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Randomized Evaluation of Anagliptin Versus Sitagliptin On Low-density lipoproteiN Cholesterol in Diabetes Trial (REASON)

Primary Purpose

Dipeptidyl-Peptidase 4 Inhibitors, LDL Cholesterol, Glycosylated Hemoglobin

Status

Completed

Phase

Phase 4

Locations

Japan

Study Type

Interventional

Intervention

Anagliptin

Sitagliptin

About this trial

This is an interventional treatment trial for Dipeptidyl-Peptidase 4 Inhibitors focused on measuring Dipeptidyl-Peptidase 4 Inhibitors, LDL Cholesterol, Glycosylated Hemoglobin, Diabetes Mellitus, Coronary Disease

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients with type 2 diabetes with cardiovascular risk factors (*) who treated with diet, exercise or antidiabetic medications
Patients who were treated with statins for 8 weeks or longer
Patients with low-density lipoprotein cholesterol equal to or greater than 100 mg/dL in the at least one of three measurements after the administration of statins
Patients with glycerated hemoglobin (HbA1c, NGSP) equal to or greater than 6.0 % (7.0 % if patients were not treated with dipeptidyl-peptidase 4 inhibitors) and lesser than 10.5 %

(*) cardiovascular risk factors were any of following conditions

Presence of stenosis (>=25%) or plaque on the previous coronary angiography or coronary CT
Presence of coronary calcification on the previous coronary CT
History of acute coronary syndrome
History of percutaneous coronary intervention or coronary artery bypass graft
History of stroke (ischemic stroke or hemorrhagic stroke)
History of transient ischemic attack
History of peripheral artery diseases or aortic disorders
Ankle-Brachial Index (AMI) equal to or less than 0.9 in the past measurement
Presence of carotid artery plaque (including Max IMT >=1.1mm) on carotid ultrasonography in the past

Exclusion Criteria:

Patients with type 1 diabetes
Patients with triglyceride equal to or greater than 400 mg/dL in the previous fasting measurements
Patients with pregnancy, possible pregnancy, or on breast-feeding
Patients with severe infections, perioperative status, or severe trauma
Patients with renal dysfunction (creatinine >= 2.4 mg/dl for men, >= 2.0 mg/dl for women)
Patients who were received glucagon-like peptide-1receptor agonists
Patients whom physician in charge considered inappropriate for the study

Sites / Locations

Department of Cardiovascular Medicine, Tomishiro Central Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Anagliptin

Sitagliptin

Arm Description

Anagliptin 100 mg bid for 52 weeks. Can increase to 200 mg bid if needed.

Sitagliptin 50 mg qd for 52 weeks. Can increase to 100 mg qd if needed

Outcomes

Primary Outcome Measures

Change in low-density lipoprotein cholesterol

Change in glycated hemoglobin

Secondary Outcome Measures

Change in fasting glucose

Change in fasting insulin

Change in 1.5-Anhydro-D-glucitol

Change in C peptide

Change in total cholesterol, triglyceride, non high dencisty lipoprotein cholesterol

Change in Apolipoprotein A1, Apolipoprotein B, Apolipoprotein E

Change in Apolipoprotein B48

Change in small dense low density lipoprotein

Change in high sensitivity C-reactive protein

Change in interleukin-6

Change in cholesterol absorption marker (campesterol; sitosterol)

Change in cholesterol synthesis marker (lathosterol)

Change in high molecular weight adiponectin

Change in ratio of albumin and creatinine in urine

Progression, unchange, remission rate of microalbumin and macroalbumin in urine

Change in estimated glomerular filtration rate

Change in glycated hemoglobin stratified by body mass index and waist circumference

Correlation between glycated hemoglobin and body mass index or waist circumference

Change in intima-media thickness or flow mediated dilation

Change in postprandial glucose, insulin and activated glucagon-like peptide-1

Change in lipid profile and molecular size measured

Change in fatty acid fraction

Full Information

NCT ID

NCT02330406

First Posted

December 30, 2014

Last Updated

August 22, 2019

Sponsor

Institute for Clinical Effectiveness, Japan

1. Study Identification

Unique Protocol Identification Number

NCT02330406

Brief Title

Randomized Evaluation of Anagliptin Versus Sitagliptin On Low-density lipoproteiN Cholesterol in Diabetes Trial

Acronym

REASON

Official Title

Effect of Anagliptin and Sitagliptin on Low-density Lipoprotein Cholesterol in Patients With Type 2 Diabetes and Cardiovascular Risk Factors: Randomized Controlled Trial

Study Type

Interventional

2. Study Status

Record Verification Date

August 2019

Overall Recruitment Status

Completed

Study Start Date

April 2015 (Actual)

Primary Completion Date

January 2018 (Actual)

Study Completion Date

March 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Institute for Clinical Effectiveness, Japan

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to determine whether Anagliptin or Sitagliptin are effective in reducing the low-density lipoprotein cholesterol in patients with type 2 diabetes and cardiovascular risk factors on statin.

