NASH in 2017 and beyond

Raluca Pais,

Université Pierre et Marie Curie, Hôpital Pitié Salpêtrière, Paris, France

Cohen et al, science 2011; Sanyal et al, Hepatol 2011

NAFLD = macrovesicular steatosis > 5% of hepatocytes.

NASH= steatosis+ ballooning + lobular inflammatory infiltration

NAFLD 90%

NASH 24-98%

NAFLD-NASH definition

Epidémiologie

Prevalence of NAFLD

00

5

10

15

20

25

30

35

5 10 15 20 25 30 35Prevalence of obesity

China

Italy

JapanMexico

Taiwan

Israel USA

Korea

India

Prev

alen

ce o

f N

AFLD

25% to 35% worldwide

Lazo et al. Semin. Liver Dis. 2008

Prevalence of NASH within NAFLD

Ekstedt N=129 Tertiary 45 55

% steatosis % NASH

CYTOL 2002 N=248 Tertiary,multicentric 45 55

Soderbergh N=118 Tertiary care 57 43

NASH CRN N=679 Tertiary,multicentric 20 59

Campos N=125 Bariatric surgery 45 55

VA Corporate Data

Warehouse

Structured Chart Review

� Persistently increased ALT

� No viral hepatitis

� No excessive alcohol

(2 yrs prior)

� Metabolic Sd

� BMI >30 kg/m²

NAFLD case definition

Recognition of ALT increase

Diagnosis of NAFLD/NASH

Lifestyle modifications

Referral specialist evaluation

RECEIPT

OF

NAFLD

CARE

Blais, Am J Gastroenterol 2014

NAFLD : an underrecognized disease

39.4% recognition of ALT increase

21.5% diagnosis of NAFLD/NASH

15% lifestyle modifications

10.5% referral specialist evaluation

60.6%

Only the magnitude and proportion of ALT

elevation were predictive of receiving NAFLD care

NO NAFLD CARE

Blais, Am J Gastroenterol 2014

Pathogenèse

Lip

oly

se d

u t

issu

ad

ipe

ux

Fructose

+

Glucose

Acetyl CoA

Lip

og

en

èse

de

no

vo

Acides

gras

libres

ACC

FAS

SCD

SREBP-1c

ChREBP

Dysfonction du tissue adipeux:

- Hypertrophie des adipocytes

- Infiltration macrophagique

- Hypoxie

- Fibrose

- � sensibilité à l’insuline

- � adiponectine

- � cytokines proinflammatoires

Carnitine

CPT1

CPT2

Triglycérides VLDLAminoacides

Choline/PC

Hypertriglycéridémie

MOGAT2

DGAT2Stéatose

PNPLA3

Necroinflammation

NASH

Fibrose

CHC

Beta oxydation

mitochondriale

Lipides lipotoxiques- Acide palmitique

- Lysophosphatidil choline

- Céramides

- Cholestérol libre

Diagnostic

Usual diagnostic circumstances for NAFLD

LFTs +

Ultrasound

LFTs +

Metabolic RF

Increased

ferritin

Cirrhosis X

Metabolic RF

+ Normal ALT

NASH

Key points : presence of steatosis (ultrasound, markers)

presence of metabolic risk factors

Marqueurs sériques non-invasifs

disponibles

• FibroTest

• ELF Panel

• Fibromètre

• Angulo

FIBROSE

� SteatoTest

� Kotronen

� FLI

STEATOSE

� NASHTest

� CK 18 ?

� NASH Dg (CK18,

adiponectin, resistin)

STEATOHEPATITE

Wieckowska, Hepatology 2006Cales, Hepatology 2005

Angulo, Hepatology 2007

Guha, Hepatology 2008

Ratziu, BioMedCentral Gastro 2006

Poynard, BMC Gastro 2006

Rosenberg, Gastroenterology 2004

Poynard, Comp Hepatol 2005

NAFLD fibrosis score

Angulo, Hepatology 2007; Boursier, Current Opin Med Diag 2012; Shah, Clin Gastroenterol Hepatol 2009

NAFLD fibrosis score

0,037 * age

+ 0,094 * BMI

+ 1,13 * IFG/diabetes

+ 0,99 * AST/ALT

– 0,013 * platelets

– 0.66 * albumin

+ 1,675

NAFLD fibrosis score

0

10

20

30

40

50

60

70

80

90

100

-1.455 < Grey zone 0.676 <

F0-2 F3/4

≈30%

91.8% 66.9%66.9%

Xiao, Hepatology 2017

0,720,78

0,83

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

F ≥2 F ≥3 F4

AU

RO

C

NFS: a good fibrosis test in diabetics?

