Effects of Antidiabetic Medications on the Postprandial State in Prediabetes

• Sponsor: The University of Texas Health Science Center, Houston (Other)
• Overall Status: Completed
• CT.gov ID: NCT02104739
• Collaborator: The Center for Clinical and Translational Sciences (CCTS) Clinical Research Unit at The University of Texas Health Science Center at Houston (Other)
• Enrollment: 21
• Location: 1
• Arms: 12
• Actual Duration (Months): 35
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Prediabetes; Obesity	Drug: Exenatide; Drug: Saxagliptin; Drug: Exenatide extended-release (ER); Other: Placebo	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Placebo pills and placebo injections provided
• Primary Purpose: Treatment
• Official Title: Comparative Effects of Antidiabetic Medications on Postprandial Hyperlipidemia, Free Fatty Acid Signaling, and Endothelial Dysfunction in Individuals With Prediabetes
• Actual Study Start Date: Apr 1, 2014
• Actual Primary Completion Date: Mar 1, 2017
• Actual Study Completion Date: Mar 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Exenatide, then Saxagliptin, then Placebo Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Names: Byetta ; Drug: Saxagliptin; Single dose orally (5 mg); Other Names: Onglyza ; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: Exenatide, then Placebo, then Saxagliptin Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Names: Byetta ; Drug: Saxagliptin; Single dose orally (5 mg); Other Names: Onglyza ; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Placebo Comparator: Saxagliptin, then Exenatide, then Placebo Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Names: Byetta ; Drug: Saxagliptin; Single dose orally (5 mg); Other Names: Onglyza ; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: Saxagliptin, then Placebo, then Exenatide Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Names: Byetta ; Drug: Saxagliptin; Single dose orally (5 mg); Other Names: Onglyza ; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: Placebo, then Exenatide, then Saxagliptin Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Names: Byetta ; Drug: Saxagliptin; Single dose orally (5 mg); Other Names: Onglyza ; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: Placebo, then Saxagliptin, then Exenatide Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablets and Placebo (normal saline) injections	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Names: Byetta ; Drug: Saxagliptin; Single dose orally (5 mg); Other Names: Onglyza ; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: Exenatide, then Saxagliptin, then Placebo, then Exenatide ER Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablet and Placebo (normal saline) injection; Subcutaneous injection (2mg) weekly for 6 weeks	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Names: Byetta ; Drug: Saxagliptin; Single dose orally (5 mg); Other Names: Onglyza ; Drug: Exenatide extended-release (ER); Subcutaneous injection (2mg) weekly for 6 weeks; Other Names: Bydureon ; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: Exenatide, then Placebo, then Saxagliptin, then Exenatide ER Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablet and Placebo (normal saline) injection; Subcutaneous injection (2mg) weekly for 6 weeks	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Names: Byetta ; Drug: Saxagliptin; Single dose orally (5 mg); Other Names: Onglyza ; Drug: Exenatide extended-release (ER); Subcutaneous injection (2mg) weekly for 6 weeks; Other Names: Bydureon ; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: Saxagliptin, then Exenatide, then Placebo, then Exenatide ER Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablet and Placebo (normal saline) injection; Subcutaneous injection (2mg) weekly for 6 weeks	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Names: Byetta ; Drug: Saxagliptin; Single dose orally (5 mg); Other Names: Onglyza ; Drug: Exenatide extended-release (ER); Subcutaneous injection (2mg) weekly for 6 weeks; Other Names: Bydureon ; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: Saxagliptin, then Placebo, then Exenatide, then Exenatide ER Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablet and Placebo (normal saline) injection; Subcutaneous injection (2mg) weekly for 6 weeks	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Names: Byetta ; Drug: Saxagliptin; Single dose orally (5 mg); Other Names: Onglyza ; Drug: Exenatide extended-release (ER); Subcutaneous injection (2mg) weekly for 6 weeks; Other Names: Bydureon ; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: Placebo, then Exenatide, then Saxagliptin, then Exenatide ER Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablet and Placebo (normal saline) injection; Subcutaneous injection (2mg) weekly for 6 weeks	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Names: Byetta ; Drug: Saxagliptin; Single dose orally (5 mg); Other Names: Onglyza ; Drug: Exenatide extended-release (ER); Subcutaneous injection (2mg) weekly for 6 weeks; Other Names: Bydureon ; Other: Placebo; Placebo tablets and Placebo (normal saline) injections
Experimental: Placebo, then Saxagliptin, then Exenatide, then Exenatide ER Exenatide Single subcutaneous injection (10 mcg); Saxagliptin Single dose orally (5 mg); Placebo tablet and Placebo (normal saline) injection; Subcutaneous injection (2mg) weekly for 6 weeks	Drug: Exenatide; Single subcutaneous injection (10 mcg); Other Names: Byetta ; Drug: Saxagliptin; Single dose orally (5 mg); Other Names: Onglyza ; Drug: Exenatide extended-release (ER); Subcutaneous injection (2mg) weekly for 6 weeks; Other Names: Bydureon ; Other: Placebo; Placebo tablets and Placebo (normal saline) injections

