Effects of Antidiabetic Medications on the Postprandial State in Prediabetes

Phase 4

Completed

• Conditions: Prediabetes; Obesity
• Interventions: Drug: Exenatide; Drug: Saxagliptin; Other: Placebo; Drug: Exenatide extended-release (ER)

• Registration Number: NCT02104739
• Lead Sponsor: The University of Texas Health Science Center, Houston

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.

Study Timeline

• Study Start: 2014-04
• Study First Submitted: 2014-04-01
• Study First Submitted QC: 2014-04-03
• Study First Posted: 2014-04-04
• Primary Completion: 2017-03
• Study Completion: 2017-03
• Results First Submitted: 2018-03-20
• Status Verified: 2018-06
• Results First Submitted QC: 2018-06-01
• Last Update Submitted: 2018-06-01
• Results First Posted: 2018-07-03
• Last Update Posted: 2018-07-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 21

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Saxagliptin, then Placebo, then Exenatide	Placebo	Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Placebo, then Exenatide, then Saxagliptin	Placebo	Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Placebo, then Saxagliptin, then Exenatide	Placebo	Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Exenatide, then Saxagliptin, then Placebo, then Exenatide ER	Placebo	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
Exenatide, then Placebo, then Saxagliptin, then Exenatide ER	Placebo	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
Saxagliptin, then Exenatide, then Placebo, then Exenatide ER	Placebo	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
Saxagliptin, then Placebo, then Exenatide, then Exenatide ER	Placebo	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
Placebo, then Exenatide, then Saxagliptin, then Exenatide ER	Placebo	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
Placebo, then Saxagliptin, then Exenatide, then Exenatide ER	Exenatide	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
Placebo, then Saxagliptin, then Exenatide, then Exenatide ER	Placebo	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
Exenatide, then Saxagliptin, then Placebo	Placebo	Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Exenatide, then Placebo, then Saxagliptin	Exenatide	Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Exenatide, then Placebo, then Saxagliptin	Placebo	Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Saxagliptin, then Exenatide, then Placebo	Exenatide	Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Saxagliptin, then Exenatide, then Placebo	Saxagliptin	Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Saxagliptin, then Exenatide, then Placebo	Placebo	Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Exenatide, then Placebo, then Saxagliptin, then Exenatide ER	Exenatide extended-release (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
Exenatide, then Saxagliptin, then Placebo, then Exenatide ER	Exenatide extended-release (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
Saxagliptin, then Exenatide, then Placebo, then Exenatide ER	Exenatide extended-release (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
Placebo, then Saxagliptin, then Exenatide, then Exenatide ER	Exenatide extended-release (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
Saxagliptin, then Placebo, then Exenatide, then Exenatide ER	Exenatide extended-release (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
Placebo, then Exenatide, then Saxagliptin, then Exenatide ER	Exenatide extended-release (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
Saxagliptin, then Placebo, then Exenatide	Saxagliptin	Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Exenatide, then Saxagliptin, then Placebo	Exenatide	Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Exenatide, then Saxagliptin, then Placebo	Saxagliptin	Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Exenatide, then Placebo, then Saxagliptin	Saxagliptin	Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Saxagliptin, then Placebo, then Exenatide	Exenatide	Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Placebo, then Exenatide, then Saxagliptin	Exenatide	Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Placebo, then Saxagliptin, then Exenatide	Saxagliptin	Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Placebo, then Exenatide, then Saxagliptin	Saxagliptin	Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Placebo, then Saxagliptin, then Exenatide	Exenatide	Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections
Exenatide, then Saxagliptin, then Placebo, then Exenatide ER	Exenatide	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
Exenatide, then Saxagliptin, then Placebo, then Exenatide ER	Saxagliptin	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
Exenatide, then Placebo, then Saxagliptin, then Exenatide ER	Saxagliptin	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
Exenatide, then Placebo, then Saxagliptin, then Exenatide ER	Exenatide	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
Saxagliptin, then Exenatide, then Placebo, then Exenatide ER	Exenatide	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
Saxagliptin, then Exenatide, then Placebo, then Exenatide ER	Saxagliptin	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
Saxagliptin, then Placebo, then Exenatide, then Exenatide ER	Exenatide	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
Saxagliptin, then Placebo, then Exenatide, then Exenatide ER	Saxagliptin	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
Placebo, then Exenatide, then Saxagliptin, then Exenatide ER	Exenatide	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
Placebo, then Exenatide, then Saxagliptin, then Exenatide ER	Saxagliptin	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
Placebo, then Saxagliptin, then Exenatide, then Exenatide ER	Saxagliptin	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

Primary Outcome Measures

Name	Time	Method
Monocyte NfkB Levels as Detected by Western Blotting	2 hours after ingestion of meal	Monocyte NfkB p65 arbitrary units are quantified by densitometric analysis of the Western blots.

Secondary Outcome Measures

Name	Time	Method
Peak Forearm Blood Flow	6 hours after meal	Peak forearm blood flow via strain gauge venous occlusion plethysmography
Triglycerides	6 hours after ingestion of meal	triglycerides
Free Fatty Acids	6 hours after meal	Free Fatty Acids

Trial Locations

Locations (1)

The University of Texas Health Science Center at Houston; 🇺🇸 Houston, Texas, United States