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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Exenatide and Postprandial Endothelial Dysfunction: Effects and Mechanisms

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Exenatide SC
* Drug: Exenatide IV
* Drug: Placebo SC
* Drug: Exendin-9
* Drug: Placebo IV


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exenatide SC (Sub-study 1)<br>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<br>* Exenatide 5-10 ug sc BID/10 days<br>* Other names: Byetta, exendin-4;Drug: Placebo SC<br>* Placebo sc BID/10days<br>* Other names: placebo;|
| Experimental: Exenatide IV (Sub-study 2)<br>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<br>* 50 ng/min intravenously for 45 minutes on 2 out of 3 study visits separated by 5-10 days<br>* Other names: exendin-4, Byetta;Drug: Exendin-9<br>* Primed (6,000 pM/kg), continuous (600 pM/kg) intravenous infusion for 75 minutes on 1 out of 3 study visits.<br>* Other names: exendin-(9-39);Drug: Placebo IV<br>* Intravenous infusion for 45 minutes on 1 out of 3 visits<br>* Other names: placebo;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes mellitus, Impaired glucose tolerance