Type 2 Diabetes Mellitus, Chronic Liver Disease
Conditions
Keywords
Ursodeoxycholic Acid, sitagliptin, bile acids, GLP-1
Brief summary
1\. Objectives 1. 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. 2. To test whether sitagliptin enhances UDCA-induced beneficial effect in GLP-1 levels and glycemic control. 3. To test safety of combination therapy of sitagliptin and UDCA in people with type 2 diabetes. 2\. Clinical hypothesis. 1. UDCA increases GLP-1 response to nutrients via provoking bile acids excretion from the liver to the intestine/colon. 2. UDCA improves glycemic control in people with type 2 diabetes. 3. Sitagliptin enhances UDCA-induced response of GLP-1 to nutrients. 4. Sitagliptin has additive beneficial effects with UDCA in glycemic control in people with type 2 diabetes. 5. Combination therapy of sitagliptin and UDCA is safe and well-tolerated in people with type 2 diabetes. 6. 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.
Interventions
DRUGUDCA
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.
DRUGSitagliptin
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.
Sponsors
Kanazawa University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. Type 2 diabetes 2. HbA1c \>=6.5% during 8 weeks prior to the study 3. Treated with none or single oral hypoglycemic agent(OHA: sulfonyl ureas, biguanides, or thiazolidinediones) over 12 weeks prior to the study
Exclusion criteria
1. Non-Type 2 diabetes 2. Medical history and/or complication of diabetic ketoacidosis 3. Medical history and/or complication of severe hypoglycemia 4. Insulin treatment within 16 weeks prior to the study 5. Treatment with alpha-glucosidase inhibitors or sitagliptin within 12 weeks prior to the study 6. Treatment with glucocorticoid 7. Unstable glycemic control 8. Hypersensitivity to or contraindication of sitagliptin and voglibose 9. Aspartate transaminase (AST) or alanine transaminase (ALT) \>=2.5 time of institutional upper normal limit 10. Uncontrolled hypertension (systolic blood pressure \>160mmHg or diastolic blood pressure \>100mmHg) 11. Severe health problems not suitable for the study 12. Pregnant or lactating women 13. Hepatitis B or C
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| the difference of haemoglobin A1c (HbA1c) and glycoalbumin (GA) | 6 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 6 months | This is performed by power-spectrum analyses of heart rate variability |
Countries
Japan
Contacts
Primary ContactToshinari Takamura, MD, PhD
Outcome results
None listed