1693 US diabetics

(code ICD-9 from 09/11 to 11/15)675 probable NASH

(AST or ALT ≥30 (M) ou 19 (W), T2DM, no

other cause, no alcohol)

1018 without NASH

Joshi, ILC2016-RS-4095

Negative

Intermediate

Positive

0,037*age

+ 0,094*BMI

+ 1,13*IFG/diabete

+ 0,99*AST/ALT

– 0,013*platelets

– 0.66*albumin

+ 1,675

Tests sanguins de fibrose – FIB4 : attention à

l’âge !

Boursier, J Hepatol 2017

Chez les patients

≥60 ans, le taux de

faux positifs était de

82.0%

3754 patients,

hépatopathie chronique

prouvée histologiquement

Transient Elastography

Factors influencing liver stiffness

De Ledinghen, Expert Med Rev Devices 2010

Boursier, J Gastroenterol 2014

Steatosis

CAP pour interpréter le Fibroscan

Petta, Hepatology 2016

Fibroscan manufacturer recommendations

M probe if skin – liver distance capsula <25mm, XL probe if ≥ 25mm

Boursier, AASLD 2017

Manufacturer

recommendations

Adjustment

Combination blood tests + Fibroscan

Petta, Liver Int 2015

0

10

20

30

40

50

60

70

80

90

100

FS < 7,9 kPa

NFS < -1,455

Biopsy FS ≥ 9,6 kPa

NFS > 0,676

F0-2 F3/4

Fibroscan +

NAFLD fibrosis score

FS < 7,9 kPa

NFS < -1,455

FS ≥ 9,6 kPa

NFS > 0,676Autres

F0/2 Biopsy F3/4

45%

96% 100%100%

When to perform liver biopsy on an

individual basis ?

• Metabolically stable ?

• Attempt diet and lifestyle change

Failure (s)

previous attempts ?Never tried

Improvement weight,

IR, ALT NNo change

Fibrosis

risk

Comorbidities

Patient

motivationTrials

FT/FS (or clinical)

+/+ +/- -/-

MONITORING

LB

Liver Biopsy

� prone to sampling error: ≥ 1 stage: 41%; ≥ 2 stages: 12%

� interobserver variability: 1 stage discordance 24%

NAS Score = Steatosis (0-3) + Inflammation (0-3) + Ballooning (0-2)

SAF Classification:

Diagnos( c**

No*NAFLD*

NAFLD*

NAFLD*

NAFLD*

NAFLD*

NASH*

NASH*

NAFLD*

NASH*

NASH*

Ratziu, Gastroenterology 2005

Bedossa, Hepatology 2012

Histoire Naturelle

Fibrosis progression

HCC

ESLD

Liver Transplantation

EXTRAHEPATIC COMPLICATIONS

NASH CRN

N = 396 pts

Sanyal, AASLD 2016

• Age > 45-50 yrs

• Diabetes

• BMI > 27 kg/m²

• Arterial HTN

• Hypertriglyceridemia (TG > 1.7 mmol/L)

• ALT>2N

• AST/ALT > 1

Ratziu, Gastroenterology 2000

Angulo, Hepatology 1999

Dixon, Gastroenterology 2001

Bedside risk factors for severe fibrosis in NASH

Fibrosis progression in patients with NAFLD

Singh et al., Clin Gastroenterology and Hepatology 2015

Metaanalysis of 11 studies of patients with NAFLD and paired liver

biopsies (N = 411 pts)

Fibrosis progression rate:

