NASH 101 What You Need to Know Now - PowerPoint Presentation

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NASH 101 What You Need to Know Now - PPT Presentation

Moderator Kris V Kowdley MD Director Liver Institute Northwest Clinical Professor Elson S Floyd College of Medicine Washington State University Seattle Washington Overview of Discussion ID: 776490

nash nafld fibrosis liver nash nafld fibrosis liver cirrhosis patients 2019 2016 2018 hepatology risk vitamin hepatol worsening hcc

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Slide1

NASH 101

What You Need to Know Now

Moderator

Kris V. Kowdley, MD

Director

Liver Institute Northwest

Clinical Professor

Elson S. Floyd College of Medicine

Washington State University

Seattle, Washington

Slide2

Overview of Discussion

Epidemiology of NAFLD

Associated burden of disease

Pathogenesis

Spectrum of disease

Risk factors for NAFLD

Clinical tools for risk assessment

Clinical outcomes

Current standard of care

Clinical trial pipeline

Slide3

NAFLD and NASH: A Global Epidemic

a. Younossi ZM, et al. Hepatology. 2016;64:73-84; b. Younossi ZM. J Hepatol. 2019;70:531-544; c. Younossi ZM. Clin Liver Dis (Hoboken). 2018;11:92-94.

Global prevalence of NAFLD is 25.2%[a]Higher in males, HispanicsIncreases with agePrevalence of NASH in general population is estimated at 1.5% to 6.5%[b,c]Prevalence differs among ethnic groups[c]

Slide4

Shetty A, Syn W-K. Fed Practitioner. 2019;36:14-19.

The Burden of NAFLD Among Americans

85 million have NAFLD

 100 million by 2030

17 to 25 million have NASH

 43 million by 2030

Slide5

NAFLD and NASH in Children in the United States: A Serious Threat

Schwimmer JB, et al. Pediatrics. 2006;118:1388-1393.

NAFLD Prevalence, %

Slide6

NAFLD and NASH in Children in the United States: A Serious Threat (cont)

a. Schwimmer JB, et al. Pediatrics. 2006;118:1388-1393.

Prevalence of NAFLD in US children is as high as 17.3%[a]More common in Hispanic boysRisk factors: family historyGestational diabetesT2D

Slide7

NAFLD Among the Elderly in the United StatesA NHANES-III Analysis

Golabi P, et al. BMC Gastroenterol. 2019;19:56.

Prevalence age 60 to 74 y: 40.3% (95% CI: 37.2–43.5%) aHR for mortality: 1.60 (95% CI: 1.24, 1.96) for 5-y and 1.22 (95% CI: 1.01, 1.49) for 10-yaHR for CV mortality: 2.12 (95% CI: 1.20, 3.75) for 5-y and 1.06 (95% CI: 0.73, 1.52) for 10-yPrevalence age >74 y: 39.2% (95% CI: 34.4, 44.0%)Diagnosis of NAFLD not associated with all-cause or CVD mortality

NAFLD defined by US Fatty Liver Index in the absence of other causes of liver disease (N = 3271)

Slide8

Bertot LC, Adams LA. Int J Mol Sci. 2016;17:774-785; Estes C, et al. Hepatology. 2018;67:123-133.

The NAFL  Cirrhosis ContinuumClinical Outcomes

NASH

NAFL

(non-NASH)

NASH

w/fibrosis

NASH

/advanced

fibrosis

Cirrhosis

w/HCC

Non-cirrhosis

w/HCC

(F1 - F4)

Progression

Regression

Slide9

Bertot LC, Adams LA. Int J Mol Sci. 2016;17:774-785; Estes C, et al. Hepatology. 2018;67:123-133.

The NAFL  Cirrhosis ContinuumClinical Outcomes

Progression

Regression

NASH

NAFL

(non-NASH)

NASH

w/fibrosis

NASH

/advanced

fibrosis

Cirrhosis

w/HCC

Non-cirrhosis

w/HCC

(F1 - F4)

Slide10

Bertot LC, Adams LA. Int J Mol Sci. 2016;17:774-785; Estes C, et al. Hepatology. 2018;67:123-133.

