Making Connections to Improve Patient Care in Obesity, Metabolism, and Liver Health

Chair and Presenter, Arun J. Sanyal, MBBS, MD, discusses metabolic dysfunction–associated steatohepatitis in this CME activity titled “Making Connections to Improve Patient Care in Obesity, Metabolism, and Liver Health.” For the full presentation, downloadable Practice Aids, and complete CME information, and to apply for credit, please visit us at https://bit.ly/4kchmXs. CME credit will be available until November 3, 2026.

1. Making Connections to Improve Patient Care
in Obesity, Metabolism, and Liver Health

Arun J. Sanyal, MBBS, MD

Director

Stravitz-Sanyal Liver Institute for Liver Disease and Metabolic Health
Virginia Commonwealth University Health System

Richmond, Virginia

Go online to access full CME information, including faculty disclosures.

Copyright © 2000-2025, PeerView

2. Our Goals for Today

Describe the pathophysiologic mechanisms underlying MASLD,
MASH, and obesity, including the roles of metabolic dysfunction,
chronic inflammation, and genetic predisposition

Identify patients at high risk for MASLD and MASH using
guideline-recommended noninvasive screening and diagnostic tools

Explain the clinical implications of emerging metabolic
therapies targeting MASH, including dual-hormone-receptor and
triple-hormone-receptor agonists

Integrate emerging incretin-based agents into evolving MASH
treatment paradigms based on recent clinical evidence

Copyright © 2000-2025, PeerView

3. Making Connections to Improve Patient Care
in Obesity, Metabolism, and Liver Health

Copyright © 2000-2025, PeerView

4. MASLD Is the Hepa
of Metabo

MASH fibrosis

+

MASH cirrhosis

Phenotype of a Systemic Disorder

MASL

Simple
steatosis

41. Sheka AC etal, JAMA 2020;328:1975-1183,

PeerView.com/GPQ827

nflammation and Ill Health!

MASLD Spectrum

Obesity

T2D

Hypertension
Hypertriglyceridemia

Metabolic syndrome

General

Population, MASH
%
40 81.8
14 436
29 68
25 83
34 71
PeerView

Copyright © 2000-2025, PeerView

5. Steatotic Liver Disease Subclassification!

Steatotic Liver Disease (SLD)

MASLD and increased alcohol intake* PY AlcohoLassocia Specific etiology
(MetALD) Sl
iver disease :
(MASLD) MASLD ALD
predominant predominant

Weekly alcohol intake, g
ion-associated MY ———— ses

atohepatitis MASLD ALD
(WASH) predominant predominant

ally alcohol intake, g

‘pebetipottoneni and na eer malen “hear Pops © ve GION marken, clue Soros, and HV Mom
ta ME etal nn Mapa 202420 101199 PeerView

PeerView.com/GPQ827 Copyright © 2000-2025,

eerView

6. Metabolic Hea Solving Global Problems via Local Solutions
The scope of
MASLD: a view the problem
of metabolic health
through the lens of the liver
From MASLD and
organ-based care
to metabolic medicine
PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

7. The Global Burden of MASLD Is Increasing

and Linked to the Obesity Pandemic

Global prevalence" of MASLD is 30.1% 2 Global prevalence of MASLD
and MASH is 5.3%! and MASH in individuals who
are overweight/obese?
Res + Systematic review and meta-analysis
3 F TRES + N=101,028
| 4 a oe Overweight, % Obese, %
. ts
E Prevalence of
> MASUD) 70 75.3
À Prevalence of
MASH cu
Regional prevalence shows some variation
+ MASLD ranges from 25.1% (Western Europe) to 44.4% (Latin America)
(| MASH ranges rom 4% (Western Europe) to 7.1% (Latin America)
+ WASLD prevalence in general popuaton (220 years) rom 1980 1 2019. MASH prevalence was clelate by muy the prevalence of MASH in patents wih
MASLD with the prevalence of MASLD in the general population. PeerView
{Yount 2 et a: Hopalogy, 202077 388-1047 2 Quek Jet al Lancet Gastoentere Hato 202518200,

