Obesity, PreDiabetes
Conditions
Brief 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.
Interventions
DRUGLiraglutide
subcutaneous liraglutide daily
DRUGSitagliptin
oral sitagliptin daily
OTHERhypocaloric diet
Reduced calorie intake to achieve weight loss.
DRUGPlacebos
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.
DRUGExendin (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.
Sponsors
American Heart Association
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Treatment with liraglutide or sitagliptin will be masked using matching placebo.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasminogen Activator Inhibitor-1 | Baseline to 2 and 14 weeks | Plasma plasminogen activator inhibitor-1 antigen |
| 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Weight | Change from baseline to 14 weeks | Weight measured in light clothing without shoes |
Countries
United States
Participant flow
Pre-assignment details
CONSORT flow details: * 329 signed consent. * 178 individuals did not meet inclusion/exclusion criteria. * 35 individuals declined to participate. * 23 individuals did not return for subsequent visits. * 93 individuals randomized. * 88 individuals completed study days.
Participants by arm
| Arm | Count |
|---|---|
| Liraglutide Subjects in the liraglutide group will receive subcutaneous liraglutide (0.6 mg/d for one week, 1.2 mg/d for one week, and then 1.8 mg/d for 12 weeks) and oral placebo.
Liraglutide: subcutaneous liraglutide daily
Placebos: 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): 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. | 46 |
| Sitagliptin Subjects in the sitagliptin group will receive subcutaneous placebo daily and sitagliptin 100 mg/d orally for 14 weeks.
Sitagliptin: oral sitagliptin daily
Placebos: 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): 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. | 23 |
| Hypocaloric Diet Subjects in the hypocaloric diet group will be given a caloric goal designed to achieve a weight loss similar to that expected in the liraglutide treatment arm based on his or her resting energy expenditure. Subjects will be provided counseling and written instructions on how to achieve their daily caloric goal, including use of their own mobile phone applications to monitor caloric intake. To assure compliance with the prescribed caloric goal, subjects will meet with the study dietitian every other week for problem solving and review of diet intake logs.
hypocaloric diet: Reduced calorie intake to achieve weight loss.
Placebos: 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): 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. | 24 |
| Total | 93 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 1 | 2 |
Baseline characteristics
| Characteristic | Liraglutide | Total | Hypocaloric Diet | Sitagliptin |
|---|---|---|---|---|
| Age, Continuous | 49.8 years STANDARD_DEVIATION 9.9 | 50.3 years STANDARD_DEVIATION 10.6 | 48.9 years STANDARD_DEVIATION 12.1 | 52.8 years STANDARD_DEVIATION 10.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 4 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 44 Participants | 88 Participants | 23 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Flow mediated dilation | 10.5 Percentage STANDARD_DEVIATION 5.2 | 10.4 Percentage STANDARD_DEVIATION 5.2 | 10.2 Percentage STANDARD_DEVIATION 5.3 | 10.4 Percentage STANDARD_DEVIATION 5.37 |
