Effects of Antidiabetic Medications on the Postprandial State in Prediabetes

Study Overview
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Brief Summary
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This project addresses cardiovascular disease risk in patients with prediabetes. Levels of lipids after eating a meal (postprandial lipids) are strong independent predictors of cardiovascular risk. Newer anti-diabetic agents - exenatide and saxagliptin - impact lipid metabolism. These medications will be studied for their effect in reducing both postprandial lipid levels and arterial dysfunction.

Detailed Description
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It is a paradox that medical efforts to control blood glucose in type 2 diabetes mellitus have not decreased the risk of cardiovascular disease. Postprandial lipid concentrations are a strong predictor of cardiovascular risk, independent of traditional cardiovascular risk factors. The new classes of antidiabetic medications - GLP-1 agonists and DPP-IV inhibitors - affect lipid as well as glucose metabolism. This study will investigate the efficacy of these medications in reducing postprandial hyperlipidemia, disrupting the concurrent proinflammatory free fatty acid signaling, and ameliorating endothelial dysfunction in individuals with prediabetes. This will consist of a single center, randomized, crossover, placebo-controlled double-blinded prospective trial involving three study arms representing the aforementioned medications: exenatide (GLP-1 agonist), saxagliptin (DPP-IV inhibitor), and placebo (control arm). Each subject will participate in each of the three arms, which are three separate, daylong outpatient studies. For each study arm, subjects will eat a standardized atherogenic high-fat test lunch. Venous blood draws and measurements of forearm blood flow will be done prior to the meal and periodically during a 6-hour period after the meal. Forearm blood flow measurements will assess for changes in endothelial function. The blood will be analyzed for multiple markers of hyperlipidemia and free fatty acid signaling. After completing the three randomized study visits, subjects are invited to participate in an optional, nonrandomized extension study. For the extension study, subjects will take exenatide ER (extended-release exenatide) weekly for total of six weeks. Then subjects return to eat a standardized atherogenic high-fat test lunch. Venous blood draws and measurements of forearm blood flow will be done prior to the meal and periodically during a 4-hour period after the meal, for the same analyses described before. The results will provide new insights into the anti-inflammatory effects of multiple antidiabetic medications via the mechanisms of postprandial hyperlipidemia, free fatty acid signaling, and endothelial function in prediabetic individuals.

Official Title
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Comparative Effects of Antidiabetic Medications on Postprandial Hyperlipidemia, Free Fatty Acid Signaling, and Endothelial Dysfunction in Individuals With Prediabetes

Conditions
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Prediabetes, Obesity

Intervention / Treatment
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* Drug: Exenatide
* Drug: Saxagliptin
* Drug: Exenatide extended-release (ER)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Prediabetes - defined as either impaired fasting glucose (fasting glucose of 100-125 mg/dL), impaired glucose tolerance (2-hour postprandial blood glucose of 140-199 mg/dL after 75 gram oral glucose challenge), and/or a hemoglobin A1C ranging from 5.7% to 6.4% Subjects are allowed, but not required, to be on statins, ACE-inhibitors, beta-blockers, angiotensin-receptor blockers, thiazide diuretics, and/or loop diuretics at doses that have been stable for at least the last 3 months BMI between 30-35 kg/m2 (±1 kg/m2) Body weight has been stable (±4-5 pounds) over the prior three months. Women of childbearing age must agree to use an acceptable method of pregnancy prevention (barrier methods, abstinence, or surgical sterilization) for the duration of the study Patients must have the following laboratory values: Hematocrit ≥ 34 vol% S. creatinine < 1.5 mg/dl in men and 1.4 mg/dl in women AST (SGOT) < 2.5 times ULN, ALT (SGPT) < 2.5 times ULN, alkaline phosphatase< 2.5 times ULN Exclusion Criteria: History of Type 1 or Type 2 diabetes mellitus History of diabetic ketoacidosis or hyperosmolar nonketotic coma Pregnant or breastfeeding women Patients must not be receiving lipid-lowering medications other than statins within the last 3 months Patient must not be receiving metformin, DPP-IV inhibitors, GLP-1 agonists, thiazolidinediones, insulin, sulfonylureas, acarbose, SGLT-2 inhibitors, corticosteroids, or immunosuppressive therapy within the last 3 months and cannot take them for the duration of the study. Patient must not be receiving NSAIDS or antioxidant vitamins within the last 1 week, and cannot take them for the duration of the study. Patients must not be on hormone replacement therapy. Patients with diabetic gastroparesis Patients with current tobacco use Patients with active malignancy Patients with history of urinary bladder cancer Patients with dietary restrictions precluding a high-fat meal Patients with a history of clinically significant heart disease (NYHA III or IV; more than non- specific ST-T wave changes on the EKG), peripheral vascular disease (history of claudication), or pulmonary disease (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation) will not be studied Subjects with a history of any serious hypersensitivity reaction to the study medications Prisoners or subjects who are involuntarily incarcerated Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness Subjects with known allergic reactions to the study medications or test meal Subjects unwilling or unable to provide informed consent Subjects determined by the investigator(s) to not be appropriate candidates for the study

