Zobair M Younossi MD, MPH, FACP, FACG, FAASLD, AGAF · Zobair M Younossi MD, MPH, FACP, FACG,...
Transcript of Zobair M Younossi MD, MPH, FACP, FACG, FAASLD, AGAF · Zobair M Younossi MD, MPH, FACP, FACG,...
Zobair M Younossi MD, MPH,
FACP, FACG, FAASLD, AGAF
Chairman and Professor of Medicine
Inova Fairfax Medical Campus, Falls Church, VA
United Sates
The Expanding World of Fatty Liver Disease
Faculty Disclosure: Research Funds and/or Consultants for Gilead Sciences, Intercept, BMS, NovoNordisk, Viking, Terns, Shionogi, Abbvie, Merck, and Novartis.
WHO 2018
The Global Epidemic of Obesity is the Main Driver of Global NASH
WHO 2018
• Since 1975, worldwide obesity has tripled
Younossi Z J of Hepatology 2019
The Rate of Obesity id Growing in Every Country and
This Trend is Expected to Continue …
Organization for Economic Co-operation and Development (OECD 2017)
2016 Global Data
• Adults: >1.9 billion (39%) overweight & >650 million (13%) obese
• Children & adolescents (5-19 yrs): 340 million overweigh or obese
• Most of the world's population live in countries where overweight and obesity kills more people than
underweight.
PHYSIOLOGICAL FACTOR • Energy intake (more than is needed)
• Energy expenditure
• Thrifty Gene
MENTAL & PHYSICAL DISABILITY Mental: Schizophrenia, downs syndrome, mental illness,
learning disabilities, and eating disorders
Physical Disability • Greatly reduced activity levels eg (wheelchair bound) from
physical impairments or age
• Combination of difficulties in regulating food intake &
energy output
ENDOCRINE DISEASES Endocrine diseases
• Hypothyroidism
• Cushing’s syndrome
• Growth hormone deficiency
• PCOS
SOCIAL FACTORS • Reduction in exercise
• Sedentary lifestyle
• TV
• Computer games
• Sedentary jobs
• Fat children become fat adults
• Pregnancy-may eat more or erratically
BEHAVIORAL FACTORS • Consumption of fast food
• Consumption of health unprocessed food
• High sugar and fat diets
• Snacking
• Alcohol consumption
• Weight gain associated with cessation of smoking
• Disorganized eating patterns and eating disorders
GENETIC FACTORS • Prader-willi syndrome
• Other syndromes
• Leptin deficiency
• Other defects and deficiencies
ENVIRONMENTAL FACTORS • Advertising and marketing of high density foods
and soft drinks
• Social deprivation
• Lifestyle changes, more cars etc
• Ethnic tendencies especially if adopting Western
lifestyle
• Steatogenic drugs
• Antiobiotics in food chain
What Drives the Global Epidemic of Obesity? Obesity Is A Complex Disease Related To Genetic And Environmental Factors
OBESITY
NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis
1. Younossi ZM. Hepatology. 2018;68(1):349-360; 2. Chalasani N, et al. Hepatology. 2018;67(1):328-35; 3. Younossi ZM, et al. Hepatology. 2011;53(4):1874-1882;
4. Younossi ZM, et al. Hepatol Commun. 2017;1(5):421-428; 5. Anstee QM, et al. Gastroenterology. 2016;150(8):1728-1744
Steatosis NASH NASH with
advanced fibrosis
Normal
Spectrum of NAFLD
NASH
HCC
NASH in the Context of the Spectrum of NAFLD
Burden
CLINICAL
PRO
ECONOMIC
• Prevalence and incidence
• Liver outcomes or surrogates of mortality
• CVD and other EHM
• Crude death rates
• Life-expectancy, expected years of life lost,
• Symptoms
• HRQOL (Physical, Mental and Social
health)
• Cost of illness
• Budgetary costs
• Indirect and intangible costs
• Resource utilization
• Cost-effectiveness
• Survival
• Patient experience
• Feel
• Resource utilization
• Value
Outcomes Surrogate Endpoints
• Function and WP FUNCTIONAL
• Functional status (disability)
• Absenteeism (WP)
• Presenteeism (WP)
• Days of work missed
• Ability to manage ADL
NASH
1. Younossi ZM, et al. Hepatology. 2016;64(5):1577-1586; 2. Younossi ZM. Clin Gastroenterol Hepatol. 2017;15(8):1144-1147, 3. Younossi Z Hepatology. 2018 Aug 2
What are Different Types of Burden in NASH?
CI, confidence interval; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitisYounossi ZM. et al. Hepatology. 2016;64(1):73-84,
Anderson et al, PLOS One, 2015Argo CK, Caldwell SH. Clin Liver Dis. 2009;13(4):511-531, Schwimmer JB, et al. Pediatrics. 2006;118(4):1388-1393
The Global Epidemic of NAFLD and NASH in Adults
North America
24.1%
Europe
23.7% Asia
27.4%
Middle East
31.8%
South America 30.5%
Africa
13.5%
..
,
• Global prevalence of NAFLD is 25.2%
• Prevalence of NASH in general population is estimated between 1.5% and 6.5%
Prevalence of NAFLD is Higher in Males and Increases with Age
CI, confidence interval; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitisYounossi ZM. et al. Hepatology. 2016;64(1):73-84,
Anderson et al, PLOS One, 2015Argo CK, Caldwell SH. Clin Liver Dis. 2009;13(4):511-531, Schwimmer JB, et al. Pediatrics. 2006;118(4):1388-1393
The Global Epidemic of NAFLD and NASH in Children The Most serious Threat!
6.5% 5.9%
6.8%
5.7%
~25%
10%
..
