Effect of Oral Anti-diabetic Medication on Liver Fat in Subjects With Type II Diabetes and Non-alcoholic Fatty Liver

Study Overview
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Brief Summary
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This randomized clinical trial aims to compare the effect of the pioglitazone and SGLT2 inhibitor combination on liver fat mass, as compared to either drug used alone, with or without background medical therapy of metformin and/or DDP4 inhibitors.

Detailed Description
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To compare the effect of pioglitazone with or without Metformin and/or DPP4 inhibitor (no SGLT2 inhibitor) on improvement of NAFLD parameters, versus The effect of SGLT inhibitor with or without metformin and/or DPP4 inhibitor (no pioglitazone) on NAFLD parameters and versus Pioglitazone with or without metformin and/or DPP4 inhibitor, plus empagliflozin on improvement of NAFLD parameters.

Official Title
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Which Oral Combination of Anti-diabetes Medication May Work Better in Subjects With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: a Randomized Control Trial

Conditions
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NAFLD, Diabetes Mellitus, Type 2, NASH - Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: Pioglitazone
* Drug: Empagliflozin
* Drug: Pioglitazone + Empagliflozin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient who give informed consent voluntarily Type 2 diabetic patient having age from 18 years to 60 years HbA1C ≥ 7.0 % Diabetes diagnosis of ≤ 5 years (longer duration more likely to be associated with use of multiple drug regimens for glycemic control which may affect liver fat mass) Either treatment naïve or on metformin alone or metformin/DPP4i combination Absolute weight < 100kg; BMI < 45 (fibro scan machine cannot accommodate heavier individuals) Documented hepatosteatosis (If the fibroscan reveals S1 (mild fatty liver: 11-33% fatty liver) to S3 (severe fatty liver: > 67% fatty liver) liver fat Exclusion Criteria: Hba1c ≥ 9% and/or blood sugar > 250mg/dl History of uncontrolled Endocrine disorder (for example uncontrolled hypothyroidism, or that requiring frequent dose adjustment, or Cushings syndrome) History of anti-obesity medication use within 3 months of consent for study enrollment or weight loss procedure(bariatric surgery) within same duration History of use of SGLT 2 inhibitors, glitazones, Glucagon-like peptide (GLP) 1 agonists 3 months prior to study enrollment as they influence liver fat History of use of insulin/sulphonylurea 3 months prior to study enrollment owing to weight gain and potential increase in liver fat conferred by these agents History of vitamin E use (400mg twice daily) within 3 months of study enrollment Drug induced liver disease or active substance abuse (cannabonnoid-derived substances like heroin, cocaine, amphetamines) based on history and/or laboratory tests Drugs known to be associated with hepatic steatosis like steroids, traditional homeopathic medication (likely to contain steroids), methotrexate, valproate, tamoxifen, amiodarone. Alcohol use (History of alcoholism or a greater than recommended alcohol intake (> 21 standard drinks on average per week in men and > 14 standard drinks on average per week in women) Severe hepatic impairment (ALT levels > 3 times upper limit normal) Hepatitis B/C hepatitis (based on positive Hepatitis B surface antigen, Anti Hepatitis C antibodies positive Autoimmune hepatitis (in case of females), based on positive Anti-nuclear Antibody (ANA) (homogenous, high titre) Positive Human Immunodeficiency Virus ( HIV) test as this could influence liver functions Pregnant or lactating women/ plans for pregnancy over proceeding 13 months Obstructive liver disease on the basis of laboratory and imaging studies Chronic renal failure, or Glomerular Filtration Rate (GFR) < 30 mls/minute (as estimated by the MDRD equation) Chronic heart failure, history of acute coronary artery disease or cerebrovascular accident within 3 months of consent for study enrollment, based on history and/or cardiac imaging History of recurrent Urinary Tract Infections (UTI's) or mycotic infections Presence of ketones on Urine Analysis

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pioglitazone<br>The starting dose would be 15mg/day for pioglitazone and 500 to 1500mg per day for metformin (depending on blood glucose levels). Starting dose for DPP4 inhibitors would be 50 to 100mg daily. | Drug: Pioglitazone<br>* Pioglitazone with (or without) metformin and/or DPP4 inhibitor (no SGLT2 inhibitor). The maximum dose for metformin would be 2.5 g/day, while for pioglitazone would be 45mg/day. The maximum dose for DPP4 inhibitor would be 100mg/day.<br>* Other names: Zolid;|
| Active Comparator: Empagliflozin<br>The starting dose would be 500-1500mg/day of metformin, plus 5/10/12.5mg empagliflozin (depending on blood glucose levels). Starting dose for DPP4 inhibitors would be 50 to 100mg daily. | Drug: Empagliflozin<br>* Empagliflozin with (or without) metformin and/or DPP4 inhibitor (no pioglitazone). The maximum dose for metformin would be 2.5g/day, while for empagliflozin would be 25mg/day depending on follow up blood sugar levels and tolerability. The maximum dose 100mg daily.<br>* Other names: Diampa;|
| Active Comparator: Pioglitazone + Empagliflozin<br>The starting dose would be 15mg/day for pioglitazone and 500 to1500mg per day for metformin and 5/10/12.5mg/25mg/day empagliflozin and 50 to 100mg daily for DPP4 inhibitors depending on blood sugar levels. | Drug: Pioglitazone + Empagliflozin<br>* Pioglitazone with (or without) metformin and/or DPP4 inhibitor, plus empagliflozin. The maximum dose for metformin would be 2.5g/day; for pioglitazone would be 45mg/day and 25mg/day for empagliflozin, and 100mg daily for DPP4 inhibitors (depending on follow up blood sugar levels and tolerability).<br>* Other names: Zolid + Diampa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in radiologic liver parameters | Number of participants reported change in liver fat content from baseline, as quantified by fibroscan | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in liver enzymes | Number of participants reported change in liver enzymes levels including ALT, AST and GGT | 12 months | 
| Change in Fibrosis-4 (FIB-4) Score and NAFLD Fibrosis Score | Number of participants reported change in FIB-4 Score and NAFLD Fibrosis Score. Fibrosis-4 scores range from 0 to 4, where <1.45 indicates absence of cirrhosis; score between 1.45 - 3.25 are deemed inconclusive and score >3.25 indicates cirrhosis. | 12 months | 
| Change in body weight | Number of participants reported change in body weight from baseline (treat to target response of at least 5% of baseline at 6 months, 10% baseline over 12 months). | 12 months | 
| Change in waist circumference (WC) | Number of participants reported change in waist circumference (WC) | 12 months | 
| Change in liver fat mass with total body fat (TBF) | Comparison of baseline and end of treatment liver fat mass with total body fat (TBF) using a Body Composition Monitor | 12 months | 
| Change in HbA1C levels (< 7.0%) | Number of participants reported change in HbA1C levels from baseline to end of treatment | 12 months | 
| Change in Fasting Blood Sugar (FBS) | Number of participants reported change in Fasting Blood Sugar (FBS) from baseline to end of treatment | 12 months | 
| Change in Lipid profile | Number of participants reported change in Fasting triglycerides (TG), Low-Density Lipoprotein (LDL), High-Density Lipoprotein (HDL) from baseline to end of treatment | 12 months |