Outcome Measures

Primary Outcome Measures

1. Monocyte NfkB Levels as Detected by Western Blotting [baseline]

   Monocyte NfkB p65 arbitrary units are quantified by densitometric analysis of the Western blots.

2. Monocyte NfkB Levels as Detected by Western Blotting [2 hours after ingestion of meal]

   Monocyte NfkB p65 arbitrary units are quantified by densitometric analysis of the Western blots.

Secondary Outcome Measures

1. Triglycerides [baseline]

   triglycerides

2. Triglycerides [2 hours after ingestion of meal]

   triglycerides

3. Triglycerides [4 hours after ingestion of meal]

   triglycerides

4. Triglycerides [6 hours after ingestion of meal]

   triglycerides

5. Free Fatty Acids [baseline]

   Free Fatty Acids

6. Free Fatty Acids [2 hours after meal]

   Free Fatty Acids

7. Free Fatty Acids [4 hours after meal]

   Free Fatty Acids

8. Free Fatty Acids [6 hours after meal]

   Free Fatty Acids

9. Peak Forearm Blood Flow [baseline]

   Peak forearm blood flow via strain gauge venous occlusion plethysmography

10. Peak Forearm Blood Flow [3 hours after meal]

    Peak forearm blood flow via strain gauge venous occlusion plethysmography

11. Peak Forearm Blood Flow [6 hours after meal]

    Peak forearm blood flow via strain gauge venous occlusion plethysmography

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The University of Texas Health Science Center at Houston	Houston	Texas	United States	77030

Sponsors and Collaborators

• The University of Texas Health Science Center, Houston
• The Center for Clinical and Translational Sciences (CCTS) Clinical Research Unit at The University of Texas Health Science Center at Houston

Investigators

• Principal Investigator: Absalaon D Gutierrez, MD, University of Texas Health Science Center at Houston, Dept. of Medicine

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 18, 2016

More Information

Publications

None provided.

• Responsible Party: Absalon D Gutierrez, Assistant Professor of Medicine, The University of Texas Health Science Center, Houston
• ClinicalTrials.gov Identifier: NCT02104739
• Other Study ID Numbers: HSC-MS-13-0791
• First Posted: Apr 4, 2014
• Last Update Posted: Jul 3, 2018
• Last Verified: Jun 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Absalon D Gutierrez, Assistant Professor of Medicine, The University of Texas Health Science Center, Houston: prediabetes; diabetes mellitus type 2; exenatide; saxagliptin; exenatide ER
• Additional relevant MeSH terms: Prediabetic State; Glucose Intolerance; Exenatide; Saxagliptin

