Effects of Antidiabetic Medications on the Postprandial State in Prediabetes

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.

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