NAFL: 1 stage over 14 years

NASH: 1 stage over 7 years

Causes of death in NASH cirrhosis

• Same as in any other cause of cirrhosis

• Same prognostic value of MELD, Child-Pugh, …

N=152 NASH-cirrhosis

8 yrs f/u

29 Deaths

Liver failure

N=19

Cardio-

vascular

N=8

Other

N=2 • Sepsis

• Variceal

hemorrhage

• HCC

+++

++

+

Sanyal, Hepatology 2006

Competitive Competitive

risk

Progression to liver-related death

• N=152 NASH-cirrhosis & 150 HCV-cirrhosis

Sanyal, Hepatology 2006

Child A

Child B

Child C

NAFLD and HCC … In Europe …

Dyson, J Hepatol 2013

Over the past decade • ALD: 28%• NAFLD: 22%• No CLD: 20%

NAFLD and HCC … GHPS experience…

N = 323 patients undergoing liver resection Pais et al, unpublished

HCC distribu on according to the e ology

of chronic liver disease and fibrosis stages

Recurrence-free survival according to the

e ology of chronic liver disease.

Pais et al, unpublished

NAFLD and HCC … GHPS experience…

Characteristics of NAFLD and HCC

Mittal, CGH 2015

Bellentani, Hepatology 2015 in press

US, retrospective: 1500

HCC VA Hospital (2005 –

2010)

8% NAFLD related HCC

Particularities of patients with NAFLD-related HCC :

- Older

- Higher prevalence of metabolic comorbidities

- Absence of cirrhosis (42%)

- No HCC screening (57%)

- Less eligible for HCC specific therapy (comorbidities, advanced

tumors)

Europe (Italy), prospective :

145 NAFLD-HCC and 611

HCV-HCC

NAFLD – liver transplantation

NAFLD – 2nd etiology of liver transplantation in US

Wong, Gatroenterology 2015

NAFLD – Center stage of the metabolic

syndrome ?

NAFLD

Hypertension

Diabetes

Cardiovascular

• Endothelial & coronary

dysfunction

• Carotid plaques

• Impaired ventricular fct and

metabolism

• CV events

Incident

diabetes

Insulin

requirements

Prevalence

essential HTN

OSA

NAFLD and early ATS – transversal studies

Sookoian, J Hepatol 2008

Jaruvongvanich, Dig Liv Dis, 2016

NAFLD and C-IMT

NAFLD and CAC > 100

NAFLD is an independent predictor for the occurrence

of early ATS - Longitudinal studies

C-IMT

1872 subjects

FU = 8 ±4 years

Coronary Calcium Score

4731 subjects

FU = 4 years

Pais, J Hepatol 2016 Sinn, Gut 2016

NAFLD is additive to established MRF in increasing the risk

of incidentT2DM

Risk factors OR, 95% CI

IR alone 3.66 (1.89 – 7.08)

Overweight/obesity 1.29 (0.62 – 2.71)

NAFLD 2.73 (1.38 – 5.41)

IR + overweight/obesity 6.16 (3.38 – 11.22)

IR + NAFLD 6.73 (3.49 – 12.97)

Overweight/obesity + NAFLD 3.23 (1.78 – 5.89)

IR + overweight/obesity + NAFLD 14.13 (8.99 – 22.2)

N = 12 853 subjects from a South Korean occupational cohort

Sung, Diabetes Care 2012

Adjusted for age, sex, alcohol, smoking status, exercise, educational status, TG, and ALT

Severity of NAFLD and incidentT2DM

Chang, Am J Gastroenterol 2013

NAFLD and type 2 diabetes – bidirectional relationship

Type 2 diabetes NAFLD

Worsening of histological features and fibrosis progression

In persons with NAFLD, screening for diabetes is

mandatory, by fasting or random blood glucose

or HbA1c (A1)

In patients with T2DM, the presence of NAFLD

should be looked for irrespective of liver

enzyme levels, since T2DM patients are at high

risk of disease progression (A2)

Increased risk of incident type 2 diabetes

NAFLD and chronic kidney disease

Cumulative incidence of CKD

Sinn, J Hepatol 2017

N = 40 000 pts

Combinded kidney-liver

transplantation

NASH + CC

Alcohol + biliary CLD

Viral hepatitis

Singal, Transplantation 2016

>>>> Hypoxia severity is significantly associated with NAS score even after adjustment for confounding metabolic factors

>>>> Hypoxia severity is an independent factor of more severe liver fibrosis

Aron-wisnewsky , C Minville et al, J Hepatol 2012;

ODI=3Normal liver

ODI=20Steatosis

and fibrosis

N= 101Obese patients

NASH fibrose et SAS

Work-up in patients with NAFLD: a

multiorgan approach

NAFLD

Extrahepatic

comorbidities

Liver

condition

•Type 2 diabetes

•Sleep apnea

•Evaluate CV risk

•Dyslipidemia

•Cofactors of fibrosis

•Pathological form

•Stage

•Prognosis

?

