Effect of Empagliflozin and Dulaglutide on MAFLD in Patients With T2D

Study Overview
=================
Brief Summary
-----------------
The co-administration of SGLT2 inhibitor and GLP-1 receptor agonist would be safe and effective on glycemic control in subjects with type 2 diabetes mellitus and MAFLD better than empagliflozin or dulaglutide alone. The SGLT2 inhibitor and GLP-1 receptor agonist would be safe and effective on fatty liver disease in subjects with type 2 diabetes mellitus and MAFLD.

Official Title
-----------------
A Randomized, Active-comparator Controlled, Parallel-group Study, to Evaluate the Effect of Empagliflozin and Dulaglutide on MAFLD in Patients With Type 2 Diabetes Mellitus

Conditions
-----------------
Metabolic-associated Fatty Liver Disease, Type 2 Diabetes

Intervention / Treatment
-----------------
* Drug: Empagliflozin
* Drug: Dulaglutide
* Drug: Empagliflozin and Dulaglutide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: age 20 or over uncontrolled HbA1c (7 10%) with metformin and/or sulfonylurea Hepatic steatosis estimated by Fibroscan (CAP ≥258 dB/m) MAFLD: presence of any conditions Overweight or obese: BMI ≥23 kg/m2 (Asian) Metabolic dysregulation: at least of two of following criteria Waist circumference: ≥90/80 cm in men and women (Asian) Blood pressure ≥130/85 mmHg or drug treatment Plasma triglycerides ≥150 mg/dL or drug treatment Plasma HDL-cholesterol <40/50 mg/dL for men and women or drug treatment Prediabetes (i.e. fasting glucose levels 100 to 125 mg/dL or 2-hour post-load glucose levels 140 to 199 mg/dL or HbA1c 5.7% to 6.4% HOMA-insulin resistance score ≥2.5 Plasma high-sensitivity CRP >2 mg/L Exclusion Criteria: Significant alcohol consumption Other competing causes for hepatic steatosis: viral hepatitis, drug-induced hepatitis, autoimmune hepatitis, hemochromatosis, Wilson's disease, alpha1 anti-trypsin deficiency, Celiac disease, Overt hypothyroidism, other secondary causes Type 1 diabetes mellitus medication usage within 3 months: vitamin E, PUFA, UDCA, fish oil, SGLT2 inhibitors, GLP1-RAs, TZDs Severe organ dysfunction liver damage: AST/ALT >x5 UNL, albumin <3.2, platelet <60k, Child-Pugh-Turcotte stage B or C kidney damage: serum creatinine ≥2.0 mg/dL or eGFR <50 mL/min/1.72m2 Hepatocellular carcinoma, active tumor, or metastasis End-stage liver disease

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin<br>Empagliflozin 10mg p.o. once daily (available to control over  25mg) | Drug: Empagliflozin<br>* Empagliflozin 10 mg p.o. once daily (available to control over  25mg)<br>* Other names: Jardiance;|
| Experimental: Dulaglutide<br>Dulaglutide 0.75mg s.c. once weekly (available to control over  1.5mg) | Drug: Dulaglutide<br>* Dulaglutide 0.75mg s.c. once a week (available to control over  1.5mg)<br>* Other names: Trulicity;|
| Experimental: Empagliflozin and Dulagludie<br>Empagliflozin 10mg p.o. once daily and dulaglutide 0.75mg s.c. once weekly | Drug: Empagliflozin and Dulaglutide<br>* Empagliflozin 10 mg p.o. once daily with Dulaglutide 0.75mg s.c. once weekly<br>* Other names: Jardiance and Trulicity;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes of HbA1c level | Patients achieving the target level | baseline, week 12, week 24 | 
| Changes of CAP score | Controlled Attenuation Parameter (CAP) score by transient elastography | baseline, week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes of LSM score | Liver stiffness measurement (LSM) score by transient elastography | baseline, week 24 | 
| Changes of noninvasive liver fibrosis markers | Noninvasive liver fibrosis markers will be calculated at baseline and at the end of the study | baseline, week 12, week 24 | 
| Changes of body weight and body composition | Body composition by bioelectrical impedance will be measured at baseline and at the end of the study | baseline, week 24 | 
| Changes of lipid levels | Cholesterol level will be measured at all visit days | baseline, week 12, week 24 | 
| Changes of ketone levels | Ketone level will be measured at all visit days | baseline, week 12, week 24 | 
| Changes of liver parenchyma by ultrasonography | improvement or deterioration | baseline, week 24 | 
| Changes of liver function parameters | Liver enzymes, albumin will be measured at all visit days. | baseline, week 12, week 24 | 
| Changes of liver fibrosis biomarkers | Type IV collagen | baseline, week 24 | 
| Changes of inflammation biomarker | high-sensitivity CRP | baseline, week 24 |