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

Exenatide and Postprandial Endothelial Dysfunction: Effects and Mechanisms

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Exenatide SC; Drug: Placebo SC; Drug: Exenatide IV; Drug: Exendin-9; Drug: Placebo IV

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.

• Study Type: Interventional
• Enrollment (Actual): 76
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85012
      • Phoenix VA Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: Byetta, exendin-4; Drug: Placebo SC; Placebo sc BID/10days; Other Names: 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 Names: 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 Names: exendin-(9-39); Drug: Placebo IV; Intravenous infusion for 45 minutes on 1 out of 3 visits; Other Names: placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reactive Hyperemia Index (RHI)	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.	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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Triglycerides	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.	0, 2, 4, 6 and 8 hours post-study drug on day 11
Plasma Glucose	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.	0, 2, 4, 6, and 8 hours post-study drug on day 11

Collaborators and Investigators

• Sponsor: Carl T. Hayden VA Medical Center
• Collaborators: American Diabetes Association; Amylin Pharmaceuticals, LLC.
• Investigators: Principal Investigator: Juraj Koska, MD, PhD, Phoenix VA Healthcare System

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: August 13, 2010
• First Submitted That Met QC Criteria: August 13, 2010
• First Posted (Estimate): August 16, 2010

Study Record Updates

• Last Update Posted (Estimate): May 20, 2014
• Last Update Submitted That Met QC Criteria: May 12, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Keywords: Type 2 diabetes mellitus, Impaired glucose tolerance
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Obesity Agents; Incretins; Exenatide
• Other Study ID Numbers: 1-10-CT-31