NAFLD – Non pharmacological treatment

Life style modifications

1. Histological improvement

Vilar Gomez, Gastroenterology 2015

293 patients; 89% with paired liver biopsy

F/u: 52 weeks

Low-fat hypocaloric diet (- 750 kcal)

Vilar Gomez, Gastroenterology 2015

N = 73 N = 16 N = 8 N = 16

Pa

tie

nts

, %

Life style modifications

2. Fibrosis

Life style modifications – physical activity

� Higher energy consumption

� Reduces body weight

� Fatigue, discomfort =>poor

long-term compliance.

� Increase muscular strength, mass

and bone density; less weight loss

� Improves dyslipidemia, HBP, IR

� Less energy consumption

Improvement in 50% of cases without weight loss

Hashida, J Hepatol 2017

Weight loss correlates with the frequency of

medical visits

Dudekula, PlosOne 2014 9(11)

� 3% - 5% weight loss to improve steatosis

� 7% - 10% for NASH resolution

� > 10% for fibrosis regression

Negative predictors of response:

- Older age

- Type 2 diabetes

- More severe NASH activity

Weight loss is difficult to maintain in real-

life settings :

- Maximum at 6 month

- 6% of initial body weight at 1 year

- 50% of initial weight loss is regained in

3 years Dansinger, Ann Int Med, 2007

BARIATRIC SURGERY

N = 381 patients

95.7% of patients had a fibrosis score ≤ F1.

80.2% of patients regressed or remained at the same stage of

fibrosis. 94/381 (24%) patients had T2DM in this cohort

Mathurin, Gastroenterology 2009

BARIATRIC SURGERY

Distribution of NAS Distribution of Fibrosis

� NASH disappeared in 85.4% of cases

� Fibrosis improved in 46%.

� The rate of disappearance of NASH was higher in patients with mild NASH than in

those with moderate or severe NASH

� 14.6% of patients had persistent NASH 1 year after bariatric surgery. These

patients had significantly lower weight loss, higher NAS and refractory IR profile

Bariatric surgery in cirrhosis

0,310,9

2,2

16,3

21,1

0

5

10

15

20

25

Mortality Adjuted Odd ratio

No cirrhosis

(n=670 950)

Compensated cirrhosis

(n=3 888)

Decompensated

cirrhosis (n=62)

Nationwide Inpatient

Sample, 1998-2007

Mosk, Clin Gastroenterol Hepatol 2011

In-h

osp

ita

lm

ort

ali

ty(%

)

• When should drug treatment be implemented?

– Naive :

• 4-6 mo of diet/lifestyle

• Treat if no effect and metabolically stable

– Counseling experienced :

• (Reinforce counseling prefessionally ?)

• Treat if metabolically stable

STEATOSIS

INFLAMMATION

FIBROSIS

A requiem for Metformin

Musso, Hepatology 2010

Glitazones - Biochemical Response

0,0

0,2

0,4

0,6

0,8

1,0

1,2

1,4

pALTM4 pALTM8p100ALTMp100ALTM pALTM20 pALTM24 pALTM28 pALTM32 pALTM36 pALTM40

M0 M16 M40

PLB - RSG

)

31

32

31/28*

32/25*

23

21

RSG - RSG

RSG - RSG

PLB - RSG

RCT OPEN-LABEL EXTENSION TRIAL

ALT

(fo

ld b

ase

lin

e)

Ratziu, Hepatology 2010

Trial Drug (mg/d)

