial biogenesis TCA Acetyl-CoA • Cholesterol metabolism VLDL • Direct anti-inflammatory & anti-fibrotic Cholesterol THR-β LDL effects (inhibits TGF-𝛽 pathway) Bile acid HDL Carbons eliminated through CO respiration Adapted from Sinha RA, et al. Nat Rev Endocrinol. 2018 2 (citric acid cycle)Abushamat L. et al (unpublished)Studies on the Effect of GLP-1RA in MASLD N =103 All patients having T2DM and AST/ALT ≤40 U/L Chandani, Cusi and Kadiyala. JCEM 2022 NEJM 2021; 384:1113-1124. Objective: To compare the effect of three different doses of semaglutide subcutaneous (s.c.) once daily versus placebo on histological resolution ↓ Mean Body Weight loss – 5% (0.1 mg), -9% (0.2mg) and -13% (0.4mg) ➢ Improvements in multiple metabolic characteristics, including body weight, HbA , and lipid profile 1c ➢ Safety profile consistent with that seen in patients with type 2 diabetes with no new safety concerns Newsome PN, et al. NEJM 2021Effect of Semaglutide in Patients with MASH Changes in Fibrosis stage Newsome PN, et al. NEJM 2021Semaglutide: Phase 3 RCT • Phase 3 RCT (NCT 04822181) – ESSENCE trial (n=1,200) of semaglutide (2.4 mg weekly for 240 weeks) in noncirrhotic NASH • Primary outcomes: histology • Secondary outcome: time to MACE • Results expected May 2028 .GLP-1 RA Safety in MASH Adverse Events • Five phase 3 RCTs (STEP) with ~ 5,000 participants evaluated safety and efficacy for • Gastrointestinal • ~70%, non-serious treatment of obesity • Gallstones (due to weight loss) • Elevations in lipase • Phase 2 RCT in non-cirrhotic NASH (n=320) • Pancreatitis (rare) ➢ NNT for weight loss >5% is 2 • Increased heart rate ➢ NNT to harm for thyroid cancer to Caution happen >1400 -1600 • DM retinopathy worsening • Hypoglycemia (in combination with insulin) • Neoplasms - not malignant (15% vs 8%)? Yabut , Drucker. Endocr Rev. 2022. .Semaglutide in MASH and Compensated Cirrhosis Phase 2, 48 wk, randomized, placebo-controlled trial, Semaglutide 2.4mg weekly versus placebo ( 2:1) for compensated NASH cirrhosis, n= 71 • No improvement in hepatic fibrosis or resolution of NASH • Reduced liver enzymes and hepatic fat, improved TG and LDL, and decreased body weight Loomba R, et al. Lancet 2023GLP1RA Side Effects Nausea Diarrhea Constipatio n Dyspepsia Hypoglycemia Decreased Vomiting appetite Headache Dizziness Fatigue Abdomina l pain Gorgojo- Martínez JJ, et al. J Clin Med 2023Tirzepetide- Dual GLP1RA and GIP Phase 3 NASH study: ClinicalTrials.gov Identifier: NCT04166773 Loomba R et al. NEJM. 2024Improvement in MASH related biomarkers Hartman ML et al. Diabetes Care. 2020 Rationale for PPAR Agonists in MASLD/MASH α Activation - Control of lipid influx - Improves FFA oxidation γ Activation - Adipose tissue insulin sensitivity - Improves glucose δ Activation - Inhibits lipogenesis - Enhances muscle performance Perazzo H, et al. Liver Int. 2017 Cusi K, et al. Gastroenterology 2012Pioglitazone (PPAR α,γ agonist) in MASLD/MASH ▪ Improves liver histology in patients with and ▪ Improves glucose and lipid profile without T2DM ▪ Resolution of NASH (58%) ▪ Prevention of diabetes ▪ Prevention of fibrosis ▪ Pioglitazone reduces CVD RCT’s of Pioglitazone in NASH ▪ PROACTIVE (Lancet 2006), 1. Belfort R. et al, N Engl J Med. 2006;355(22):2297-2307.▪ CHICAGO (JAMA 2007), 2. Aithal G.. Gastroenterology 2008;135:1176–1184 ▪ PERISCOPE (JAMA 2008), 3. Sanyal A.J. et al, N Engl J Med, 362 (2010):1675-1685 ▪ IRIS Study (NEJM 2016; Circulation 2017 4. Cusi K. et al, Ann Intern Med, 2016;165:305-15. 