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

8. Future Predictions Based on Current Prevalence of MASLD

By 2030, there will be >40 million individuals living with advanced fibrosis or cirrhosis in the United States, Western Europe, China, and Japan

MASLD Represents a Significant Burden of Disease”

100

Patients, Millions
8 8 8 8 à

3

usa

mr mrt Mr mrs Mrs

350

200
ca} 250
200
20
150
2
100
10 >
o o
France Germany Italy Spain United
Kingdom

0

o
China

Japan

Prevalence of

=
E
g
5
=
3
=

13

10

s

o

MASLD Rates Are Associated
With Rises in T2D and Obesity?

653

140

= 59
MASLD Advanced Cirhosis

Fibrosis
182

81

Without Obesity With Obesity

* Westem Europe fo include France, Untied Kingdom, Spain aly, and Germany. ® Dynamic Markov modeling of MASLD in 8 countries (comprising over 25% of total

‘word population).

1. Estes Cet al. J Hopatol 2018:60:308-004. 2. Amjera Vet al. J Hepatol. 2022:78:471-478.

PeerView.com/GPQ827

PeerView

Copyright © 2000-2025, PeerView

9. Solving Global Problems via Local Solutions
The scope of
MASLD: a view the problem
of metabolic health
through the lens of the liver
From MASLD and
organ-based care
to metabolic medicine
PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

10. MASLD: A Key Determinant of Metabolic Health**

MASLD Precedes Development of T2D
Clinical data linking liver

Obesity, Diabetes, and MASLD Relative Incidence to metabolic comorbidities
10
08
06
04
0.2
o

2000 2010 2020
res iyi se y, aller init tend Biological links between liver and
eave a metabolic dysfunction
pss govcns/manesándes him 2. Ogden CL et a JAMA, 204431806914. 3. Finkelstein EA et a. Am J Prev Med. 2012342562570. PeerVi
À ie tacks ede goviewlede255Dite 42850 DS pal. ipsum cdo gounohadslauus pl. 8. Gregg EW ell Popul Heath Mot. 2013:11:1. eerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

11. Individuals With MASLD Have Increased

Metabolic Health Outcomes’

Study Population

+ 129 articles
+ Studies reporting longitudinal

outcomes associated with MASLD

32.4% affected by MASLD

1. Chan KE el a. Cin Gastroentoro Hepatol 2024 22-488 408014

PeerView.com/GPQ827

®
@

Clinical Outcomes Associated With MASLD
Metabolic syndrome

Cancer

Cardiovascular diseases
HR = 1.43 (95% Cl, 1.27-1.60), P<.01

Hypertension
HR = 1.75 (95% CI, 1.46-2.08), P<.01

Diabetes
HR = 2.56 (95% Cl, 2.10-3.13), P<.01

Pre-diabetes
HR = 1.69 (95% Cl, 1.22-2.35), P<.01

Additional Highlights

Patients w
60 [95% Cl, 2.106
(P = 01) risk of incider

PeerView

Copyright © 2000-2025, PeerView

12. Metabolic Syndrome Traits Increase the Risk of Major Adverse

Liver Outcomes in Individuals With Type 2 Diabetes!

Methods

‘Study population: 230,996 individuals from the

‘Swedish National Diabetes Register between

1998 and 2021

Outcome: MALO, including compensated
cirrhosis, decompensated cirrhosis and its
complications, and hepatocellular carcinoma

Total Population Adjusted HR (95% Cl)

1 Mets trait (only T2D)
2 Mets trait
3 Mets trait
4 MetS trait
5 Mets trait
6 Mets trait

1. Shan Y etal. Diabolos Care. 2024:47:978.085.

PeerView.com/GPQ827

Reference
1.55 (1.01-2.38)
2.35 (1.54-3.59)
2.69 (1.76-4.11)
3.42 (2.22-5.27)
4.09 (2.5-6.68)

Cumulative Incidence, %

‘Cumulative Incidence of Major Adverse Liver Outcomes
by Number of Metabolic Syndrome Traits at Baseline