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	Exenatide, Then Saxagliptin, Then Placebo	Exenatide, Then Placebo, Then Saxagliptin	Saxagliptin, Then Exenatide, Then Placebo	Saxagliptin, Then Placebo, Then Exenatide	Placebo, Then Exenatide, Then Saxagliptin	Placebo, Then Saxagliptin, Then Exenatide	Exenatide Extended-release (Extension Phase)
Arm/Group Description	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	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	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	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	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	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	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
Period Title: First Intervention (1 Day)
STARTED	2	5	2	8	0	3	0
COMPLETED	2	4	2	7	0	3	0
NOT COMPLETED	0	1	0	1	0	0	0
Period Title: First Intervention (1 Day)
STARTED	1	4	2	7	0	2	0
COMPLETED	1	4	2	7	0	2	0
NOT COMPLETED	0	0	0	0	0	0	0
Period Title: First Intervention (1 Day)
STARTED	1	4	2	7	0	2	0
COMPLETED	1	4	2	7	0	2	0
NOT COMPLETED	0	0	0	0	0	0	0
Period Title: First Intervention (1 Day)
STARTED	1	4	2	7	0	2	0
COMPLETED	1	4	2	7	0	2	0
NOT COMPLETED	0	0	0	0	0	0	0
Period Title: First Intervention (1 Day)
STARTED	1	4	2	7	0	2	0
COMPLETED	1	4	2	7	0	2	0
NOT COMPLETED	0	0	0	0	0	0	0
Period Title: First Intervention (1 Day)
STARTED	0	0	0	0	0	0	8
COMPLETED	0	0	0	0	0	0	7
NOT COMPLETED	0	0	0	0	0	0	1
Period Title: First Intervention (1 Day)
STARTED	0	0	0	0	0	0	8
COMPLETED	0	0	0	0	0	0	7
NOT COMPLETED	0	0	0	0	0	0	1

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	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
Overall Participants	16
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50 (8)
Sex: Female, Male (Count of Participants)
Female	7 43.8%
Male	9 56.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 25%
Not Hispanic or Latino	12 75%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 6.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	8 50%
White	3 18.8%
More than one race	1 6.3%
Unknown or Not Reported	3 18.8%
Region of Enrollment (Count of Participants)
United States	16 100%
Height (meters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meters]	1.7 (0.11)
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	93.96 (11.98)
Body Mass Index (BMI) (kilograms per meter squared) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms per meter squared]	32.53 (1.92)

Outcome Measures

1. Primary Outcome

Title	Monocyte NfkB Levels as Detected by Western Blotting
Description	Monocyte NfkB p65 arbitrary units are quantified by densitometric analysis of the Western blots.
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide	Saxagliptin	Placebo	Exenatide Extended-release (ER)
Arm/Group Description	Exenatide: Single subcutaneous injection (10 mcg)	Saxagliptin: Single dose orally (5 mg)	Placebo: Placebo tablets and Placebo (normal saline) injections	Exenatide extended-release (ER): Subcutaneous injection (2mg) weekly for 6 weeks
Measure Participants	16	16	16	7
Mean (Standard Error) [NfkB p65 arbitrary units]	62.79 (4.05)	72.03 (6.38)	67.68 (6.38)	84.19 (6.45)

2. Primary Outcome

Title	Monocyte NfkB Levels as Detected by Western Blotting
Description	Monocyte NfkB p65 arbitrary units are quantified by densitometric analysis of the Western blots.
Time Frame	2 hours after ingestion of meal

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide	Saxagliptin	Placebo	Exenatide Extended-release (ER)
Arm/Group Description	Exenatide: Single subcutaneous injection (10 mcg)	Saxagliptin: Single dose orally (5 mg)	Placebo: Placebo tablets and Placebo (normal saline) injections	Exenatide extended-release (ER): Subcutaneous injection (2mg) weekly for 6 weeks
Measure Participants	16	16	16	7
Mean (Standard Error) [NfkB p65 arbitrary units]	67.39 (6.44)	68.39 (5.82)	71.37 (5.82)	93.47 (5.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide
	Comments	Exenatide at baseline and 2 hours after ingestion of meal is compared.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.27
	Comments
	Method	Non-parametric Wilcoxon paired rank sum
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Saxagliptin
	Comments	Saxagliptin at baseline and 2 hours after ingestion of meal is compared.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.59
	Comments
	Method	Non-parametric Wilcoxon paired rank sum
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	Placebo at baseline and 2 hours after ingestion of meal is compared.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.51
	Comments
	Method	Non-parametric Wilcoxon paired rank sum
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Exenatide Extended-release (ER)
	Comments	Exenatide extended-release (ER) at baseline and 2 hours after ingestion of meal is compared.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.31
	Comments
	Method	Non-parametric Wilcoxon paired rank sum
	Comments

