Obesity, Prediabetes
Conditions
Keywords
prediabetes, diabetes mellitus type 2, exenatide, saxagliptin, exenatide ER
Brief summary
This project addresses cardiovascular disease risk in patients with prediabetes. Levels of lipids after eating a meal (postprandial lipids) are strong independent predictors of cardiovascular risk. Newer anti-diabetic agents - exenatide and saxagliptin - impact lipid metabolism. These medications will be studied for their effect in reducing both postprandial lipid levels and arterial dysfunction.
Detailed description
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.
Interventions
DRUGSaxagliptin
Single dose orally (5 mg)
DRUGExenatide
Single subcutaneous injection (10 mcg)
DRUGExenatide extended-release (ER)
Subcutaneous injection (2mg) weekly for 6 weeks
OTHERPlacebo
Placebo tablets and Placebo (normal saline) injections
Sponsors
The Center for Clinical and Translational Sciences (CCTS) Clinical Research Unit at The University of Texas Health Science Center at Houston
The University of Texas Health Science Center, Houston
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Placebo pills and placebo injections provided
Eligibility
Sex/Gender
ALL
Age
30 Years to 70 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Monocyte NfkB Levels as Detected by Western Blotting | baseline | Monocyte NfkB p65 arbitrary units are quantified by densitometric analysis of the Western blots. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Triglycerides | baseline | triglycerides |
| Free Fatty Acids | baseline | Free Fatty Acids |
| Peak Forearm Blood Flow | baseline | Peak forearm blood flow via strain gauge venous occlusion plethysmography |
Countries
United States
Participant flow
Pre-assignment details
21 subjects were enrolled. 20 were randomized, and these 20 participated in each of three arms (the exenatide, saxagliptin, and placebo arms), with the order of receipt being randomized. There was an extension phase (that is, the exenatide extended-release (ER) arm) in which 8 of the 21 enrolled participated.
Participants by arm
| Arm | Count |
|---|---|
| All Participants This was a crossover study in which the 21 who were enrolled participated in each of three arms (the exenatide, saxagliptin, and placebo arms). There was an extension phase (that is, the exenatide extended-release (ER) arm) in which 8 of the 21 enrolled participated.
Exenatide arm: Single subcutaneous injection (10 mcg) Saxagliptin arm: Single dose orally (5 mg) Placebo arm: Placebo tablets and Placebo (normal saline) injections Exenatide extended-release (ER) arm: Subcutaneous injection (2mg) weekly for 6 weeks | 16 |
| Total | 16 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 50 years STANDARD_DEVIATION 8 |
| Body Mass Index (BMI) | 32.53 kilograms per meter squared STANDARD_DEVIATION 1.92 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Height | 1.7 meters STANDARD_DEVIATION 0.11 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 16 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 9 Participants |
| Weight | 93.96 kilograms STANDARD_DEVIATION 11.98 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 7 |
| other Total, other adverse events | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 7 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 7 |
Outcome results
Primary
Monocyte NfkB Levels as Detected by Western Blotting
Monocyte NfkB p65 arbitrary units are quantified by densitometric analysis of the Western blots.
Time frame: baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Monocyte NfkB Levels as Detected by Western Blotting | 62.79 NfkB p65 arbitrary units | Standard Error 4.05 |
| Saxagliptin | Monocyte NfkB Levels as Detected by Western Blotting | 72.03 NfkB p65 arbitrary units | Standard Error 6.38 |
| Placebo | Monocyte NfkB Levels as Detected by Western Blotting | 67.68 NfkB p65 arbitrary units | Standard Error 6.38 |
| Exenatide Extended-release (ER) | Monocyte NfkB Levels as Detected by Western Blotting | 84.19 NfkB p65 arbitrary units | Standard Error 6.45 |
Primary
Monocyte NfkB Levels as Detected by Western Blotting
Monocyte NfkB p65 arbitrary units are quantified by densitometric analysis of the Western blots.