| Plasminogen Activator Inhibitor-1, plasma | 20.2 U/mL STANDARD_DEVIATION 9.2 | 19.4 U/mL STANDARD_DEVIATION 8.7 | 18.5 U/mL STANDARD_DEVIATION 8 | 18.5 U/mL STANDARD_DEVIATION 8.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 13 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 38 Participants | 75 Participants | 19 Participants | 18 Participants |
| Region of Enrollment United States | 46 participants | 93 participants | 24 participants | 23 participants |
| Sex: Female, Male Female | 33 Participants | 63 Participants | 14 Participants | 16 Participants |
| Sex: Female, Male Male | 13 Participants | 30 Participants | 10 Participants | 7 Participants |
| Urine Albumin-Creatinine ratio | 12.04 mg/g STANDARD_DEVIATION 23.6 | 9.6 mg/g STANDARD_DEVIATION 17.3 | 6.3 mg/g STANDARD_DEVIATION 3.8 | 7.85 mg/g STANDARD_DEVIATION 7.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 23 | 0 / 24 |
| other Total, other adverse events | 26 / 46 | 6 / 23 | 6 / 24 |
| serious Total, serious adverse events | 0 / 46 | 1 / 23 | 1 / 24 |
Outcome results
Primary
Change in Flow-mediated Dilation
Brachial artery diameter is measured under basal conditions and during reactive hyperemia (Flow Mediated Dilation as %)
Time frame: Baseline to 2 and 14 weeks
Population: Incomplete data due to missed study visits and missing samples in the following time periods/arms (n= number of participants with missing data):~* Liraglutide/Placebo: Week 2 (n=5); Week 14 (n=4)~* Liraglutide/Exendin: Week 2 (n=11); Week 14 (n=12)~* Sitagliptin/Placebo: Week 2 (n=2)~* Sitagliptin/Exendin: Week 2 (n=3); Week 14 (n=2)~* Diet/Placebo: Week 2 (n=1); Week 14 (n=6)~* Diet/Exendin: Week 2 (n=7); Week 14 (n=11)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide | Change in Flow-mediated Dilation | Baseline to 2 weeks (Placebo infusion) | 0.71 Percentage | Standard Deviation 4.82 |
| Liraglutide | Change in Flow-mediated Dilation | Baseline to 2 weeks (Exendin infusion) | 0.48 Percentage | Standard Deviation 5.81 |
| Liraglutide | Change in Flow-mediated Dilation | Baseline to 14 weeks (Placebo infusion) | 1.43 Percentage | Standard Deviation 5.33 |
| Liraglutide | Change in Flow-mediated Dilation | Baseline to 14 weeks (Exendin infusion) | 1.73 Percentage | Standard Deviation 5.22 |
| Sitagliptin | Change in Flow-mediated Dilation | Baseline to 14 weeks (Exendin infusion) | 1.42 Percentage | Standard Deviation 5.88 |
| Sitagliptin | Change in Flow-mediated Dilation | Baseline to 2 weeks (Placebo infusion) | 2.06 Percentage | Standard Deviation 6.42 |
| Sitagliptin | Change in Flow-mediated Dilation | Baseline to 14 weeks (Placebo infusion) | 1.59 Percentage | Standard Deviation 5.74 |
| Sitagliptin | Change in Flow-mediated Dilation | Baseline to 2 weeks (Exendin infusion) | 0.13 Percentage | Standard Deviation 4.49 |
| Hypocaloric Diet | Change in Flow-mediated Dilation | Baseline to 14 weeks (Exendin infusion) | 0.42 Percentage | Standard Deviation 4.28 |
| Hypocaloric Diet | Change in Flow-mediated Dilation | Baseline to 2 weeks (Exendin infusion) | 1.43 Percentage | Standard Deviation 7.09 |
| Hypocaloric Diet | Change in Flow-mediated Dilation | Baseline to 14 weeks (Placebo infusion) | 1.01 Percentage | Standard Deviation 5.38 |
| Hypocaloric Diet | Change in Flow-mediated Dilation | Baseline to 2 weeks (Placebo infusion) | 1.24 Percentage | Standard Deviation 5.09 |
Primary
Change in Plasminogen Activator Inhibitor-1
Plasma plasminogen activator inhibitor-1 antigen
Time frame: Baseline to 2 and 14 weeks
