Clinical trial NCT02330406: Randomized Evaluation of Anagliptin Versus Sitagliptin On Low-density lipoproteiN Cholesterol in Diabetes Trial
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
Overall status: COMPLETED
Phase: PHASE4
Conditions: 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
Lead sponsor: Institute for Clinical Effectiveness, Japan
Sponsor class: OTHER
First posted: 2015-01-05
Enrollment: 353
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

1. Presence of stenosis (\>=25%) or plaque on the previous coronary angiography or coronary CT
2. Presence of coronary calcification on the previous coronary CT
3. History of acute coronary syndrome
4. History of percutaneous coronary intervention or coronary artery bypass graft
5. History of stroke (ischemic stroke or hemorrhagic stroke)
6. History of transient ischemic attack
7. History of peripheral artery diseases or aortic disorders
8. Ankle-Brachial Index (AMI) equal to or less than 0.9 in the past measurement
9. 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

Primary outcomes:
measure: Change in low-density lipoprotein cholesterol
timeFrame: 52-weeks
measure: Change in glycated hemoglobin
timeFrame: 52-weeks
Secondary outcomes:
measure: Change in fasting glucose
timeFrame: 52-weeks
measure: Change in fasting insulin
timeFrame: 52-weeks
measure: Change in 1.5-Anhydro-D-glucitol
timeFrame: 52-weeks
measure: Change in C peptide
timeFrame: 52-weeks
measure: Change in total cholesterol, triglyceride, non high dencisty lipoprotein cholesterol
timeFrame: 52-weeks
measure: Change in Apolipoprotein A1, Apolipoprotein B, Apolipoprotein E
timeFrame: 52-weeks
measure: Change in Apolipoprotein B48
timeFrame: 52-weeks
measure: Change in small dense low density lipoprotein
timeFrame: 52-weeks
measure: Change in high sensitivity C-reactive protein
timeFrame: 52-weeks
measure: Change in interleukin-6
timeFrame: 52-weeks
measure: Change in cholesterol absorption marker (campesterol; sitosterol)
timeFrame: 52-weeks
measure: Change in cholesterol synthesis marker (lathosterol)
timeFrame: 52-weeks
measure: Change in high molecular weight adiponectin
timeFrame: 52-weeks
measure: Change in ratio of albumin and creatinine in urine
timeFrame: 52-weeks
measure: Progression, unchange, remission rate of microalbumin and macroalbumin in urine
timeFrame: 52-weeks
measure: Change in estimated glomerular filtration rate
timeFrame: 52-weeks
measure: Change in glycated hemoglobin stratified by body mass index and waist circumference
timeFrame: 52-weeks
measure: Correlation between glycated hemoglobin and body mass index or waist circumference
timeFrame: 52-weeks
measure: Change in intima-media thickness or flow mediated dilation
timeFrame: 52-weeks
measure: Change in postprandial glucose, insulin and activated glucagon-like peptide-1
timeFrame: 52-weeks
measure: Change in lipid profile and molecular size measured
timeFrame: 52-weeks
measure: Change in fatty acid fraction
timeFrame: 52-weeks
Other outcomes:
Locations:
city: Tomishiro
country: Japan
facility: Department of Cardiovascular Medicine, Tomishiro Central Hospital
state: Okinawa
Study officials:
affiliation: Professor of Medicine, Department of Clinical Pharmacology & Therapeutics, University of the Ryukyus
name: Shinichiro Ueda, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.