3. Secondary Outcome

Title	Triglycerides
Description	triglycerides
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

Data for the exenatide extended-release (ER) arm was only collected at baseline and 2 hours.

Arm/Group Title	Exenatide	Saxagliptin	Placebo	Exenatide Extended-release (ER)
Arm/Group Description	Exenatide: Single subcutaneous injection (10 mcg)	Saxagliptin: Single dose orally (5 mg)	Placebo: Placebo tablets and Placebo (normal saline) injections	Exenatide extended-release (ER): Subcutaneous injection (2mg) weekly for 6 weeks
Measure Participants	16	16	16	7
Mean (Standard Error) [milligrams per deciliter]	108 (11)	101 (11)	102 (14)	106 (14)

4. Secondary Outcome

Title	Triglycerides
Description	triglycerides
Time Frame	2 hours after ingestion of meal

Outcome Measure Data

Analysis Population Description

Data for the exenatide extended-release (ER) arm was only collected at baseline and 2 hours.

Arm/Group Title	Exenatide	Saxagliptin	Placebo	Exenatide Extended-release (ER)
Arm/Group Description	Exenatide: Single subcutaneous injection (10 mcg)	Saxagliptin: Single dose orally (5 mg)	Placebo: Placebo tablets and Placebo (normal saline) injections	Exenatide extended-release (ER): Subcutaneous injection (2mg) weekly for 6 weeks
Measure Participants	16	16	16	7
Mean (Standard Error) [milligrams per deciliter]	119 (13)	130 (16)	163 (19)	168 (26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide, Exenatide Extended-release (ER)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	ANOVA
	Comments

5. Secondary Outcome

Title	Triglycerides
Description	triglycerides
Time Frame	4 hours after ingestion of meal

Outcome Measure Data

Analysis Population Description

Data for the exenatide extended-release (ER) arm was only collected at baseline and 2 hours.

Arm/Group Title	Exenatide	Saxagliptin	Placebo	Exenatide Extended-release (ER)
Arm/Group Description	Exenatide: Single subcutaneous injection (10 mcg)	Saxagliptin: Single dose orally (5 mg)	Placebo: Placebo tablets and Placebo (normal saline) injections	Exenatide extended-release (ER): Subcutaneous injection (2mg) weekly for 6 weeks
Measure Participants	16	16	16	0
Mean (Standard Error) [milligrams per deciliter]	124 (12)	153 (24)	206 (24)

6. Secondary Outcome

Title	Triglycerides
Description	triglycerides
Time Frame	6 hours after ingestion of meal

Outcome Measure Data

Analysis Population Description

Data for the exenatide extended-release (ER) arm was only collected at baseline and 2 hours.

Arm/Group Title	Exenatide	Saxagliptin	Placebo	Exenatide Extended-release (ER)
Arm/Group Description	Exenatide: Single subcutaneous injection (10 mcg)	Saxagliptin: Single dose orally (5 mg)	Placebo: Placebo tablets and Placebo (normal saline) injections	Exenatide extended-release (ER): Subcutaneous injection (2mg) weekly for 6 weeks
Measure Participants	16	16	16	0
Mean (Standard Error) [milligrams per deciliter]	161 (24)	179 (27)	200 (22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide, Saxagliptin
	Comments	The reported p-value compares exenatide and saxagliptin over all time points (2 hours, 4 hours, 6 hours).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Exenatide, Placebo
	Comments	The reported p-value compares exenatide and placebo over all time points (2 hours, 4 hours, 6 hours).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANOVA
	Comments

7. Secondary Outcome

Title	Free Fatty Acids
Description	Free Fatty Acids
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

Data for the exenatide extended-release (ER) arm was only collected at baseline and 2 hours.