Population: Due to missed study visits and missing samples, there is incomplete data for the following arms/time periods:~Liraglutide: Baseline: 2 participants/Week 14: 3 participants; Sitagliptin: Baseline: 1 participants/Week 14: 1 participants; Diet: Baseline: 3 participants/Week 14: 6 participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide | Change in Plasminogen Activator Inhibitor-1 | Baseline to 2 weeks | -2.4 units/mL | Standard Deviation 7.8 |
| Liraglutide | Change in Plasminogen Activator Inhibitor-1 | Baseline to 14 weeks | -3.7 units/mL | Standard Deviation 8.7 |
| Sitagliptin | Change in Plasminogen Activator Inhibitor-1 | Baseline to 2 weeks | -1.3 units/mL | Standard Deviation 8.3 |
| Sitagliptin | Change in Plasminogen Activator Inhibitor-1 | Baseline to 14 weeks | 1.3 units/mL | Standard Deviation 6.3 |
| Hypocaloric Diet | Change in Plasminogen Activator Inhibitor-1 | Baseline to 2 weeks | 1.1 units/mL | Standard Deviation 6.9 |
| Hypocaloric Diet | Change in Plasminogen Activator Inhibitor-1 | Baseline to 14 weeks | -3.6 units/mL | Standard Deviation 6.6 |
Primary
Urine Albumin-to-creatinine Ratio
Ratio of urine albumin to creatinine in a spot urine collected after overnight rest
Time frame: Baseline to 13 weeks
Population: Due to missed study visits and missing samples, there is incomplete data for the following arms/time periods:~Liraglutide: 2 participants; Diet: 6 participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide | Urine Albumin-to-creatinine Ratio | Baseline | 12.0 mg/g | Standard Deviation 23.6 |
| Liraglutide | Urine Albumin-to-creatinine Ratio | 13 Weeks | 10.5 mg/g | Standard Deviation 14.8 |
| Sitagliptin | Urine Albumin-to-creatinine Ratio | Baseline | 7.9 mg/g | Standard Deviation 7.6 |
| Sitagliptin | Urine Albumin-to-creatinine Ratio | 13 Weeks | 9.2 mg/g | Standard Deviation 10.7 |
| Hypocaloric Diet | Urine Albumin-to-creatinine Ratio | Baseline | 6.3 mg/g | Standard Deviation 3.8 |
| Hypocaloric Diet | Urine Albumin-to-creatinine Ratio | 13 Weeks | 10.1 mg/g | Standard Deviation 19.4 |
Secondary
Blood Pressure
The mean of three systolic blood pressure measurements one minute apart using a oscillometric recording device with patient in supine position
Time frame: Baseline, and after 2 weeks and 14 weeks of treatment
Population: Due to missed study visits there is incomplete data for the following arms/time periods:~Liraglutide 14 weeks- 2 participants; Diet 14 weeks: 5 participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide | Blood Pressure | 2 weeks | 122.9 mmHg | Standard Deviation 6.3 |
| Liraglutide | Blood Pressure | Baseline | 124.1 mmHg | Standard Deviation 7.7 |
| Liraglutide | Blood Pressure | 14 weeks | 122.2 mmHg | Standard Deviation 7.8 |
| Sitagliptin | Blood Pressure | 2 weeks | 117.5 mmHg | Standard Deviation 11.3 |
| Sitagliptin | Blood Pressure | Baseline | 120.2 mmHg | Standard Deviation 11.3 |
| Sitagliptin | Blood Pressure | 14 weeks | 118.2 mmHg | Standard Deviation 13.9 |
| Hypocaloric Diet | Blood Pressure | Baseline | 127.7 mmHg | Standard Deviation 8.3 |
| Hypocaloric Diet | Blood Pressure | 14 weeks | 119.7 mmHg | Standard Deviation 11.1 |
| Hypocaloric Diet | Blood Pressure | 2 weeks | 121.7 mmHg | Standard Deviation 6.8 |
Secondary
Fasting Glucose
Blood glucose collected after overnight fast
Time frame: Baseline, and after 2 weeks and 14 weeks of treatment
Population: Due to missed study visits there is incomplete data for the following arms/time periods:~Liraglutide Baseline-1, 2 weeks 1, 14 weeks- 2 participants; Sitagliptin 2 weeks 1, 14 weeks- 1 participants; Diet 14 weeks: 5 participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide | Fasting Glucose | 2 weeks | 84.26 mg/dl | Standard Deviation 7.9 |
