Effects of Ipragliflozin on Excessive Fat in Type 2 Diabetes Patients With Non-alcoholic Fatty Liver Disease Treated With Metformin and Pioglitazone

Study Overview
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Brief Summary
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In this study, the investigators investigate beneficial effects of ipragliflozin, newly developted SGLT2 inhibitor, on reduction in visceral fat area and degree of fatty liver in subjects with T2DM when added to metformin and pioglitazone therapy.

Detailed Description
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Pioglitazone, a peroxisome proliferator-activated receptor-γ (PPARγ) agonist increase insulin sensitivity in peripheral tissue and liver by protecting non-adipose tissues against excessive lipid overload and by balancing the secretion of adipocytokines. However, PPARγ is a key transcription factor that induces the differentiation adipocyte maturation and stimulates the induction of enzymes involved in lipogenesis. As a result, the effect of pioglitazone is generally accompanied by weight gain and an increase in amount of subcutaneous fat. Obesity would coexist with fatty liver disease and both conditions aggravate hyperglycemia in diabetes. According to recent study, up-regulated PPARγ expression in liver was reported in obesity with hepatic steatosis which implies pioglitazone might induce fatty liver disease. A novel oral antidiabetic drug, sodium glucose cotransporter 2 (SGLT2) inhibitor reduces renal glucose reabsorption and increasing renal glucose excretion thereby promoting energy loss. As a result, it prevents weight gain and fluid retention which might counteract the unfavorable effects of pioglitazone treatment. No study has been conducted on the additional effect on obesity and fatty liver of ipragliflozin in T2DM patients treated with pioglitazone and metformin. In this study, the investigators investigate beneficial effects of ipragliflozin, newly developted SGLT2 inhibitor, on reduction in visceral fat area and degree of fatty liver in subjects with T2DM when added to metformin and pioglitazone therapy.

Conditions
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Type 2 Diabetes With Non-alcoholic Fatty Liver (NAFLD)

Intervention / Treatment
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* Drug: Ipragliflozin
* Drug: metformin with pioglitazone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetic patients Diagnosed as NAFLD Age of 20 75 On metformin + pioglitazone treatment with stable dose for at least 8 weeks Adequate glycemic control: HbA1c ≤ 9.5% Overweight & obese: BMI ≥ 23 kg/m2 Subject is male, or subject is female who is highly unlikely to conceive Understands the study procedure, alternatives, and risks and voluntarily agrees to participate by giving written informed consent Exclusion Criteria: Type 1 diabetes, Secondary diabetes, gestational diabetes Heavy alcoholics (men ≥210 g of alcohol per week, women ≥140 g of alcohol per week) Underlying chronic liver disease (hemochromatosis, liver cell carcinoma, autoimmune liver disease, liver cirrhosis, chronic viral hepatitis [except hepatitis B carrier], Wilson's disease) Patients on medication causes hepatic steatosis (e.g.amiodarone, methotrexate, tamoxifen, valproate, corticosteroids, etc) Allergy or hypersensitivity to target medication or any of its components Renal failure, moderate or severe renal impairment (estimated glomerular filtration rate < 60 mL/min/1.73 m2), or ongoing dialysis Abnormal liver function (AST/ALT > x10 upper normal limit) On taking weight loss medication History of alcohol or drug abuse in the previous 3 months Premenopausal women who are nursing or pregnant Human immunodeficiency virus (HIV) or human immunodeficiency virus (AIDS) Diabetic ketoacidosis Severe infection, severe trauma

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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 |
| --- | --- |
| Experimental: Group IMP<br>Group IMP (Ipragliflozin with Metformin with Pioglitazone) | Drug: Ipragliflozin<br>* Patients treated with ipragliflozin (50 mg/day) as add on therapy to metformin and pioglitazone dual therapy (triple therapy) for 6 months. During whole periods of study, subjects are educated for nutrition and exercise. (Experimental Group)<br>* Other names: Suglat®;|
| Active Comparator: Group MP<br>Group MP (Metformin with Pioglitazone) | Drug: metformin with pioglitazone<br>* Patients maintain metformin and pioglitazone dual therapy for 6 months. During whole periods of study, subjects are educated for nutrition and exercise. (Control group)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| changes in visceral fat area | The visceral fat area is measured by dual-energy x-ray absorptiometry (DEXA) at baseline and after 6 months treatment | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in subcutaneous fat area | The subcutaneous fat area is measured by dual-energy x-ray absorptiometry (DEXA) and fat computed tomography (CT) at baseline and after 6 months treatment. | 6 months after treatment | 
| Changes in liver fat | Changes in the degree of fatty liver is measured by fibroscan using controlled attenuation parameter (CAP) score. | 6 months after treatment |