Arm/Group Title	Exenatide	Saxagliptin	Placebo	Exenatide Extended-release (ER)
Arm/Group Description	Exenatide: Single subcutaneous injection (10 mcg)	Saxagliptin: Single dose orally (5 mg)	Placebo: Placebo tablets and Placebo (normal saline) injections	Exenatide extended-release (ER): Subcutaneous injection (2mg) weekly for 6 weeks
Measure Participants	16	16	16	7
Mean (Standard Error) [millimoles per liter]	0.45 (0.04)	0.49 (0.05)	0.51 (0.04)	0.65 (0.05)

8. Secondary Outcome

Title	Free Fatty Acids
Description	Free Fatty Acids
Time Frame	2 hours after meal

Outcome Measure Data

Analysis Population Description

Data for the exenatide extended-release (ER) arm was only collected at baseline and 2 hours.

Arm/Group Title	Exenatide	Saxagliptin	Placebo	Exenatide Extended-release (ER)
Arm/Group Description	Exenatide: Single subcutaneous injection (10 mcg)	Saxagliptin: Single dose orally (5 mg)	Placebo: Placebo tablets and Placebo (normal saline) injections	Exenatide extended-release (ER): Subcutaneous injection (2mg) weekly for 6 weeks
Measure Participants	16	16	16	7
Mean (Standard Error) [millimoles per liter]	0.35 (0.05)	0.18 (0.02)	0.17 (0.01)	0.19 (0.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide, Exenatide Extended-release (ER)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments
	Method	ANOVA
	Comments

9. Secondary Outcome

Title	Free Fatty Acids
Description	Free Fatty Acids
Time Frame	4 hours after meal

Outcome Measure Data

Analysis Population Description

Data for the exenatide extended-release (ER) arm was only collected at baseline and 2 hours.

Arm/Group Title	Exenatide	Saxagliptin	Placebo	Exenatide Extended-release (ER)
Arm/Group Description	Exenatide: Single subcutaneous injection (10 mcg)	Saxagliptin: Single dose orally (5 mg)	Placebo: Placebo tablets and Placebo (normal saline) injections	Exenatide extended-release (ER): Subcutaneous injection (2mg) weekly for 6 weeks
Measure Participants	16	16	16	0
Mean (Standard Error) [millimoles per liter]	0.43 (0.06)	0.24 (0.02)	0.23 (0.02)

10. Secondary Outcome

Title	Free Fatty Acids
Description	Free Fatty Acids
Time Frame	6 hours after meal

Outcome Measure Data

Analysis Population Description

Data for the exenatide extended-release (ER) arm was only collected at baseline and 2 hours.

Arm/Group Title	Exenatide	Saxagliptin	Placebo	Exenatide Extended-release (ER)
Arm/Group Description	Exenatide: Single subcutaneous injection (10 mcg)	Saxagliptin: Single dose orally (5 mg)	Placebo: Placebo tablets and Placebo (normal saline) injections	Exenatide extended-release (ER): Subcutaneous injection (2mg) weekly for 6 weeks
Measure Participants	16	16	16	0
Mean (Standard Error) [millimoles per liter]	0.29 (0.06)	0.31 (0.02)	0.33 (0.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide, Saxagliptin
	Comments	The reported p-value compares exenatide and saxagliptin over all time points (2 hours, 4 hours, 6 hours).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Exenatide, Placebo
	Comments	The reported p-value compares exenatide and placebo over all time points (2 hours, 4 hours, 6 hours).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANOVA
	Comments

11. Secondary Outcome

Title	Peak Forearm Blood Flow
Description	Peak forearm blood flow via strain gauge venous occlusion plethysmography
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