Time frame: 2 hours after ingestion of meal
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Monocyte NfkB Levels as Detected by Western Blotting | 67.39 NfkB p65 arbitrary units | Standard Error 6.44 |
| Saxagliptin | Monocyte NfkB Levels as Detected by Western Blotting | 68.39 NfkB p65 arbitrary units | Standard Error 5.82 |
| Placebo | Monocyte NfkB Levels as Detected by Western Blotting | 71.37 NfkB p65 arbitrary units | Standard Error 5.82 |
| Exenatide Extended-release (ER) | Monocyte NfkB Levels as Detected by Western Blotting | 93.47 NfkB p65 arbitrary units | Standard Error 5.69 |
Comparison: Exenatide at baseline and 2 hours after ingestion of meal is compared.p-value: 0.27Non-parametric Wilcoxon paired rank sum
Comparison: Saxagliptin at baseline and 2 hours after ingestion of meal is compared.p-value: 0.59Non-parametric Wilcoxon paired rank sum
Comparison: Placebo at baseline and 2 hours after ingestion of meal is compared.p-value: 0.51Non-parametric Wilcoxon paired rank sum
Comparison: Exenatide extended-release (ER) at baseline and 2 hours after ingestion of meal is compared.p-value: 0.31Non-parametric Wilcoxon paired rank sum
Secondary
Free Fatty Acids
Free Fatty Acids
Time frame: baseline
Population: Data for the exenatide extended-release (ER) arm was only collected at baseline and 2 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Free Fatty Acids | 0.45 millimoles per liter | Standard Error 0.04 |
| Saxagliptin | Free Fatty Acids | 0.49 millimoles per liter | Standard Error 0.05 |
| Placebo | Free Fatty Acids | 0.51 millimoles per liter | Standard Error 0.04 |
| Exenatide Extended-release (ER) | Free Fatty Acids | 0.65 millimoles per liter | Standard Error 0.05 |
Secondary
Free Fatty Acids
Free Fatty Acids
Time frame: 2 hours after meal
Population: Data for the exenatide extended-release (ER) arm was only collected at baseline and 2 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Free Fatty Acids | 0.35 millimoles per liter | Standard Error 0.05 |
| Saxagliptin | Free Fatty Acids | 0.18 millimoles per liter | Standard Error 0.02 |
| Placebo | Free Fatty Acids | 0.17 millimoles per liter | Standard Error 0.01 |
| Exenatide Extended-release (ER) | Free Fatty Acids | 0.19 millimoles per liter | Standard Error 0.05 |
p-value: 0.018ANOVA
Secondary
Free Fatty Acids
Free Fatty Acids
Time frame: 4 hours after meal
Population: Data for the exenatide extended-release (ER) arm was only collected at baseline and 2 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Free Fatty Acids | 0.43 millimoles per liter | Standard Error 0.06 |
| Saxagliptin | Free Fatty Acids | 0.24 millimoles per liter | Standard Error 0.02 |
| Placebo | Free Fatty Acids | 0.23 millimoles per liter | Standard Error 0.02 |
Secondary
Free Fatty Acids
Free Fatty Acids
Time frame: 6 hours after meal
Population: Data for the exenatide extended-release (ER) arm was only collected at baseline and 2 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Free Fatty Acids | 0.29 millimoles per liter | Standard Error 0.06 |
| Saxagliptin | Free Fatty Acids | 0.31 millimoles per liter | Standard Error 0.02 |
| Placebo | Free Fatty Acids | 0.33 millimoles per liter | Standard Error 0.05 |
Comparison: The reported p-value compares exenatide and saxagliptin over all time points (2 hours, 4 hours, 6 hours).p-value: <0.05ANOVA
Comparison: The reported p-value compares exenatide and placebo over all time points (2 hours, 4 hours, 6 hours).p-value: <0.05ANOVA
Secondary
Peak Forearm Blood Flow
Peak forearm blood flow via strain gauge venous occlusion plethysmography
Time frame: 6 hours after meal
Population: Though 16 completed the exenatide, saxagliptin, and placebo arms, data is only reported for 15 because the study team was unsuccessful in collecting data for the first study patient. Data for the exenatide extended-release (ER) arm was only collected at baseline and 3 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Peak Forearm Blood Flow | 14.25 mL per minute per 100mL of tissue | Standard Error 1.09 |
| Saxagliptin | Peak Forearm Blood Flow | 15.87 mL per minute per 100mL of tissue | Standard Error 1.81 |
| Placebo | Peak Forearm Blood Flow | 13.45 mL per minute per 100mL of tissue | Standard Error 0.68 |
