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

Type 2 Diabetes Mellitus Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01337440
• Other study ID #: KanazawaU-1
• Status: Recruiting
• Phase: Phase 4
• First received: September 16, 2010
• Last updated: April 15, 2011
• Start date: April 2010
• Est. completion date: March 2013

Study information

• Verified date: April 2011
• Source: Kanazawa University
• Contact: Toshinari Takamura, MD, PhD
• Phone: +81-76-265-2233
• Email: ttakamura[@]m-kanazawa.jp
• Is FDA regulated: No
• Health authority: Japan: Ministry of Health, Labor and Welfare
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: March 2013
• Est. primary completion date: March 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Liver Disease
• Diabetes Mellitus, Type 2
• Liver Diseases
• Type 2 Diabetes Mellitus

Intervention

Drug:
• UDCA
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.
• Sitagliptin
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.

Locations

Country	Name	City	State
Japan	Internal medicine, Kanazawa university hospital	Kanazawa	Ishikawa

Sponsors (1)

Lead Sponsor	Collaborator
Kanazawa University

Country where clinical trial is conducted

Japan, 

References & Publications (8)

Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007 Jul 11;298(2):194-206. Review. — View Citation

Hamaguchi E, Takamura T, Sakurai M, Mizukoshi E, Zen Y, Takeshita Y, Kurita S, Arai K, Yamashita T, Sasaki M, Nakanuma Y, Kaneko S. Histological course of nonalcoholic fatty liver disease in Japanese patients: tight glycemic control, rather than weight re — View Citation

Lazaridis KN, Gores GJ, Lindor KD. Ursodeoxycholic acid 'mechanisms of action and clinical use in hepatobiliary disorders'. J Hepatol. 2001 Jul;35(1):134-46. Review. — View Citation

Sakurai M, Takamura T, Ota T, Ando H, Akahori H, Kaji K, Sasaki M, Nakanuma Y, Miura K, Kaneko S. Liver steatosis, but not fibrosis, is associated with insulin resistance in nonalcoholic fatty liver disease. J Gastroenterol. 2007 Apr;42(4):312-7. Epub 2007 Apr 26. — View Citation

Takamura T, Sakurai M, Nakamura M, Shimizu A, Ota T, Misu H, Takeshita Y, Tsuchiyama N, Kurita S, Ando H, Kaneko S. Factors associated with improvement of fasting plasma glucose level by mealtime dosing of a rapid-acting insulin analog in type 2 diabetes. Diabetes Res Clin Pract. 2007 Mar;75(3):278-84. Epub 2006 Oct 27. — View Citation

Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, Rizzo G, Macchiarulo A, Yamamoto H, Mataki C, Pruzanski M, Pellicciari R, Auwerx J, Schoonjans K. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 2009 Sep;10(3):167-77. doi: 10. — View Citation

Tsuchiyama N, Takamura T, Ando H, Sakurai M, Shimizu A, Kato K, Kurita S, Kaneko S. Possible role of alpha-cell insulin resistance in exaggerated glucagon responses to arginine in type 2 diabetes. Diabetes Care. 2007 Oct;30(10):2583-7. Epub 2007 Jul 20. — View Citation

Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, Messaddeq N, Harney JW, Ezaki O, Kodama T, Schoonjans K, Bianco AC, Auwerx J. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006 Jan — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Change from Baseline in Glucagon-like peptide-1 (GLP-1) response to lipid meal test (fat 55%)		6 months	No
Secondary	Change from Baseline in energy expenditure		6months	No
Secondary	Change from Baseline in fasting plasma glucose level		6months	No
Secondary	change from baseline in autonomic nerve function	This is performed by power-spectrum analyses of heart rate variability	6 months	No