,
Pre
vale
nc
e
of
NA
FL
D,
%
1.5
8.6 10.2
11.8
0
5
10
15
AfricanAmerican
White Asian Hispanic
NAFLD Prevalence in Children Age 2 to 19 Years per
Race/Ethnicity
• More common in Hispanic boys
• Pathology is different: Zone 1 or 3, Mainly portal,
Portal-periportal fibrosis, Rare ballooning
• Risks: family history, gestational diabetes, T2D
• Prevalence of NAFLD in US children is 2.6-17.3%
• Autopsy study from UCSD (N=742) - Prevalence: 9.6%, rates increasing with age
• Systematic review of 49,419 with diabetes in 22 countries
• Overall global NAFLD prevalence among diabetics is 55.5%
• Overall prevalence of NASH in biopsied diabetics is 67.3%
• Overall prevalence of advanced fibrosis (fibrosis ≥ F3) 17.2%
Younossi ZM. J of Hepatology. 2019
Golabi P, et al. Medicine. 2018;97(13):e0214; Younossi ZM, et al. Nat Rev Gastroenterol Hepatol. 2018;15(1):11-20; Ong JP, et al. Obes Surg. 2005;15(3):310-315;
Morita S, et al. Obes Surg. 2015;25(12):2335-2343; Praveenraj P, et al. Obes Surg. 2015;25(11):2078-2087; Younossi ZM et al. Hepatology. 2018 Sep 4. doi: 10.1002/hep.3025
NAFLD in People with Diabetes
Pre
vale
nce (
%)
0
5
10
15
20
25
30
35
40
USA
YOUNOSSI Z
2012
TURKEY
AKYUZ U
2015
KOREA
CHO HC
2016
KOREA
SINN DH
2012
KOREA
KIM HJ
2004
INDIA
DAS K
2010
CHINA
FAN J
2005
HK
WEI JL
2015
JAPAN
NISHIOJI K
2015
JAPAN
EGUCHI Y
2012
NAFLD in Lean Individuals
Disease Burden In Different Subgroups
F1 F2 F3 F4
Normal Non-NASH NASH
NASH with
Fibrosis
NASH with
Advanced
Fibrosis
2.3% per yr
Non-Cirrhotic HCC
Cirrhotic HCC
What Are The Potential Outcomes of NAFLD?
Younossi Z et al. Hepatology 2018, Younossi Z et al. Hepatology 2018, Younossi Z J of Hepatology 2019
0.529% per yr
NAFLD 25%
NASH 1.5% and 6.5%
The Most Common
Cause of Death
GENOTYPE • DNA Sequence ENVIRONMENT
• Diet
• Microbiome
• Xenobiotics
1 0 8 9 10
Fibrolysis Fibrogenesis
What are Some Predictors of Adverse Outcomes in NAFLD?
• Biopsy-proven NAFLD (N=289) with
59.2% biopsy-proven NASH
• After FU 150 months, NASH has
higher risk of liver-related mortality
than non-NASH (P=0.003)
Stepanova M, et al. Dig Dis Sci. 2013;58(10):3017-3023; Ong JP, et al. J Hepatol. 2008;49(4):608-612, Golabi P, Younossi Z, et al. Medicine (Baltimore). 2018;97(13):e0214; Dulai PS,
et al. Hepatology. 2017; Younossi ZM, et al. Hepatology. 2011.
• NHANES III NAFLD cohort (3,613) • Follow-up: December 31st, 2011
• NAFLD with all MS components associated
with overall, CV and liver mortality
• Lower survival with increasing components
of MS (p<0.001)
0.30 0.64
4.28 7.92
23.30
0
5
10
15
20
25
0 1 2 3 4
Mort
alit
y R
ate
(per
1,0
0 P
YF
)
Fibrosis Stage
• Systematic review to include
1495 NAFLD patients
providing 17,452 patient-
years of FU
Presence of NASH Denotes
Progressive Disease
Increasing Components of Metabolic
Syndrome Predicts Mortality
Stage of Fibrosis Predicts
Mortality
Worrisome Pattern and Future Predictions
The Global Burden of NASH
• NHANES 1988-1994 and 1999-2016
• 58,731 adult subjects with CLD
• Yearly trend analyses showed that the
only liver disease with consistently
increasing prevalence was NAFLD
(Kendall tau=0.64, P=0.0123)
• In contrast, a decreasing trend was noted
for CHC (tau=-0.42, p=0.07).
• Drivers of NAFLD: MVA showed that
after adjustment for age, gender, and
ethnicity, obesity – 10.4 (9.5 - 11.3),
T2DM – 3.7 (3.2 - 4.2), hypertension – 2.3
(2.1 - 2.5), hyperlipidemia - 1.8 (1.6 - 2.1))
are major independent predictors of
NAFLD.
The Epidemic of NAFLD is Growing The Changing Face of Chronic Liver Diseases in the United
States in the Past Three Decades
0%
20%
40%
60%
80%
100%
120%
140%
160%
180%
200%
1988-1994 1999-2004 2005-2008 2009-2012 2013-2016
rela
tive t
o 1
988
-1994
ALD CHB CHC NAFLD
Younossi Z et al. Clin Gastro and Hep 20111-587, Younossi Z 2019 (Submitted)
• US National Center for Health Statistics multiple-cause mortality
data
• Between 2007 and 2017 in the U.S, there were 28,132,187
reported deaths with 700,402 LD-related deaths
– Liver Causes of Death (ICD-9 codes)
– Complication of Liver Disease: 373,345 Cirrhosis; 101,132
HCC; 225,925 no cirrhosis or HCC
– Etiology of LD: 240,961 NAFLD; 197,815 ALD; 73,892 CH-
C; 6,375 CH-B; 19,110 other LDs, and 162,249 Unknown.
2007 to 2017 (APC)
Age-standardized-death-
rate-per-100,00
Age-standardized-years-of-
potential-life-lost-per-1000
LD severity 16.71 to 18.48 (1.13) 3.68 to 3.84 (0.63)
Cirrhosis 8.79 to 10.51 (1.99) 1.87 to 2.23 (1.99)
HCC 2.18 to 2.78 (1.93) 0.40 to 0.46 (1.08)
Etiology
NAFLD 5.61 to 6.42 (1.48) 1.11 to 1.18 (0.63)
ALD 4.50 to 5.96 (3.24) 1.16 to 1.54 (3.24)
CH-C 2.01 to 1.19 (-5.04) 0.48 to 0.25 (-6.30)
CH-B 0.23 to 0.13 (-5.35) 0.06 to 0.03 (-6.33)
1 Significantly increasing from 2007 to 2017 (P<.05) 2 Significantly decreasing from 2007 to 2017 (P<.05) 3 Significantly decreasing from 2007 to 2014 (P<.05) and faster
decreasing from 2014 to 2017 (P<.05)
Data markers denote observed rates; lines are fitted rates based
on joinpoint analysis.
Source: National Center for Health Statistics (2007-2017)
NAFLD Related Death is on the Rise Temporal Trends in Liver Deaths in the United States (2007-2017)
Paik J, Younossi ZM DDW 2019
• Markov model
– Incidence of NAFLD based on historical and
projected changes in prevalence of obesity and T2D
Cases of F3 due to NASH
Cases of F4 due to NASH
4.5 M
3.5 M 1.3 M
2 M
NAFLD
NASH
NASH with F3/F4
~25-30% of US Adult Population Have NAFLD
83.1 Million
16.5 Million
3.3 Million
Un
me
t N
ee
d
Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Hepatology. 2018 Jan;67(1):123-133.
