Identifying NASH in Patients With Diabetes: What You Need to Know

Juan Pablo Frias, MD, FACE

Dr. Juan Pablo Frias is Medical Director and Principal Investigator of National Research Institute in Los Angeles, California.

He completed his undergraduate studies at the University of Florida and received his medical degree from Vanderbilt University School of Medicine, Nashville, Tennessee. After serving 5 years as a General Medical Officer in the US Navy, he completed his training in Internal Medicine at Vanderbilt University and the University of Tennessee, and his Fellowship in Endocrinology, Diabetes, and Metabolism at the University of California, San Diego. Dr. FrĂ­as has held academic positions at the University of Colorado Health Sciences Center, the Barbara Davis Center for Diabetes, and the University of California San Diego School of Medicine, where he is currently on the clinical faculty. He has been involved in diabetes and metabolismrelated research for over 20 years and has authored numerous publications in this field.

Kenneth Cusi, MD, FACP, FACE

Dr. Kenneth Cusi serves as Chief of the Division of Endocrinology, Diabetes & Metabolism in the Department of Medicine at the University of Florida. He received his medical degree in Argentina from the University of Buenos Aires School of Medicine and is board certified in both Internal Medicine and Endocrinology, Diabetes, and Metabolism. He completed his residency at the Center of Medical Education and Clinical Research (CEMIC) in Buenos Aires, Argentina, and a clinical fellowship at Baylor College of Medicine in Houston, Texas. Prior to joining the University of Florida, Dr. Cusi was a faculty member for over 15 years in the Diabetes Division at the University of Texas Health Science Center at San Antonio (UTHSCSA) and the Veterans Health Administration System in Texas, which is one of the leading diabetes programs in the country. A fellow of the American College of Physicians (ACP) and the American Association of Clinical Endocrinologists (AACE), he has actively participated in many clinical diabetes programs and in the training of many young researchers and clinicians. He is the principal investigator of various ongoing clinical translational research projects in obesity, type 2 diabetes mellitus (T2DM), and nonalcoholic fatty liver disease (NAFLD).

Stephen A. Harrison, MD

Dr. Stephen Harrison earned his medical degree from the University of Mississippi School of Medicine in Jackson. He completed his internal medicine residency and gastroenterology fellowship at Brooke Army Medical Center and a fourthyear advanced liver disease fellowship at Saint Louis University, Missouri. He is board certified in both Internal Medicine and Gastroenterology. Dr. Harrison served as a Professor of Medicine at the Uniformed Services University of the Health Sciences and is currently a Visiting Professor of Hepatology at the Radcliffe Department of Medicine, University of Oxford, United Kingdom. Past Associate Editor for Hepatology, he is currently an Associate Editor for Alimentary Pharmacology and Therapeutics. He is a peer reviewer for over 20 medical journals and internationally known for studies in hepatitis C and nonalcoholic fatty liver disease with close to 200 peer-reviewed publications in these fields. Dr. Harrison most recently served as a Colonel in the United States Army. Retiring in 2016, he concluded 20 years of dedicated service to his country.

During his army tenure, he served as the Director of Graduate Medical Education at Brooke Army Medical Center, Associate Dean for the San Antonio Uniformed Services Health Education Consortium, and Gastroenterology Consultant to the Army Surgeon General. Currently, Dr. Harrison serves as the Medical Director for Pinnacle Clinical Research and the President of Summit Clinical Research.

Moderator Medical Director National Research Institute Los Angeles, California

Professor of Medicine Chief, Division of Endocrinology, Diabetes and Metabolism The University of Florida Gainesville, Florida

Medical Director Pinnacle Clinical Research San Antonio, Texas

Brent Neuschwander-Tetri, MD Professor of Internal Medicine Associate Chair for Clinical Trials Director, NASH Studies Unit Saint Louis University School of Medicine St. Louis, Missouri

Dr. Brent Neuschwander-Tetri completed his undergraduate studies at the University of Oregon and received his medical degree from Yale University, New Haven, Connecticut. He completed his internship and residency in internal medicine at the University of Wisconsin, Madison. He went on to a fellowship in gastroenterology and hepatology at the University of California, San Francisco (UCSF), working in the UCSF Liver Center Laboratory with Monty Bissell, Scott Friedman, and Jackie Maher. In 1991 he joined Bruce Bacon and the faculty at Saint Louis University in the Division of Gastroenterology and Hepatology. From 2010 to 2019 he served as Division Director before moving to a position as the Associate Chair for Clinical Trials in the Department of Internal Medicine. He is actively involved in clinical care of patients with liver disease, laboratory research, and clinical trials. His laboratory work has demonstrated severe NASH in mice fed trans fat, and he continues this work to understand why trans fat damage the liver. He is a founding member of the National Institutes of Health–supported NASH Clinical Research Network, the group that conducted the PIVENS and FLINT treatment trials for NASH, and he is a steering committee member of the international TARGET NASH consortium.

TARGET AUDIENCE

This activity is intended for endocrinologists, diabetologists, diabetes nurse specialists, and diabetes educators engaged in the management of patients with diabetes who are at risk of nonalcoholic steatohepatitis (NASH).

EDUCATIONAL OBJECTIVES

Upon completion of this activity, participants will be better able to

• Describe the epidemiology and interlinked pathophysiology of NASH and diabetes

• Utilize available noninvasive assessment tools for screening and diagnosis of NASH in patients with diabetes

• Evaluate the benefits and limitations of lifestyle modification and available antidiabetic therapies in patients with diabetes and NASH

PROGRAM OVERVIEW

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of potentially progressive liver disorders, ranging from simple hepatic steatosis to such severe forms as NASH and cirrhosis.1 The prevalence of both NAFLD and NASH has been steadily trending upward for years, mirroring the rapid and well-documented expansions of patient populations with obesity and type 2 diabetes mellitus (T2DM).2-4 More patients with T2DM have moderate to severe fibrosis, characteristic of NASH, than patients without T2DM.5 Thus, endocrinologists and other clinicians with a focus on diabetes management are essential to accelerating the identification of patients with NASH. Importantly, however, appropriate diagnostic and management approaches for patients with T2DM who have advanced fibrosis markedly differ from those for patients who have received an NAFLD diagnosis, and best-practice strategies are quickly evolving.6 Without any US Food and Drug Administration–approved treatments, lifestyle modification and antidiabetic therapies are the mainstay of treatment for NASH, though there are several ongoing clinical trials of therapies to treat NASH.7 During this Clinical Issues™ program, expert faculty will highlight epidemiologic and pathophysiologic relationships between NASH and T2DM, review clinical application of available noninvasive diagnostic and staging techniques, and discuss current and future management options.

REFERENCES 1.

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Haas JT, Francque S, Staels B. Annu Rev Physiol. 2016;78:181-205.

Hassan K, Bhalla V, El Regal ME, A-Kader HH. World J Gastroenterol. 2014;20(34):12082-12101.

Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Hepatology. 2018;67(1):123-133.

Calzadilla Bertot L, Adams LA. Int J Mol Sci. 2016;17(5):E774.

Koehler EM, Plompen EP, Schouten JN, et al. Hepatology. 2016;63(1):138-147.

Singh A, Lopez R, Le P, Alkhouri N. J Hepatol. 2017;66(suppl 1):S150.

Chalasani N, Younossi Z, Lavine JE, et al. Hepatology. 2018;67(1):328-357.

DISCLOSURE OF CONFLICTS OF INTEREST

Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COIs are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high-quality CME activities and related materials that promote improvements or quality in health care and not a specific proprietary business interest of a commercial interest.

