Sitagliptin and Endothelial Dysfunction

Preventive Effects of Sitagliptin on Endothelial Dysfunction Induced by Forearm Ischemia-Reperfusion Injury Model

Over the years, numbers of cardioprotective drugs have been evaluated to attenuate lethal ischemia-reperfusion (IR) injuries. There is little study whether sitagliptin protects against endothelial dysfunction induced by IR injury in humans.

Study Overview

• Status: Unknown
• Conditions: Healthy
• Intervention / Treatment: Drug: Sitagliptin

Detailed Description

Glucagon-like peptide-1 (GLP-1) is a novel insulinotropic peptide which is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4). In addition to its attractive merit in type 2 diabetes, interest in the cardioprotective effects of GLP-1 has been increased with various reports and evidence. Previously, the investigators could show exenatide, GLP-1 receptor agonist protects ischemic/reperfusion injury-induced endothelial dysfunction through opening of KATP (ATP-sensitive potassium) channels in human ischemic/reperfusion injury model. But, recent clinical studies showed 2 different DPP-4 inhibitors, alogliptin and saxagliptin, did not decrease major adverse cardiovascular events even though improving glycemic control. The investigators will investigate the role of sitagliptin in human ischemic/reperfusion (IR) injury model of forearm conductance vessels as previous described method.

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Weon Kim, MD, PhD; Phone Number: 82-2-958-8170; Email: mylovekw@hanmail.net
• Study Contact Backup: Name: Jong Shin Woo, MD, PhD; Phone Number: 82-2-958-8176; Email: snowball77@hanmail.net

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 130-872
    • Recruiting
    • Kyung Hee University Hospital
    • Contact: Weon Kim, MD, PhD; Phone Number: 82 2-958-8170; Email: mylovekw@hanmail.net
    • Contact: Jong Shin Woo, MD; Phone Number: 82 2-958-8176; Email: snowball77@hanmail.net
    • Sub-Investigator: Jong Shin Woo, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• healthy volunteer age 20 to 40 years
• non-smoker

Exclusion Criteria:

• High blood pressure (>140/90 mmHg) or any antihypertensive medications
• diabetes
• any cardiovascular disease
• kidney disease
• thyroid disease
• cerebrovascular disease
• liver disease (bilirubin level >2 mg/dl)
• pregnancy
• body mass index >25 kg/m2

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sitagliptin; All participant will exam brachial artery endothelium-dependent flow-mediated dilatation (FMD). After then, pneumatic cuff wiil be inflated to 200 mmHg for 15 minutes to induce brachial artery ischemia. At the end of ischemia, 15 minutes of reperfusion was performed to induce reperfusion injury. After ischemia-reperfusion (IR) injury, brachial artery FMD will be measured again. After randomization, sitagliptin group will be treated by single dose of sitagliptin (Januvia) 50mg. In 2 hours later, brachial artery FMD measurement, IR injury and brachial artery FMD measurement will be measured again.	Drug: Sitagliptin; The brachial FMD before and after IR injury will be assessed. After randomization, study medication will be treated. In 2 hours later, the brachial FMD before and after IR injury will be assessed again. All volunteers had a wash-out period of 7 days. Seven days later, the subjects returned to crossover study medication (ie, sitagliptin or placebo), and the protocol described above was repeated.; Other Names: Januvia
Placebo Comparator: Placebo; After brachial artery FMD measurement, IR injury for each 15 minutes will be performed, and brachial artery FMD will be measured again. After randomization, placebo group will be treated by nothing. In 2 hours later, brachial artery FMD measurement, IR injury and brachial artery FMD measurement will be measured again.
Other: Sitagliptin and glibenclimide; If sitagliptin treatment show preventive effects of IR injury, the investigator will perform additional experiment to explore the mechanism (Protocol 2 study). Additional 15 healthy volunteers will be treated 5 mg of glibenclamide (Euglucon) 1 hour before administration of 50 m g of sitagliptin. In 2 hours after sitagliptin administration, FMD measurement before and after IR injury will be performed as described above.	Drug: Sitagliptin; The brachial FMD before and after IR injury will be assessed. After randomization, study medication will be treated. In 2 hours later, the brachial FMD before and after IR injury will be assessed again. All volunteers had a wash-out period of 7 days. Seven days later, the subjects returned to crossover study medication (ie, sitagliptin or placebo), and the protocol described above was repeated.; Other Names: Januvia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The difference of FMD [brachial artery endothelium-dependent flow-mediated dilatation] after IR injury (brachial FMD before and after IR injury will be assessed)	2 hours after study drug treatment

Secondary Outcome Measures

Outcome Measure	Time Frame
The difference of FMD after IR injury in co-treatment of glibenclimide and sitagliptin ((brachial FMD before and after IR injury will be assessed)	3.5 hours after study drug treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Adverse events such as hypoglycemia	3 weeks

Collaborators and Investigators

• Sponsor: Kyunghee University Medical Center
• Investigators: Principal Investigator: Weon Kim, MD, PhD, Kyunghee University Medical Center

Study record dates

Study Major Dates

• Study Start: February 1, 2015
• Primary Completion (Anticipated): June 1, 2015
• Study Completion (Anticipated): August 1, 2015

Study Registration Dates

• First Submitted: March 14, 2015
• First Submitted That Met QC Criteria: April 1, 2015
• First Posted (Estimate): April 2, 2015

Study Record Updates

• Last Update Posted (Estimate): April 2, 2015
• Last Update Submitted That Met QC Criteria: April 1, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: human; Sitagliptin; Endothelium; Ischemia-Reperfusion Injury
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Reperfusion Injury; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Sitagliptin Phosphate
• Other Study ID Numbers: SIGNAL