Future Burden of NASH and Adverse Outcomes in the USA
20% of NAFLD is NASH
27% NAFLD will be NASH
2015 2030
By 2030, there are projected to be
nearly 800,000 excess liver deaths
21.6% 22.9%
25.4%
22.9% 21.9%
17.6% 17.9%
23.6%
26.4%
29.5%
27.6%
24.7%
22.2%
18.8%
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
FRANCE GERMANY ITALY SPAIN UK CHINA JAPAN
PR
EV
EL
AN
CE
OF
NA
FL
D
3.6% 4.1%
4.4% 3.9%
4.1%
2.4% 3.0%
5.0% 6.0% 6.3%
5.9% 5.5%
3.4% 3.6%
0.0%
2.0%
4.0%
6.0%
8.0%
FRANCE GERMANY ITALY SPAIN UK CHINA JAPAN
2016 2030
PR
EV
EL
AN
CE
OF
N
AS
H
Future Burden of NAFLD NASH in Europe and Asia: Prevalence
Estimated number with
NAFLD in the USA and
EU: 155.4 million1, 2
Estimated number with
NASH in the USA and
EU: 28.9 million1,2
Estimated number of
F3/F4 fibrosis due to
NASH in the USA and
EU: 5.8 million1,2
1. Estes C, et al. Hepatology 2018;67:123–33 ;
2. Razavi H, et al. Disease Burden Report for Europe 2017
Number of Patients with NAFLD, NASH and Advanced
Fibrosis in USA and EU
Estes et al. J Hepatol 2018;69:896
Future Burden of NASH in Europe and Asia: Adverse Outcomes
Chronic kidney disease
Gallstone disease
Polycystic ovary syndrome
Cerebrovascular disease
Cardiac disease
Vascular disease
Obstructive sleep apnea
Diabetes
Malignancy
Osteoarthritis
NAFLD
Non-Hepatic Diseases Associated with NAFLD
COD, cause of death; CVD, cardiovascular disease; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; SS, simple steatosis
Angulo P, et al. Gastroenterology. 2015;149(2):389-397; Söderberg C, et al. Hepatology. 2010;51(2):595-602; Ekstedt M, et al. Hepatology. 2006;44(4):865-873; Dam-Larsen S, et al. Scand J Gastroenterol. 2009;44(10):1236-1243; Rafiq N, et al. Clin Gastroenterol Hepatol. 2009;7(2):234-238, Hicks. AASLD 2018. Abstr 31
Author N FU (yr)
CVD Death
Findings
Angulo, 2015 619 12.6
38.3% CVD most common COD Fibrosis predicts death
Söderberg, 2010 118 24 30% Death in NASH,
CVD most common COD
Ekstedt, 2006 129 13.
7 16%
CVD death NASH
CVD most common COD in NASH but no SS
Dam-Larsen, 2009 170 20.4
38% No difference between
SS and control
Rafiq, 2009 173 18.5
12.7% CVD most common COD
Patient Characteristic
NAFLD (n=3869)
Control (n=15,209)
Fold Increase
Median age, yrs 53 NR
Women, % 52 NR
Diagnosed with malignancy, n (%)
580 (15) 1521 (10)
Site of malignancy,
incidence/100,000 PY
• Liver
• Stomach
• Pancreas • Lung
26.8
9.8
19.6 34.1
6.6
2.8
7.2 16.9
4
3.5
2.7 2
Younossi ZM et al. Liver Int. 2017; 37(8):1209-1218, Younossi Z et al Liver Int 2018, Younossi Z Clinical Gastro and Hepatology 2019
• NASH with Stage 2–3 fibrosis (N=72):
NASH with Advanced Fibrosis Have Impaired Patient Reported
Outcomes
40
50
60
70
80
90
100
Mean P
RO
score
, 0-1
00 s
cale
Cirrhosis Bridging fibrosis population norm
p<0.05 b/w cirrhosis and bridging fibrosis
• Biopsy proven NASH (N=1667 from STELLAR with PROs
• Economic models to assess burden of
NAFLD using interlinked Markov chains
– Over 64 million people with NAFLD, with
annual direct medical costs of about $103
billion
• Economic burden of NASH
– Markov models (prevalence
and incidence)
– 6.65 million adults with NASH in the and 232
thousand incident cases in the U.S. (2017).
– In the U.S., there are 688 thousand cases of
advanced NASH
– Lifetime direct costs of all NASH will be
$222.6 billion
– Lifetime direct costs of the advanced NASH
population will be $95.4 billion.
Markov Model Structure
HCC LT
PLT
Death
F0 F1 F2 F3 CC DCC
Younossi ZM, et al. Hepatology. 2016;64(5):1577-1586; Younossi ZM, et al. Hepatology. 2018 Sep 4. doi: 10.1002/hep.30254. [Epub ahead of print
NASH with Advanced Fibrosis Have Significant Economic Burden
NASH Patients with Advanced Fibrosis have the Profound Economic Impact
• To address increased CV mortality risk all NAFLD subjects are
candidates for life style modification and treatment of metabolic risk
factors
• To address the increased risk of liver-related mortality, NASH
subjects should be considered treatment candidates
• NASH patients with advanced fibrosis are at most urgent need for
treatment
• How to identify and stage NASH?
• What is the current evidence for treatment of NASH?
Non-alcoholic Steatohepatitis (NASH) Treatment Candidates
NAFLD Sensitivity Specificity
Liver Enzymes
• ALT 45% 85%
• GGT1 63% 65%
Ultrasound2 85% 94%
• Any degree3 61% 100%
• Cutoff ≥ 20%3 CT without contrast4 100% 90%
• Cutoff > 30% 79% 97%
MRI5
• Cutoff PDFF 6.4%, grade ≥1 86% 83%
• Cutoff PDFF 17.4%, grade ≥2 64% 96%
Spectroscopy ~100% ~100%
Liver Biopsy 98% to 100% 100%
1. Alam S, et al. Bangabandhu Sheikh Mujib Med Univ J. 2015;8(1):61-67; 2. Hernaez R, et al. Hepatology. 2011;54(3):1082-1090; 3. Dasarathy S, et al. J Hepatol. 2009;51(6):1061-1067; 4. Rogier J, et al. Liver Transpl. 2015;21(5):690-695; 5. Tang A, et al. Radiology. 2015;274(2):416-425. Younossi ZM, Hepatology. 2017 6. Wong VW et al. Nat Rev Gastroenterol Hepatol 2018;15:461
Diagnostic Tests for NAFLD
Diagnostic Tests for NASH
Wong VW et al. Nat Rev Gastroenterol Hepatol 2018;15:461
NASH Study AUROC AUROC
NASH
• Feldstein, et al. CK-18
• Feldstein, et al. CK-18, sFasL
• Feldstein, et al. oxNASH (13-HODE/LA, age, BMI, AST)
• Younossi, et al. NASH diagnostics
• Poynard, et al. NASH test
• Palekar, et al. HA + clinical
• Loomba, et al. Lipidomic
0.83
0.93
0.83
0.98
0.79
0.76
1.00
0.82
0.79
N/A
0.72
0.78
N/A
N/A
Liver Biopsy
FIB-4
Score
Parameter
Age, years
AST
ALT
Platelet count, cells x 109
BMI
Albumin, g/L
Impaired fasting glucose/DM?
