Effects of Antidiabetic Medications on the Postprandial State in Prediabetes

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

Sponsors

Lead Sponsor: The University of Texas Health Science Center, Houston

Collaborator: The Center for Clinical and Translational Sciences (CCTS) Clinical Research Unit at The University of Texas Health Science Center at Houston

Source 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.

Overall Status Completed
Start Date April 2014
Completion Date March 2017
Primary Completion Date March 2017
Phase Phase 4
Study Type Interventional
Primary Outcome
Measure Time Frame
Monocyte NfkB Levels as Detected by Western Blotting baseline
Monocyte NfkB Levels as Detected by Western Blotting 2 hours after ingestion of meal
Secondary Outcome
Measure Time Frame
Triglycerides baseline
Triglycerides 2 hours after ingestion of meal
Triglycerides 4 hours after ingestion of meal
Triglycerides 6 hours after ingestion of meal
Free Fatty Acids baseline
Free Fatty Acids 2 hours after meal
Free Fatty Acids 4 hours after meal
Free Fatty Acids 6 hours after meal
Peak Forearm Blood Flow baseline
Peak Forearm Blood Flow 3 hours after meal
Peak Forearm Blood Flow 6 hours after meal
Enrollment 21
Condition
Intervention

Intervention Type: Drug

Intervention Name: Exenatide

Description: Single subcutaneous injection (10 mcg)

Other Name: Byetta

Intervention Type: Drug

Intervention Name: Saxagliptin

Description: Single dose orally (5 mg)

Other Name: Onglyza

Intervention Type: Drug

Intervention Name: Exenatide extended-release (ER)

Description: Subcutaneous injection (2mg) weekly for 6 weeks

Other Name: Bydureon

Intervention Type: Other

Intervention Name: Placebo

Description: Placebo tablets and Placebo (normal saline) injections

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

- 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

Gender: All

Minimum Age: 30 Years

Maximum Age: 70 Years

Healthy Volunteers: Accepts Healthy Volunteers

Overall Official
Last Name Role Affiliation
Absalaon D Gutierrez, MD Principal Investigator University of Texas Health Science Center at Houston, Dept. of Medicine
Location
Facility: The University of Texas Health Science Center at Houston
Location Countries

United States

Verification Date

June 2018

Responsible Party

Type: Principal Investigator

Investigator Affiliation: The University of Texas Health Science Center, Houston

Investigator Full Name: Absalon D Gutierrez

Investigator Title: Assistant Professor of Medicine

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 12
Arm Group

Label: Exenatide, then Saxagliptin, then Placebo

Type: Experimental

Description: Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections

Label: Exenatide, then Placebo, then Saxagliptin

Type: Experimental

Description: Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections

Label: Saxagliptin, then Exenatide, then Placebo

Type: Placebo Comparator

Description: Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections

Label: Saxagliptin, then Placebo, then Exenatide

Type: Experimental

Description: Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections

Label: Placebo, then Exenatide, then Saxagliptin

Type: Experimental

Description: Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections

Label: Placebo, then Saxagliptin, then Exenatide

Type: Experimental

Description: Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections

Label: Exenatide, then Saxagliptin, then Placebo, then Exenatide ER

Type: Experimental

Description: 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

Label: Exenatide, then Placebo, then Saxagliptin, then Exenatide ER

Type: Experimental

Description: 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

Label: Saxagliptin, then Exenatide, then Placebo, then Exenatide ER

Type: Experimental

Description: 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

Label: Saxagliptin, then Placebo, then Exenatide, then Exenatide ER

Type: Experimental

Description: 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

Label: Placebo, then Exenatide, then Saxagliptin, then Exenatide ER

Type: Experimental

Description: 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

Label: Placebo, then Saxagliptin, then Exenatide, then Exenatide ER

Type: Experimental

Description: 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

Study Design Info

Allocation: Randomized

Intervention Model: Crossover Assignment

Primary Purpose: Treatment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description: Placebo pills and placebo injections provided

Source: ClinicalTrials.gov