Verso linee guida europee su NAFLD/NASH

Verso linee
guida europee
su
NAFLD/NASH
Giulio Marchesini
SSD Malattie del
Metabolismo e Dietetica
Clinica
“Alma Mater Studiorum”
Università di Bologna
Disclosures
Giulio Marchesini
• Advisory Board: Sanofi
• Honoraria: Sanofi, Merck Sharp & Dome, Novartis
• Clinical Studies: Boehringer Ingelheim, Sanofi, Lilly,
Novo Nordisk, GILEAD, GENFIT, Janssen
Fatty liver - Publications
NAFLD – Le dimensioni del problema
Gli epatologi vedono solo i
casi più severi e non hanno
coscienza delle dimensioni
del problema
Obesità: 1 miliardo
di persone
sovrappeso o
obese nel mondo
Diabete: 380
milioni nel
mondo, ma 550
nel 2030
Bhala, Curr Pharma Des 2013
Documenti di riferimento
2003
CPG – Open questions
Nascimbeni, J Hepatol 2013
EASL – EASD - EASO
G Marchesini
CP Day
J-F Dufour
A Canbay
V Nobili
V Ratziu
H Tilg
M Roden
A Gastaldelli
H Yki-Jarvinen
F Schick
R Vettor
L Mathus-Vliegen
G Frühbeck
GPC alignement
Spectrum of NAFLD and Risk of
Disease Progression
NAFL
Steatosis
alone
NASH
Steatosis &
inflammation
NASH
Potential for progression
Abbreviations: NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.
Pais R, et al. J Hepatol. 2013;59:550-556. Graphic courtesy of Vlad Ratziu, MD.
Genetic and NAFLD
PNPLA3
TM6SF2
Petta, World J Gastroenterol in press
Genetic and NAFLD
Genetic and NAFLD
Dongiovanni, Hepatology 2015
Progression of fibrosis in NASH
NASH + stage
0+1 fibrosis
3%
16%
52%
9%
F2 fibrosis
16%
25%
Advanced
(F3) fibrosis
25%
38%
25%
Singh, Clin Gastroenterol Hepatol 2015
16%
Cirrhosis
Non invasive markers
• Supplementary Table for NAFLD/NASH
Treatment
• Insulin sensitizers
– Metformin, Pioglitazone
• Cytoprotective/Antioxidants
– UDCA, Vitamin E
• New treatments (?)
– Debate on GLP-1, obeticholic acid & Elafibranor
Agreed outcome:
NASH resolution, no worsening of fibrosis
• Supplementary Table for NAFLD/NASH
Target-Based Drug Classes for NASH
Class
Drug
Breakthrough status*
Farnesoid X receptor (FXR) agonist
Obeticholic acid
Anti-lysyl oxidase-like 2 monoclonal
antibody
Simtuzumab
Fatty acid/bile acid conjugate
Aramchol
Dual inhibitor of CCR2 and CCR5
Cenicriviroc
Dual peroxisome proliferatoractivated receptor alpha/delta
agonist (Elafibranor)
GFT505
Galectin-3-inhibitor
GR-MD-02
*US Food and Drug Administration.