NFS Cutoff
Value1 Stage
<-1.455 F0−F2
-1.455 to 0.676 Indeterminate
>0.676 F3−F4
FIB-4 Cutoff
Value2 Stage
<1.45 F0−F2
1.45 to 3.25 Indeterminate
>3.25 F3−F4
NAFLD Fibrosis Score
APRI: The lower the APRI score (<0.5), the
greater the NPV (and ability to rule
out cirrhosis) and the higher the
value (>1.5) the greater the PPV
(and ability to rule in cirrhosis
1. Angulo P, et al. Hepatology. 2007;45(8):846-854; 2. Sterling RK, et al. Hepatology. 2006;43(6):1317-1325.
Noninvasive Diagnosis of Liver Fibrosis Commonly Used Fibrosis Scores
Technique Visualize liver
Transient
elastography (TE) US
• Liver stiffness expressed in kPa; correlates with liver
fibrosis stage
• Controlled Attenuation Parameter (CAP™) expressed
in dB/meter
• Accurate in detecting advanced fibrosis
• Predicts risk of decompensation
• Correlates well with portal pressure
• Most widely used
Acoustic radiation
force impulse
(ARFI)
US • Employs high intensity acoustic beam to mechanically
excite tissue and monitor tissue displacement response
• No need for an external compression
• Degree of displacement is interpreted into degree of
lightness and darkness
Shear wave
elastography
(SWE)
US • Shear waves are generated from acoustic pulses
forced at five different tissue depth levels and SW
velocity estimated by ultrafast Doppler-like acquisition
of 5,000 frames/sec.
• SW is converted to tissue stiffness as kilopascals
Magnetic
resonance
elastography
(MRE)
MR • Most accurate of the imaging modalities
• Costly, no point-of-care access
• MRI Methods to Estimate Proton Density Fat Fraction
• MRI-PDFF shown to have high correlation to
morphometric fat3
<[VALU
E] 7.25 7.00
9.90 8.75 8.70
0
1
2
3
4
5
6
7
8
9
10
United States Europe France and HongKong
Fibrosis Severity
Median LSM
(range)
Without F3-F4
fibrosis
6.6 kPa
(5.3-8.9)
With F3-F4
fibrosis
14.4 kPa
(12.1-
24.3)
Noninvasive Diagnosis of Liver Fibrosis Radiologic Tests To Measure Liver Stiffness or Elasticity
Median Values
F0 6.93 kPa
F1 7.7 kPa
F2 9.6 kPa
F3 13.95 kPa
F4 23.73 kPa
Stiffness cutoff: 3.63 kPa
- Sensitivity 0.86
- Specificity 0.91
AUC for advanced fibrosis:
0.924
F1 – 1.24 m/s F2 – 1.48 m/s F3 – 1.61 m/s F4 – 1.75 m/s
MRI More Accurate Than Transient Elastography in
Steatosis and Liver Fibrosis • 142 patients with NAFLD (biopsy-proven; BMI 28.1 kg/m2)
• FIB-4 had the highest diagnostic performance to assess
liver fibrosis
• In Japanese patients with NAFLD, MRE had higher diagnostic
accuracy for fibrosis relative to scoring systems and TE
• MRI-PDFF was superior to CAP for steatosis grade
CAP, controlled attenuation parameter; TE, transient elastography. Imajo K, et al. Gastroenterology. 2016;150(3):626-637.
0.80 0.89 0.89
0.97
0.78 0.82 0.88 0.92
0.0
0.2
0.4
0.6
0.8
1.0
1.2
≥1 ≥2 ≥3 ≥4
MRE TE
AU
RO
C
MRE vs TE for Identification of Fibrosis Stagea
0.96 0.90
0.79 0.88
0.73 0.70
0.0
0.2
0.4
0.6
0.8
1.0
1.2
≥1 ≥2 ≥3
MRI-PDFF CAP
AU
RO
C
MRI-PDFF vs CAP for Detection of Steatosis Gradea
MRE
SWE
VCTE/fibroscan
Accu
rac
y
Accessib
ility
Evaluate alcohol consumption
Exclude alternative causes of ALT
Confirmation of NAFLD
Noninvasive risk stratification
Suspected NAFLD Hepatic steatosis on imaging with elevated serum ALT
If noninvasive profile indeterminate, obtain liver biopsy and combine results with noninvasive tests
Intermediate-risk profile •BMI >29.9 •Some metabolic syndrome features •FIB4 <3, APRI <1.5, NFS -1.454-0.676 •Elevated ALT •Fibroscan® 7-10 kPa •Possibly NASH with <F3
High-risk profile •Age >50 years •T2DM •FIB4 >3, APRI >1.5, NFS>0.676 •Elevated ALT •Fibroscan® >10 kPa •Most likely F3-F4 •Consider biopsy if clinical trials
Low-risk profile •BMI <29.9 •Age <40 years •Absent T2DM or metabolic syndrome •Low FIB4, APRI, and NFS •Normal or elevated ALT •Fibroscan® <6 kPa •Most likely steatosis only
NASH
Multi-prong Approach to
Manage Obesity Public Health
Interventions
Integrated Treatment Strategies for NAFLD and NASH
Therapeutic Targets:
• Improving Hepatic
Metabolism
• Improving insulin
sensitivity
• Improving
inflammation
• Improving fibrosis
Patient Target:
• NASH
• NASH with
Advanced
Fibrosis
NASH
Multi-prong Approach to
Manage Obesity Public Health
Interventions
Integrated Treatment Strategies for NAFLD and NASH
Current Therapeutic
Options:
• Weight loss with diet
• Exercise
• Weight loss procedures
• Currently available
medications
Patient Target:
• NASH
• NASH with
Advanced
Fibrosis
aAt least one stage.
N=293 patients with NASH were encouraged to adopt lifestyle changes for weight loss over 52 weeks.
1. Romero-Gómez M, et al. J Hepatology. 2017;67:829–846; 2. Chalasani N, et al. Hepatology. 2018;67(1):328-357.3. Cochrane Database Syst Rev. 2011 Jun 15;(6)
Current Management of NAFLD and NASH Weight Loss: Success and Impact on Fibrosis
• Weight loss
– 3%-5% to improve steatosis, but 7%-10%
to improve the majority of the histologic
features of NASH, including fibrosis
• Sustainability of weight loss:
– Seven trials, total of 373 patients
underwent weight loss programs 1 month
to 1 year
– 15% with “success”, most of these regain
weight.
– No strong evidence of sustained benefit.
