Effects of Antidiabetic Medications on the Postprandial State in Prediabetes

• ClinicalTrials.gov Identifier: NCT02104739
• Recruitment Status: Completed
• First Posted: April 4, 2014
• Results First Posted: July 3, 2018
• Last Update Posted: July 3, 2018
• 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
• Information provided by (Responsible Party): Absalon D Gutierrez, The University of Texas Health Science Center, Houston

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Prediabetes; Obesity	Drug: Exenatide; Drug: Saxagliptin; Drug: Exenatide extended-release (ER); Other: Placebo	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 21 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Placebo pills and placebo injections provided
• Primary Purpose: Treatment
• Official Title: Comparative Effects of Antidiabetic Medications on Postprandial Hyperlipidemia, Free Fatty Acid Signaling, and Endothelial Dysfunction in Individuals With Prediabetes
• Actual Study Start Date: April 2014
• Actual Primary Completion Date: March 2017
• Actual Study Completion Date: March 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Exenatide, then Saxagliptin, then Placebo; Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Name: Byetta; Drug: Saxagliptin; Single dose orally (5 mg); Other Name: Onglyza; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: Exenatide, then Placebo, then Saxagliptin; Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Name: Byetta; Drug: Saxagliptin; Single dose orally (5 mg); Other Name: Onglyza; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Placebo Comparator: Saxagliptin, then Exenatide, then Placebo; Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Name: Byetta; Drug: Saxagliptin; Single dose orally (5 mg); Other Name: Onglyza; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: Saxagliptin, then Placebo, then Exenatide; Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Name: Byetta; Drug: Saxagliptin; Single dose orally (5 mg); Other Name: Onglyza; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: Placebo, then Exenatide, then Saxagliptin; Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Name: Byetta; Drug: Saxagliptin; Single dose orally (5 mg); Other Name: Onglyza; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: Placebo, then Saxagliptin, then Exenatide; Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Name: Byetta; Drug: Saxagliptin; Single dose orally (5 mg); Other Name: Onglyza; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: 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	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Name: Byetta; Drug: Saxagliptin; Single dose orally (5 mg); Other Name: Onglyza; Drug: Exenatide extended-release (ER); Subcutaneous injection (2mg) weekly for 6 weeks; Other Name: Bydureon; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: 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	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Name: Byetta; Drug: Saxagliptin; Single dose orally (5 mg); Other Name: Onglyza; Drug: Exenatide extended-release (ER); Subcutaneous injection (2mg) weekly for 6 weeks; Other Name: Bydureon; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: 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	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Name: Byetta; Drug: Saxagliptin; Single dose orally (5 mg); Other Name: Onglyza; Drug: Exenatide extended-release (ER); Subcutaneous injection (2mg) weekly for 6 weeks; Other Name: Bydureon; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: 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	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Name: Byetta; Drug: Saxagliptin; Single dose orally (5 mg); Other Name: Onglyza; Drug: Exenatide extended-release (ER); Subcutaneous injection (2mg) weekly for 6 weeks; Other Name: Bydureon; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: 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	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Name: Byetta; Drug: Saxagliptin; Single dose orally (5 mg); Other Name: Onglyza; Drug: Exenatide extended-release (ER); Subcutaneous injection (2mg) weekly for 6 weeks; Other Name: Bydureon; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: 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	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Name: Byetta; Drug: Saxagliptin; Single dose orally (5 mg); Other Name: Onglyza; Drug: Exenatide extended-release (ER); Subcutaneous injection (2mg) weekly for 6 weeks; Other Name: Bydureon; Other: Placebo; Placebo tablets and Placebo (normal saline) injections

Outcome Measures

Primary Outcome Measures :

1. Monocyte NfkB Levels as Detected by Western Blotting [ Time Frame: baseline ]
   Monocyte NfkB p65 arbitrary units are quantified by densitometric analysis of the Western blots.
2. 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 Outcome Measures :

1. Triglycerides [ Time Frame: baseline ]
   triglycerides
2. Triglycerides [ Time Frame: 2 hours after ingestion of meal ]
   triglycerides
3. Triglycerides [ Time Frame: 4 hours after ingestion of meal ]
   triglycerides
4. Triglycerides [ Time Frame: 6 hours after ingestion of meal ]
   triglycerides
5. Free Fatty Acids [ Time Frame: baseline ]
   Free Fatty Acids
6. Free Fatty Acids [ Time Frame: 2 hours after meal ]
   Free Fatty Acids
7. Free Fatty Acids [ Time Frame: 4 hours after meal ]
   Free Fatty Acids
8. Free Fatty Acids [ Time Frame: 6 hours after meal ]
   Free Fatty Acids
9. Peak Forearm Blood Flow [ Time Frame: baseline ]
   Peak forearm blood flow via strain gauge venous occlusion plethysmography
10. Peak Forearm Blood Flow [ Time Frame: 3 hours after meal ]
    Peak forearm blood flow via strain gauge venous occlusion plethysmography
11. Peak Forearm Blood Flow [ Time Frame: 6 hours after meal ]
    Peak forearm blood flow via strain gauge venous occlusion plethysmography

Eligibility Criteria

• Ages Eligible for Study: 30 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

United States, Texas

The University of Texas Health Science Center at Houston

Houston, Texas, United States, 77030

Sponsors and Collaborators

The University of Texas Health Science Center, Houston

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

Investigators

• Principal Investigator: Absalaon D Gutierrez, MD; University of Texas Health Science Center at Houston, Dept. of Medicine

  Study Documents (Full-Text)

Documents provided by Absalon D Gutierrez, The University of Texas Health Science Center, Houston:

Study Protocol and Statistical Analysis Plan  [PDF] February 18, 2016

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Absalon D Gutierrez, Assistant Professor of Medicine, The University of Texas Health Science Center, Houston
• ClinicalTrials.gov Identifier: NCT02104739
• Other Study ID Numbers: HSC-MS-13-0791
• First Posted: April 4, 2014
• Results First Posted: July 3, 2018
• Last Update Posted: July 3, 2018
• Last Verified: June 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Absalon D Gutierrez, The University of Texas Health Science Center, Houston:

prediabetes; diabetes mellitus type 2; exenatide; saxagliptin; exenatide ER

Additional relevant MeSH terms:

Prediabetic State; Glucose Intolerance; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hyperglycemia; Exenatide; Saxagliptin; Hypoglycemic Agents; Physiological Effects of Drugs; Anti-Obesity Agents; Incretins; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Dipeptidyl-Peptidase IV Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action