Comparative Effects of Antidiabetic Medications on Postprandial Hyperlipidemia, Free Fatty Acid Signaling, and Endothelial Dysfunction in Individuals With Prediabetes
Overview
- Phase
- Phase 4
- Intervention
- Placebo
- Conditions
- Prediabetes
- Sponsor
- The University of Texas Health Science Center, Houston
- Enrollment
- 21
- Locations
- 1
- Primary Endpoint
- Monocyte NfkB Levels as Detected by Western Blotting
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
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
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.
Investigators
Absalon D Gutierrez
Assistant Professor of Medicine
The University of Texas Health Science Center, Houston
Eligibility Criteria
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
Arms & Interventions
Placebo, then Exenatide, then Saxagliptin
Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Intervention: Placebo
Exenatide, then Saxagliptin, then Placebo
Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Intervention: Exenatide
Exenatide, then Saxagliptin, then Placebo
Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Intervention: Saxagliptin
Exenatide, then Saxagliptin, then Placebo
Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Intervention: Placebo
Exenatide, then Placebo, then Saxagliptin
Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Intervention: Exenatide
Exenatide, then Placebo, then Saxagliptin
Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Intervention: Saxagliptin
Exenatide, then Placebo, then Saxagliptin
Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Intervention: Placebo
Saxagliptin, then Exenatide, then Placebo
Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Intervention: Exenatide
Saxagliptin, then Exenatide, then Placebo
Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Intervention: Saxagliptin
Saxagliptin, then Exenatide, then Placebo
Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Intervention: Placebo
Saxagliptin, then Placebo, then Exenatide
Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Intervention: Exenatide
Saxagliptin, then Placebo, then Exenatide
Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Intervention: Saxagliptin
Saxagliptin, then Placebo, then Exenatide
Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Intervention: Placebo
Placebo, then Exenatide, then Saxagliptin
Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Intervention: Exenatide
Placebo, then Exenatide, then Saxagliptin
Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Intervention: Saxagliptin
Placebo, then Saxagliptin, then Exenatide
Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Intervention: Exenatide
Placebo, then Saxagliptin, then Exenatide
Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Intervention: Saxagliptin
Placebo, then Saxagliptin, then Exenatide
Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Intervention: Placebo
Exenatide, then Saxagliptin, then Placebo, then Exenatide ER
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
Intervention: Exenatide
Exenatide, then Saxagliptin, then Placebo, then Exenatide ER
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
Intervention: Saxagliptin
Exenatide, then Saxagliptin, then Placebo, then Exenatide ER
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
Intervention: Exenatide extended-release (ER)
Exenatide, then Saxagliptin, then Placebo, then Exenatide ER
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
Intervention: Placebo
Exenatide, then Placebo, then Saxagliptin, then Exenatide ER
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
Intervention: Exenatide
Exenatide, then Placebo, then Saxagliptin, then Exenatide ER
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
Intervention: Saxagliptin
Exenatide, then Placebo, then Saxagliptin, then Exenatide ER
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
Intervention: Exenatide extended-release (ER)
Exenatide, then Placebo, then Saxagliptin, then Exenatide ER
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
Intervention: Placebo
Saxagliptin, then Exenatide, then Placebo, then Exenatide ER
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
Intervention: Exenatide
Saxagliptin, then Exenatide, then Placebo, then Exenatide ER
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
Intervention: Saxagliptin
Saxagliptin, then Exenatide, then Placebo, then Exenatide ER
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
Intervention: Exenatide extended-release (ER)
Saxagliptin, then Exenatide, then Placebo, then Exenatide ER
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
Intervention: Placebo
Saxagliptin, then Placebo, then Exenatide, then Exenatide ER
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
Intervention: Exenatide
Saxagliptin, then Placebo, then Exenatide, then Exenatide ER
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
Intervention: Saxagliptin
Saxagliptin, then Placebo, then Exenatide, then Exenatide ER
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
Intervention: Exenatide extended-release (ER)
Saxagliptin, then Placebo, then Exenatide, then Exenatide ER
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
Intervention: Placebo
Placebo, then Exenatide, then Saxagliptin, then Exenatide ER
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
Intervention: Exenatide
Placebo, then Exenatide, then Saxagliptin, then Exenatide ER
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
Intervention: Saxagliptin
Placebo, then Exenatide, then Saxagliptin, then Exenatide ER
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
Intervention: Exenatide extended-release (ER)
Placebo, then Exenatide, then Saxagliptin, then Exenatide ER
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
Intervention: Placebo
Placebo, then Saxagliptin, then Exenatide, then Exenatide ER
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
Intervention: Exenatide
Placebo, then Saxagliptin, then Exenatide, then Exenatide ER
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
Intervention: Saxagliptin
Placebo, then Saxagliptin, then Exenatide, then Exenatide ER
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
Intervention: Exenatide extended-release (ER)
Placebo, then Saxagliptin, then Exenatide, then Exenatide ER
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
Intervention: Placebo
Outcomes
Primary Outcomes
Monocyte NfkB Levels as Detected by Western Blotting
Time Frame: 2 hours after ingestion of meal
Monocyte NfkB p65 arbitrary units are quantified by densitometric analysis of the Western blots.
Secondary Outcomes
- Peak Forearm Blood Flow(6 hours after meal)
- Triglycerides(6 hours after ingestion of meal)
- Free Fatty Acids(6 hours after meal)