Effects of Antidiabetic Medications on the Postprandial State in Prediabetes

Obesity Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02104739
• Other study ID #: HSC-MS-13-0791
• Status: Completed
• Phase: Phase 4
• Start date: April 2014
• Est. completion date: March 2017

Study information

• Verified date: June 2018
• Source: The University of Texas Health Science Center, Houston
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: March 2017
• Est. primary completion date: March 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 30 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Glucose Intolerance
• Obesity
• Prediabetes
• Prediabetic State

Intervention

Drug:
• Exenatide
Single subcutaneous injection (10 mcg)
• Saxagliptin
Single dose orally (5 mg)
• Exenatide extended-release (ER)
Subcutaneous injection (2mg) weekly for 6 weeks

Other:
• Placebo
Placebo tablets and Placebo (normal saline) injections

Locations

Country	Name	City	State
United States	The University of Texas Health Science Center at Houston	Houston	Texas

Sponsors (2)

Lead Sponsor	Collaborator
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

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Monocyte NfkB Levels as Detected by Western Blotting	Monocyte NfkB p65 arbitrary units are quantified by densitometric analysis of the Western blots.	baseline
Primary	Monocyte NfkB Levels as Detected by Western Blotting	Monocyte NfkB p65 arbitrary units are quantified by densitometric analysis of the Western blots.	2 hours after ingestion of meal
Secondary	Triglycerides	triglycerides	baseline
Secondary	Triglycerides	triglycerides	2 hours after ingestion of meal
Secondary	Triglycerides	triglycerides	4 hours after ingestion of meal
Secondary	Triglycerides	triglycerides	6 hours after ingestion of meal
Secondary	Free Fatty Acids	Free Fatty Acids	baseline
Secondary	Free Fatty Acids	Free Fatty Acids	2 hours after meal
Secondary	Free Fatty Acids	Free Fatty Acids	4 hours after meal
Secondary	Free Fatty Acids	Free Fatty Acids	6 hours after meal
Secondary	Peak Forearm Blood Flow	Peak forearm blood flow via strain gauge venous occlusion plethysmography	baseline
Secondary	Peak Forearm Blood Flow	Peak forearm blood flow via strain gauge venous occlusion plethysmography	3 hours after meal
Secondary	Peak Forearm Blood Flow	Peak forearm blood flow via strain gauge venous occlusion plethysmography	6 hours after meal