Fast Track status*
Fast Track status*
Fast Track status*
Fast Track status*
LEAN Trial design
52 patients¶
Randomised, Double-blind
(stratified: site (n=4), diabetes)
Experimental Group
n=26
Liraglutide 0.6mg OD
(Days 1 – 7)
Liraglutide 1.2mg OD
Control Group
Inclusion criteria:
NASH Biopsy < 6mths
Age 18-70
T2DM or non-T2DM
BMI ≥ 25
(HbA1c <9.0%; no insulin)
(Days 8 – 14)
Liraglutide 1.8mg OD
Armstrong, BMJ open, 2013
Placebo 0.6mg OD
(Days 1 – 7)
Placebo 1.2mg OD
(Days 8 – 14)
Week 48 (visit 7)
(Days 15 – 336)
¶ Sample Size:
-A’Herns phase II design
-To warrant further
investigation = improvement
in at least
8 out of 21 patients
n=26
Placebo 1.8mg OD
(Days 15 – 336)
Primary End-point:
Disappearance in NASH
+
no worsening of fibrosis
‘Drug washout’
Week 72 (visit 8)
Secondary End-points:
Histology; safety; biomarkers;
Metabolic, questionnaires
Histological end-points
Liraglutide
(n=23)
Primary outcome
Resolution of definite NASH
+ no worsening of fibrosis
9 (39.1%)
Placebo
(n=22)
*
2 (9.1%)
Secondary outcomes
Kleiner Fibrosis
n (%) improvement
n (%) worsening
-0.2 (0.8)
6 (26.1%)
2 (8.7%)*
0.2 (1.0)
3 (13.6%)
8 (36.4%)
Total NAFLD Activity Score
-1.3 (1.6)
-0.8 (1.2)
Hepatocyte ballooning
n (%) improvement
-0.5 (0.6)
14 (60.9%)
-0.2 (0.6)
7 (31.8%)
Steatosis
n (%) improvement
-0.7 (0.8)
19 (82.6%)*
-0.4 (0.8)
10 (45.5%)
Lobular inflammation
n (%) improvement
-0.1 (0.6)
11 (47.8%)
-0.2 (0.5)
12 (54.5%)
*p<0.05 vs. placebo (Chi-squared)
Mean (SD) change from baseline to week 48 biopsy
Comprehensive lifestyle approach
Area
Suggested intervention
Supportive literature*
Energy restriction
•
500-1000 kcal energy defect, to
induce a weight loss of 500-1000
g/week
Calorie restriction drives weight loss and the
reduction of liver fat, independent of the
macronutrient composition of the diet [138]
•
7-10% total weight loss target
•
Long-term maintenance approach,
combining physical activity according
to the principles of cognitivebehavioural treatment
Low-to-moderate fat and moderateto-high carbohydrate intake
Low-carbohydrate ketogenic diets or
high-protein
A 12-month intensive lifestyle intervention
with an average 8% weight loss leads to
significant reduction of hepatic steatosis
[139].
Hepatic fat increases along with total body fat
regain, but most of the beneficial metabolic
effects are maintained and progression to
T2DM is delayed [140].
Adherence to the Mediterranean diet has
been reported to reduce liver fat on 1H-MRS,
when compared with a low fat/high
carbohydrate diet in a cross-over comparison
[141, 142].
In the general population, an association has
been reported between high fructose intake
and NAFLD [9]
Macronutrient
composition
•
•
Fructose intake
•
Avoid fructose containing beverages
and foods
Comprehensive lifestyle approach
Area
Suggested intervention
Supportive literature*
Alcohol intake
•
Strictly keep alcohol below the risk
threshold (30g, men; 20g, women)
Coffee drinking
•
No liver-related limitations
Exercise/physical
activity
•
150-200 min/week of moderate
intensity aerobic physical activities in
3-5 sessions are generally preferred
(brisk walking, stationery cycling)
Resistance training is also effective
and promotes musculoskeletal
fitness, with effects on metabolic risk
factors.
High rates of inactivity-promoting
fatigue and daytime sleepiness
reduce compliance with exercise.
In epidemiological surveys, moderate alcohol
intake (namely, wine) below the risk threshold
is associated with lower prevalence of NAFLD,
NASH and even lower fibrosis at histology
[143-145]. Total abstinence is mandatory in
NASH-cirrhosis to reduce the HCC risk [146].
Protective in NAFLD, as in liver disease of
other aetiologies, reducing histological
severity and liver-related outcomes [147].
Physical activity follows a dose-effect
relationship and vigorous (running) rather
than moderate exercise (brisk walking) carries
the full benefit, including for NASH and
fibrosis [141, 148, 149]
Any engagement in physical activity or
increase over previous levels is however
better than continuing inactivity.
•
•
Proportion of patients achieving
improvement in histological outcomes
60
50
47
48
50
39
40
30
25
19
20
15
10
72/293
138/293
NASH
resolution
NAS
142/293
147/293
115/293
56/293
44/293
Fibrosis
regression
Portal
inflam.