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exenatide, then Saxagliptin, then Placebo<br>Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections | Drug: Exenatide<br>* Single subcutaneous injection (10 mcg)<br>* Other names: Byetta;Drug: Saxagliptin<br>* Single dose orally (5 mg)<br>* Other names: Onglyza;Other: Placebo<br>* Placebo tablets and Placebo (normal saline) injections<br>|
| Experimental: Exenatide, then Placebo, then Saxagliptin<br>Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections | Drug: Exenatide<br>* Single subcutaneous injection (10 mcg)<br>* Other names: Byetta;Drug: Saxagliptin<br>* Single dose orally (5 mg)<br>* Other names: Onglyza;Other: Placebo<br>* Placebo tablets and Placebo (normal saline) injections<br>|
| Placebo Comparator: Saxagliptin, then Exenatide, then Placebo<br>Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections | Drug: Exenatide<br>* Single subcutaneous injection (10 mcg)<br>* Other names: Byetta;Drug: Saxagliptin<br>* Single dose orally (5 mg)<br>* Other names: Onglyza;Other: Placebo<br>* Placebo tablets and Placebo (normal saline) injections<br>|
| Experimental: Saxagliptin, then Placebo, then Exenatide<br>Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections | Drug: Exenatide<br>* Single subcutaneous injection (10 mcg)<br>* Other names: Byetta;Drug: Saxagliptin<br>* Single dose orally (5 mg)<br>* Other names: Onglyza;Other: Placebo<br>* Placebo tablets and Placebo (normal saline) injections<br>|
| Experimental: Placebo, then Exenatide, then Saxagliptin<br>Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections | Drug: Exenatide<br>* Single subcutaneous injection (10 mcg)<br>* Other names: Byetta;Drug: Saxagliptin<br>* Single dose orally (5 mg)<br>* Other names: Onglyza;Other: Placebo<br>* Placebo tablets and Placebo (normal saline) injections<br>|
| Experimental: Placebo, then Saxagliptin, then Exenatide<br>Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections | Drug: Exenatide<br>* Single subcutaneous injection (10 mcg)<br>* Other names: Byetta;Drug: Saxagliptin<br>* Single dose orally (5 mg)<br>* Other names: Onglyza;Other: Placebo<br>* Placebo tablets and Placebo (normal saline) injections<br>|
| Experimental: Exenatide, then Saxagliptin, then Placebo, then Exenatide ER<br>Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablet and Placebo (normal saline) injection; Subcutaneous injection (2mg) weekly for 6 weeks | Drug: Exenatide<br>* Single subcutaneous injection (10 mcg)<br>* Other names: Byetta;Drug: Saxagliptin<br>* Single dose orally (5 mg)<br>* Other names: Onglyza;Drug: Exenatide extended-release (ER)<br>* Subcutaneous injection (2mg) weekly for 6 weeks<br>* Other names: Bydureon;Other: Placebo<br>* Placebo tablets and Placebo (normal saline) injections<br>|
| Experimental: Exenatide, then Placebo, then Saxagliptin, then Exenatide ER<br>Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablet and Placebo (normal saline) injection; Subcutaneous injection (2mg) weekly for 6 weeks | Drug: Exenatide<br>* Single subcutaneous injection (10 mcg)<br>* Other names: Byetta;Drug: Saxagliptin<br>* Single dose orally (5 mg)<br>* Other names: Onglyza;Drug: Exenatide extended-release (ER)<br>* Subcutaneous injection (2mg) weekly for 6 weeks<br>* Other names: Bydureon;Other: Placebo<br>* Placebo tablets and Placebo (normal saline) injections<br>|
