The Effect of Empagliflozin on NAFLD in Asian Patients With Type 2 Diabetes

Non-Alcoholic Fatty Liver Disease( NAFLD) is common in patients with type 2 diabetes. Empagliflozin, an FDA-approved oral medication used to treat type 2 diabetes, has been shown to reduce production and deposition of fat in the liver in animal experiments. There is little published evidence that this is so in Asian patients with type 2 diabetes. The investigators designed this pilot study to determine if use of empagliflozin for 6 months in patients with type 2 diabetes can improve scan, blood marker and biopsy features of NAFLD.

Study Overview

• Status: Unknown
• Conditions: NAFLD; Type2 Diabetes
• Intervention / Treatment: Drug: Empagliflozin

Detailed Description

Empagliflozin, an FDA-approved SGLT2 (Sodium glucose transporter 2) inhibitor used to treat type 2 diabetes, has been shown to reduce hepatic de novo lipogenesis and hepatic steatosis in animal models. There is little published evidence that this is so in Asian patients with type 2 diabetes. The investigators designed this open label proof of concept trial to determine if use of empagliflozin for 6 months in patients with type 2 diabetes can improve biomarkers and histological features of biopsy proven NAFLD.

Hypotheses

1. 6 months of empagliflozin will result in improved histology on liver biopsy in type 2 dm patients with NAFLD

2.6 months of empagliflozin will result in changes in liver enzymes, adipocytokines and FGF levels in type 2 dm patients with NAFLD

3.6 months of empagliflozin will result in improved liver stiffness measurement in type 2 dm patients with NAFLD

Study protocol

This is a prospective open-label proof-of-concept study. The investigators plan to recruit 25 Asian patients with biopsy-proven NASH and type 2 diabetes and commence them on empagliflozin 25 mg daily for 6 months. Upon recruitment clinical information will be obtained via an interview and use of a structured questionnaire. Anthropometric measurements will be obtained at baseline and 6 months. A repeat liver biopsy will be performed after 6 months of empagliflozin therapy. MRI and fibroscan of the liver will be conducted at baseline and 6 months. Fasting blood samples will be drawn for glucose, insulin, c-peptide, triglyceride, HDL, LDL, total cholesterol, NEFA(non-esterified fatty acid), HbA1c , liver function test(including albumin, AST, ALT, gamma GT, uric acid, inflammatory markers, FGF(fibroblast growth factor) and other biomarkers at baseline and 6 months.

Patients will be reviewed by a physician at 1 month and 6 months for development of any potential adverse events while on empagliflozin therapy.

Patients will be instructed not to make any significant changes to diet and lifestyle in these 6 months in order to assess to full effect of the intervention with no possible confounding factors.

• Study Type: Interventional
• Enrollment (Anticipated): 25
• Phase: Phase 4

Contacts and Locations

Study Locations

• Malaysia
  • Wilayah Persekutuan
    • Kuala Lumpur, Wilayah Persekutuan, Malaysia
      • Recruiting
      • University of Malaya
      • Contact: Shireene R Vethakkan, MD; Phone Number: 0162093355; Email: shireene.vethakkan@gmail.com
      • Sub-Investigator: Wah K Chan, MRCP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• biopsy proven NASH
• Type 2 DM
• HbA1c :>6.5%
• BMI < 45kg/m2
• Any anti-diabetic agent except SGLT2 inhibitors, TZDs(thiazolidinediones), DPP4(Dipeptidyl peptidase4) inhibitors and GLP1 RAs(Glucagon-like Peptide 1-Receptor Agonists)

Exclusion Criteria:

• eGFR <45 ml/min
• structural and functional urogenital abnormalities, that predispose for urogenital infections
• Investigational product use in the last 6 months
• SGLT2 inhibitor, TZD, DPP4 inhibitor and GLP1 RA use within the past 6 months
• DKA(Diabetic Ketoacidosis) or HHS(Hyperosmoloar Hyperglycaemic Syndrome) within the last 6 months
• Pregnancy
• Presence of major contraindications to magnetic resonance imaging (cardiac pacemakers, claustrophobia, foreign bodies and implanted medical devices with ferromagnetic properties).
• Liver cirrhosis
• Type 1 diabetes
• Severe uncorrected insulin insufficiency
• Significant alcohol intake
• HIV infection
• Use of Traditional Chinese Medication or alternative therapies
• Coexisting causes of chronic liver disease - chronic viral hepatitis(B & C), autoimmune liver disease, hemochromatosis, Wilson's etc.
• Use of medications associated with steatosis eg. Methotrexate, anticonvulsants, antiretroviral therapy etc.
• h/o stroke
• Steroid therapy
• Endogenous Cushing's
• Familial hypertriglyceridemia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Interventional arm; Patients with NAFLD and Type 2 Diabetes prescribed 25mg empagliflozin(JARDIANCE) daily for 6 months	Drug: Empagliflozin; 25 mg daily for 6 months; Other Names: Jardiance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in histological Grade as evaluated with Non-alcoholic Steatohepatitis Clinical Research Network Scoring System	liver biopsy	baseline, 6 months
Change in serum FGF 21	blood test	baseline and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in fibroscan and elastography measure of liver stiffness	imaging	baseline and 6 months
Change in Liver enzymes	blood test - AST,ALT, gamma GT	baseline and 6 months
Change in steatosis	histological	baseline and 6 months
Change in lobular inflammation	histological	baseline and 6 months
Change in ballooning	histological	baseline and 6 months
Change in fibrosis	histological	baseline and 6 months
Change in metabolic outcome -HbA1c	serum concentration	baseline and 6 months
Change in metabolic outcome - fasting NEFA	serum concentration	baseline and 6 months
Change in metabolic outcome - fasting Tg	serum concentration	baseline and 6 months
Change in serum FGF 19	serum concentration	baseline and 6 months
Change in serum adiponectin	serum concentration	baseline and 6 months
Change in serum IL-6	serum concentration	baseline and 6 months
Change in serum TNF alpha	serum concentration	baseline and 6 months
Change in serum uric acid	serum concentration	baseline and 6 months
Change in MRI features of NASH	serum concentration	baseline and 6 months

