Cardiovascular Effects of GLP-1 Receptor Activation

• Liraglutide (Drug): subcutaneous liraglutide daily
• Sitagliptin (Drug): oral sitagliptin daily
• hypocaloric diet (Other): Reduced calorie intake to achieve weight loss.
• Placebos (Drug): 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.
• Exendin (9-39) (Drug): 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.

Primary outcomes

• Change in Flow-mediated Dilation [Baseline to 2 and 14 weeks]: Brachial artery diameter is measured under basal conditions and during reactive hyperemia (Flow Mediated Dilation as %)
• Urine Albumin-to-creatinine Ratio [Baseline to 13 weeks]: Ratio of urine albumin to creatinine in a spot urine collected after overnight rest
• Change in Plasminogen Activator Inhibitor-1 [Baseline to 2 and 14 weeks]: Plasma plasminogen activator inhibitor-1 antigen

Secondary outcomes

• Blood Pressure [Baseline, and after 2 weeks and 14 weeks of treatment]: The mean of three systolic blood pressure measurements one minute apart using a oscillometric recording device with patient in supine position
• Heart Rate [Baseline, and after 2 weeks and 14 weeks of treatment]: The mean of three measurements with the patient in the supine position
• Fasting Glucose [Baseline, and after 2 weeks and 14 weeks of treatment]: Blood glucose collected after overnight fast
• Fasting Insulin [Baseline, and after 2 weeks and 14 weeks of treatment]: Plasma insulin collected after overnight fast

Other outcomes

• Change in Weight [Change from baseline to 14 weeks]: Weight measured in light clothing without shoes

Sex: All, ages: 18 Years to 65 Years

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

Participant flow

Outcome results

• Change in Flow-mediated Dilation (Primary), Mean, Percentage: Liraglutide 0.71 +/- 4.82; Sitagliptin 2.06 +/- 6.42; Hypocaloric Diet 1.24 +/- 5.09
• Urine Albumin-to-creatinine Ratio (Primary), Mean, mg/g: Liraglutide 12.0 +/- 23.6; Sitagliptin 7.9 +/- 7.6; Hypocaloric Diet 6.3 +/- 3.8
• Change in Plasminogen Activator Inhibitor-1 (Primary), Mean, units/mL: Liraglutide -2.4 +/- 7.8; Sitagliptin -1.3 +/- 8.3; Hypocaloric Diet 1.1 +/- 6.9
• Blood Pressure (Secondary), Mean, mmHg: Liraglutide 124.1 +/- 7.7; Sitagliptin 120.2 +/- 11.3; Hypocaloric Diet 127.7 +/- 8.3
• Heart Rate (Secondary), Mean, Beats per minute: Liraglutide 64.9 +/- 7.5; Sitagliptin 67.2 +/- 9.0; Hypocaloric Diet 63.8 +/- 8.8
• Fasting Glucose (Secondary), Mean, mg/dl: Liraglutide 95.3 +/- 8.6; Sitagliptin 97.6 +/- 10.0; Hypocaloric Diet 94.5 +/- 12.0
• Fasting Insulin (Secondary), Mean, uU/mL: Liraglutide 22.7 +/- 16.8; Sitagliptin 23.3 +/- 14.4; Hypocaloric Diet 26.7 +/- 21.2
• Change in Weight (Other pre specified), Mean, kg: Liraglutide -2.72 +/- 3.44; Sitagliptin -0.71 +/- 2.12; Hypocaloric Diet -4.95 +/- 3.98

Adverse events

Time frame: After randomization to 14 weeks

Serious adverse events by term

Other adverse events by term

Limitations and caveats: Study enrollment and conduct interrupted due to COVID-19 pandemic. Exendin not available for all study participants.

• Study Protocol and Statistical Analysis Plan (PDF, 2021-02-02)

• James M. Luther, M.D., Principal investigator, Vanderbilt University Medical Center