• Bariatric surgery and endoscopy
% Weight Loss (WL)
NASH Resolution 10% 26% 64% 90%
Fibrosis Regressiona 45% 38% 50% 81%
Steatosis Improvement 35% 65% 76% 100%
% Patients Achieving WL 70% 12% 9% 10%
5% 7% 10%
Mean weight loss (%)
52 weeks of lifestyle intervention
Probability of improving NASH components
according to weight loss1,2
AASLD Guidance 2018
Weight Loss and Exercise
Weight loss can be effective but hard to achieve and
sustain
Exercise alone may prevent or reduce steatosis, but its ability
to improve other aspects of liver histology remains unknown
MRE-PDFF Pre- and Post-IGB Placement
Current Management of NASH Bariatric Procedures
Post-Bariatric
• NASH (N=21) treated endoscopically with Orbera™
Intragastric Balloon (Apollo Endosurgery, Austin, TX)
• EUS-liver biopsy and MRE at the time of placement
and removal
• Total body weight loss 12.8% (0–32.5)
• NAS ≥2 improvement 73%
• Fibrosis improved in 20%
• MRE and PDFF improved 3 (severe) 1 (mild)
2 (moderate) No NASH
Brunt inflammatory
score
0%
20%
40%
60%
80%
100%
Baseline 1 year 5 years
p˂0.001 ns
Biopsies courtesy of Dr. Prithi Bhathal 2011; EUS, endoscopic ultrasound; IGB, intragastric balloon; MRE, magnetic resonance elastography; NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD
Activity Score; NASH, non-alcoholic steatohepatitis; PDFF, proton density fat fraction
Froylich D, et al. Surg Obes Relat Dis. 2016;12(1):127-131; Lassailly G, et al. EASL 2018, Paris, France. #FRI-484; Dixon JB, et al. Obes Surg. 2006;16(10):1278-1286; Bazerbachi F, et al.
DDW 2018. Washington DC, USA. Abstract 795
Pre-Bariatric
• Caspase inhibitors • Ursodeoxycholic acid • Anti-obesity medications • Betaine • N-Acetyl-cysteine • Lecithin • Silymarin • Beta-carotene • Omega 3 Fatty Acid (Pufa, ‘Fish Oil’) • Anti-TNF agents (Pentoxifylline) • ACE inhibitors/ARBs • Metformin • Probiotics (VSL#3) • Lipid Lowering agents (statins)
• GLP-1 Agonist
• SGL2 Inhibitors
• Pioglitazone
• Vitamin E
Current Evidence Does not Support Efficacy
for Treating NASH
Products of Significant Interest but
Evidence is not Available
Not FDA Approved but AASLD
Guidance Supports Use
Pharmacologic Treatment for NAFLD and NASH Currently, No Approved Drug!
Authors N Dose Comparators Outcomes
Arendt 80 1000 IU/d Placebo Improved steatosis (assessed by CT scan)
vs placebo
Sanyal 247 800 IU/d Pioglitazone,
placebo Improved steatosis, inflammation, and
ballooning vs placebo
Lavine 173 800 IU/d Metformin,
placebo Improved steatohepatitis and ballooning vs
placebo
Harrison 45 1000 IU/d Placebo Improved fibrosis vs baseline
Sanyal 20 400 IU/d Vitamin E +
pioglitazone Improved steatosis vs baseline
Dufour 48 800 IU/d UDCA +
placebo Improved steatosis, inflammation, and
ballooning vs baseline
Current Management of NASH Vitamin E
• AASLD Guidance document:
• Vitamin E: At 800 IU/day improves histology in nondiabetic with NASH
• Risks and benefits should be discussed
• Not recommended for NASH in diabetic patients, NAFLD without a liver biopsy,
NASH cirrhosis, or cryptogenic cirrhosis
Current Management of NASH PPAR-γ Agonist
Author N Drug Time
DM
?
Cirrhosi
s
AL
T Fat
Ba
l Infl Fibrosis
Caldwell
2001
10 Troglit
400 mg 3-6
months 1/10 Yes
Ye
s ? No
?Ye
s No
Promrat
2004
18 Pio
30 mg
12
No No Ye
s Yes
Ye
s Yes Yes
Aithal
2008
7
4
Pio
30 mg 12 mo No Yes
Ye
s Yes
Ye
s Yes Yes
Belfort
2006
5
5
Pio
45 mg 6 mo Yes No
Ye
s Yes
Ye
s Yes ---
Ratziu
2008
6
3
Rosi
8 mg 12 mo Yes No
Ye
s Yes --- --- ---
Sanyal
2010
2
4
7
Pio
30 mg 96 wk No No
Ye
s Yes --- Yes ---
Mahady
2011* n/a n/a n/a n/a Yes
Musso G, et al. JAMA Intern Med. 2017;177(5):633-640;
Cusi K. Gastroenterology. 2012;142(4):711-725.
Study or
Subgroup Weight, % Odds Ratio M-H, Random, 95% CI
Aithal et al,
2009 13.2
7.49 (0.37-
151.50)
Belfort et al,
2006 14.0
16.54 (0.89-
308.98)
Cusi et al,
2016 13.8
9.97 (0.52-
190.16)
Sanyal et al,
2004 14.0
1.00 (0.05-
18.57)
Sanyal et al,
2010 45.0
3.28 (0.64-
16.78)
Total (95%
CI) 100.0
4.53 (1.52-
13.52)
0.01 0.1 1 10 100
RCT, randomized controlled trial.
Heterogeneity: Tau2=0.00; Chi2=2.39, df=4 (P=0.66); I2=0%.
Test for overall effect: z=2.72 (P=0.007).
Current Management of NASH Pioglitazone in NASH
N=101 NASH with prediabetes or T2DM. All participants were
placed on a 500 kcal/d deficit diet and randomized to placebo or
pioglitazone
30 mg/day (titrated to 45 mg/d after 2 months) for 18 months.
Cusi K, et al. Ann Intern Med. 2016;165(5):305-315.
• Potential AEs: bone loss, diastolic dysfunction, weight gain?
• Pioglitazone-AASLD 2018 – Pioglitazone improves liver histology in patients with and without T2DM with biopsy-
proven NASH
– Risks and benefits should be discussed with each patient
– Should not be used for NAFLD without biopsy-proven NASH
Current Management of NASH Lipid Lowering Agents
• Patients with NAFLD or NASH are not at higher risk for serious liver injury from statins
• Statins can be used to treat dyslipidemia in patients with NAFLD and NASH
• While statins may be used in patients with NASH cirrhosis, they should be avoided in
patients with decompensated cirrhosis
• No indication for treatment of NASH AASLD Guidance 2018
NASH
Multi-prong Approach to
Manage Obesity Public Health
Interventions
Integrated Treatment Strategies for NAFLD and NASH
Therapeutic Targets:
• Improving Hepatic
Metabolism
• Improving insulin
sensitivity
• Improving
inflammation
• Improving fibrosis
Patient Target:
• NASH
• NASH with
Advanced
Fibrosis
Treatment Targets: Remember the Pathophysiology of NASH Multi-Step Promoters of NASH and Fibrosis Progression
DAMP, danger-associated molecular patterns; ECM, extracellular matrix; IL-1β, interleukin-1beta; PAMP, pathogen-associated molecular patterns; PDGF, platelet-derived growth factor;
TGF-β, transforming growth factor beta; TNF, tumor necrosis factor; TNF-β, tumor necrosis factor-beta.