| Liraglutide | Fasting Glucose | Baseline | 95.3 mg/dl | Standard Deviation 8.6 |
| Liraglutide | Fasting Glucose | 14 weeks | 85.2 mg/dl | Standard Deviation 7.3 |
| Sitagliptin | Fasting Glucose | 2 weeks | 93.9 mg/dl | Standard Deviation 8.1 |
| Sitagliptin | Fasting Glucose | Baseline | 97.6 mg/dl | Standard Deviation 10 |
| Sitagliptin | Fasting Glucose | 14 weeks | 96.6 mg/dl | Standard Deviation 5.6 |
| Hypocaloric Diet | Fasting Glucose | Baseline | 94.5 mg/dl | Standard Deviation 12 |
| Hypocaloric Diet | Fasting Glucose | 14 weeks | 91.2 mg/dl | Standard Deviation 9.8 |
| Hypocaloric Diet | Fasting Glucose | 2 weeks | 92.4 mg/dl | Standard Deviation 11.3 |
Secondary
Fasting Insulin
Plasma insulin collected after overnight fast
Time frame: Baseline, and after 2 weeks and 14 weeks of treatment
Population: Due to missed study visits or missing data there is incomplete data for the following arms/time periods:~Liraglutide 2 weeks 3, 14 weeks- 3 participants; Sitagliptin 2 weeks 2, 14 weeks- 1 participants; Diet 14 weeks: 5 participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide | Fasting Insulin | 2 weeks | 18.3 uU/mL | Standard Deviation 12.5 |
| Liraglutide | Fasting Insulin | Baseline | 22.7 uU/mL | Standard Deviation 16.8 |
| Liraglutide | Fasting Insulin | 14 weeks | 20.3 uU/mL | Standard Deviation 14.7 |
| Sitagliptin | Fasting Insulin | 2 weeks | 29.4 uU/mL | Standard Deviation 25.4 |
| Sitagliptin | Fasting Insulin | Baseline | 23.3 uU/mL | Standard Deviation 14.4 |
| Sitagliptin | Fasting Insulin | 14 weeks | 26.0 uU/mL | Standard Deviation 19 |
| Hypocaloric Diet | Fasting Insulin | Baseline | 26.7 uU/mL | Standard Deviation 21.2 |
| Hypocaloric Diet | Fasting Insulin | 14 weeks | 20.3 uU/mL | Standard Deviation 13.7 |
| Hypocaloric Diet | Fasting Insulin | 2 weeks | 19.7 uU/mL | Standard Deviation 16.5 |
Secondary
Heart Rate
The mean of three measurements with the patient in the supine position
Time frame: Baseline, and after 2 weeks and 14 weeks of treatment
Population: Due to missed study visits there is incomplete data for the following arms/time periods:~Liraglutide 14 weeks- 2 participants; Diet 14 weeks: 5 participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide | Heart Rate | 14 weeks | 68.9 Beats per minute | Standard Deviation 5.6 |
| Liraglutide | Heart Rate | Baseline | 64.9 Beats per minute | Standard Deviation 7.5 |
| Liraglutide | Heart Rate | 2 weeks | 68.9 Beats per minute | Standard Deviation 6.4 |
| Sitagliptin | Heart Rate | 14 weeks | 65.9 Beats per minute | Standard Deviation 8.5 |
| Sitagliptin | Heart Rate | Baseline | 67.2 Beats per minute | Standard Deviation 9 |
| Sitagliptin | Heart Rate | 2 weeks | 66.2 Beats per minute | Standard Deviation 9.2 |
| Hypocaloric Diet | Heart Rate | 14 weeks | 61.7 Beats per minute | Standard Deviation 7.9 |
| Hypocaloric Diet | Heart Rate | 2 weeks | 63.2 Beats per minute | Standard Deviation 9.5 |
| Hypocaloric Diet | Heart Rate | Baseline | 63.8 Beats per minute | Standard Deviation 8.8 |
Other Pre-specified
Change in Weight
Weight measured in light clothing without shoes
Time frame: Change from baseline to 14 weeks
Population: Due to missed study visits or missing data there is incomplete data for the following arms/time periods:~Liraglutide 2 participants; Diet 5 participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide | Change in Weight | -2.72 kg | Standard Deviation 3.44 |
| Sitagliptin | Change in Weight | -0.71 kg | Standard Deviation 2.12 |
| Hypocaloric Diet | Change in Weight | -4.95 kg | Standard Deviation 3.98 |