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

NCT ID: NCT02964715

Last Updated: 2017-05-31

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE4

Total Enrollment

25 participants

Study Classification

INTERVENTIONAL

Study Start Date

2016-11-30

Study Completion Date

2018-11-30

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Type2 Diabetes NAFLD

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

open label

Study Groups

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Interventional arm

Patients with NAFLD and Type 2 Diabetes prescribed 25mg empagliflozin(JARDIANCE) daily for 6 months

Group Type EXPERIMENTAL

Empagliflozin

Intervention Type DRUG

25 mg daily for 6 months

Interventions

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Empagliflozin

25 mg daily for 6 months

Intervention Type DRUG

Other Intervention Names

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Jardiance

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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University of Malaya

OTHER

Sponsor Role lead

Responsible Party

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Shireene Vethakkan

Associate Professor Dr.

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Shireene R Vethakkan, MD

Role: PRINCIPAL_INVESTIGATOR

University of Malaya

Locations

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University of Malaya

Kuala Lumpur, Kuala Lumpur, Malaysia

Site Status RECRUITING

Countries

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Malaysia

Central Contacts

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Shireene R Vethakkan, MD

Role: CONTACT

0162093355

Wah K Chan, MRCP

Role: CONTACT

0163655232

Facility Contacts

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Shireene R Vethakkan, MD

Role: primary

0162093355

References

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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.

Reference Type BACKGROUND
PMID: 26981940 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 27289126 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 23707905 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 26856933 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 26785389 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 27462372 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 23840612 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25685689 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 15915461 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 20207596 (View on PubMed)

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.

Reference Type DERIVED
PMID: 30684076 (View on PubMed)

Other Identifiers

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ERF-4

Identifier Type: -

Identifier Source: org_study_id

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