Collaborators and Investigators

• Sponsor: University of Malaya
• Investigators: Principal Investigator: Shireene R Vethakkan, MD, University of Malaya

Publications and helpful links

General Publications

• Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005 Jun;41(6):1313-21. doi: 10.1002/hep.20701.
• Zinman B, Lachin JM, Inzucchi SE. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2016 Mar 17;374(11):1094. doi: 10.1056/NEJMc1600827. No abstract available.
• Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis. Diabetes Care. 2016 Jul;39(7):1108-14. doi: 10.2337/dc16-0330.
• Hazlehurst JM, Woods C, Marjot T, Cobbold JF, Tomlinson JW. Non-alcoholic fatty liver disease and diabetes. Metabolism. 2016 Aug;65(8):1096-108. doi: 10.1016/j.metabol.2016.01.001. Epub 2016 Jan 11.
• Tahara A, Kurosaki E, Yokono M, Yamajuku D, Kihara R, Hayashizaki Y, Takasu T, Imamura M, Li Q, Tomiyama H, Kobayashi Y, Noda A, Sasamata M, Shibasaki M. Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice. Eur J Pharmacol. 2013 Sep 5;715(1-3):246-55. doi: 10.1016/j.ejphar.2013.05.014. Epub 2013 May 23.
• Ballestri S, Nascimbeni F, Romagnoli D, Lonardo A. The independent predictors of non-alcoholic steatohepatitis and its individual histological features.: Insulin resistance, serum uric acid, metabolic syndrome, alanine aminotransferase and serum total cholesterol are a clue to pathogenesis and candidate targets for treatment. Hepatol Res. 2016 Oct;46(11):1074-1087. doi: 10.1111/hepr.12656. Epub 2016 Mar 30.
• Jojima T, Tomotsune T, Iijima T, Akimoto K, Suzuki K, Aso Y. Empagliflozin (an SGLT2 inhibitor), alone or in combination with linagliptin (a DPP-4 inhibitor), prevents steatohepatitis in a novel mouse model of non-alcoholic steatohepatitis and diabetes. Diabetol Metab Syndr. 2016 Jul 26;8:45. doi: 10.1186/s13098-016-0169-x. eCollection 2016.
• Alisi A, Ceccarelli S, Panera N, Prono F, Petrini S, De Stefanis C, Pezzullo M, Tozzi A, Villani A, Bedogni G, Nobili V. Association between Serum Atypical Fibroblast Growth Factors 21 and 19 and Pediatric Nonalcoholic Fatty Liver Disease. PLoS One. 2013 Jun 26;8(6):e67160. doi: 10.1371/journal.pone.0067160. Print 2013.
• Dushay JR, Toschi E, Mitten EK, Fisher FM, Herman MA, Maratos-Flier E. Fructose ingestion acutely stimulates circulating FGF21 levels in humans. Mol Metab. 2014 Oct 8;4(1):51-7. doi: 10.1016/j.molmet.2014.09.008. eCollection 2015 Jan.
• Vanni E, Bugianesi E, Kotronen A, De Minicis S, Yki-Jarvinen H, Svegliati-Baroni G. From the metabolic syndrome to NAFLD or vice versa? Dig Liver Dis. 2010 May;42(5):320-30. doi: 10.1016/j.dld.2010.01.016. Epub 2010 Mar 6.
• Lai LL, Vethakkan SR, Nik Mustapha NR, Mahadeva S, Chan WK. Empagliflozin for the Treatment of Nonalcoholic Steatohepatitis in Patients with Type 2 Diabetes Mellitus. Dig Dis Sci. 2020 Feb;65(2):623-631. doi: 10.1007/s10620-019-5477-1. Epub 2019 Jan 25.

Study record dates

Study Major Dates

• Study Start: November 1, 2016
• Primary Completion (Anticipated): November 1, 2018
• Study Completion (Anticipated): November 1, 2018

Study Registration Dates

• First Submitted: October 30, 2016
• First Submitted That Met QC Criteria: November 10, 2016
• First Posted (Estimate): November 16, 2016

Study Record Updates

• Last Update Posted (Actual): May 31, 2017
• Last Update Submitted That Met QC Criteria: May 27, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Liver Diseases; Fatty Liver; Diabetes Mellitus; Diabetes Mellitus, Type 2; Non-alcoholic Fatty Liver Disease; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: ERF-4

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO