The Study of Exenatide Action on Vessel Function in Type 2 Diabetes and Prediabetes

This study has been completed.
Sponsor:
Collaborators:
American Diabetes Association
Amylin Pharmaceuticals, LLC.
Information provided by (Responsible Party):
Juraj Koska, Carl T. Hayden VA Medical Center
ClinicalTrials.gov Identifier:
NCT01181986
First received: August 13, 2010
Last updated: May 12, 2014
Last verified: May 2014
  Purpose

The purpose of this investigation is to evaluate whether exenatide, a type 2 diabetes medication, will improve the function of the innermost part of the arterial wall called the endothelium after a fat-enriched meal and to determine how this occurs. The results of this study will help to determine and understand a novel action of this group of diabetes medications based on the action of naturally occuring gut substances called incretins. This may have a significant impact on cardiovascular health in patients with early and longstanding diabetes.


Condition Intervention Phase
Type 2 Diabetes Mellitus
Drug: Exenatide SC
Drug: Exenatide IV
Drug: Placebo SC
Drug: Exendin-9
Drug: Placebo IV
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Exenatide and Postprandial Endothelial Dysfunction: Effects and Mechanisms

Resource links provided by NLM:


Further study details as provided by Carl T. Hayden VA Medical Center:

Primary Outcome Measures:
  • Reactive Hyperemia Index (RHI) [ Time Frame: 0, 2, 4, 6 and 8 hours on Day 11 (Sub-study 1); 0 and 120 minutes on test Days 1, 2 & 3 (Sub-study 2) ] [ Designated as safety issue: No ]
    Greater RHI reflects greater endothelial function. It is calculated as average post-ischemia pulse magnitude divided by average pre-ischemia pulse magnitude. Results are expressed as least-square means of ANCOVA models.


Secondary Outcome Measures:
  • Plasma Triglycerides [ Time Frame: 0, 2, 4, 6 and 8 hours post-study drug on day 11 ] [ Designated as safety issue: No ]
    Triglycerides concentrations were measured before and 2, 4, 6 and 8 hours following study drug. Results are expressed as least-square means of ANCOVA models adjusted for sampling time and intervention sequence.

  • Plasma Glucose [ Time Frame: 0, 2, 4, 6, and 8 hours post-study drug on day 11 ] [ Designated as safety issue: No ]
    Plasma glucose was measured before and 2, 4, 6 and 8 hours following study drug administration. Results are expressed as least-square means of ANCOVA models adjusted for sampling time and intervention sequence.


Enrollment: 76
Study Start Date: August 2010
Study Completion Date: December 2012
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Exenatide SC (Sub-study 1)
Study groups will be individuals with recent onset (<3 years) or established (>5 years) T2D. The plan is to achieve 40 complete studies of subcutaneous injection of exenatide BID (Byetta®, 5 or 10 µg) or identically looking Placebo SC for 10 days, separated by 14-day washout period. On the next day after each treatment phase, a single dose of the assigned medication will be injected just before a fat-enriched breakfast meal. A lunch meal of similar caloric and nutrient content will be administered 4 hours following the breakfast meal. Endothelial function will be measured just prior to the injection and every 2 hours during 8-hour post-breakfast period.
Drug: Exenatide SC
Exenatide 5-10 ug sc BID/10 days
Other Name: Byetta, exendin-4
Drug: Placebo SC
Placebo sc BID/10days
Other Name: placebo
Experimental: Exenatide IV (Sub-study 2)
Study group will be individuals with recent onset (<1 year) T2D on diet and impaired glucose tolerance. The plan is to achieve 35 complete studies. The intervention will include 3 randomly ordered visits with intravenous infusion of exenatide in the presence (v1) or absence (v2) of GLP-1 receptor inhibitor exendin-9, and a control test with Placebo IV without exendin-9 (v3). Endothelial function will be measured at baseline and 2 hours later during the final 15 minutes of the infusion cocktails. Study participants will remain fasting during the test visit (3 hours total).
Drug: Exenatide IV
50 ng/min intravenously for 45 minutes on 2 out of 3 study visits separated by 5-10 days
Other Name: exendin-4, Byetta
Drug: Exendin-9
Primed (6,000 pM/kg), continuous (600 pM/kg) intravenous infusion for 75 minutes on 1 out of 3 study visits.
Other Name: exendin-(9-39)
Drug: Placebo IV
Intravenous infusion for 45 minutes on 1 out of 3 visits
Other Name: placebo