The NAFL  Cirrhosis ContinuumClinical Outcomes

Progression

Regression

NASH

NAFL

(non-NASH)

NASH

w/fibrosis

NASH

/advanced

fibrosis

Cirrhosis

w/HCC

Non-cirrhosis

w/HCC

(F1 - F4)

Slide11

The Main Drivers of NAFLD

ObesityDiabetesMetabolic syndrome

Slide12

More Americans Are Obese Than Are Overweight

a. Younossi ZM. J Hepatol. 2019;70:531-544; b. Fryar CD, et al. NCHS. 2016.

The World2016: > 1.9 billion overweight adults (39%) and > 650 million obese adults (13%) worldwide[a] The United StatesNHANES data estimate that 32.5% of Americans are overweight, 37.7% are obese, and 7.7% are extremely obese[b]

Slide13

*Who underwent biopsy. a. Bril F, Cusi K. Diabetes Care. 2017;40:419-430; b. Younossi ZM. Clin Liver Dis (Hoboken). 2018;11:92-94.

Type 2 Diabetes

Prevalence among adults in United States (NHANES, 2011-2012): 84 million[a] Prediabetes in 38%T2D in 14.3%Global prevalence of NAFLD and NASH* among patients with T2D is 57.80% and 65.26%, respectively[b]

Slide14

Alexander M, et al. BMC Medicine. 2019;17:95.

Identifying Patients at High Risk of Developing Advanced Liver Disease

Real-world population study of 18,782,281 adults from primary care databases in 4 European countries: 136,703 patients with codes for NAFLD/NASHMore likely to have diabetes, hypertension, and obesity than matched controlsHR for cirrhosis = 4.73 (95% CI 2.43, 9.19)HR for HCC = 3.51 (95% CI 1.72, 7.16)HR for either cirrhosis or HCC was higher in patients with NASH and those with high-risk FIB-4 scores

Strongest

independent predictor of a diagnosis of HCC or cirrhosis

was baseline diagnosis of diabetes

Slide15

The NAFLD/NASH Phenotype

a. Siddiqui MS, et al. Clin Gastroenterol Hepatol. 2015;13:1000-1008.e3; b. Lindenmeyer CC, et al. Clin Liver Dis. 2018;22:11-21; c. Lim S, et al. Obes Rev. 2019;20:599-611; d. Faasse S, et al. F1000Res. 2018;7:170; Targher G, et al. J Hepatol. 2016:65:589-600; f. Franque SM, et al. J Hepatol. 2016;65:425-433; g. Mahfood HT, et al. Diabetes Metab Syndr. 2017;11:S209-S216.

Atherogenic lipid profile[a]High triglycerides, increased VLDL-C, remnant particles, small LDL-C particlesCardiometabolic syndrome[b-d]  CV risk [e-g]

Slide16

*Or being on medicine to treat high blood sugar.NIH website. Metabolic syndrome. 2019.

Metabolic Syndrome

CriterionDefinitionAbdominal obesityWaistline 35 in (89 cm) for women or 40 in (102 cm) for menDyslipidemiaSerum TG level 150 mg/dL (1.7 mmol/L)Serum HDL-C level <40 mg/dL (men) or <50 mg/dL (women)Elevated FBS*100 mg/dL (5.6 mmol/L)Hypertension130/85 mm Hg

Slide17

Additional Risk of Developing NAFLD/NASH

a. Chalasani N, et al. Hepatology. 2018;67:328-357; b. EASL, EASD, EASO. J Hepatol. 2016;64:1388-1402.

