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

Purpose

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.

Condition	Intervention	Phase
Type 2 Diabetes Mellitus Chronic Liver Disease	Drug: UDCA Drug: Sitagliptin	Phase 4

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

Resource links provided by NLM:

MedlinePlus related topics: Diabetes Diabetes Type 2 Liver Diseases

Drug Information available for: Ursodiol Sitagliptin Sitagliptin phosphate

U.S. FDA Resources

Further study details as provided by Kanazawa University:

Primary Outcome Measures:

the difference of haemoglobin A1c (HbA1c) and glycoalbumin (GA) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
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 Outcome Measures:

Change from Baseline in Glucagon-like peptide-1 (GLP-1) response to lipid meal test (fat 55%) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
Change from Baseline in energy expenditure [ Time Frame: 6months ] [ Designated as safety issue: No ]
Change from Baseline in fasting plasma glucose level [ Time Frame: 6months ] [ Designated as safety issue: No ]
change from baseline in autonomic nerve function [ Time Frame: 6 months ] [ Designated as safety issue: No ]
This is performed by power-spectrum analyses of heart rate variability

Estimated Enrollment:	20
Study Start Date:	April 2010
Estimated Study Completion Date:	March 2013
Estimated Primary Completion Date:	March 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: UDCA pretreatment 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 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. Other Name: Sitagliptin sold under the trade name Januvia
Active Comparator: Sitagliptin pretreatment 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 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. Other Name: Ursodeoxycholic acid (UDCA) goes by the trade names Urso.

Eligibility

Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01337440

Contacts

Contact: Toshinari Takamura, MD, PhD

+81-76-265-2233

ttakamura@m-kanazawa.jp

Locations

Japan
Internal medicine, Kanazawa university hospital	Recruiting
Kanazawa, Ishikawa, Japan, 920-8641
Contact: Toshinari Takamura, MD, PhD +81-76-265-2233 ttakamura@m-kanazawa.jp
Sub-Investigator: Kosuke R Shima, MD

Sponsors and Collaborators

Kanazawa University

More Information

Publications:

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 reduction, ameliorates liver fibrosis. Diabetes Care. 2010 Feb;33(2):284-6. Epub 2009 Oct 30.

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 26;439(7075):484-9. Epub 2006 Jan 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.

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.

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.

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.

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.

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.

Responsible Party:	BANYU TOKYO, Merck & Co., Inc.
ClinicalTrials.gov Identifier:	NCT01337440 History of Changes
Other Study ID Numbers:	KanazawaU-1
Study First Received:	September 16, 2010
Last Updated:	April 15, 2011
Health Authority:	Japan: Ministry of Health, Labor and Welfare

Keywords provided by Kanazawa University:

Ursodeoxycholic Acid
sitagliptin
bile acids
GLP-1

Additional relevant MeSH terms:

Diabetes Mellitus
Diabetes Mellitus, Type 2
Liver Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Digestive System Diseases
Ursodeoxycholic Acid
Sitagliptin
Dipeptidyl-Peptidase IV Inhibitors

Cholagogues and Choleretics
Gastrointestinal Agents
Therapeutic Uses
Pharmacologic Actions
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on June 17, 2013