Benedict M, Zhang X. World J Hepatol. 2017;9(16):715-732; Bedossa P. Liver Int. 2017;37(suppl 1):85-89; Younossi ZM, et al. Hepatology. 2011;53(6):1874-1882.
Bacterial
translocation
(endotoxins)
DAMPs
Kupffer cells
Inflammatory
macrophages
PAMPs
Secondary
Inflammation
and Injury
IL-1ß
TNF
Inflammatory
monocytes
Maturation
Oxidative Stress
Inflammatory Mechanisms
ECM
deposition
(collagen
formation)
Activation/
trans-
differentiation
Hepatic
stellate cells
Activated
myofibroblast Activated
myofibroblasts
Scar
formation/
Fibrosis TGF-ß
PDGF Proliferation
Fibrosis
Endothelial Cell
Dysfunction
Fat accumulation
preceeds injury
Hepatocyte
Visceral Adiposity Insulin
Resistance
Dysbiosis
TARGETS RELATED TO
INSULIN RESISTANCE AND/OR LIPID METABOLISM
TARGETS RELATED TO
LIPOTOXICITY & OXIDATIVE
STRESS
TARGETS RELATED TO
INFLAMMATION AND IMMUNE ACTIVATION
TARGETS RELATED TO CELL DEATH
(APOPTOSIS AND NECROSIS)
TARGETS RELATED TO
FIBROGENESIS & COLLAGEN TURNOVER
PPARγ: Pioglitazone PPARα/∂: Elafibranor
GLP-1: Liraglutide PPARα/∂/γ: IVA337
Semaglutide PPARα/γ: Saroglitazar
MPCi: PXL065 THRβ: MGL-3196
SGLT1/2: LIK066 mTOT: MSDC-0602K
GLP-1/GR: MEDI0382 FXR: OCA,GS-9674,
KHKi: PF-06835919 LIN-452,LMB-763
ACCi: GS-0976, TGR5: INT-767,INT-777
PF-05221304 ASBT: Volixibat
DGAT2i: PF-06865571 FGF19: NGM282
SCD1: Aramchol AMPKi: PXL770
FGF21: BMS-986036 Vitamin E
CCR2/5: Cenicriviroc AOC3: BI 1467335 TLR4: JKB-121 Anti-LPS: IMM-124E
ASK1: Selonsertib Caspases: Emricasan
LOXL2: Simtuzumab Galectin: GR-MD-02
Normal Liver Steatosis without NASH NASH Cirrhosis
Some of New Targets for Treatment of NASH
Regimens in Development for Treatment of NASH
• Many drugs under
evaluation for treatment
of NASH
– >85 clinical trials
(active or planned)
– 4 Phase 3 Clinical Trials
PHASE 2
PHASE 3
MARKETED
U.S. National Institutes of Health. ClinicalTrials.gov. Accessed June 11, 2018:
1. https://clinicaltrials.gov/ct2/show/NCT03028740. Last updated February 13, 2018; 2. https://clinicaltrials.gov/ct2/show/NCT02704403. Last updated
May 14, 2018; 3. https://clinicaltrials.gov/ct2/show/NCT02548351. Last updated May 28, 2018; 4. https://clinicaltrials.gov/ct2/show/NCT03439254. Last
updated May 24, 2018; 5. https://clinicaltrials.gov/ct2/show/NCT03053050. Last updated May 14, 2018;
6. https://clinicaltrials.gov/ct2/show/NCT03053063. Last updated February 26, 2018.
Cenicriviroc (CCR2/CCR5)1
Elafibranor (PPARα/σ)2
Obeticholic acid (FXR)3,4
Selonsertib (ASK-1)5,6
17 12
23
13
21 19
0
10
20
30
40
50
Protocol-defined primary end point Updated definition
Placebo (n=92) Elafibranor 80 mg (n=93) Elafibranor 120 mg (n=89)
GOLDEN 505-Peroxisome Proliferator-Activated Receptors (PPAR α/δ Pathways) Elafibranor
Pa
tie
nts
, %
OR (95% CI) 1.53 (0.70–3.34), P=0.28
OR (95% CI) 2.31 (1.02–5.24), P=0.045
aP<0.05 vs placebo; bP<0.01 vs placebo; *Resolution of NASH without worsening of fibrosis at EOS; **More stringent definition of resolution of NASH recommended by regulatory agencies; ***NASH
confirmed by biopsy ≤6 months before randomization. N=276 (n=274 ITT) patients aged 18–75 with a histologic diagnosis of noncirrhotic NASH were randomized to placebo, elafibranor 80 mg, and
elafibranor 120 mg for 1 year. CI, confidence interval; EOS, end of study; ITT, intention-to-treat; NASH, non-alcoholic steatohepatitis; OR, odds ratio; PPAR, peroxisome proliferator-activated receptor
Ratziu V, et al. Gastroenterology. 2016;150(5):1147-1159; ClinicalTrials.gov. NCT02704403. https://clinicaltrials.gov/ct2/show/NCT02704403
Elafibranor 120 mg
Placebo
Interim analysis
2022 patients with F2-3
202 patients with F1;
All with biopsy-
confirmed NASH
Screen*** 0 Week 18 Week 48 EOS
Study Period (Months)
= biopsy
* **
RESOLVE-IT: Long-Term Evaluation of Elafibranor for NASH
19
16
0
5
10
15
20
25
≥2-Point Improvement in NAS AND No Worsening of Fibrosis
Placebo CVC
Su
bje
cts
, %
N=144
P=0.519
6
10 [VALUE]
20
0
5
10
15
20
25
Complete Resolution of NASHAND No Worsening of
Fibrosis
Improvement in FibrosisStage AND No Worsening of
NASH
Placebo CVC
P=0.494
P=0.023
N=145
Cenicriviroc: CENTAUR and NASH-AURORA studies
86% of patients with baseline F3 who improved maintained benefit at year 2
30
17
3
60
15 11
0
20
40
60
80
≥1 stage fibrosis improvement
≥1 stages fibrosis improvement AND No Worsening of Fibrosis
≥2 stage fibrosis improvement AND No Worsening of Fibrosis
Placebo CVC
Year 1 Results Year 2 Results
N=242 patients with NASH continued to year 2. Patients underwent biopsies at baseline, year 1, and year 2 to assess fibrosis, NASH, and NAS
CVC, cenicriviroc; NASH, non-alcoholic steatohepatitis; NAS, NAFLD Activity Score; QD, once daily
Ratziu V, et al. ILC. April 11-15, 2018. Paris, France. Abstract GS-002; Friedman SL, et al. Hepatology. 2018;67(5):1754-1767; ClinicalTrials.gov. NCT03028740.