Comparison: The reported p-value compares exenatide and saxagliptin over all time points (3 hours, 6 hours).p-value: >0.05ANOVA
Comparison: The reported p-value compares exenatide and placebo over all time points (3 hours, 6 hours).p-value: >0.05ANOVA
Secondary
Peak Forearm Blood Flow
Peak forearm blood flow via strain gauge venous occlusion plethysmography
Time frame: baseline
Population: Though 16 completed the exenatide, saxagliptin, and placebo arms, data is only reported for 15 because the study team was unsuccessful in collecting data for the first study patient. Data for the exenatide extended-release (ER) arm was only collected at baseline and 3 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Peak Forearm Blood Flow | 12.65 mL per minute per 100mL of tissue | Standard Error 1.17 |
| Saxagliptin | Peak Forearm Blood Flow | 12.79 mL per minute per 100mL of tissue | Standard Error 1.47 |
| Placebo | Peak Forearm Blood Flow | 12.18 mL per minute per 100mL of tissue | Standard Error 1.17 |
| Exenatide Extended-release (ER) | Peak Forearm Blood Flow | 16.18 mL per minute per 100mL of tissue | Standard Error 1.25 |
Secondary
Peak Forearm Blood Flow
Peak forearm blood flow via strain gauge venous occlusion plethysmography
Time frame: 3 hours after meal
Population: Though 16 completed the exenatide, saxagliptin, and placebo arms, data is only reported for 15 because the study team was unsuccessful in collecting data for the first study patient. Data for the exenatide extended-release (ER) arm was only collected at baseline and 3 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Peak Forearm Blood Flow | 13.18 mL per minute per 100mL of tissue | Standard Error 1.21 |
| Saxagliptin | Peak Forearm Blood Flow | 13.25 mL per minute per 100mL of tissue | Standard Error 1.04 |
| Placebo | Peak Forearm Blood Flow | 15.11 mL per minute per 100mL of tissue | Standard Error 1.29 |
| Exenatide Extended-release (ER) | Peak Forearm Blood Flow | 16.54 mL per minute per 100mL of tissue | Standard Error 2.23 |
p-value: 0.5ANOVA
Secondary
Triglycerides
triglycerides
Time frame: baseline
Population: Data for the exenatide extended-release (ER) arm was only collected at baseline and 2 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Triglycerides | 108 milligrams per deciliter | Standard Error 11 |
| Saxagliptin | Triglycerides | 101 milligrams per deciliter | Standard Error 11 |
| Placebo | Triglycerides | 102 milligrams per deciliter | Standard Error 14 |
| Exenatide Extended-release (ER) | Triglycerides | 106 milligrams per deciliter | Standard Error 14 |
Secondary
Triglycerides
triglycerides
Time frame: 2 hours after ingestion of meal
Population: Data for the exenatide extended-release (ER) arm was only collected at baseline and 2 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Triglycerides | 119 milligrams per deciliter | Standard Error 13 |
| Saxagliptin | Triglycerides | 130 milligrams per deciliter | Standard Error 16 |
| Placebo | Triglycerides | 163 milligrams per deciliter | Standard Error 19 |
| Exenatide Extended-release (ER) | Triglycerides | 168 milligrams per deciliter | Standard Error 26 |
p-value: 0.02ANOVA
Secondary
Triglycerides
triglycerides
Time frame: 4 hours after ingestion of meal
Population: Data for the exenatide extended-release (ER) arm was only collected at baseline and 2 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Triglycerides | 124 milligrams per deciliter | Standard Error 12 |
| Saxagliptin | Triglycerides | 153 milligrams per deciliter | Standard Error 24 |
| Placebo | Triglycerides | 206 milligrams per deciliter | Standard Error 24 |
Secondary
Triglycerides
triglycerides
Time frame: 6 hours after ingestion of meal
Population: Data for the exenatide extended-release (ER) arm was only collected at baseline and 2 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Triglycerides | 161 milligrams per deciliter | Standard Error 24 |
| Saxagliptin | Triglycerides | 179 milligrams per deciliter | Standard Error 27 |
| Placebo | Triglycerides | 200 milligrams per deciliter | Standard Error 22 |
Comparison: The reported p-value compares exenatide and saxagliptin over all time points (2 hours, 4 hours, 6 hours).p-value: <0.05ANOVA
Comparison: The reported p-value compares exenatide and placebo over all time points (2 hours, 4 hours, 6 hours).p-value: <0.05ANOVA