Detailed Description

Diabetes is a significant cause of cardiovascular and cerebrovascular events. Especially, diabetic patients with cardiovascular risk factors were significantly higher risk for cardiovascular and cerebrovasculara event. Therefore, several medical management strategies including anti-diabetic medications and statins were considered for those patients. However, in spite of such treatment, still many patients have cardiovascular and cerebrovascular events. One of the hypothesis is the residual risk such as elevated low-density lipoprotein cholesterol (LDLC) even with statin therapy. Anagliptin, one of the dipeptidyl peptidase-4 (DPP4) inhibiors, was reported to reduce LDLC and may have pontential to decrease the cardiovascular and cerebrovascular risk for such patients on statins. We, thus, conduct a randomized controlled trial to compare Anagliptin or Sitagliptin in terms of change of LDLC for 52 weeks as well as glycemic control.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Dipeptidyl-Peptidase 4 Inhibitors, LDL Cholesterol, Glycosylated Hemoglobin, Diabetes Mellitus, Coronary Disease

Keywords

Dipeptidyl-Peptidase 4 Inhibitors, LDL Cholesterol, Glycosylated Hemoglobin, Diabetes Mellitus, Coronary Disease

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

InvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

353 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Anagliptin

Arm Type

Active Comparator

Arm Description

Anagliptin 100 mg bid for 52 weeks. Can increase to 200 mg bid if needed.

Arm Title

Sitagliptin

Arm Type

Active Comparator

Arm Description

Sitagliptin 50 mg qd for 52 weeks. Can increase to 100 mg qd if needed

Intervention Type

Drug

Intervention Name(s)

Anagliptin

Other Intervention Name(s)

Suiny

Intervention Description

Suiny 100 mg

Intervention Type

Drug

Intervention Name(s)

Sitagliptin

Other Intervention Name(s)

Januvia, Glactiv

Intervention Description

Januvia 50 mg Glactiv 50 mg

Primary Outcome Measure Information:

Title

Change in low-density lipoprotein cholesterol

Time Frame

52-weeks

Title

Change in glycated hemoglobin

Time Frame

52-weeks

Secondary Outcome Measure Information:

Title

Change in fasting glucose

Time Frame

52-weeks

Title

Change in fasting insulin

Time Frame

52-weeks

Title

Change in 1.5-Anhydro-D-glucitol

Time Frame

52-weeks

Title

Change in C peptide

Time Frame

52-weeks

Title

Change in total cholesterol, triglyceride, non high dencisty lipoprotein cholesterol

Time Frame

52-weeks

Title

Change in Apolipoprotein A1, Apolipoprotein B, Apolipoprotein E

Time Frame

52-weeks

Title

Change in Apolipoprotein B48

Time Frame

52-weeks

Title

Change in small dense low density lipoprotein

Time Frame

52-weeks

Title

Change in high sensitivity C-reactive protein

Time Frame

52-weeks

Title

Change in interleukin-6

Time Frame

52-weeks

Title

Change in cholesterol absorption marker (campesterol; sitosterol)

Time Frame

52-weeks

Title

Change in cholesterol synthesis marker (lathosterol)

Time Frame

52-weeks

Title

Change in high molecular weight adiponectin

Time Frame

52-weeks

Title

Change in ratio of albumin and creatinine in urine

Time Frame

52-weeks

Title

Progression, unchange, remission rate of microalbumin and macroalbumin in urine

Time Frame

52-weeks

Title

Change in estimated glomerular filtration rate

Time Frame

52-weeks

Title

Change in glycated hemoglobin stratified by body mass index and waist circumference

Time Frame

52-weeks

Title

Correlation between glycated hemoglobin and body mass index or waist circumference

