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