T2D+5 Mets

T20+2 Mets

T20+1 Mets

Time Since Follow-Up, y

PeerView

Copyright © 2000-2025, PeerView

13. Stage Is Linked
omes and Mortal

Liver Decompensation All-Cause Mortality

rasage à
= 020
3 E Floresta 4
Bos À 01
& E
8 02 ® 00
3 E
Firosesage2 E
Eos 2 E 005, FRS stage 2
3 Fu à
= é
5 2 y y ë 70 ° 2 z 5 3 o
Follow-Up, y Follow-Up, y

Causes of death in stages 0-2 mainly because of CRM; sepsis vs cancer and liver-related in stages 3-4 |

1. Sanyal al. Eng! J Med, 2021385:1550-1509. PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

14. the NCD Metro System’?

Outcomes. Outcomes
Cardiometabolic Liver
Cancer Cardiometabolic
Liver Cancer

MASH + MASH +
MASLD MASH fibrosis cirrhosis Outcomes Cemetery

CrOv0109 O10
O

(an option for the few privileged ones)

4. Sanyal Al etal N Engl J Med 2021 305:1550-509. 2 Taylor RS eta. Gastroenterology. 2020;150:1611-1625 012 i
3. Hagatom et al J Hapa 2017 87:1265-1273. PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

15. MASLD: A Key Determinant of Metabolic Health1*

MASLD Precedes Development of T2D

Cli | data linking li to metaboli
Obesity, Diabetes, and MASLD Relative Incidence Bade ON
10 + More liver disease, more metabolic

0% disease
06
04
02
o

+ More metabolic outcomes in MASLD
after correcting for other confounders
1980 1990 2000 2010 2020 2030
‘= Obesity incidence trend = Diabetes incidence trend Biological links between liver and
7 FARINE essence of MASLO; metabolic dysfunction

1. https /www.cde.govinchs/nhanesindex.himl. 2. Ogden CL et al. JAMA. 2014;311:806-814. 3. Finkelstein EA et al. Am J Prev Med. 2012:42:563-570. P Vi
Men ataca ode govvewodcs2es0ede 12680 DS! pal Hips Inn ede gorilas usa pat 8. Grego EW ell. Pope oath Met 20181118. eerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

16. Adipose Tissue Plays an Important Role
n Systemic Inflammation Related to Obesity’

GHRH-IGFs Gonadal hormones

‘Adipose tissue (obesity)
1. Release of free fatty acids
2. Decreased adiponectin

Collagen-expressit
= 3. Source of inflammatory adipokines

Lipid-associated
‘macrophage

Key consequences: insulin resistance and metabolic dysfunction.

e
+. ac RO, Lumeng CN. Nt Rev Endocrinol.2024 205061. 2 Lafonan M, Gard J. Diabetes Metab 200834:347-327. PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

17. Connecting MASLD to Insulin Resistance!

15 I Control
y owas
E IM ASH
5£ 10
HE
Ez
rs
gE 5
o
2
[o]
o

10 40
Insulin Dose, mU/m2/min
PeerView

1. Sanyal AJ etal Gastroontoretogy. 2001:120-1183-1102,

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

18. Metabolic Flexibility Is Needed
for Whole Body Energy Homeostas

Low insulin

FFA oxidation

Glucose oxidation

Gluconeogenesis

Glycogen

+. Mota Meta. Metabolism, 2018:65:1049-1061. 2. Cheung O, Sanyal AJ. Semi in Liver Dis, 2008:28:351-359. PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

19. A Hallmark of Diet-Induced Obes

Food

(fat, sugars)

High insulin
L FFA oxidation
Myosteatosis

“ML glucose oxidation

1. Mota Met al, Metabtsm, 2016 5:1040-1061.2. Cheung O, Sanyal A. Semin in Liver Dis, 200828:35-350, PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