Detailed Description:

Two independent, double-blinded, crossover substudies will be conducted to test the effect of exenatide on daylong post-meal and fasting endothelial function. We will measure endothelial function measured by peripheral arterial tonometry (EndoPAT2000, Itamar Inc.). Patients with recent onset (<3 years) or established (>5 years, Substudy 1 only) diabetes and impaired sugar tolerance (Substudy 2 only) will be studied. The plan is to complete studies in 75 patients (40 in Substudy 1 and 35 in Substudy 2).

In Substudy 1 patients will get twice a day a skin injection of exenatide (Byetta) or identically looking placebo for 10 days, separated by 14-day period. On the next day after each treatemnt period (day 11), they get just one injection and eat a fat-enriched breakfast. A fatty lunch of similar caloric content will be given 4 hours following the breakfast. Endothelial function will be measured just prior to the injection and every 2 hours for total 8 hours.

In Substudy 2, patients on 3 different days will get infusion of exenatide withg or without a blocking drug exendin-9, and a control test with placebo without exendin-9. Endothelial function will be measured before the infusion and 2 hours later during the final 15 minutes of the infusion cocktails. Patients will not eat any meal during the test visits.

  Eligibility

Ages Eligible for Study:   35 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • US Veterans
  • type 2 diabetes mellitus (T2D) diagnosed within 3 years with good glycemic control on diet, metformin, or sulfonylurea agents or combinations of these agents (HbA1c ≤8.0%)
  • T2D diagnosed ≥ 5 years prior to study enrollment
  • Impaired glucose tolerance

Exclusion Criteria:

  • T2D not meeting inclusion above criteria for duration of diabetes or HbA1c values
  • known or suspected T1D (early onset age, low body mass index, lack of family history)
  • TZD use in the prior 3 months
  • prior regular use of insulin
  • Creatinine >2.0 mg/dl or other laboratory or clinical evidence of kidney disease
  • anemia
  • known active liver disease or hepatic enzyme elevation two-and-a half times above normal
  • acute bacterial or viral illness or evidence of other active infection in the past 4 weeks
  • stable or unstable angina or other major illness in the past 6 months
  • Raynaud's disease or any rheumatic disease affecting fingers
  • current regular use of anti-inflammatory medications or antioxidants, including over the counter medications and high dose salicylates (>1 g/day);
  • subjects receiving lipid lowering or anti-hypertension medications must be on stable doses for at least 2 months prior to participation.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01181986

Locations
United States, Arizona
Phoenix VA Medical Center
Phoenix, Arizona, United States, 85012
Sponsors and Collaborators
Carl T. Hayden VA Medical Center
American Diabetes Association
Amylin Pharmaceuticals, LLC.
Investigators
Principal Investigator: Juraj Koska, MD, PhD Phoenix VA Healthcare System
  More Information

No publications provided

Responsible Party: Juraj Koska, Research Health Scientist, Carl T. Hayden VA Medical Center
ClinicalTrials.gov Identifier: NCT01181986     History of Changes
Other Study ID Numbers: 1-10-CT-31
Study First Received: August 13, 2010
Results First Received: December 26, 2013
Last Updated: May 12, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Carl T. Hayden VA Medical Center:
Type 2 diabetes mellitus, Impaired glucose tolerance

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Endocrine System Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Exenatide
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Hypoglycemic Agents
Incretins
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 30, 2014