0
Steatosis Lob. Inflam. Ballooning
Components of NAS
NASH resolution and NAS improvement
rates according to WL (%) categories
P<0.001*
P<0.001*
100%
100%
90%
90%
88%
26%
26%
80%
70%
64%
62%
60%
50%
40%
32%
30%
26%
20%
10%
0%
10%
21/205
9/34
16/25
26/29
Steatohepatitis resolution
Weight loss <5%
Weight loss 5-7%
Vilar-Gomez, Gastroenterology 2015
66/205
21/34
22/25
29/29
Two points improvement in NAS
Weight loss 7-10%
Weight loss ≥10%
Weight loss and fibrosis at histology
90%
84%
80%
74%
70%
63%
60%
55%
50%
45%
40%
30%
20%
18%
16%
21%
16%
10%
8%
33/205
6/34
4/25 13/29
129/205 25/34
21/25
16/29
43/205
3/34
0%
0%
0/25
0/29
0%
Regressed
Weight loss <5%
Vilar-Gomez, Gastroenterology 2015
Stabilized
Weight loss 5-7%
Weight loss 7-10%
Worsened
Weight loss >10%
Bariatric surgery and NASH resolution
Lassailly, Gastroenterology 2015
Flow-chart
Legend:
1 Steatosis biomarkers: Fatty Liver
Index, SteatoTest, NAFLD Fat
score (see Tables)
2 Liver tests: ALT AST, γGT
3Any increase in ALT, AST or γGT
4 Serum fibrosis markers: NAFLD
Fibrosis Score, FIB-4,
Commercial tests (FibroTest,
FibroMeter, ELF)
5 Low risk: indicative of no/mild
fibrosis; Medium/high risk:
indicative of significant fibrosis
or cirrhosis (see Tables)
Weight loss for a Healthy Liver
Class
Treatment/Drug
CBT program
Study duration Sample
Primary Outcome
Results
12 months
31 overweight/ obese
NASH
Behavior treatment
1 year
293 NASH
NAS improvement ≥ 3
points
Post-treatment NAS ≤ 2
points
NASH remission, no
worsening of fibrosis
Change in NAS score ≥ 3,
61% vs. 21% in C; P =0.04
Post-treatment NAS ≤ 2,
67% vs. 20% in C
NASH remission, 25%
∆ NAS score ≥ 2, 25%
Bariatric surgery (mainly
LAGB or GBP)
1 year
109 morbidly obese
NASH
72 weeks
283 non-cirrhotic NASH
(interim analysis on 219
cases)
48 weeks
52 NASH patients (45
available at F-UP)
12 months; 270 NASH
patients (234 at F-UP)
NASH remission
NASH remission, 85%
Fibrosis improvement in
34%
Change in NAS score ≥ 2,
45% vs. 21% in PL;
NASH remission, 22% vs.
13% in PL; P =0.08
NASH remission (39% vs.
9% in PL; P =0.035)
FXR agonists
Obeticholic acid (FLINT
trial)
GLP-1R agonists
Liraglutide (LEAN
program)
Dual PPAR α/δagonists
GENFIT505 (GOLDEN
trial)
Marchesini, Gastroenterology 2015
NAS improvement ≥ 2
points), no worsening of
fibrosis
NASH remission, no
worsening of fibrosis
NASH resolution, no
worsening of fibrosis
NASH resolution GFT505
vs. PL; P =0.016,
RR=2.03)
Conclusions
• The data have been retrieved by an extensive PubMed search
up to 04/2015.
• The final statements are graded according to level of evidence
and strength of recommendation, which are adjustable to local
regulations and/or team capacities.
• The document is intended both for practical use and for
advancing the research and knowledge of NAFLD in adults, with
specific reference to paediatric NAFLD, whenever necessary.
• The final purpose is to improve patient care and awareness of
the importance of NAFLD, and to assist stakeholders in the
decision-making process by evidence-based data, also
considering the burden of clinical management for the
healthcare system.