Type

Belfort2006

FLIRT2008

Tetri2003

Promrat2004

Sanyal2004

Glitazones - Histological Improvement

Aithal2008

Pio/45 RCT/PLB

Rosi/8 RCT/PLB

Rosi/8 Open label

Pio/30 Open label

Pio/30

+Vit ERCT/Vit E

Pio/30 RCT/PLB

Sanyal2010

Pio/30 RCT/PLB

STEATOSIS

YES

YES

YES

YES

YES

NO

YES

BALLOONING

YES

NO

YES

YES

NO*

YES

INFLAMMATION

YES

NO

YES

YES

NO

NO*

YES YES

Trial Drug (duration)

Type

Belfort2006

Pio/6mo RCT/PLB

FLIRT2008

Rosi/12mo RCT/PLB

Tetri2003

Rosi/12mo Open label

Promrat2004

Pio/12mo Open label YES

Sanyal2004

Pio/6mo

+Vit ERCT/Vit E

NO

NO

NO

NO

Glitazones - Histological Improvement

IMPROVEMENTIN FIBROSIS

Drug A Drug B

∆ A vs. ∆ B

Aithal2008

Pio/30 RCT/PLB YES

Sanyal2010

Pio/30 RCT/PLB NO

Histological improvement in Vit E RCTs

Steatosis BallooningNASH

resolutionFibrosisInflammation

Harrison/1yr - - - - -

PIVENS/2yrs + + + + -

TONIC/2yrs - - + + -

Nobili/2yrs - - - - -

+ denotes improvement;

vs. placebo

Results of large UDCA RCTs

Lindor 2 yrs Low

Leuschner 2 yrs Medium No

URSONASH 1 yr High

Lindor, Hepatology 2004; Leuschner, Hepatology 2010; Ratziu, J Hepatol 2011

Study Duration DoseHistological

improvementALT

vs PLB

No No

No*

Yes

NAFLDNAFLD

NASHNASH

Liver

related

events

Liver

related

events

FIBROSIS

Proinflammatory

Pathways

SIMTUZUMAB

GR-MD-02

IMM – 124E

OCA

ARAMCHOL

LIRAGLUTIDE

NGM282

BMS 986036

Insulin

resistance

Obesity

Dyslipidemia

Oxidative

stress

ELAFIBRANOR

GS - 4997

CENICRIVIROC

ELAFIBRANOR – Phase IIb GOLDEN trial

Dual PPAR α/δ

274 adult patients with histological evidence of NASH ;

International RCT (Europe, US)

Elafibranor 80 mg Elafibranor 80 mg Elafibranor 120 mg Elafibranor 120 mg Placebo Placebo

1 year1 year

1 Endpoint:

Resolution of NASH with no

worsening of fibrosis

1 Endpoint:

Resolution of NASH with no

worsening of fibrosis

2nd Endpoint: Change in NAS, fibrosis, liver

enzymes, lipids, metabolic markers,

safety

2nd Endpoint: Change in NAS, fibrosis, liver

enzymes, lipids, metabolic markers,

safety

Ratziu, Gastroenterology 2016

GOLDEN 505 Primary Endpoint in ITT PopulationResolution of NASH without worsening of fibrosis

Protocol defined (resolution of any

of: steatosis or ballooning or

lobular inflammation)

17

2321

0

5

10

15

20

25

30

Placebo ELF 80 ELF 120

P = 0.28

1213

19

0

5

10

15

20

25

30

Placebo ELF 80 ELF 120

P = 0.28

Ratziu, Gastroenterology 2016

Modified definition (no

ballooning, none or mild

lobular inflammation)

31

2023

20 20

28

14

27

40

0

5

10

15

20

25

30

35

40

45

Mild (3) Moderate (4-5) Severe (6-8)

Placebo Elafibranor 80 mg Elafibranor 120 mg

NAS 2-point reduction according to Baseline NAS severity in

the ITT Population (n 274)

Ratziu, Gastroenterology 2016

-7,96

-25,45

5%

-3

-2,5

-2

-1,5

-1

-0,5

0

0,5

NAS Steatosis Ballooning Inflammation Fibrosis

GFT505 120 mg Responders GFT505 120 mg Non responders

***

p=0.06

***

**

***

NASH components

Ch

an

ge

in S

core

** : p<0.01

*** : p<0.001

Beneficial on NASH components and fibrosis improvement in

Responders to Elafibranor 120 mg

���� steatosis (���� lipid utilization)