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/Group Title	Exenatide	Saxagliptin	Placebo	Exenatide Extended-release (ER)
Arm/Group Description	Exenatide: Single subcutaneous injection (10 mcg)	Saxagliptin: Single dose orally (5 mg)	Placebo: Placebo tablets and Placebo (normal saline) injections	Exenatide extended-release (ER): Subcutaneous injection (2mg) weekly for 6 weeks
Measure Participants	15	15	15	7
Mean (Standard Error) [mL per minute per 100mL of tissue]	12.65 (1.17)	12.79 (1.47)	12.18 (1.17)	16.18 (1.25)

12. Secondary Outcome

Title	Peak Forearm Blood Flow
Description	Peak forearm blood flow via strain gauge venous occlusion plethysmography
Time Frame	3 hours after meal

Outcome Measure Data

Analysis Population Description

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/Group Title	Exenatide	Saxagliptin	Placebo	Exenatide Extended-release (ER)
Arm/Group Description	Exenatide: Single subcutaneous injection (10 mcg)	Saxagliptin: Single dose orally (5 mg)	Placebo: Placebo tablets and Placebo (normal saline) injections	Exenatide extended-release (ER): Subcutaneous injection (2mg) weekly for 6 weeks
Measure Participants	15	15	15	7
Mean (Standard Error) [mL per minute per 100mL of tissue]	13.18 (1.21)	13.25 (1.04)	15.11 (1.29)	16.54 (2.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide, Exenatide Extended-release (ER)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5
	Comments
	Method	ANOVA
	Comments

13. Secondary Outcome

Title	Peak Forearm Blood Flow
Description	Peak forearm blood flow via strain gauge venous occlusion plethysmography
Time Frame	6 hours after meal

Outcome Measure Data

Analysis Population Description

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/Group Title	Exenatide	Saxagliptin	Placebo	Exenatide Extended-release (ER)
Arm/Group Description	Exenatide: Single subcutaneous injection (10 mcg)	Saxagliptin: Single dose orally (5 mg)	Placebo: Placebo tablets and Placebo (normal saline) injections	Exenatide extended-release (ER): Subcutaneous injection (2mg) weekly for 6 weeks
Measure Participants	15	15	15	0
Mean (Standard Error) [mL per minute per 100mL of tissue]	14.25 (1.09)	15.87 (1.81)	13.45 (0.68)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide, Saxagliptin
	Comments	The reported p-value compares exenatide and saxagliptin over all time points (3 hours, 6 hours).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Exenatide, Placebo
	Comments	The reported p-value compares exenatide and placebo over all time points (3 hours, 6 hours).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	ANOVA
	Comments

Adverse Events

Time Frame	Subjects were followed during the study and for 30 days following the last dose. During the cross-over study, subjects were followed for a min of 53 days to a max of 150 days after taking the 1st dose [(3 days for 3, 1-day study arms) + (20 days to 117 days total for 2 washout periods) + 30 = 53 days]. (Washout was at least 20 days but could be 117 days since the cross-over study could span 120 days.) During the extension study, subjects were followed for 72 days after taking the 1st dose.
Arm/Group Title	Exenatide		Saxagliptin		Placebo		Exenatide Extended-release (ER)
Arm/Group Description	Exenatide: Single subcutaneous injection (10 mcg)		Saxagliptin: Single dose orally (5 mg)		Placebo: Placebo tablets and Placebo (normal saline) injections		Exenatide extended-release (ER): Subcutaneous injection (2mg) weekly for 6 weeks
All Cause Mortality
	Exenatide		Saxagliptin		Placebo		Exenatide Extended-release (ER)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)		0/16 (0%)		0/7 (0%)
Serious Adverse Events
	Exenatide		Saxagliptin		Placebo		Exenatide Extended-release (ER)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)		0/16 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Exenatide		Saxagliptin		Placebo		Exenatide Extended-release (ER)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)		0/16 (0%)		0/7 (0%)

Limitations/Caveats

Lower than expected sample size.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.