20. + Excess free fatty acids

+ Glucose
+ Inflammatory cytokines

+ Inflammasome
+ TLR4
+ Inflammatory cytokines

+ Adaptive immune system

Cirrhosis

+ Oxidative stress
+ UPR
+ Mitochondrial stress

+ Stellate cell activation

_— — Islet cell loss
Disease activity Disease stage

1. Sanyal Al Nat Rev Gastoener! Hepatol 2018;18:37-288, PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

21. Is MASH a Liver Disease or a Systemic Disorder?!

CRM diseases e
(eg, ASCVD) I © ©

Fatty streak Atheroma Stable plaque Unstable plaque

There is a shared Advanced

biology between eee

MASH and other

CRM diseases tee Steatohepatitis
Fat hepatocytes. (MASH without (MASH with
fibrosis) fibrosis) Cross;
O mms © mor
Le mures oe À
MASH á >

Liver disease progression is associated with progression of disease in other organs, such as the heart

1. Finney AC aa. Front Cardovase Med, 2023.10:1118861 PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

22. Liver Simple Steatosis Is a Central D

MASLD Extends the Spectrum of Dysli

3 B250
2 El
gs E 200
[ei 3
ss quo
28 E
3 2 100
Ex 2
eu G 50

3

a

30

o
HMGCR SREBP2 LDLR

Genes HMGCR (Relative Expression)

1. Min HK el al. Call Motab.2012:16:665-674,

PeerView.com/GPQ827

KE Control
m MASH

Sitosterol

Markers Whose Ratio
to Cholesterol Was Measured

PeerView

Copyright © 2000-2025, PeerView

23. An Integrated Model of Metabolic Dysfunction-Related

Heal isorders

Metabolically
unhealthy
adiposity

Clinically
silent

Clinically
obvious

PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, Peerview

24. Solving Global Problems via Local Solutions
The scope of
MASLD: a view the problem
of metabolic health
through the lens of the liver
From MASLD and
organ-based care
to metabolic medicine
PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

25. ree Simple Steps to Managing MASLD

Is MASLD
present?

PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

26. Holistic View of MASLD

Genetics

Nutrition!
insulin resistance
vs alcohol

Steatosis

— E) oi

MASH and competing threats progress colinearly

pollutants
Glycomia-elated Chronic
ES Vascular Cardiac. A
decline = i disease I | sy | oe |

Diet and exercise

+ Microangiopathies

PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

27. Presence of MASLD Can Be Estimated F k Factor Profile!

BMI 230 Cardiovascular disease

60%-95% Two or more features ¿ 69% ~12% of

also have MASLD of metabolic syndrome also have MASLD lean

90% individuals

Type 2 diabet © Hypertensi: pa
'ype 2 diabetes lypertension MASLD

50%-74% also have MASLD 50%-74%

also have MASLD also have MASLD

MASLD is seen as the liver manifestation of metabolic syndrome

1. Godoy-Matos AF et al Diabet! Metab
4. Younossi ZM et al. Diabetes Care. 2020:4
7. Estes Cet al Hepatology. 2018.87-123-1

2020;1260. 2, Dela Ret al In Bo Sel 2018:15:610-616. 3, Zhao YC et al. Hypertension. 2020.75276-204,
Bedogn © eta heputony, 260740 1887-1391. 6. Kasper Pal al Cu Ros Carel 2021110821 937 PeerView
‚chi M et al. Ann intern Med. 2005;143:722-728. eervie

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

28. Three Simple Steps to Managing MASLD

Is intervention
needed?

PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

29. Diagnostic Algorithm for Risk Stratification
in Individuals With MASLD!

and the Prevention of Cirrho

Viral hepatitis
(HCV, HBV)
Alcohol (PEth)

Groups with the
highest risk of
future cirrhosis:

+ Type 2 diabetes

+ Prediabetes

+ Obesity with
21 CV factors

1. CusiK et al. Diabetes Caro. 20258:1-28.

PeerView.com/GPQ827

Is FIB-4 21.3

Lower risk

of future cirrhosi

Is LSM
28.0 kPa?