���� Oxidative stress (CAT, SOD)

���� ALT, GGT, ALP

���� Hepatic hemodynamics

���� Atherogenic lipid profile

���� Endothelial dysf. (ET-1, RGS5, Nox)

���� Vessel Ox stress (CAT, GPx1, HO1)

���� Vessel inflam (ICAM1, MCP1)

���� Triglyceride clearance (APOC3)

���� VLDL-APOB & ����LDL-APOB

���� sd-LDL cholesterol level

���� HDL cholesterol level (APOA1/A2)

���� NEFA utilization (ACOX, CPT1, EHHADH)

���� NEFA level (lipolysis, β-oxidation)

���� NF-κB, ���� TLRs

���� TNFα, IL-1β

���� IL-6, CRP, SAA, HG, fibrinogen

���� Kupffer cell activation (BCL6)

���� Insulin sensitivity (Fgf21)

���� Hepatic glucose output (PEPCK, FAS, ACC, PDG, G6PDH)

���� insulin

���� Fibrogenesis (TGFβ1, αSMA, Col1α1)

���� Oxidative stress (CAT, SOD)

���� Inflammation(MCP-1, IL-6, TNFα)

FIBROSIS

LIVER

DYSFUNCTION

INFLAMMATION

CVD RISK

LIPID

METABOLISM

GLUCOSE

HOMEOSTASIS

PPARα/δ

ELAFIBRANOR – Pleiotropic effects

Relative Change (%) * : p<0.05

** : p<0.01

-16,03

-26,8

-10,11

-26,34

-31,3

-35

-30

-25

-20

-15

-10

-5

0

FPG Fasting Insulin Fructosamin C-peptide FFA

Glycemic parameters in diabetics

Effect size GFT505 120mg vs placebo (relative change %)

*

**

*

**

p=0,06

Re

lati

ve

Ch

an

ge

(%

)

-0,55

-0,43

0,11

-0,24

-0,17

TG CHOL HDL-C LDL-C VLDL-C

Effect size GFT505 120mg vs placebo (Absolute change - mmol/L)

***

**

***

***

***

** : p<0.01

*** : p<0.001

ELAFIBRANOR –effects on

glucose homeostasis and

lipids metabolism

FLINT Phase 2 Trial DesignThe Farnesoid X Receptor Ligand Obeticholic Acid (OCA) in NASH Treatment

N=283

Patients w/

Histological Evidence

of NASH

Placebo QD

Screening (Biopsy)

Follow up

OCA 25 mg QD Follow up

72 week Treatment Period 24 week off-drug

Primary endpoint: Histological improvement defined as:

• No worsening in fibrosis; and

• Decrease in NAS of ≥ 2 points

Interim Analysis when 50% of patients

completed treatment and had an end-

of-treatment liver biopsy

NASH CRN

Tetri, Lancet 2014

Top-line results of the FLINT trial

Tetri, Lancet 2014

NAS 2 pt reduction 46% (N:110) 21% (N:109) <0.001

Resolution of NASH 22% 13% 0.09

Improvement in fibrosis(>1 stage)

35% 13% 0.01

Change in fibrosis 0.011.9 -0.2 1.8 +0.1

All individual components of NAS improved

OCA Placebo

3538

31

19

53

61

46

35

0

10

20

30

40

50

60

70

80

Lobular

inflammation

Steatosis Hepatocellular

ballooning

Fibrosis

Pa

tie

nts

wit

h I

mp

rov

em

en

t (%

)

P <.01

FLINT—Improved Secondary

Histologic Outcomes at Week 72

P =.001

Abbreviation: OCA, obeticholic acid.

Neuschwander-Tetri BA, et al. Lancet. 2015;385:956-965.

