Efficacy and Safety of Ursodeoxycholic Acid (UDCA) Added to the DPP-4 Inhibitor in People With Type 2 Diabetes and Chronic Liver Diseases

Study Overview
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Brief Summary
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1. Objectives To test whether Ursodeoxycholic Acid (UDCA) increases Glucagon-like peptide-1 (GLP-1) response to nutrients and improves glycemic control in people with type 2 diabetes. To test whether sitagliptin enhances UDCA-induced beneficial effect in GLP-1 levels and glycemic control. To test safety of combination therapy of sitagliptin and UDCA in people with type 2 diabetes. 2. Clinical hypothesis. UDCA increases GLP-1 response to nutrients via provoking bile acids excretion from the liver to the intestine/colon. UDCA improves glycemic control in people with type 2 diabetes. Sitagliptin enhances UDCA-induced response of GLP-1 to nutrients. Sitagliptin has additive beneficial effects with UDCA in glycemic control in people with type 2 diabetes. Combination therapy of sitagliptin and UDCA is safe and well-tolerated in people with type 2 diabetes. The combination therapy may loose weight by unique mechanisms of each agent; GLP-1 inhibits appetite by acting on CNS and gastrointestinal motility, whereas UDCA-enhanced circulating primary bile acids increases energy expenditure through the pathway involving G protein-coupled bile acid receptor 1 (Gpbar1, or M-Bar, TGR-5) and subsequent activation of type 2 iodothyronine deiodinase (D2) in brown adipose and muscle tissues, as reported previously.

Official Title
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The Efficacy and Safety of Ursodeoxycholic Acid (UDCA) Added to the Dipeptidyl Peptidase-4 Inhibitor, Sitagliptin in People With Type 2 Diabetes and Chronic Liver Diseases

Conditions
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Type 2 Diabetes Mellitus, Chronic Liver Disease

Intervention / Treatment
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* Drug: UDCA
* Drug: Sitagliptin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes HbA1c >=6.5% during 8 weeks prior to the study Treated with none or single oral hypoglycemic agent(OHA: sulfonyl ureas, biguanides, or thiazolidinediones) over 12 weeks prior to the study Exclusion Criteria: Non-Type 2 diabetes Medical history and/or complication of diabetic ketoacidosis Medical history and/or complication of severe hypoglycemia Insulin treatment within 16 weeks prior to the study Treatment with alpha-glucosidase inhibitors or sitagliptin within 12 weeks prior to the study Treatment with glucocorticoid Unstable glycemic control Hypersensitivity to or contraindication of sitagliptin and voglibose Aspartate transaminase (AST) or alanine transaminase (ALT) >=2.5 time of institutional upper normal limit Uncontrolled hypertension (systolic blood pressure >160mmHg or diastolic blood pressure >100mmHg) Severe health problems not suitable for the study Pregnant or lactating women Hepatitis B or C
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 |
| --- | --- |
| Active Comparator: UDCA pretreatment<br>Ursodeoxycholic Acid (UDCA) for 12 weeks, then Sitagliptin add-on therapy for additional 12 weeks. UDCA dosage: dosing from 600 mg for initial 4 weeks. Then, if there is no adverse effect, UDCA is escalated to 900 mg, po, tid. | Drug: Sitagliptin<br>* UDCA for 12 weeks, then Sitagliptin add-on therapy for additional 12 weeks. UDCA dosage: dosing from 600 mg for initial 4 weeks. Then, if there is no adverse effect, UDCA is escalated to 900 mg, po, tid.<br>* Other names: Sitagliptin sold under the trade name Januvia;|
| Active Comparator: Sitagliptin pretreatment<br>Sitagliptin: 50 mg, po, qd for 12 weeks, then UDCA add-on therapy for additional 12 weeks. UDCA dosage: dosing from 600 mg for initial 4 weeks. Then, if there is no adverse effect, UDCA is escalated to 900 mg, po, tid. | Drug: UDCA<br>* Sitagliptin: 50 mg, po, qd for 12 weeks, then UDCA add-on therapy for additional 12 weeks. UDCA dosage: dosing from 600 mg for initial 4 weeks. Then, if there is no adverse effect, UDCA is escalated to 900 mg, po, tid.<br>* Other names: Ursodeoxycholic acid (UDCA) goes by the trade names Urso.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the difference of haemoglobin A1c (HbA1c) and glycoalbumin (GA) | the difference of haemoglobin A1c (HbA1c) and glycoalbumin (GA) treating by Ursodeoxycholic Acid (UDCA)or sitagliptin monotherapy, and combination therapy of both two drugs for 3 monthes. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Glucagon-like peptide-1 (GLP-1) response to lipid meal test (fat 55%) |  | 6 months | 
| Change from Baseline in energy expenditure |  | 6months | 
| Change from Baseline in fasting plasma glucose level |  | 6months | 
| change from baseline in autonomic nerve function | This is performed by power-spectrum analyses of heart rate variability | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ursodeoxycholic Acid, sitagliptin, bile acids, GLP-1