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Effects of Antidiabetic Medications on the Postprandial State in Prediabetes

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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:
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

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.

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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

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prediabetes

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




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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02104739


Locations
Layout table for location information
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
Layout table for investigator information
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:

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

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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:
Layout table for 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