P <.05

P <.01

Placebo (n = 109)

OCA 25 mg (n = 110)

72

Lipid Concentrations

1: Data from Tetri et al. The Lancet. Published online November 7, 2014. 2: All p-values compared to placebo. *p<0.05

3: Converted mean values using factor of 38.6 for cholesterol and 88.5 for triglycerides.

mg

/dl

+18

-27

mg

/dl

+29

-19

mg

/dl

+4

-6

mg

/dl

+19

-19

Tetri, Lancet 2014

Experimental Group

n=25

Liraglutide 0.6mg OD

(Days 1 – 7)

Liraglutide 1.2mg OD

(Days 8 – 14)

Liraglutide 1.8mg OD

(Days 15 – 336)

Control Group

n = 25

Placebo 1.2mg OD

(Days 8-14)

Placebo 1.8mg OD

(Days 15-336)

Placebo 0.6mg OD

(Days 1-7)

50 patientsRandomised, Double-blinded

(stratified: site, diabetes)

Liver Biopsy

Week 48 (visit 7)

LEAN ‘Liraglutide’s Efficacy & Action in NASH’

Inclusion criteria:

Normal BMI at inclusion

NASH Biopsy < 6mths

Age 18-70

T2DM or non-T2DM

(HbA1c <9.0%; no insulin)

Primary End-point:

Resolution of NASH

(disappearance of ballooning)

without worsening of fibrosis

Secondary End-points:

Changes in NAS

Safety; liver biomarkers;

metabolic

Armstrong, The Lancet, 2015

Liraglutide : primary end-point and

evolution of histological lesions

Liraglutide

(n = 23)

Placebo

(n = 22)p

Disparition de NASH et absence

d’aggravation de fibrose9 (39,1 %) 2 (9,1 %) < 0,05

Score de fibrose Kleiner

Amélioration, n (%)

Aggravation, n (%)

-0,2

6 (26,1 %)

2 (8,7 %)

0,2

3 (13,6 %)

8 (36,4 %)

ns

ns

< 0,05

Score NAS total -1,3 -0,8 ns

Ballonnisation

Amélioration, n (%)

-0,5

14 (60,9 %)

-0,2

7 (31,8 %)

Ns

0.05

Stéatose

Amélioration, n (%)

-0,7

19 (82,6 %)

-0,4

10 (45,5 %)

ns

< 0,05

Inflammation lobulaire

Amélioration, n (%)

-0,1

11 (47,8 %)

-0,2

12 (54,5 %)

ns

ns

Armstrong, The Lancet, 2015

Liraglutide

(n = 26)

Placebo

(n = 26)p

Métabolique

IMC (kg/m2)

Poids (kg)

TA systolique (mmHg)

HbA1c (%)

Glycémie (mmol/l)

HDL cholestérol (mmol/l)

-1,84

-5,25

-5,0

-0,49

-1,04

0,07

-0,27

-0,58

-3,0

0,04

0,73

-0,04

0,005

0,003

ns

0,074

0,006

0,014

Tests hépatiques

ALAT (UI/ml)

ASAT (UI/ml)

GGT (UI/ml)

Cytokératine 18 (UI/ml)

ELF test

-26,6

-15,8

-33,7

-185

-0,25

-10,2

-8,6

-7,2

-92

0,09

ns

ns

0,013

0,097

0,052

Liraglutide :effect on metabolic parameters and LFTs

Armstrong, The Lancet, 2015

Liraglutide : histological benefit independent of weight loss,

glycemic control or the presence of T2DM

Why is the response rate stuck between Why is the response rate stuck between

40 – 50%

Clinical

PhenotypesHistological

Phenotypes

Multiple

pathogenetic

pathways

COMPLEXITY OF

NAFLD

Potential approach to solve the problem

Therapeutic choice

Individual approaches to

Individual patient

Combination therapy

Nodal target of

strategic importance

NAFLD : treatment options

Lifestyle

modification

Bariatric

surgery

« specific » pharmacological treatment

Endoscopic treatement

« non specific » pharmacological treatment

Anti-inflammatory (pentoxyfylline)

Endoscopic bypass Intragastric balloon

FXR Agonist PPAR α/δ Agonist Cenicriviroc

Probiotics Others (ARA2, PUFA…)

Hepato-protective (UDCA)Antioxidant (vit E)

ASK-1 inhibitors Others…

Endoscopic sleeve Others…

Antidiabetics : Glitazones, GLP1 agonist