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

NCT ID: NCT01337440

Last Updated: 2011-04-18

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE4

Total Enrollment

20 participants

Study Classification

INTERVENTIONAL

Study Start Date

2010-04-30

Study Completion Date

2013-03-31

Brief Summary

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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.

Detailed Description

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Conditions

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Type 2 Diabetes Mellitus Chronic Liver Disease

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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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.

Group Type ACTIVE_COMPARATOR

Sitagliptin

Intervention Type DRUG

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.

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.

Group Type ACTIVE_COMPARATOR

UDCA

Intervention Type DRUG

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.

Interventions

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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.

Intervention Type 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.

Intervention Type DRUG

Other Intervention Names

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Ursodeoxycholic acid (UDCA) goes by the trade names Urso. Sitagliptin sold under the trade name Januvia

Eligibility Criteria

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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
Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Kanazawa University

OTHER

Sponsor Role lead

Responsible Party

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Merck & Co., Inc.

Locations

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Internal medicine, Kanazawa university hospital

Kanazawa, Ishikawa-ken, Japan

Site Status RECRUITING

Countries

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Japan

Central Contacts

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Toshinari Takamura, MD, PhD

Role: CONTACT

+81-76-265-2233

Facility Contacts

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Toshinari Takamura, MD, PhD

Role: primary

+81-76-265-2233

References

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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. doi: 10.1007/s00535-006-1948-. Epub 2007 Apr 26.

Reference Type BACKGROUND
PMID: 17464461 (View on PubMed)

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. doi: 10.1016/j.diabres.2006.07.019. Epub 2006 Oct 27.

Reference Type BACKGROUND
PMID: 17069922 (View on PubMed)

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. doi: 10.2337/dc07-0066. Epub 2007 Jul 20.

Reference Type BACKGROUND
PMID: 17644622 (View on PubMed)

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. doi: 10.2337/dc09-0148. Epub 2009 Oct 30.

Reference Type RESULT
PMID: 19880582 (View on PubMed)

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. doi: 10.1038/nature04330. Epub 2006 Jan 8.

Reference Type RESULT
PMID: 16400329 (View on PubMed)

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. doi: 10.1001/jama.298.2.194.

Reference Type RESULT
PMID: 17622601 (View on PubMed)

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: 10.1016/j.cmet.2009.08.001.

Reference Type RESULT
PMID: 19723493 (View on PubMed)

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. doi: 10.1016/s0168-8278(01)00092-7.

Reference Type RESULT
PMID: 11495032 (View on PubMed)

Shima KR, Ota T, Kato KI, Takeshita Y, Misu H, Kaneko S, Takamura T. Ursodeoxycholic acid potentiates dipeptidyl peptidase-4 inhibitor sitagliptin by enhancing glucagon-like peptide-1 secretion in patients with type 2 diabetes and chronic liver disease: a pilot randomized controlled and add-on study. BMJ Open Diabetes Res Care. 2018 Mar 17;6(1):e000469. doi: 10.1136/bmjdrc-2017-000469. eCollection 2018.

Reference Type DERIVED
PMID: 29607050 (View on PubMed)

Other Identifiers

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KanazawaU-1

Identifier Type: -

Identifier Source: org_study_id

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