Upload
others
View
2
Download
0
Embed Size (px)
Citation preview
NaimAlkhouri,MDDirectoroftheMetabolicCenter
TexasLiverInstitute
NAFLDandNASH:UrgentNeedforDiagnosisandManagementoftheGrowingProblem
• EpidemiologyandNaturalHistoryofNAFLD.
• CurrentChallenges:• Screeningisnotindicatedeveninhigh-riskpopulations• ThereisnoFDA-approvedtreatmentforNAFLD
• DiscussthemanagementofNAFLDtoday.
Overview
MetabolicSyndrome• InsulinResistance• Dyslipidemia• Hypertension
NAFLDistheHepaticManifestationofObesity/IR
NAFLD
Adults• Overall: ~ 30%• Obese: ~ 50-70%• SeverelyObese: 85%• DM2: ~ 65-75%
Children• Overall: ~ 10%• 15-19years: ~ 17%• Obese: ~ 50%
Loombaetal.NatureReviews2013;Schwimmer etal.Pediatrics 2006.
NAFLDPrevalence
80-100Million
NAFL NASH/ Fibrosis
NASH Cirrhosis HCC
TheNAFLDSpectrum
AnnualCumulativeIncidenceofHCC
Ascha MSetal.Hepatology.2010.
2.6%/Year
4%/Year
Prop
ortio
nwith
HCC
2.50.0 7.55.0 12.510.0 17.515.0 20.00.0
0.2
0.4
0.6
0.8
1.0HCVNASHP=0.099
Yearssincecirrhosisdiagnosis
HCCintheAbsenceofCirrhosisinUSVeterans
El-Serag Hetal. CGH2015
Percen
t
NAFLD HCV HBV Alcoholabuse
Idiopathic
66.2
33.8
88.9
11.0
92.3
7.7
91.1
8.9
65.4
34.6
0
20
40
60
80
100
Cirrhosis Nocirrhosis
FrequencyofNASHasaCauseofLiverTransplantationinAdults
Charltonetal.Gastroenterology.2011
ALD HBV NASH PSC PBC AIH
200120022003200420052006200720082009
Freq
uenc
y as
indi
catio
n (%
)
0
5
10
15
20
• HCVistheunderlyingcauseoflivertransplantationinadultsin~35%
Screeningisnotindicatedeveninhigh-riskpopulations
AASLDNAFLDGuidelines2012
Challenge1
à PortalhypertensioncomplicationsarefrequentlythefirstpresentationofNAFLDinpatientsundergoingLTevaluation
• 124consecutivepatientswhounderwentLTevaluationforNAFLD-cirrhosis.
• 60%haddiabetes,meanBMIof33.2kg/m2.• 85/124(68.5%)hadnoknowledgeofpre-existingNAFLDpriorto
presentingwithsymptomsofportalhypertension.
WhathappensifwedonotscreenforNAFLD?
AlkhouriNetal.DigDisSci.2016
PresentingSymptoms
52
15
21
8 8 Ascites
BleedingVarices
HepaticEncephalopathy
Cytopenia
OtherSymptoms
AlkhouriNetal.DigDisSci.2016
CurrentScreeningforNAFLD:ALTandUltrasonography
LeeSSetal.WJG.2014
DegreeofSteatosis
0
20
40
60
80
5-9% 10-19% 20-29% ≥30%
Sensitivity(%
)
USCannotStagetheSeverityofFibrosisinPatientswithNAFLD
StagingtheSeverityofSteatosisandFibrosisinNAFLD:VCTE+CAP
Actuator
ShouldweScreenDiabeticPatientsforFattyLiverandAdvancedFibrosis?• KwokR.etal.TheChineseUniversityofHongKong• CAPandLSMweremeasuredbyFibroscan®inconsecutivepatientswho
attendedthediabetesclinic
KwoketalGut.2016
PrevalenceofNAFLDandAdvancedFibrosis
42.3%
31.6%
5.1% 20.9% S3
S2
S1
S0
Steatosis gradebyCAP(n=1639):Overall,79.1%ofpatientshadfattyliver.
