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

NCT01337440 | Unknown Phase 4 DMC

• 1 other identifier: KanazawaU-1
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

1\. Objectives

1. 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. 2.To test whether sitagliptin enhances UDCA-induced beneficial effect in GLP-1 levels and glycemic control.
3. 3.To test safety of combination therapy of sitagliptin and UDCA in people with type 2 diabetes.
4. 4.UDCA increases GLP-1 response to nutrients via provoking bile acids excretion from the liver to the intestine/colon.
5. 5.UDCA improves glycemic control in people with type 2 diabetes.
6. 6.Sitagliptin enhances UDCA-induced response of GLP-1 to nutrients.
7. 7.Sitagliptin has additive beneficial effects with UDCA in glycemic control in people with type 2 diabetes.
8. 8.Combination therapy of sitagliptin and UDCA is safe and well-tolerated in people with type 2 diabetes.
9. 9.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.

Conditions

Type 2 Diabetes Mellitus; Chronic Liver Disease

Keywords

Ursodeoxycholic Acid; sitagliptin; bile acids; GLP-1

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• 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

Study Arms (2)

UDCA pretreatment

ACTIVE COMPARATOR

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

Sitagliptin pretreatment

ACTIVE COMPARATOR

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

Interventions

UDCA 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.

Also known as: Ursodeoxycholic acid (UDCA) goes by the trade names Urso.

Sitagliptin pretreatment

Sitagliptin 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.

Also known as: Sitagliptin sold under the trade name Januvia

UDCA pretreatment

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Kanazawa University: lead

Study Sites (1)

Internal medicine, Kanazawa university hospital

Kanazawa, Ishikawa-ken, 920-8641, Japan

RECRUITING

Related Publications (9)

• 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.

  PMID: 17464461 BACKGROUND

• 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.

  PMID: 17069922 BACKGROUND

• 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.

  PMID: 17644622 BACKGROUND

• 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.

  PMID: 19880582 RESULT

• 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.

  PMID: 16400329 RESULT

• 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.

  PMID: 17622601 RESULT

• 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.

  PMID: 19723493 RESULT

• 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.

  PMID: 11495032 RESULT

• 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.

  PMID: 29607050 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Ursodeoxycholic Acid; Sitagliptin Phosphate

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Deoxycholic Acid; Cholic Acids; Bile Acids and Salts; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Cholanes; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines

Central Study Contacts

Toshinari Takamura, MD, PhD

CONTACT

+81-76-265-2233; ttakamura@m-kanazawa.jp

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: September 16, 2010
• First Posted: April 18, 2011
• Study Start: April 1, 2010
• Primary Completion: March 1, 2013
• Study Completion: March 1, 2013
• Last Updated: April 18, 2011

Record last verified: 2011-04

Locations

JP (1)