IFFIB-4
>2.67

Managed by primary care
(and interprofessional team)

+ Repeat FIB-4 every 1-2 years

Optimize lifestyle and
treatment of comorbidities

Managed by liver specialist
(and interprofessional team)

+ Additional imaging and

biomarker risk strati
+ Treatment + long-term follow-up

PeerView

Copyright © 2000-2025, PeerView

30. Making the Case for FIB:
for Global Purposes!

CBCiplatelets + hepatic panel
Widely available

Surrogate for fibrosis, a key

prognostic marker

= Associated with prognosis

— Change in FIB-4 further
linked to prognosis

Linked to outcomes in general
population and in known
populations with disease

1. Sanyal AJ etal. Cn GastroonterelHopato, 2023/21 2026-2030.

PeerView.com/GPQ827

Deaths
Liver events
MACE

HCC

Class A
(n=554)
FIB-4 <1.3

0.07
0.21
0.83

as a Key Public Health Strategy

Included Using FIB-4
and/or LSM Criteria

Class B Class C
(n = 536) (n = 846)
FIB-4 1.31-2.6 | FIB-4>2.6
0.42 3.08
1.32 9.33
1.60 2.54
0.07 1.08
PeerView

Copyright © 2000-2025, PeerView

31. Changes in Liver Stiffness Over Time Provide

Useful Risk-Related Information!

| 1,403 adult participants in NASH CRN studies

‘Annual prospective follow-up with annual VCTE exam.
4.4 years mean follow-up with 89 LRE

Risk of LRE begins to rise at LSM 10 kPa

“
1
te a os A
5 s
Eo 33, da peor
5: Ê ER
E: s 5: 3% 7
2 33 Es
2 2 6 1014182226303 38424650545862667074 I
LM stayed <IOKPA. "LSM progress o 210%Pa en SSM stayed 210 kPa LSM regressed o 10 Pa
sos À are
ge
1. Game S etal. J Hepat 202481:800408. PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

32. isk Strati

ication’

e Rule of

The Rule of 5 quickly estimates the risk of decompensation and liver-related death, irrespective of etiology

5kPa e 15 kPa 20 kPa
Normal H
— H >
Exclude cACLD Assume cACLD |
1 Assume CSPH:
* HCV, HBV, ALD
MASH in those without obesity
1. de Franchi Reta. Hepao. 2022,7:950.974 PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

33. cally Accurate and C ally Viable Way to Use

LSM Data for C

Lifestyle
modifications LSM <8-10
Prescription treatment
Prescription treatment
Cirrhosis assessment via ELF FIBA >26
HCC surveillance LSM >20 or >15 with thrombocytopenia

PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

34. Three Simple Steps to Managing MASLD

What
medications?
How do | follow
them?

Is MASLD Is intervention
needed?

PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

35. Addressing MASLD Across the Disease Spectrum!

At-risk MASH
MASH + high activity + 2F2 fibrosis
(N = 6-8 million)

Will an elimination

Davon MASLD: fatty liver, steatohepatitis, fibrosis stages 0-1
progressions N = ~60 million
Main cause of death: cardiometabolic, cancers
4. Estes © eta Hopalolgy. 201887123433. PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

36. Core Principles: Simple Rules Can Fit Everyone’

~— American Heart Association
A Life's Essential 8

Diet
Physical activity
. Quit tobacco
Life’s Healthy sleep
Essential 8 Manage weight

Control cholesterol
Manage blood sugar
Manage blood pressure

1. ps env heart ergleheathy-lvinghealty-Sestyleies-essenta Sites-essential3 fact sheet PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, Peerview

37. Weight Loss Can Eliminate Steatosis in Early Stages of Disease’?

Retatrutide Data
4 Participants Achieving Liver Fat <5%:
Change in Body Weight: c
Retatrutide vs Placebo Retatrutide vs Placebo, %
APRO SRETAIMg HRETASmg MRETASMG RETA 1200

o nn P80 en . O
¿ an =
5 so
3 RETA 1m *
+ "de & E
j i
y RETA 4 mg Se 5 »
ES E
H RerAsm a
$ 0 o

RETA 12 mg (ID, 2 mg) ° Weka Wohle
PÉMAN ETES
Time, wk Liver Fat Content <5%
2 2.05 versus P80, > P< 901 versus FOO .
1. Jasrebofl AM ell. N Eng! J Mod 2023, 900:514:520.2. Sanyal Ade al Nat Med, 2028,902037.2048. PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