11.6% 5.8%
82.7%
F4
F3
<F3
FibrosisstagebyLS(n=1877):Overall,17.4%ofpatientshadadvancedfibrosisorcirrhosis.
KwoketalGut.2016
ThereisnoFDA-approvedtreatmentforNAFLD
Challenge2
• Elafibranor:PPARα-δagonist(RESOLVEIT)
• Obeticholic acid(OCA):FXRagonist(REGENERATE)
• Cenicriviroc (CVC):CCR2/CCR5inhibitor(STELLARIS)
• Selonsertib: Apoptosissignal-regulatingkinase(ASK1)inhibitor(STELLAR-3and-4)
TheRacetoCureNASH:FourMedicationsinPhaseIIIControlledTrials
- Steatosis
- MetabolicStress- BileAcids
- Inflammation- CellInjury- Apoptosis
- Fibrosis
DNLFFAIR
Highresponserateinmoderate/severeNASH
• Elafibranor:PPARα-δagonist• PhaseIItrialof274patientswithbiopsy-provenNASH,NAS≥3,AnyFibrosisStage (N=274)
PrimaryEndpoint:ReversalofNASH
Ratziu Vetal.Gastroenterology 2016
ElafibranorEfficacyat52Weeks(GOLDEN)
Neuschwander-Tetri etal.Lancet 2015
OCAEfficacyat72Weeks(FLINT)• OCA:FXRagonist,25mgdaily• PhaseIIb trialof283patientswithNASH(NAS≥4)
Pts(%)
n/N=
21
45
100
80
60
40
20
0 ImprovementinNAS≥2PointsWithNoWorsening
ofFibrosis
1322
ResolutionofNASH
P=.08(NS)
P=.0002
ImprovementinFibrosis
P=.004
1935
OCA25mg/dayPlacebo
• RuleoutotheretiologiesofelevatedALTorfattyinfiltrationoftheliver
• Assessforco-morbidities(DM2,HTN,Dyslipidemia,OSA)• Assessseverity(NASH,advancedfibrosis)• Treatment:
• Lifestyle• Pharmacologic
HowDoIManageMyPatientwithNAFLD
LaboratoryAssessmentforNAFLD
ChronicLiverDiseasePanel NASHPanel
AssessmentoftheSeverityofNAFLD
PatientwithNAFLD
NFS+VCTE
NFS<-1.455and
LSM<7kPaDiscordantresults
NFS>0.676and
LSM>10kPa
• Noadvancedfibrosis• Considerrepeatingevery2-3years LiverBiopsy
• Advancedfibrosis• Screenforcirrhosiscomplications
• USevery6months
AlgorithmforAssessingtheSeverityofNAFLD
Treatment:%WeightLossAssociatedWithHistologicalImprovement
HannahWN,etal.Clin LiverDis.2016
Weight loss ≥ 10%
Bacchi Eetal.Hepatology.2013
BothResistanceTrainingandAerobicTrainingReduceHepaticFatContent
Baseline Baseline
AerobicTrainingResistanceTraining
*
Hepaticfatcon
tent,%
0
10
20
30
40
AerobicTraining
Percen
tchangefro
mbaseline
Inhep
aticfatcon
tent,%
-45
-10
-20
-30
0
ResistanceTraining
-25
-15
-5
-4-35
Moderate/VigorousExercise:30-45min/day
ChangingtheAttitudeTowardHealthyLifestyleinTexas
• 247patientswithNASHandw/oDM• Pioglitazone:30mg/d• VitaminE:800IU/d• Placebo
• Primaryoutcome: ImprovementinhistologicfeaturesofNASH• VitaminEwassuperiortoplacebo(43%vs.19%);however,therewasno
benefitofpioglitazonefortheprimaryoutcome(34%vs.19%)
Sanyal AJetal.NEngl JMed.2010
ResolutionofNASHwithVitaminEandPioglitazoneComparedtoExperimentalDrugs
Pts(%)
3621 22
13
85
6
47
21
39
9
Vitamin E 800 IU/day
Pioglitazone 30 mg/day
OCA 25 mg/day
100
80
60
40
20
0Cenicriviroc150 mg/day
P = .05
P = .001
P = .08
TreatmentPlacebo
n/N= 9/23
70/82
• Resultsfromdifferentstudies(notheadtoheadcomparison)• Patientpopulationandtimepointsaredifferent
8
P = .49
SanyalAetal.NEJM 2010
• VitaminE:Increasedoverallmortality/stroke/prostatecancer
• Pioglitazone:Increasedriskofbladdercancer,osteoporosis/?HF
ManagementofNAFLD:LessonsfromType2Diabetes
Copyright 2017 American Medical Association. All rights reserved.