Other Risk FactorsGeneticsEnvironmentPolycystic ovary syndrome

Recommendations

AASLD: Suspect NAFLD and NASH in patients

with T2D

and determine patient's risk of advanced fibrosis

[a]

EASL-EASD-EASO: Screen for NAFLD in patients with high risk for CVD,

including T2D

or metabolic syndrome

[b]

Slide18

a. Singh S, et al. Clin Gastroenterol Hepatol. 2015;13:643-654; b. Golabi P, et al. Medicine. 2018;97:31-36; c. Stine JG, et al. Aliment Pharmacol Ther. 2018;48:696-703; d. Onzi G, et al. Hepatoma Res. 2019;5:1-7; e. Younossi ZM, et al. Clin Gastroenterol Hepatol. 2019;17:748-755; f. Franque SM, et al. J Hepatol. 2016;65:425-433.

Clinical Implications of Progression of NAFLD

Cirrhosis[a]Liver transplantation[b]HCC[c-e]CVD[f]

Slide19

NAFLD and Liver-Related Mortality

Dulai PS, et al. Hepatology. 2017;65:1557-1565.

Meta-analysis of 5 cohort studies of patients with NAFLD (N = 1495) who were followed for 17,452 patient-yLiver-related and all-cause mortality increased exponentially as the stage of fibrosis increased

Slide20

NAFLD and CV Mortality

a. Lindenmeyer CC, et al. Clin Liver Dis. 2018;22:11-21; b. Targher G, et al. J Hepatol. 2016:65:589-600.

Twice as likely to die of CVD than liver disease[a]>65% increased risk of developing both fatal and nonfatal CV events[b]

Slide21

Fibrosis

Cirrhosis

HCC

Steatosis

 l

ipotoxicity



ROS

Endothelial reticulum stress

Unfolded protein response

Obesity,insulin resistance  Lipolysis  FFA

Mitochondrial dysfunction

Inflammation

Stellate cell

activation

Apoptosis

Pathogenesis of NAFLD and NASH

Slide22

Is It NAFLD or NASH?

NAFLD

Steatosis >5% in the absence of other secondary causes of hepatic fatNo liver injury = NAFLVariable degrees of fibrosis = steatofibrosis

Steatosis

Creative Commons Attribution License 3.0 Joaquín Cabezas, et al. Nonalcoholic Fatty Liver Disease: A Pathological View, Liver Biopsy - Indications, Procedures, Results, Nobumi Tagaya, IntechOpen. 2012. Available from: https://www.intechopen.com/books/liver-biopsy-indications-procedures-results/nonalcoholic-fatty-liver-disease-a-pathological-view

Slide23

Is It NASH or NAFLD?

NASH

Steatosis >5%Lobular inflammationHepatocellular ballooningVariable degrees of fibrosis

Fibrosis

Mononuclear

inflammatory

infiltrate

Ballooning

hepatocyte

Slide24

a. Alkhouri N, et al. Gastroenterol Hepatol (N Y). 2012;8:66-668; b. Kruger FC, et al. S Afr Med J. 2011;101:477-480; c. Angulo P, et al. Gastroenterology. 2013;145:782-789; d. Angulo P, et al. Hepatology. 2007;45:846-854; e. Cichoż-Lach H, et al. Med Sci Monit. 2012;18:CR735-740.

Serum-Based Single Tests for Identifying Patients With NAFLD at Increased Risk for Worse Outcomes

TestVariables IncludedFIB-4[a]Age, ALT, AST, platelet countAPRI[b]AST, platelet countNAFLD fibrosis score[c,d]Age, ALT, AST, platelet count, BMI, albumin, impaired fasting glucose/diabetesBARD[e]ALT, AST (AST/ALT ratio), BMI, T2DELF™[a]TIMP-1, PIIINP, HA

Algorithms

Coming

Slide25

a. Dulai PS, et al. J Hepatol. 2016;65:1006-1016; b. Jayakumar S, et al. J Hepatol. 2019;70:133-141.