38. Addressing MASLD Across the Disease Spectrum!

MASH
‘Advanced fibrosis (F3/F4)
(N = 2 million)
At-risk MASH
Can weight loss Steatohepatitis + NAS 24 + fibrosis
regress activity ==) At-risk MASH Pe
and fibrosis? MASH + high activity + 2F2 fibrosis
(N = 6-8 million) FIB-4 1.3-2.6

Liver stiffness: 10-20 kPa without
thrombocytopenia by VCTE

MASLD: fatty liver, steatohepatitis, fibrosis stages 0-1
N = -60 million

Main cause of death: cardiometabolic, cancers

1. Estes O et al Hepatology. 201997.129-139, PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

39. Resmetirom: First Drug to Be Conditionally Approved

for MASH With Fibrosis*

21 Stage Fibrosis Improvement:

21 Stage Fibrosis improvement: 22 Stage Fibrosis Improvement Worsening
Conventional Reading Categorical Fibrosis Cenador steatosis BON Coen stats reductos

ients, %

Placebo — Reametrom Resmeticar Pacabo Reamer” Resmatrem
ers) mg 10m era mg 10 wm mm 10
mei) me IS

me oa)

‘Also reduces LDL-C, but long-term clinical outcomes awaited

Biopsy not needed for determining who needs therapy and for assessment of treatment response
+ Not indicated for cirrhosis

4. Hasson SA et al. N Engl J Med. 2026200497509. PeerView
PeerView.com/GPQ827

Copyright © 2000-2025, PeerView

40. Pioglitazone and Vitamin E Can Produce

Similar Histological Benefit in MASH as Approved Therapi

Main Outcomes Umbrella Review on the Effects

of Vitamin E Intervention on Liver Fibrosis
Histologie Improvement in NASH (primary outcome)

"Improvement in fbrosis
‘= Resolution of NASH

3

ES 405% Ch Weight

Vedas A tal. (2021) -025 (047 10-004) 3274

8

# Un Met. 2021) 9.09 (11200112) 121
de ‘Abdo abous Metal. (2020) 022(042t0-002) 3783
3 ‘Amana etl. (2019) -052(-140%9026) 195
Es

‘Salo Ket a. (2015)
Overal (8 = 0%, P = 970)

023 (04719001) 2827
024 (0361-012) 100

2
NOTE: Weighs are tom
a random eta ana
En y 7
2 p= 001 v placebo 7
1 Sanyal Ad ta N Eng! J Med. 2010:262:1875-1885. 2. Yang MY et al. J Dig Dis. 2023,24:380-380. PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

41. The Metabolic Effects of GLP-1 Span Multiple Organs,

Including the Liver'!®

Heart
Kidneys + cardioprotection
1 natriuresis
tee G Platelets
© 4 coagulation
\ | f Potential effects of GLP-1 in MASH
Blood vessels : À

| blood pressure ar de a ucose metabolism

Pancreas
| glucose and hypoglycemia
Brain | glucagon secretion

boy welt ! u. ecran and boeynihasie
ir

Fat and liver
| inflammation

1. Drucker Du. Call Metab. 2016:24:15-30, 2. Zhao X etal. Front Endocrinol. 2021;12:721136. 3, Wang X et al. Word J Gastroenterol, 2014;20:14821-14830, PeerView
4 Sharma S et al, PLOS One. 2011.5:025280. 5. Perez Garcia A et al. Nutñents 2021.13:2582.

PeerView.com/GPQ827 Copyright © 2000-2025, Peerview

42. Phase 3 ESSENCE: Semaglutide Improves

MASH Resolu'

Proportion of Participants, %

100

90

80

70

60

50

40

30

EDP: 28.9
(95% CI, 21.3-36.5); P < .0001

3360534

Resolution of Steatohepatitis With
No Worsening of Liver Fibrosis

1. Sanyal AJ etal Eng! J Med, 2025:302:2080-2000,

PeerView.com/GPQ827

ion and Fibrosis Severity’

= Semaglutide 2.4 mg (n = 534) = Placebo (n = 266)