Dipeptidyl peptidase 4 inhibitors maintain endogenous GLP1concentrations, modestly lower blood glucose, are weight neutral,and do not cause hypoglycemia.
Injectable GLP1RA increases GLP1 to pharmacological levels,robustly lowers blood glucose level, and facilitates weight losswithout a risk for hypoglycemia (except when used with insulin orsulfonylureas). Glucagon-like peptide 1 can be associated with tran-sient nausea and vomiting (lasting 1-3 months). It is essential to com-municate with the patient about the risk of nausea prior to titrationwith GLP1RA agents and, if needed, treat the gastrointestinal ad-verse effects to improve adherence. Recently published trials on car-diovascular outcomes demonstrate a cardiovascular benefit of 2agents in this class: liraglutide7 and semaglutide.8
Sodium Glucose Transporter 2Sodium glucose transporter 2 inhibitors decrease renal reabsorptionof glucose in the proximal tubule by blocking the sodium glucose
transporter 2, leading to glycosuria. These agents effectively lowerhemoglobin A1c level without causing hypoglycemia. Potential adverseeffects include polyuria, diuresis, blood pressure lowering, weight loss,ketoacidosis, and increased genital infections. These agents, however,do not increase the risk of urinary tract infections. The empagliflozincardiovascular outcomes trial demonstrated a significant decreasein all-cause mortality and heart failure9 and the FDA recently recom-mended approval for a cardiovascular indication.
Effective Use of InsulinA patient with hemoglobin A1c level greater than 9% (goal of <7%)taking metformin and noninsulin medications will require insulintherapy.3,6 Patient- or clinician-guided titration of basal insulin to fast-ing blood glucose goals is safe and effective. A common strategy isto start with a low dose of long-acting insulin at bedtime (approxi-mately 10 units) and titrate to a fasting blood glucose level of lessthan 120 mg/dL. This starting dose will not cause hypoglycemia, butinsulin titration is crucial (30-50 units usually will be needed).
Basal insulin can be added to any regimen. It is safe and effectiveto combine basal insulin with metformin, GLP1RA, SGLT2, or pioglita-zone to achieve glucose control. Two formulations of single-injectiontherapycombininglong-actinginsulinandGLP1wererecentlyapprovedbytheFDA.Thiscombinationdemonstratesexcellentglucose-loweringeffects, weight neutrality or weight loss, and minimal cases of hypo-glycemia. Consideration of efficacy, adverse effects, and cost of eachmedication is necessary to improve adherence and outcomes.
SummaryPatient-centered diabetes management can be accomplished withlifestyle modification and combination therapy. Metformin is an op-timal first-line agent; newer GLP1 and SGLT2 agents have efficacyfor glucose lowering coupled with weight loss and potential cardio-vascular risk reduction; and insulin therapy is generally safe and ef-fective for patients not controlled with noninsulin agents. In younger,healthy, newly diagnosed patients, a hemoglobin A1c level less than7% should be the goal; in older individuals with comorbidities, lessstringent goals with a focus on safety and avoidance of hypoglyce-mia are critical. Antihyperglycemic therapy should be combined withevidence-based treatment of cholesterol and blood pressure for car-diovascular risk reduction. Although the cardiovascular benefits ofSGLT2 and GLP1 agents merit consideration, these medications arenot replacements for statin therapy or blood pressure manage-ment for reducing the risk of cardiovascular disease.