Imaging Tests for Identifying Patients Likely to Have Advanced Fibrosis

Test

Points for Consideration

Vibration-controlled transient elastography (VCTE)

Can be used at POC with training

Can determine advanced fibrosis

2D shear wave elastography

Can be used at POC

with training

Can determine advanced fibrosis

Magnetic resonance elastography (MRE)

Most accurate modality

[a,b]

Requires referral to radiology department

Slide26

Current Standard of Care: Lifestyle Interventions

a. Ratziu V. Liver Int. 2017;37:90-96.

Weight lossLow-carbohydrate dietIncreased physical activity and exerciseOptimal management of diabetes

Slide27

a. Vilar-Gomez E, et al. Gastroenterology. 2015;149:367-378; b. Promrat K, et al. Hepatology. 2010;51:121-129; c. Harrison SA, et al Hepatology. 2009;49:80-86.

Current Standard of Care: Weight Loss

Fibrosis

NASH Resolution

Ballooning/Inflammation

Steatosis

Weight Loss ≥10%

[a]

Weight Loss ≥7%

[a]

Weight Loss ≥5%

[a-c]

Weight Loss ≥3%

[a-c]

Slide28

Exercise Mobilizes Hepatic Fat Mobilization in Patients With NAFLD

Golabi P, et al. World J Gastroenterol. 2016;22:6318-6327.

Systematic review (8 RCTs and prospective cohort studies) in adults (N = 433)Dietary interventions plus exercise augment hepatic fat reductionModerate-intensity exercise mobilizes intrahepatic triglycerides (30.2% in the exercise-only group and 49.8% in diet plus exercise group)

Exercise 3-4 times/wk,

20-30 min/sessions

Slide29

a. Lassailly G, et al. J Hepatol. 2013;58:1249-1251; b. Chalasani N, et al. Hepatology. 2018;67:328-357.

Bariatric Surgery: An Option for Patients With NASH

Morbid obesity and cirrhosis[a]Compared with noncirrhotic and nonobese patients with cirrhosis, severely obese patients with cirrhosis have highest risk of mortalityBariatric surgery may be considered for severely obese persons (BMI >40 or >35 with comorbidity) who clearly wish to lose weight[a]Induces long-term weight loss; decreases morbidity, incidence of cancer, and mortalityImproves steatosis in 90% of casesResolves steatohepatitis in >80% of casesMortality rates increased 2-fold in compensated cirrhosis, 21-fold in decompensated cirrhosis

“Foregut bariatric surgery can be considered in otherwise eligible obese individuals with NAFLD or NASH - Premature to consider it an established option to treat NASH specifically”.

[b]

Slide30

a. Cusi K, et al. Ann Int Med. 2016;165:305-315; b. Armstrong MJ, et al. Lancet. 2016;387:679-690; c. Lavine JE, et al. JAMA. 2011;305:1659-1668; d. Sanyal AJ, et al. N Engl J Med. 2010;362:1675-1685.

Treatment of NAFLD and NASH

Drug

Target

Trial

Pioglitazone (

thiazolidinedione

)

PPAR

γ receptor

PIVENS

[a]

Liraglutide (

incretin mimetic

)

GLP-1 receptor

LEAN

[b]

Vitamin E (antioxidant)

Oxidative stress

TONIC

[c,d]

Slide31

Pioglitazone for NASH

Cusi K, et al. Ann Intern Med. 2016;165:305-315.

PPAR agonistPPAR agonist: upregulates adiponectin, anti-steatogenic and insulin-sensitizing properties, increases synthesis and uptake of fatty acids by adipocytes (vs liver, muscle)StudyHypocaloric diet + pioglitazone 45 mg/d vs placebo for 18 mo followed by 18-mo, open-label pioglitazonePrimary outcome: reduction of ≥2 in NAS without worsening of fibrosisResultsPioglitazone improved fibrosis (P <.039)More weight gain with pioglitazone

Slide32

a. Chalasani N, et al. Hepatology. 2018;67:328-357; b. Cusi K, et al. Ann Intern Med. 206;165:305-315; c. Aithal GP, et al. Gastroenterology. 2008;135:1176-1184; d. Sanyal AJ, et al. N Engl J Med. 2010;362:1675-1685; e. Filipova E, et al. Diabetes Ther. 2017;8:705-726; f. Portillo-Sanchez P, et al. J Diabetes. 2019;11:223-231.

