Cardiovascular Effects of GLP-1 Receptor Activation
Condition: Obesity; PreDiabetes
MeSH terms: Prediabetic State
Intervention: Liraglutide; Sitagliptin; hypocaloric diet; Placebos; Exendin (9-39)
Intervention description: subcutaneous liraglutide daily; oral sitagliptin daily; Reduced calorie intake to achieve weight loss.; Subjects in the liraglutide arm will receive a placebo for sitagliptin. Those in the sitagliptin arm will receive a placebo for liraglutide. All subjects will receive a placebo for Exendin 9-39.; All subjects will receive Exendin (9-39) or matching placebo in crossover fashion during study days on the first and third days of the second week after randomization and again on the 5th and 7th days of the 14th week of treatment.
Intervention MeSH terms: Sitagliptin Phosphate; Liraglutide
Phase: Phase 4
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Treatment with liraglutide or sitagliptin will be masked using matching placebo.
Enrollment: 329.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No

Summary:

      This project tests the principle hypothesis that stable glucagon like peptide-1 (GLP-1)
      analogues have specific GLP1R-dependent beneficial effects on vascular endothelial function,
      fibrinolysis and inflammation in obesity that exceed the benefits of weight loss, and that
      genetic or other individual factors that modulate GLP1R sensitivity can modify the effect of
      these analogues on cardiovascular risk.
    

Eligibility criteria:

        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