EDP: 14.4
(95% Cl, 7.5-21.4); P< .0001

tt in Liver Fibrosis With
No Worsening of Steatohepatitis

PeerView

Copyright © 2000-2025, PeerView

43. ESSENCE: Confirmatory Secondary Endpoints

(ITT Population)!

mSemaglutide 2.4 mg (n = 534)

ETD: -8.5
(95% Cl, -9.6 to -7.4); P< .0001

2 ——
Á 0 2
3 g
g 25 E
E 3
B s =
- a
3
2 5
5 75 s
E E
A 5
5 a
gon E
= a

-125

Change in Body Weight

1. Sanyal AJ et a. Eng! J Med, 2025:302-2080 2009.

PeerView.com/GPQ827

35
30
25
20
15
10

5

o

EDP: 16.6
(95% Cl, 10.2 to 22.9); P< 0001

1

Resolution of Steatohepatit
Improvement in Liver

= Placebo (n = 266)

ETD:13
(95% Cl, 0.0 to 2.7); P= .0488

EA

oo 2

5

Mean Change From Baseline
5

5

Improvement in SF-36 Bodily Pain

PeerView

Copyright © 2000-2025, PeerView

44. ints

ESSENCE: Confirmatory Secondary End|
(ITT Population)!

m Semaglutide 2.4 mg (n= 534) — "Placebo (n = 266)

ETD:-85 EDP: 186 ETD:13

q Semaglutide was granted FDA approval
on August 16, 2025 to treat noncirrhotic MASH
with moderate to advanced liver fibrosis,
in conjunction with a reduced-calorie diet
and increased physical activity
¿ EE ¿ al

alee. Resolution of Steatohepatitis With
Change in Body Weight Improvement in Liver Fibrosis

0488

5

75)

Mean Change From Baseline, %

Improvement in SF-36 Bodily Pain

PeerView

1. Sanyal AJ et al M Engl J Med, 2025.302.2080.2000.

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

45. Phase 3 Trial: Improvement in MASH With No Worseni

Survodutide Data
Paired Biopsy Results All Data
P< 0001 P=.0010
zo P0001 ¿o ETT
i P<.0001 1
Es Es peer
HB El
zo zo
é &
5 4 5 40
2 £
s 5
5» 5»
2 2
2 2
& Lo
Survodutide, Survodutide, Survodutide, Placebo ‘Survodutide, Survodutide, Survodutide, Placebo
24mg Am S0m9 (n=66) 24mg 48mg S0m9 (n=)
we) =) (n= 4) (n=93) m) (n=82)
Actual Treatment
PeerView
1. Sanyal AJ etal. Engl J Med, 2025:302 20802000, 2. Sanyal AJ et a EASL 2024, Presentation 68:06

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

46. Phase 2 HARMONY: Efruxifermin (EFX) Produced
Prolonged and Incremental Fibrosis Response Over Time!

21 Stage Fibrosis Improvement Without

Worsening of MASH (LBAS)
100
Diference: 52
(95% C1, 31 to 73), P<.0001
"m
$
5
& Diference: 22
© 60 (05% Cl, -1 1045), P= 70
5 ———1
&
= 40
5
E
$ 2
&
o
Placebo EFX 28 mg EFX 50 mg
2 ia wer defined as improved fons y 21 sage wh no worsening of MASH.

y endpoint responders
1. Noureddin Meta. Lancet. 2025:408.749:730.

PeerView.com/GPQ827

Primary endpoint
responders® at
week 24, n

Proportion with
sustained
response at week
96, n (%)

Primary endpoint
nonresponders at
week 24, n

Proportion with
a response at
week 96, n (%)

Placebo

(n=34)

2(40)

29

6(21)

10(83) — 11(82)

2(14) 10 (63)

PeerView

Copyright © 2000-2025, PeerView

47. Addressing MASLD Across the Disease Spectrum!

We have now made a FIB-4 >2.6
breakthrough for those =» LSM >20 or >15 + thrombocytopenia
with cirrhosis: efruxifermin ELF >113