Time Frame

52-weeks

Title

Change in intima-media thickness or flow mediated dilation

Time Frame

52-weeks

Title

Change in postprandial glucose, insulin and activated glucagon-like peptide-1

Time Frame

52-weeks

Title

Change in lipid profile and molecular size measured

Time Frame

52-weeks

Title

Change in fatty acid fraction

Time Frame

52-weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

20 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients with type 2 diabetes with cardiovascular risk factors (*) who treated with diet, exercise or antidiabetic medications Patients who were treated with statins for 8 weeks or longer Patients with low-density lipoprotein cholesterol equal to or greater than 100 mg/dL in the at least one of three measurements after the administration of statins Patients with glycerated hemoglobin (HbA1c, NGSP) equal to or greater than 6.0 % (7.0 % if patients were not treated with dipeptidyl-peptidase 4 inhibitors) and lesser than 10.5 % (*) cardiovascular risk factors were any of following conditions Presence of stenosis (>=25%) or plaque on the previous coronary angiography or coronary CT Presence of coronary calcification on the previous coronary CT History of acute coronary syndrome History of percutaneous coronary intervention or coronary artery bypass graft History of stroke (ischemic stroke or hemorrhagic stroke) History of transient ischemic attack History of peripheral artery diseases or aortic disorders Ankle-Brachial Index (AMI) equal to or less than 0.9 in the past measurement Presence of carotid artery plaque (including Max IMT >=1.1mm) on carotid ultrasonography in the past Exclusion Criteria: Patients with type 1 diabetes Patients with triglyceride equal to or greater than 400 mg/dL in the previous fasting measurements Patients with pregnancy, possible pregnancy, or on breast-feeding Patients with severe infections, perioperative status, or severe trauma Patients with renal dysfunction (creatinine >= 2.4 mg/dl for men, >= 2.0 mg/dl for women) Patients who were received glucagon-like peptide-1receptor agonists Patients whom physician in charge considered inappropriate for the study

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Shinichiro Ueda, MD, PhD

Organizational Affiliation

Professor of Medicine, Department of Clinical Pharmacology & Therapeutics, University of the Ryukyus

Official's Role

Principal Investigator

Facility Information:

Facility Name

Department of Cardiovascular Medicine, Tomishiro Central Hospital

City

Tomishiro

State/Province

Okinawa

ZIP/Postal Code

901-0243

Country

Japan

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

32539832

Citation

Furuhashi M, Sakuma I, Morimoto T, Higashiura Y, Sakai A, Matsumoto M, Sakuma M, Shimabukuro M, Nomiyama T, Arasaki O, Node K, Ueda S. Treatment with anagliptin, a DPP-4 inhibitor, decreases FABP4 concentration in patients with type 2 diabetes mellitus at a high risk for cardiovascular disease who are receiving statin therapy. Cardiovasc Diabetol. 2020 Jun 15;19(1):89. doi: 10.1186/s12933-020-01061-0.

Results Reference

derived

PubMed Identifier

31733647

Citation

Chihara A, Tanaka A, Morimoto T, Sakuma M, Shimabukuro M, Nomiyama T, Arasaki O, Ueda S, Node K. Differences in lipid metabolism between anagliptin and sitagliptin in patients with type 2 diabetes on statin therapy: a secondary analysis of the REASON trial. Cardiovasc Diabetol. 2019 Nov 16;18(1):158. doi: 10.1186/s12933-019-0965-3.

Results Reference

derived

PubMed Identifier

31189978

Citation

Morimoto T, Sakuma I, Sakuma M, Tokushige A, Natsuaki M, Asahi T, Shimabukuro M, Nomiyama T, Arasaki O, Node K, Ueda S. Randomized Evaluation of Anagliptin vs Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) Trial: A 52-week, open-label, randomized clinical trial. Sci Rep. 2019 Jun 12;9(1):8537. doi: 10.1038/s41598-019-44885-x. Erratum In: Sci Rep. 2020 Feb 21;10(1):3548.

Results Reference

derived

PubMed Identifier

29435776

Citation

Ueda S, Shimabukuro M, Arasaki O, Node K, Nomiyama T, Morimoto T. Effect of Anagliptin and Sitagliptin on Low-Density Lipoprotein Cholesterol in Type 2 Diabetic Patients with Dyslipidemia and Cardiovascular Risk: Rationale and Study Design of the REASON Trial. Cardiovasc Drugs Ther. 2018 Feb;32(1):73-80. doi: 10.1007/s10557-018-6776-z.

Results Reference

derived

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Randomized Evaluation of Anagliptin Versus Sitagliptin On Low-density lipoproteiN Cholesterol in Diabetes Trial

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