5. Bril F. et al, Diabetes Care 2019;42:1–8 6. Huang J.F. et al, Hepatol Int. 2021 Oct;15(5):1136-1147Piaglitazone Improves Steatohepatitis N=101 with prediabetes or T2DM Cusi K, et al. Annals of Internal Medicine. 2016Effect of Pioglitazone on Liver Fibrosis in Patients with NASH Majzoub AM et al. Aliment Pharmacol Ther. 2021.Revitalization of Pioglitazone Combo with SGLT2i or GLP1RA Weight loss (kg) with semaglutide added to pioglitazone DeFronzo RA. Diabetes Obes Metab. 2016 Ahrén B. Lancet Diabetes Endocrinol. 2017;5(5):341-354 Dapa +Pio: Rosenstock J Diabetes Care. 2012Back to Our Patient- T2DM and New Diagnosis of MASH 60F with Class 2 obesity (BMI 36), HTN, hyperlipidemia and a 15 year history of T2D and abnormal aminotransferase levels for many years. Statin was stopped due to elevated liver enzymes. Currently on amlodipine, enalapril, metformin, omeprazole. Recent evaluation has revealed the following: Laboratory Test Result Alb 4.0 g/dL HCV & HBV: ALP 112 U/L Noninvasive Testing: negative ALT 92 U/L • FIB4 2.4 ASMA, ANA: • VCTE 16kPa AST 80 U/L Liver Biopsy: normal TBil 0.6 mg/dL A1AT, iron profile: active steatohepatitis with normal plt 210 extensive bridging fibrosis but HbA1c 7.6% not cirrhosis TG 210 LDL 120Resmetirom (REZDIFFRA) Achieves MASH Resolution and Fibrosis Improvement Harrison SA et al. NEJM. 2024REZDIFFRA • Statin Use • Rosuvastatin and simvastatin: Limit daily statin dosage to 20 mg • Pravastatin and atorvastatin: Limit daily statin dosage to 40 mg • Monitor for statin related reactions including elevated liver tests, myopathy, myalgias, rhabdomyolysis. • Clopidogrel (Plavix) • <100 kg, reduce the dosage of REZDIFFRA to 60 mg once daily • ≥100 kg, reduce the dosage of REZDIFFRA to 80 mg once daily • Status of Hypothyroid disease • Hepatotoxicity: While rare, this has been observed with the use of Resmetirom. Monitor patients as suggested in Table below for elevations in liver tests and for the development of liver related adverse reactions. Discontinue Resmetirom and continue to monitor the patient if hepatotoxicity is suspected. • Gallbladder related adverse reactions: Cholelithiasis, acute cholecystitis, and obstructive pancreatitis were observed more often in Resmetirom treated patients than placebo treated patients. If an acute event is suspected, interrupt Resmetirom treatment until the event is resolved.Semaglutide Achieved MASH Resolution and No Worsening of Fibrosis • Improvements in multiple metabolic characteristics, including body weight, HbA ,1cnd lipid profile • Safety profile consistent with that seen in patients with type 2 diabetes with no new safety concerns Newsome PN, et al. NEJM 2021Statins Are Safe in MASLD Ongoing, Phase 2 study: STAT- NASH Trial De Denus D, et al. Pharmacotherapy. 2004PIVENS: 96-Wk Results of Pioglitazone and Vitamin E in Patients With NASH Double-blind, placebo-controlled, randomized phase III study in adults with biopsy-proven NASH and no diabetes or cirrhosis (N = 247) Placebo (n = 83) Vitamin E 800 IU QD (n = 84) Pioglitazone 30 mg QD (n = 80) %100 c % b ≤ .001 P = .004 t P = .04 P = .08 e 80 P = .005 69 P = .12 P = .001 m P = .001 P = .02 60 P = .01 v 60 54 P = .24 54 p 50 P = .05 47 I 43 41 44 44 t 40 34 31 31 35 36 W 29 t 19 21 e 20 a P 0 Histologic Features Steatosis Fibrosis Lobular Hepatocellular Resolution of NASH Inflammation Ballooning of NASH Improves Steatosis, NO IMPACT on Fibrosis Sanyal A, et al. NEJM. 2010Thank you