Cardiovascular Effects of GLP-1 Receptor Activation

Inclusion Criteria:

1. Men and women,

2. Age 18 to 65 years, and

3. FPG (100-125 mg/dL) or, IGT (two-hour plasma glucose 140-199 mg/dL) or, HbA1C 5.7-6.4%

4. BMI≥30 kg/M2

5. The ability to provide informed consent before any trial-related activities.

Exclusion Criteria:

1. Diabetes type 1 or type 2, as defined by a FPG of 126 mg/dL or greater, a two-hour
plasma glucose of 200 mg/dL or greater, or the use of anti-diabetic medication

2. Resistant hypertension, defined as hypertension requiring the administration of more
than three anti-hypertensive agents including a diuretic to achieve control

3. Use of spironolactone

4. Known or suspected allergy to trial medications, excipients, or related products.

5. Family or personal history of multiple endocrine neoplasia type 2 (MEN2) or familial
medullary thyroid carcinoma

6. Personal history of non-familial medullary thyroid carcinoma

7. History of pancreatitis

8. Contraindications to study medications, worded specifically as stated in the product's
prescribing information

9. Pregnancy or breast-feeding. Women of child-bearing potential will be required to have
undergone tubal ligation or to be using an oral contraceptive or barrier methods of
birth control

10. Subjects who have participated in a weight-reduction program during the last six month
or whose weight has increased or decreased more than two kg over the preceding six
months

11. Cardiovascular disease such as myocardial infarction within six months prior to
enrollment, presence of angina pectoris, significant arrhythmia, congestive heart
failure (left ventricular hypertrophy acceptable), deep vein thrombosis, pulmonary
embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis
or hypertrophic cardiomyopathy

12. Treatment with anticoagulants

13. History of serious neurologic disease such as cerebral hemorrhage, stroke, or
transient ischemic attack

14. History or presence of immunological or hematological disorders

15. Diagnosis of asthma requiring regular inhaler use

16. Clinically significant gastrointestinal impairment that could interfere with drug
absorption

17. Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino
transaminase [ALT] >3.0 x upper limit of normal range)

18. Individuals with an eGFR<30 mL/min/1.73 m2 or with a UACR >1000µg/mg, where eGFR is
determined by the four-variable Modification of Diet in Renal Disease (MDRD) equation,
where serum creatinine is expressed in mg/dL and age in years: eGFR
(mL/min/1.73m2)=186 • Scr-1.154 • age-0.203 • (1.212 if black) • (0.742 if female)

19. Hematocrit <35%

20. Any underlying or acute disease requiring regular medication which could possibly pose
a threat to the subject or make implementation of the protocol or interpretation of
the study results difficult

21. Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days
in 1 month)

22. Treatment with lithium salts

23. History of alcohol or drug abuse

24. Treatment with any investigational drug in the one month preceding the study

25. Previous randomization in this trial

26. Mental conditions rendering a subject unable to understand the nature, scope and
possible consequences of the study

27. Inability to comply with the protocol, e.g., uncooperative attitude, inability to
return for follow-up visits, and unlikelihood of completing the study