Pioglitazone for NASH: AASLD Guidance

May be used to treat patients with biopsy-proven NASH

[a]

Improved liver histology in patients with biopsy-proven NASH,

with and without

concomitant T2D

[

a-d]

Should not be used in NAFLD without biopsy-proven NASH

[a]

Recent meta-analysis refutes concern about bladder cancer

[e]

Concerns

2.5 kg to 4.7 kg increase in body weight with 12 to 36 mo of treatment

[a]

Bone density loss (spine) during therapy in patients with NASH

and T2D

or prediabetes

[f]

Edema

Slide33

*Without worsening of fibrosis.Bril F, et al. Diabetes Care. 2019;42:1-8.

Pioglitazone Plus Vitamin E Better Than Placebo in Patients With NASH and T2D

Key finding: Vitamin E alone was not different from PBO in achieving improvement in the primary liver histological outcome, and was less effective than the combination of vitamin E and pioglitazone

Treatment vs PBO

Primary Endpoint:

2-Point Reduction

in the NAS

Secondary Endpoint: Resolution of NASH*

Pioglitazone + vitamin E

54% vs 19%,

003

43% vs 12%,

005

Vitamin E

31% vs 19%,

33% vs 12%,

Slide34

PIVENS Trial: Vitamin E vs Pioglitazone for NASH

Sanyal AJ, et al. N Engl J Med. 2010;362:1675-1685.

Vitamin E 800 IU/d vs pioglitazone 30 mg/d vs PBOPrimary endpoint: NAS improvement by > 2 points, including > 1-point improvement in ballooning + 1-point improvement in either lobular inflammation or steatosis score + no increase in fibrosis

N = 247

Slide35

Vitamin E: Safety Concerns

a. Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994;33:1029-1035; b. Miller ER 3rd, et al. Ann Int Med. 2005;142:37-46; c. Klein EA, et al. JAMA. 2011;306:1549-1556; d. Kristal AR, et al. J Natl Cancer Inst. 2014;106:djt456.

Cancer prevention study[a] Increase in hemorrhagic strokeLarge meta-analysis[b]Pooled all-cause mortality difference significant at P =.035 No significant impact of low-dose vitamin E

SELECT: follow-up trial

of >35,000

men enrolled 2001-2004

[c]

4 arms: PBO, vitamin E 400 IU/d, selenium, or both

HR = 1.17 for vitamin E monotherapy group (

008)

Absolute increase = 1.6/1000 person-y

Case-cohort analysis from SELECT

[d]

Increased risk in patients with low nail selenium levels

Slide36

Vitamin E for NASH: AASLD Guidance

Chalasani N, et al. Hepatology. 2018;67:328-357.

AASLD Guidance[a] 800 IU/d (D-alpha-tocopherol) improves liver histology in nondiabetic adults with biopsy-proven NASH; may be considered for this populationNot yet recommended for:NASH in patients with T2DNAFLD without liver biopsyNASH cirrhosisCryptogenic cirrhosis

Slide37

Fibrosis

Cirrhosis

HCC

Steatosis

 l

ipotoxicity



ROS

Endothelial reticulum stress

Unfolded protein response

Obesity,insulin resistance  Lipolysis  FFA

Mitochondrial dysfunction

Liraglutide, semaglutide

pioglitazone, obeticholic acid, firsocostat

Elafibranor, resmetirom,

VK 2809, obeticholic acid, aramchol, firsocostat

Vitamin E

Inflammation

Stellate cell

activation

Cenicriviroc

Elafibranor

Apoptosis

Obeticholic

acid

Aramchol

Targets

for Treatment

Slide38

*Biopsy data from paired liver biopsiesNote: Since the time of the recording, resmetirom moved into a phase 3 clinical triala. Harrison SA, et al. Aliment Pharmacol Ther. 2016;44:1183-1198; b. Harrison SA, et al. Lancet. 2018;391:1174-1185; c. Loomba R, et al. EASL 2019. 2019;70:e150; d. Alkhouri N, et al. Expert Opin Investig Drugs. 2019;19:1-7; e. Newsome P, et al. J Hepatology. 2018;68:S581.

