Clinical trial NCT02964715: The Effect of Empagliflozin on NAFLD in Asian Patients With Type 2 Diabetes
Official title: The Effect of Empagliflozin on NAFLD in Asian Patients With Type 2 Diabetes
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Type2 Diabetes
NAFLD
Lead sponsor: University of Malaya
Sponsor class: OTHER
First posted: 2016-11-16
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in histological Grade as evaluated with Non-alcoholic Steatohepatitis Clinical Research Network Scoring System
timeFrame: baseline, 6 months
measure: Change in serum FGF 21
timeFrame: baseline and 6 months
Secondary outcomes:
measure: Change in fibroscan and elastography measure of liver stiffness
timeFrame: baseline and 6 months
measure: Change in Liver enzymes
timeFrame: baseline and 6 months
measure: Change in steatosis
timeFrame: baseline and 6 months
measure: Change in lobular inflammation
timeFrame: baseline and 6 months
measure: Change in ballooning
timeFrame: baseline and 6 months
measure: Change in fibrosis
timeFrame: baseline and 6 months
measure: Change in metabolic outcome -HbA1c
timeFrame: baseline and 6 months
measure: Change in metabolic outcome - fasting NEFA
timeFrame: baseline and 6 months
measure: Change in metabolic outcome - fasting Tg
timeFrame: baseline and 6 months
measure: Change in serum FGF 19
timeFrame: baseline and 6 months
measure: Change in serum adiponectin
timeFrame: baseline and 6 months
measure: Change in serum IL-6
timeFrame: baseline and 6 months
measure: Change in serum TNF alpha
timeFrame: baseline and 6 months
measure: Change in serum uric acid
timeFrame: baseline and 6 months
measure: Change in MRI features of NASH
timeFrame: baseline and 6 months
Other outcomes:
Locations:
city: Kuala Lumpur
country: Malaysia
facility: University of Malaya
state: Wilayah Persekutuan
Study officials:
affiliation: University of Malaya
name: Shireene R Vethakkan, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.