https://clinicaltrials.gov/ct2/show/NCT03028740
Biopsy at
Month 12
Placebo QD
CVC 150 mg QD
Placebo QD
CVC 150 mg QD
Screening
Biopsy
Biopsy at
Month 60
NASH-AURORA Study Primary Endpoint at Year 1: improvement in fibrosis AND no worsening of NASH (N 1000)
0
20
40
60
80
Histologicalimprovement
Resolutionof NASH
Improvement infibrosis
Improvement inhepatocyteballooning
Improvements insteatosis
Improvement inlobular inflammation
Obeticholic acid Placebo
Pa
tie
nts
, %
Obeticholic Acid: FLINT and
REGENERATE Studies Improvements in Histology over 72 Weeks
a b,c
a d b d
aP≤0.001; bP<0.05; cResolution of NASH defined as not NAFLD or NAFLD but not NASH; dP<0.01; N=219 adult patients with biopsy-confirmed NASH or borderline NASH and histological NAS of ≥4
were randomized to receive oral obeticholic acid 25 mg once daily or placebo for 72 weeks
NASH, non-alcoholic steatohepatitis; QD, once daily
Neuschwander-Tetri BA, et al. Lancet. 2015;385(9972):956-965
Primary: improvement in fibrosis (with no worsening of NASH) or resolution of
NASHa (with no worsening of fibrosis) at 18 months
Secondary: time to event analysis of composite outcome events at study end
N≈2,400
Biopsy-confirmed NASH
Primarily F2/F3
F1 (≤10%) also evaluated
Obeticholic acid 10 mg QD
Obeticholic acid 25 mg QD
Placebo QD (n=92)
Outcomes Interventions Patients
REGENERATE
Obeticholic Acid: REGENERATE Press Release
Adverse events were generally mild to moderate in severity and the most common
were consistent with the known profile of OCA. • The frequency of serious adverse events was similar across treatment arms (11% in placebo,
11% in OCA 10 mg and 14% in OCA 25 mg) and no SAE occurred in >1% in any treatment arm.
• There were 3 deaths in the study (2 in placebo: bone cancer and cardiac arrest, 1 in OCA 25 mg:
glioblastoma) and none were considered related to treatment.
• The most common adverse event reported was dose-related pruritus (19% in placebo, 28% in
OCA 10 mg and 51% in OCA 25 mg). The large majority of pruritus events were mild to
moderate, with severe pruritus occurring in a small number of patients (<1% in placebo, <1% in
OCA 10 mg and 5% in OCA 25 mg).
• A higher incidence of pruritus associated treatment discontinuation was observed for
OCA 25 mg (<1% in placebo, <1% in OCA 10 mg and 9% in OCA 25 mg). According to the
clinical study protocol, investigator assessed severe pruritus mandated treatment
discontinuation.
• Consistent with observations from previous NASH studies, OCA treatment was associated with
an increase in LDL cholesterol, with a peak increase of 22.6 mg/dL at 4 weeks and
subsequently reversing and approaching baseline at month 18 (4.0 mg/dL increase from
baseline). Triglycerides rapidly and continually decreased in the OCA treatment arms through
month 18.
• There were few and varied serious cardiovascular events and incidence was balanced across the
three treatment arms (2% in placebo, 1% in OCA 10 mg and 2% in OCA 25 mg).
• With respect to hepatobiliary events, more patients (3%) on OCA 25 mg experienced gallstones
or cholecystitis compared to <1% on placebo and 1% on OCA 10 mg.
• While numerically higher in the OCA 25 mg treatment arm, serious hepatic adverse events were
uncommon with <1% incidence in each of the three treatment arms.
http://ir.interceptpharma.com/press-releases. February 19, 2019
Selonsertib: Phase 2 and 3 Clinical Trials
Fibrosis Improvement (≥1 stage from baseline)
Progression to Cirrhosis
43
30 20
0
20
40
60
Selonsertib18 mg±SIM
Selonsertib6 mg±SIM
Simtuzumab
13/30 8/27
2/10
Su
bje
cts
, %
3 7
20
0
10
20
30
Selonsertib18 mg±SIM
Selonsertib6 mg±SIM
Simtuzumab
1/30 2/27
2/10
N=72 patients 18–70 years of age who had either F2 or F3 confirmed by biopsy and at least 3 features of metabolic syndrome were randomized to 6 mg or 18 mg of SEL alone, 6 mg or
18 mg of SEL + SIM, or 125 mg of SIM for 24 weeks
NASH, non-alcoholic steatohepatitis; QD, once daily; SEL, selonsertib; SIM, simzutumab
Loomba R, et al. Hepatology. 2018;67(2):549-559
Histologic Analysis Clinical Efficacy
Endpoint
Liver Biopsy
SEL 18 mg QD
SEL 6 mg QD
Placebo QD
Week 0 Year 5 Week 48
• Double-blind, randomized, placebo-controlled,
Phase 3 trials (N=800 each)
• Key inclusion criteria
– Histologic evidence of NASH and NASH CRN F3/F4
fibrosis
• Primary histologic endpoint
– ≥1 stage improvement in fibrosis without worsening of
NASH
STELLAR-3 (F3) and STELLAR-4 (F4) STELLAR-4 Press Release:
“In the study of 877 enrolled patients who
received study drug, 14.4 percent of patients
treated with selonsertib 18 mg (p=0.56 vs.
placebo) and 12.5 percent of patients treated
with selonsertib 6 mg (p=1.00) achieved a ≥ 1-
stage improvement in fibrosis according to the
NASH Clinical Research Network (CRN)
classification without worsening of NASH after 48
weeks of treatment, compared with 12.8 percent
of patients who received placebo. Selonsertib
was generally well-tolerated and safety results
were consistent with prior studies.”