The faculty reported the following financial relationships or relationships to products or devices they or their spouses/life partners have with commercial interests related to the content of this CME activity: Juan Pablo Frias, MD, FACE Consulting Fees: Eli Lilly and Company, Gilead Sciences, Inc., Merck & Co., Inc., Novo Nordisk, sanofi-aventis U.S. LLC; Speakers Bureau: Merck & Co., Inc., sanofi-aventis U.S. LLC; Contracted Research: AbbVie Inc., Akcea Therapeutics, Allergan, Inc., AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb Company, Cirius Therapeutics, CymaBay Therapeutics, Elcelyx Therapeutics, Inc., Eli Lilly and Company, Enanta Pharmaceuticals, Inc., Genentech, Intercept Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Johnson & Johnson, Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals Incorporated, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Mylan N.V., NGM Biopharmaceuticals Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., sanofi-aventis U.S. LLC Kenneth Cusi, MD, FACP, FACE Nothing to disclose Stephen A. Harrison, MD Consulting Fees: 3-V Biosciences, Akero Therapeutics, Inc., Albereo, Axcella Health, Inc., Blade Therapeutics, Bristol-Myers Squibb Company, Cirius Therapeutics, CiVI Biopharma Inc., CLDF, Contravir Pharmaceuticals, Consynance Therapeutics, Inc., Corcept Therapeutics Inc., CymaBay Therapeutics, Echosens, Galectin Therapeutics Inc., Galmed Pharmaceuticals Ltd., Genfit S.A., Gilead Sciences, Inc., HighTide Therapeutics Inc., HistoIndex Pte. Ltd., Innovate Biopharmaceuticals, IQVIA, Intercept Pharmaceuticals, Inc., Lipocine Inc., Madrigal Pharmaceuticals, Inc., Medpace, Inc., Metacrine, Inc., NGM Biopharmaceuticals Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Perspectum Diagnostics, Pfizer Inc., Pharmaceutical Product Development, LLC, Prometheus Laboratories Inc., Prometic Life Sciences Inc.; Stocks: Akero Therapeutics, Inc., Galectin Therapeutics Inc., Genfit S.A.,

Madrigal Pharmaceuticals, Inc., Metacrine, Inc.; Speakers Bureau: Alexion Pharmaceuticals, Inc.; Grants/Research Support: Axcella Health, Inc., Cirius Therapeutics, Conatus Pharmaceuticals Inc., CymaBay Therapeutics, Galectin Therapeutics Inc., Galmed Pharmaceuticals Ltd., Genfit S.A., Gilead Sciences, Inc., HighTide Therapeutics Inc., Immuron Ltd., Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., NGM Biopharmaceuticals Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Second Genome, Inc.; Tobira Therapeutics/Allergan, Inc. Brent Neuschwander-Tetri, MD Consulting Fees: Allergan, Inc., Arrowhead Pharmaceuticals, Inc., Blade Therapeutics, Boehringer Ingelheim, BristolMyers Squibb Company, Coherus BioSciences, Inc., Consynance Therapeutics, Inc., DURECT Corporation, Enanta Pharmaceuticals, Inc., Gelesis Inc., Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Lipocine Inc., Madrigal Pharmaceuticals, Inc., Medimmune, LLC, Merck & Co, Inc., Metacrine, Inc., NGM Biopharmaceuticals Inc., pH Pharma Co., Ltd., Prometheus Laboratories Inc., Siemens AG The PIM planners and managers have nothing to disclose. The Integritas Communications planners and managers have nothing to disclose.

JOINT ACCREDITATION STATEMENT

In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and Integritas Communications.

Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

PHYSICIAN CONTINUING MEDICAL EDUCATION

The Postgraduate Institute for Medicine designates this live activity for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

CONTINUING NURSING EDUCATION

The maximum number of hours awarded for this Continuing Nursing Education activity is 1.5 contact hours.

CALIFORNIA BOARD OF REGISTERED NURSING

Provider approved by the California Board of Registered Nursing, Provider Number 13485, for 1.5 contact hours.

DISCLOSURE OF UNLABELED USE

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the US Food and Drug Administration. The planners of this activity do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

DISCLAIMER

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

PROGRAM AGENDA 7:00 pm – 7:05 pm Introductions and Preactivity Questionnaire

Juan Pablo Frias, MD, FACE 7:05 pm – 7:25 pm

Appreciating the Scope and Pathophysiological Complexity of the NASH Problem Brent Neuschwander-Tetri, MD

7:25 pm – 7:50 pm Recognizing Patients at Highest Risk—What You Need to Know and DO Today Including Clinical Tools-in-Action Audience Participation

Stephen A. Harrison, MD 7:50 pm – 8:15 pm

Practical NASH-Management Strategies Kenneth Cusi, MD, FACP, FACE

8:15 pm – 8:30 pm

Postactivity Questionnaire and Question & Answer Session Juan Pablo Frias, MD, FACE

CLINICAL PRACTICE GUIDELINES

The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.