ARTICLE INFORMATION
Published Online: March 1, 2017.doi:10.1001/jama.2017.0241
Conflict of Interest Disclosures: The authors havecompleted and submitted the ICMJE Form forDisclosure of Potential Conflicts of Interest.Dr Reusch reported receiving grant funding fromAstraZeneca and Merck; and serving on the boardof directors for the American Diabetes Association.No other disclosures were reported.
REFERENCES
1. US Centers for Disease Control and Prevention.Diabetes statistics. http://www.cdc.gov/diabetes/data/statistics/2014statisticsreport.html. AccessedJanuary 4, 2017.
2. American Diabetes Association. Diabetesstatistics. http://www.diabetes.org. AccessedJanuary 4, 2017.
3. Inzucchi SE, Bergenstal RM, Buse JB, et al.Management of hyperglycemia in type 2 diabetes,2015. Diabetes Care. 2015;38(1):140-149.
4. Sherr D, Lipman RD. The diabetes educator andthe diabetes self-management educationengagement. Diabetes Educ. 2015;41(5):616-624.
5. Holden SE, Jenkins-Jones S, Currie CJ.Association between insulin monotherapy versusinsulin plus metformin and the risk of all-causemortality and other serious outcomes. PLoS One.2016;11(5):e0153594.
6. Garber AJ, Abrahamson MJ, Barzilay JI, et al.Consensus statement by the American Association
of Clinical Endocrinologists and American College ofEndocrinology on the comprehensive type 2diabetes management algorithm—2016 executivesummary. Endocr Pract. 2016;22(1):84-113.
7. Marso SP, Daniels GH, Brown-Frandsen K, et al.Liraglutide and cardiovascular outcomes in type 2diabetes. N Engl J Med. 2016;375(4):311-322.
8. Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6Investigators. Semaglutide and cardiovascularoutcomes in patients with type 2 diabetes. N Engl JMed. 2016;375(19):1834-1844.
9. Zinman B, Wanner C, Lachin JM, et al;EMPA-REG OUTCOME Investigators. Empagliflozin,cardiovascular outcomes, and mortality in type 2diabetes. N Engl J Med. 2015;373(22):2117-2128.
Figure. Glucose Management for Patients With Type 2 Diabetes
1 Diabetes education on self-managementLifestyle interventions
3%-5% weight loss150 min/wk exercise
2 Add metformin
3 Add a second antihyperglycemic drug
SUPioBasalinsulinaDPP4 SGLT2aGLP1RAa
HbA1c
Weight
Hypoglycemia
MACE
HF
No effect No effectNo effect No effect
No effect
No effect
No effect
No effect
No effectto
HbA1c Glucose management for patients with type 2 diabetes
6.5%
5.7%
>9.0%
AAD
IAT
BE
BE
SE
SR
EP
DIA
TB
EE
S
4 Add basal insulina ± prandial insulina or SGLT2a or GLP1RAa
DPP4 indicates dipeptidyl peptidase 4 inhibitors; GLP1RA, glucagon-likepeptide 1 receptor agonists; HbA1c, hemoglobin A1c; HF, heart failure;MACE, major adverse cardiovascular events; Pio, pioglitazone; SGLT2, sodiumglucose transporter 2 inhibitors; and SU, sulfonylureas.a Indicates a higher-cost drug.
Opinion Viewpoint
E2 JAMA Published online March 1, 2017 (Reprinted) jama.com
Copyright 2017 American Medical Association. All rights reserved.
Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/jama/0/ on 03/01/2017
Reusch JEBetal.JAMA 2017
NAFL
NASH
Advanced Fibrosis
LifestyleIntervention:• 7-10%weightloss+• Exercise
1
ManageCo-morbidities• Metformin/ACE-I/Statin
2
NASHSpecificRx• VitaminE,Pioglitazone• Obeticholic Acid(OCA),
Elafibranor
3
Anti-fibrotics• Cenicriviroc (CVC),
Selonsertib• Emricasan
4
• NAFLDisverycommonandapotentiallyseriousliverdiseaseevenamongchildrenandyoungadults.
• ScreeningforNAFLDinprimarycare,diabetesorobesityclinicsshouldbeconsidered.
• NASH-specifictherapiesarecomingsoonandshouldchangetheattitudetowardscreeningandtreatment.
TakeHomeMessages