MASH

‘Advanced fibrosis (F3/F4)
Multiple therapeutic options (N = 2 million)
+ Vit and piogitazone
+ Thyroxine B receptors
+ GLP-1-based treatment

At-risk MASH
MASH + high activity + 2F2 fibrosis
(N = 6-8 million)

Treat underlying
obesity and T2D

MASLD: fatty liver, s
N

Main cause of death: cardiometabolic, cancers

'atohepatitis, fibrosis stages 0-1
60 million

PeerView

1. Estes © et al Hepatology. 2018,87:123-138,

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

48. Phase 2 SYMMETRY: Efruxifermin (EFX) Reverses Cirrhosis!

Reduction in Fibrosis 21 Stage Without MASH

Worsening at Week 96
100 EFX EFX

28 mg 50mg
(n=41) (n=46)

80 Difference: 16 n n
(95% Cl, 2 to 30) Primary endpoint
ce responders? 8 9 12
a at week 36, n
8 Proportion with
S sustained response 4(50) 6(67) 9(75)
= Difference: 10
a 4 (95% Cl, -4 to 24) at week 96, n (%)
—_—_ + Primary endpoint.
20 nonresponders. 39 32 34
u at week 36, n
Proportion with
o+ FA + a response at 3 (8) 6(19) 9 (26)
Placebo EFX 28 mg EFX 50 mg week 96, n (%)
(n=61) (n=57) (n=63)
+ Pray endpait responder were defined as imroved fra y 1 stage vit no worsening of MASH. Pei

1.Noureddin Meta. N Engl J Mod, 2025,392.2413-2424.

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

49. Bariatric Surgery in Individuals With MASH

and Compensated Cirrhosis May Improve Outcomes!

Major Adverse Liver Outcomes Progression From Compensated
o Decompensated Cirrhosis,

a
e °°] Acted HR = 028 (98% c1. 012000 e] achat» 0.2 (95% ci, 006-068)
ja ‘0
2
ge 3%
3 H
Ex» En
g A
3» in
Eo do
A o So
jus Time Since index Dato y u
Percentage Change In Body rei Claige NS
Lanester in Patients With Diabetes
E, —
ES os =
EF poe
og =
gar ‘non baten group déterence at 10 y
2 arrete
= 2 P= 015
Time Since Index Date, y Time Since index Dat, y Fi
+. Amini Atala Med 20253198995. PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView

50. A Pragmatic Approach to Managing MASH and Steatohepatitis'

Top-down approach
Tice auvatnce
Vcenatone
rai fr at scant pata hypertension
Leste interven Cavett
Uae Iirvntion Enden vario as nad
CEN Moor MELO retro nep center
O Very high Evaluate and manage fraltyisarcopenia
+ Bilal city y Tres oscar ev

Sleep
Mental health

‘Comorbidity care for all
High Many options for mid-level
Hear disease ls ver rela risk strata
Vascular disease Aloe AAC cuco” + Resmetrom (thyroxine $.
Cancer screening receptor agonists)
Vitamin E and pioglitazone

Moderately increased risk + GLP-1-based Rx

(Main risks are cardiometabolic, cancers, liver)

Low liver risk Bottom-up approach
+ Recunderlying obesity,
72D, and cardiac risks

PeerView

4. Shah N, Sanyal Al. Am Gastroontero,2025.120.75-82,

PeerView.com/GPQ827 Copyright © 2000-2025, Peerview

51. Conclusions

+ MASLD and MASH arise from interconnected mechanisms of obesity, insulin
resistance, chronic inflammation, and genetic susceptibility

+ Guideline-endorsed noninvasive tools (eg, fibrosis scores, elastography) enable
timely detection of patients at highest risk for progression

+ Dual-hormone-receptor and triple-hormone-receptor agonists show promising
effects on weight, glycemic control, and histologic improvement in MASH

— Incretin-based agents are reshaping care, offering potential to address both
metabolic disease and liver fibrosis

+ Integrating metabolic, hepatic, and lifestyle interventions supports personalized
management and improved long-term outcomes

PeerView

PeerView.com/GPQ827 Copyright © 2000-2025, PeerView