Clinical trial NCT01337440: Efficacy and Safety of Ursodeoxycholic Acid (UDCA) Added to the DPP-4 Inhibitor in People With Type 2 Diabetes and Chronic Liver Diseases
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Type 2 Diabetes Mellitus
Chronic Liver Disease
Keywords: Ursodeoxycholic Acid
sitagliptin
bile acids
GLP-1
Lead sponsor: Kanazawa University
Sponsor class: OTHER
First posted: 2011-04-18
Enrollment: 20
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: the difference of haemoglobin A1c (HbA1c) and glycoalbumin (GA)
timeFrame: 6 months
Secondary outcomes:
measure: Change from Baseline in Glucagon-like peptide-1 (GLP-1) response to lipid meal test (fat 55%)
timeFrame: 6 months
measure: Change from Baseline in energy expenditure
timeFrame: 6months
measure: Change from Baseline in fasting plasma glucose level
timeFrame: 6months
measure: change from baseline in autonomic nerve function
timeFrame: 6 months
Other outcomes:
Locations:
city: Kanazawa
country: Japan
facility: Internal medicine, Kanazawa university hospital
state: Ishikawa
Study officials:
References:
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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. doi: 10.1016/j.diabres.2006.07.019. Epub 2006 Oct 27.
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. doi: 10.2337/dc07-0066. Epub 2007 Jul 20.
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 reduction, ameliorates liver fibrosis. Diabetes Care. 2010 Feb;33(2):284-6. doi: 10.2337/dc09-0148. Epub 2009 Oct 30.
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 26;439(7075):484-9. doi: 10.1038/nature04330. Epub 2006 Jan 8.
citation: 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.
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: 10.1016/j.cmet.2009.08.001.
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. doi: 10.1016/s0168-8278(01)00092-7.
citation: 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.