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

Type2 Diabetes Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02964715
• Other study ID #: ERF-4
• Status: Recruiting
• Phase: Phase 4
• First received: October 30, 2016
• Last updated: May 27, 2017
• Start date: November 2016
• Est. completion date: November 2018

Study information

• Verified date: May 2017
• Source: University of Malaya
• Contact: Shireene R Vethakkan, MD
• Phone: 0162093355
• Email: shireene.vethakkan[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 25
• Est. completion date: November 2018
• Est. primary completion date: November 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• NAFLD
• Non-alcoholic Fatty Liver Disease
• Type2 Diabetes

Intervention

Drug:
• Empagliflozin
25 mg daily for 6 months

Locations

Country	Name	City	State
Malaysia	University of Malaya	Kuala Lumpur	Wilayah Persekutuan

Sponsors (1)

Lead Sponsor	Collaborator
University of Malaya

Country where clinical trial is conducted

Malaysia, 

References & Publications (10)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Vanni E, Bugianesi E, Kotronen A, De Minicis S, Yki-Järvinen 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. Review. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in histological Grade as evaluated with Non-alcoholic Steatohepatitis Clinical Research Network Scoring System	liver biopsy	baseline, 6 months
Primary	Change in serum FGF 21	blood test	baseline and 6 months
Secondary	Change in fibroscan and elastography measure of liver stiffness	imaging	baseline and 6 months
Secondary	Change in Liver enzymes	blood test - AST,ALT, gamma GT	baseline and 6 months
Secondary	Change in steatosis	histological	baseline and 6 months
Secondary	Change in lobular inflammation	histological	baseline and 6 months
Secondary	Change in ballooning	histological	baseline and 6 months
Secondary	Change in fibrosis	histological	baseline and 6 months
Secondary	Change in metabolic outcome -HbA1c	serum concentration	baseline and 6 months
Secondary	Change in metabolic outcome - fasting NEFA	serum concentration	baseline and 6 months
Secondary	Change in metabolic outcome - fasting Tg	serum concentration	baseline and 6 months
Secondary	Change in serum FGF 19	serum concentration	baseline and 6 months
Secondary	Change in serum adiponectin	serum concentration	baseline and 6 months
Secondary	Change in serum IL-6	serum concentration	baseline and 6 months
Secondary	Change in serum TNF alpha	serum concentration	baseline and 6 months
Secondary	Change in serum uric acid	serum concentration	baseline and 6 months
Secondary	Change in MRI features of NASH	serum concentration	baseline and 6 months