https://www.businesswire.com/news/home/20190211005738/en/ Febuary 11,
2019
Insulin Sensitivity Hepatic Fibrosis and Inflammation Hepatic Metabolism
Agent Proposed mechanism of
action Agent Proposed mechanism of action Agent Proposed mechanism of action
Lanifibranor
Improved lipid/glucose
metabolism;
anti-inflammatory (PPAR
α/δ pathways)
Emricasan Prevention of caspase activation and
apoptosis (caspase inhibitor) Aramchol
Inhibition of monosaturated fatty
acid synthesis (SCD-1 inhibitor)
MSDC-0602K
Mitochondrial
metabolism and FA
oxidation (mTOT
activator)
GR-MD-02 Inhibition of fibrosis pathways
(Galectin-3 inhibitor) BMS986036
Improvement of lipid/glucose
metabolism; anti-inflammatory
(FGF21 analog)
Saroglitazar
Improved lipid/glucose
metabolism;
anti-inflammatory (PPAR
α/γ pathways)
EDP 305 Regulation of hepatic glucose/lipid
metabolism (FXR agonist) NGM282
Improvement of lipid/glucose
metabolism;
anti-inflammatory (FGF19
analog)
Semaglutide
Improved lipid/glucose
metabolism;
weight loss (GLP-1RA)
GS 9674 Regulation of hepatic glucose/lipid
metabolism (FXR agonist) BI1467335
Amine oxidase/RNAi inhibitor
(VAP-1inhibitor)
Tropifexor Regulation of hepatic glucose/lipid
metabolism (FXR agonist) GS-0976
Inhibition of hepatic de novo
lipogenesis (ACC inhibitor)
Volixbat Inhibition of bile uptake (IBAT inhibitor) IMM-124E Immunomodulation of gut LPS-
related inflammation (anti-LPS)
Simtuzumab Inhibit fibrogenesis by preventing
collagen cross-linkage (anti-LOXL2) MGL-3196
Reduction of hep lipid synthesis
(THR β-selective agonist)
VK2809 Reduction of hep lipid synthesis
(THR β-selective agonist)
Early Phase Clinical Trials in NASH
9/23 14/23 2/23 7/23
aP≤0.05
Armstrong MJ, et al. Lancet. 2016;387(10019):679-690; Dhir G, Cusi K. J
Investig Med. 2018;66(1):7-10.
Current Management of NASH Liraglutide (GLP-1 Agonists): LEAN
Longitudinal Pattern of Weight
Loss with GLP1 Agonists
83% of patients had weight loss >5%
Newsome P, et al. AASLD 2018, San Francisco, USA. #105
19/50 23/54 21/46
Change in body weight
ALT normalization at Week 52
-6.0
-8.6
-11.6 -11.2
-13.8
-2.3
-20.0
-15.0
-10.0
-5.0
0.0
0.05mg 0.1 mg0.2 mg0.3 mg0.4 mg PBO
Esti
mat
ed m
ean
red
uct
ion
in
bo
dy
wei
ght
to W
eek
52
(%
)
29 25
38 43 46
18
0
20
40
60
80
100
0.05 mg 0.1 mg 0.2 mg 0.3 mg 0.4 mg PBO
Pro
port
ion w
ith n
orm
al A
LT
at
EO
T (
%)
14/76
Effect of semaglutide on liver enzymes in subjects with obesity
and elevated ALT: Data from a randomized Phase 2 trial
Mean ALT ratio: BL to Week 52 Mean ALT ratio: BL to Week 52
Adjusted for weight change
Oral semaglutide: • 44% wt loss >5%
• 2-7% drug D/C due to AEs
• 80% achieve A1c <7%
Diabetes 2018 Jul; 67(Supplement 1)
Lancet vol 392, 10148, p637-649, Aug 2018.
• Semaglutide improves ALT
– Improvement seems to be associated with weight loss
– Histology based studies are ongoing
• GLP-1RAs-AASLD 2018
• It is premature to consider GLP-1 agonists to specifically treat liver disease in patients
with NAFLD or NASH
Mechanism of Action Disease Process/
Pathway Target(s)
ASK1 inhibitor (selonsertib)
and non-steroidal FXR agonist
(GS-9674) and/or ACC inhibitor
(GS-0976)1
Inflammation, fibrosis,
and lipogenesis
Combined PPAR alpha and delta
agonist (elafibranor) and an FXR
agonist2
Inflammation, fibrosis, and
lipogenesis
Chemokine CCR2/CCR5 receptor
blocker (cenicriviroc) in
combination with a FXR agonist3,4
Inflammatory and fibrosis
Targeting Multiple Pathways Combinations with Complementary Mechanisms of Action
ACC, acetyl-CoA carboxylase; ASK-1, apoptosis signal-regulating kinase 1; CCR, chemokine (C-C motif) receptor; FXR, farnesoid X receptor; MRI-PDFF; magnetic resonance imaging proton density
fat fraction; NASH, non-alcoholic steatohepatitis; PPAR, peroxisome proliferator-activated receptor; SEL, selonsertnib
1. Lawitz E, et al. ILC. April 11-15, 2018; Paris, France. Abstract PS105; 2. Ratziu V, et al. ILC. April 19-23, 2017; Amsterdam, The Netherlands. Abstract LBP-542; 3. Oseini AM, Sanyal AJ. Liver Int.
2017;37 Suppl 1:97-103; 4. Rotman Y, Sanyal AJ. Gut. 2017;66(1):180-190
Combination of an apoptosis signal-regulating
kinase (ASK1) inhibitor (selonsertib) with an
acetyl-CoA carboxylase inhibitor (GS-0976) or
a farnesoid X receptor agonist (GS-9674) in
NASH1
Physical activity Aerobic & Resistance activity
independently: - Reduce liver fat but no evidence for NASH and fibrosis
Dietary composition Modifications of diet without weight loss
- Reduce liver fat but no evidence for NASH and fibrosis
Weight reduction Consistently beneficial
- Steatosis ≥ 5% - NASH ≥ 7% - Fibrosis ≥ 10%
Integrated Treatment Strategies for NAFLD and NASH Multidisciplinary Team
Bariatric Experts (Medical, Endoscopi, Surgical)
Nutrition Experts
Exercise Specialists
DM Experts
Primary Care TeleMedicine
Hepatology/GI
Multidisciplinary Integrated Teams Efficacy Evidence in NASH
Current Medications Vitamin E and pioglitazone Clinical trials
How long to treat? Long term Multidisciplinary team
• NAFLD is the liver complications of obesity and is growing in all refions of the world
• NASH is the progressive form of NAFLD with increasing clinical burden
• NASH in the setting of components of MS can be more progressive
• Patients with NASH and fibrosis are the most urgent need to treatment
• Although liver biopsy is the gold standard to diagnose NASH, a number of non-invasive
tests are being developed
• Prevention of NAFLD must parallel the public health efforts to deal with epidemic of obesity
and DM
• Current SOC treatment for NASH options are limited
• A large number of potential agents are in clinical trials
• The future treatment of NASH will be similar to treatment of T2DM.
• For those with NASH and advanced fibrosis, induction followed by maintenance therapy
may be required
The Expanding World of Fatty Liver Disease