Chalasani N, et al. Hepatology. 2018;67(1):328-357.

EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.

European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), and European Association for the Study of Obesity (EASO). J Hepatol. 2016;64(6):1388-1402.

CLINICAL RESOURCES

Histological Scoring System for Nonalcoholic Fatty Liver Disease.

Transplant Pathology Internet Services, 2009.

MELD Score (Model for End-Stage Liver Disease) (12 and older).

MD+CALC online calculator, 2016.

NAFLD (Non-Alcoholic Fatty Liver Disease) Fibrosis Score.

MD+CALC online calculator.

Fibrosis-4 (FIB-4) Index for Liver Fibrosis.

MD+CALC online calculator.

AST to Platelet Ratio Index (APRI).

MD+CALC online calculator.

PATIENT RESOURCES

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Health Information Center.

The NIDDK website for NAFLD and NASH provides comprehensive patient-centered information and resources, including an overview of clinical trial participation.

SUGGESTED READING

Nonalcoholic fatty liver disease incidence and impact on metabolic burden and death: a 20 year-community study.

Allen AM, et al. Hepatology. 2018;67(5):1726-1736.

Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.

Armstrong MJ, et al. Lancet. 2016;387(10019):679-690.

Non-alcoholic fatty liver disease: an expanded review.

Benedict M, Zhang X. World J Hepatol. 2017;9(16):715-732.

Management of nonalcoholic fatty liver disease in patients with type 2 diabetes: a call to action.

Bril F, Cusi K. Diabetes Care. 2017;40(3):419-430.

The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD).

Buzzetti E, et al. Metabolism. 2016;65(8):1038-1048.

Combination therapy of metformin and statin may decrease hepatocellular carcinoma among diabetic patients in Asia.

Chen HH, et al. Medicine (Baltimore). 2015;94(24):e1013.

American College of Gastroenterology (ACG) Patient Education and Resource Center.

Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications.

The ACG website provides a basic overview of NAFLD and includes patient-centered podcasts.

Cusi K. Gastroenterology. 2012;142(4):711-725.

American Liver Foundation.

Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.

The American Liver Foundation website offers broad-based information and links to additional educational resources and support services for patients living with liver disease.

Cusi K, et al. Ann Intern Med. 2016;165(5):305-315.

Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes.

Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening.

Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis.

Cenicriviroc treatment for adults with non-alcoholic steatohepatitis: year 2 analysis of the phase 2b CENTAUR study.

Components of metabolic syndrome increase the risk of mortality in nonalcoholic fatty liver disease (NAFLD).

Management of NAFLD: a stage-based approach.

Cusi K, et al. Diabetes Obes Metab. 2018;21(4):812-821.

Dulai PS, et al. Hepatology. 2017;65(5):1557-1565.

Golabi P, et al. Medicine (Baltimore). 2018;97(13):e0214.

Noninvasive imaging methods to determine severity of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

Hannah WN Jr, Harrison SA. Hepatology. 2016;64(6):2234-2243.

A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease.

Musso G, Gambino R, Cassader M, Pagano G. Hepatology. 2010;52(1):79-104

Non-alcoholic fatty liver disease.

Neuschwander-Tetri BA. BMC Med. 2017;15(1):45.

Ratziu V, et al. Gastroenterology. 2016;150(5):1147-1159.

Ratziu V, et al. J Hepatol. 2018;68(suppl 1):S1-S2.

Rinella ME, Sanyal AJ. Nat Rev Gastroenterol Hepatol. 2016;13(4):196-205.

Treatment of NAFLD with diet, physical activity and exercise.

Romero-Gómez M, et al. J Hepatol. 2017;67(4):829-846.

Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease.

Wong VW, et al. Hepatology. 2010;51(2):454-462.

Positive results from REGENERATE: a phase 3 international, randomized, placebocontrolled study evaluating obeticholic acid treatment for NASH. Younossi Z, et al. J Hepatol. 2019;70(suppl 1):e5.