Partial List of Drugs in Phase 2 Trials for NASH

Drug

MOA

Primary Endpoint*

GR-MD-02

[a]

Galectin-3 inhibitor

Reduction of HVPG at 1 y

NGM282

[b]

FGF19 analogue

Change in hepatic fat fraction assessed by MRI-PDFF at 12 wk

VK2809

[c]

THR-

agonist

Change in hepatic fat: absolute change in liver fat from baseline, median relative change in liver fat from baseline,

≥30% relative reduction in liver fat

Fircosostat

[d]

Acetyl-CoA carboxylase inhibitor

Relative reduction in liver fat from baseline

Semaglutide

[e]

GLP-1 receptor agonist

Change in ALT level

Slide39

Note: Since the time of the recording, resmetirom and aramchol moved into phase 3 clinical trialsa. Sanyal AJ, et al. Hepatology. 2019;70:23A; b. ClinicalTrials.gov. NCT0303439254; c. ClinicalTrials.gov. NCT03028740; d. ClinicalTrials.gov. NCT02704403; e. ClinicalTrials.gov. NCT03900429; f. ClinicalTrials.gov. NCT04104321.

Current Ongoing Phase 3 Trials for NASH

Drug

MOA

Trial

Primary Endpoint

Obeticholic acid

FXR agonist

REGENERATE

[a]

REVERSE

[b]

≥1 stage fibrosis improvement with no NASH worsening OR

resolution of NASH with no

fibrosis worsening

≥1 stage fibrosis improvement AND no worsening of steatohepatitis

Cenicriviroc

CCR2/CCR5 antagonist

AURORA

[c]

≥1 stage fibrosis improvement

AND no worsening of steatohepatitis

Elafibranor

PPAR

α/σ

agonist

RESOLVE-IT

[d]

Resolution of NASH without fibrosis worsening

Resmetirom

Selective

THR-β agonist

MAESTRO-NASH

[e]

Resolution of NASH

Composite long-term outcome: all-cause mortality, cirrhosis, and liver-related clinical outcomes

Aramchol

Fatty acid bile acid conjugate

ARMOR

[f]

Resolution of NASH without fibrosis worsening

≥1 stage fibrosis improvement

AND no worsening of steatohepatitis

Slide40

*Improvement of fibrosis with no worsening of NASH; ꝉ Resolution of NASH with no worsening of fibrosisSanyal AJ, et al. Hepatology. 2019;70:23A.

REGENERATE: Ongoing Phase 3, Double-Blind, PBO-Controlled Study: 18-Month Secondary Analysis

Full-efficacy group with NASH and fibrosis stages F2/F3 and and F1 with 1 risk factor were randomized 1:1:1 to PBO (n=407), OCA 10 mg (n=407), or OCA 25 mg daily (n=404)Endpoints: fibrosis improvement (1 stage) with no worsening of NASH, or resolution of NASH with no worsening of fibrosisNearly twice as many patients treated with OCA 25 mg met the primary fibrosis and NASH endpoints compared to PBOMild-to-moderate pruritus was the most common AE (19% PBO, 28% OCA 10 mg, 51% OCA 25 mg)

Full Efficacy Population (Stage F1-F3)

PBO

(n=407)

OCA 10 mg

(n=407)

OCA 25 mg

(n=404)

Endpoint 1*, %

10.6

15.7

(

= .029)