| Experimental: Saxagliptin, then Exenatide, then Placebo, then Exenatide ER<br>Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablet and Placebo (normal saline) injection; Subcutaneous injection (2mg) weekly for 6 weeks | Drug: Exenatide<br>* Single subcutaneous injection (10 mcg)<br>* Other names: Byetta;Drug: Saxagliptin<br>* Single dose orally (5 mg)<br>* Other names: Onglyza;Drug: Exenatide extended-release (ER)<br>* Subcutaneous injection (2mg) weekly for 6 weeks<br>* Other names: Bydureon;Other: Placebo<br>* Placebo tablets and Placebo (normal saline) injections<br>|
| Experimental: Saxagliptin, then Placebo, then Exenatide, then Exenatide ER<br>Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablet and Placebo (normal saline) injection; Subcutaneous injection (2mg) weekly for 6 weeks | Drug: Exenatide<br>* Single subcutaneous injection (10 mcg)<br>* Other names: Byetta;Drug: Saxagliptin<br>* Single dose orally (5 mg)<br>* Other names: Onglyza;Drug: Exenatide extended-release (ER)<br>* Subcutaneous injection (2mg) weekly for 6 weeks<br>* Other names: Bydureon;Other: Placebo<br>* Placebo tablets and Placebo (normal saline) injections<br>|
| Experimental: Placebo, then Exenatide, then Saxagliptin, then Exenatide ER<br>Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablet and Placebo (normal saline) injection; Subcutaneous injection (2mg) weekly for 6 weeks | Drug: Exenatide<br>* Single subcutaneous injection (10 mcg)<br>* Other names: Byetta;Drug: Saxagliptin<br>* Single dose orally (5 mg)<br>* Other names: Onglyza;Drug: Exenatide extended-release (ER)<br>* Subcutaneous injection (2mg) weekly for 6 weeks<br>* Other names: Bydureon;Other: Placebo<br>* Placebo tablets and Placebo (normal saline) injections<br>|
| Experimental: Placebo, then Saxagliptin, then Exenatide, then Exenatide ER<br>Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablet and Placebo (normal saline) injection; Subcutaneous injection (2mg) weekly for 6 weeks | Drug: Exenatide<br>* Single subcutaneous injection (10 mcg)<br>* Other names: Byetta;Drug: Saxagliptin<br>* Single dose orally (5 mg)<br>* Other names: Onglyza;Drug: Exenatide extended-release (ER)<br>* Subcutaneous injection (2mg) weekly for 6 weeks<br>* Other names: Bydureon;Other: Placebo<br>* Placebo tablets and Placebo (normal saline) injections<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Monocyte NfkB Levels as Detected by Western Blotting | Monocyte NfkB p65 arbitrary units are quantified by densitometric analysis of the Western blots. | baseline | 
| Monocyte NfkB Levels as Detected by Western Blotting | Monocyte NfkB p65 arbitrary units are quantified by densitometric analysis of the Western blots. | 2 hours after ingestion of meal | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Triglycerides | triglycerides | baseline | 
| Triglycerides | triglycerides | 2 hours after ingestion of meal | 
| Triglycerides | triglycerides | 4 hours after ingestion of meal | 
| Triglycerides | triglycerides | 6 hours after ingestion of meal | 
| Free Fatty Acids | Free Fatty Acids | baseline | 
| Free Fatty Acids | Free Fatty Acids | 2 hours after meal | 
| Free Fatty Acids | Free Fatty Acids | 4 hours after meal | 
| Free Fatty Acids | Free Fatty Acids | 6 hours after meal | 
| Peak Forearm Blood Flow | Peak forearm blood flow via strain gauge venous occlusion plethysmography | baseline | 
| Peak Forearm Blood Flow | Peak forearm blood flow via strain gauge venous occlusion plethysmography | 3 hours after meal | 
| Peak Forearm Blood Flow | Peak forearm blood flow via strain gauge venous occlusion plethysmography | 6 hours after meal | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prediabetes, diabetes mellitus type 2, exenatide, saxagliptin, exenatide ER