Effects of Antidiabetic Medications on the Postprandial State in Prediabetes

NCT ID: NCT02104739

Last Updated: 2018-07-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-04-30
• Study Completion Date: 2017-03-31

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.

Conditions

Prediabetes; Obesity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Exenatide, then Saxagliptin, then Placebo

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

Group Type: EXPERIMENTAL

Exenatide

Intervention Type: DRUG

Single subcutaneous injection (10 mcg)

Saxagliptin

Intervention Type: DRUG

Single dose orally (5 mg)

Placebo

Intervention Type: OTHER

Placebo tablets and Placebo (normal saline) injections

Exenatide, then Placebo, then Saxagliptin

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

Group Type: EXPERIMENTAL

Exenatide

Intervention Type: DRUG

Single subcutaneous injection (10 mcg)

Saxagliptin

Intervention Type: DRUG

Single dose orally (5 mg)

Placebo

Intervention Type: OTHER

Placebo tablets and Placebo (normal saline) injections

Saxagliptin, then Exenatide, then Placebo

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

Group Type: PLACEBO_COMPARATOR

Exenatide

Intervention Type: DRUG

Single subcutaneous injection (10 mcg)

Saxagliptin

Intervention Type: DRUG

Single dose orally (5 mg)

Placebo

Intervention Type: OTHER

Placebo tablets and Placebo (normal saline) injections

Saxagliptin, then Placebo, then Exenatide

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

Group Type: EXPERIMENTAL

Exenatide

Intervention Type: DRUG

Single subcutaneous injection (10 mcg)

Saxagliptin

Intervention Type: DRUG

Single dose orally (5 mg)

Placebo

Intervention Type: OTHER

Placebo tablets and Placebo (normal saline) injections

Placebo, then Exenatide, then Saxagliptin

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

Group Type: EXPERIMENTAL

Exenatide

Intervention Type: DRUG

Single subcutaneous injection (10 mcg)

Saxagliptin

Intervention Type: DRUG

Single dose orally (5 mg)

Placebo

Intervention Type: OTHER

Placebo tablets and Placebo (normal saline) injections

Placebo, then Saxagliptin, then Exenatide

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

Group Type: EXPERIMENTAL

Exenatide

Intervention Type: DRUG

Single subcutaneous injection (10 mcg)

Saxagliptin

Intervention Type: DRUG

Single dose orally (5 mg)

Placebo

Intervention Type: OTHER

Placebo tablets and Placebo (normal saline) injections

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

Group Type: EXPERIMENTAL

Exenatide

Intervention Type: DRUG

Single subcutaneous injection (10 mcg)

Saxagliptin

Intervention Type: DRUG

Single dose orally (5 mg)

Exenatide extended-release (ER)

Intervention Type: DRUG

Subcutaneous injection (2mg) weekly for 6 weeks

Placebo

Intervention Type: OTHER

Placebo tablets and Placebo (normal saline) injections

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

Group Type: EXPERIMENTAL

Exenatide

Intervention Type: DRUG

Single subcutaneous injection (10 mcg)

Saxagliptin

Intervention Type: DRUG

Single dose orally (5 mg)

Exenatide extended-release (ER)

Intervention Type: DRUG

Subcutaneous injection (2mg) weekly for 6 weeks

Placebo

Intervention Type: OTHER

Placebo tablets and Placebo (normal saline) injections

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

Group Type: EXPERIMENTAL

Exenatide

Intervention Type: DRUG

Single subcutaneous injection (10 mcg)

Saxagliptin

Intervention Type: DRUG

Single dose orally (5 mg)

Exenatide extended-release (ER)

Intervention Type: DRUG

Subcutaneous injection (2mg) weekly for 6 weeks

Placebo

Intervention Type: OTHER

Placebo tablets and Placebo (normal saline) injections

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

Group Type: EXPERIMENTAL

Exenatide

Intervention Type: DRUG

Single subcutaneous injection (10 mcg)

Saxagliptin

Intervention Type: DRUG

Single dose orally (5 mg)

Exenatide extended-release (ER)

Intervention Type: DRUG

Subcutaneous injection (2mg) weekly for 6 weeks

Placebo

Intervention Type: OTHER

Placebo tablets and Placebo (normal saline) injections

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

Group Type: EXPERIMENTAL

Exenatide

Intervention Type: DRUG

Single subcutaneous injection (10 mcg)

Saxagliptin

Intervention Type: DRUG

Single dose orally (5 mg)

Exenatide extended-release (ER)

Intervention Type: DRUG

Subcutaneous injection (2mg) weekly for 6 weeks

Placebo

Intervention Type: OTHER

Placebo tablets and Placebo (normal saline) injections

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

Group Type: EXPERIMENTAL

Exenatide

Intervention Type: DRUG

Single subcutaneous injection (10 mcg)

Saxagliptin

Intervention Type: DRUG

Single dose orally (5 mg)

Exenatide extended-release (ER)

Intervention Type: DRUG

Subcutaneous injection (2mg) weekly for 6 weeks

Placebo

Intervention Type: OTHER

Placebo tablets and Placebo (normal saline) injections

Interventions

Exenatide

Single subcutaneous injection (10 mcg)

Intervention Type: DRUG

Saxagliptin

Single dose orally (5 mg)

Intervention Type: DRUG

Exenatide extended-release (ER)

Subcutaneous injection (2mg) weekly for 6 weeks

Intervention Type: DRUG

Placebo

Placebo tablets and Placebo (normal saline) injections

Intervention Type: OTHER

Other Intervention Names

Byetta; Onglyza; Bydureon

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

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

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

OTHER

Sponsor Role: collaborator

The University of Texas Health Science Center, Houston

OTHER

Sponsor Role: lead

Responsible Party

Absalon D Gutierrez

Assistant Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Absalaon D Gutierrez, MD

Role: PRINCIPAL_INVESTIGATOR

University of Texas Health Science Center at Houston, Dept. of Medicine

Locations

The University of Texas Health Science Center at Houston

Houston, Texas, United States

Countries

United States

References

Hamidi V, Riggs K, Zhu L, Bermudez Saint Andre K, Westby C, Coverdale S, Dursteler A, Wang H, Miller Iii C, Taegtmeyer H, Gutierrez AD. Acute Exenatide Therapy Attenuates Postprandial Vasodilation in Humans with Prediabetes: A Randomized Controlled Trial. Metab Syndr Relat Disord. 2020 Jun;18(5):225-233. doi: 10.1089/met.2019.0102. Epub 2020 Mar 31.

Reference Type: DERIVED

PMID: 32228379 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

HSC-MS-13-0791

Identifier Type: -

Identifier Source: org_study_id