Type 2 Diabetes Mellitus
Conditions
Keywords
Type 2 diabetes mellitus, Impaired glucose tolerance
Brief summary
The purpose of this investigation is to evaluate whether exenatide, a type 2 diabetes medication, will improve the function of the innermost part of the arterial wall called the endothelium after a fat-enriched meal and to determine how this occurs. The results of this study will help to determine and understand a novel action of this group of diabetes medications based on the action of naturally occuring gut substances called incretins. This may have a significant impact on cardiovascular health in patients with early and longstanding diabetes.
Detailed description
Two independent, double-blinded, crossover substudies will be conducted to test the effect of exenatide on daylong post-meal and fasting endothelial function. We will measure endothelial function measured by peripheral arterial tonometry (EndoPAT2000, Itamar Inc.). Patients with recent onset (\<3 years) or established (\>5 years, Substudy 1 only) diabetes and impaired sugar tolerance (Substudy 2 only) will be studied. The plan is to complete studies in 75 patients (40 in Substudy 1 and 35 in Substudy 2). In Substudy 1 patients will get twice a day a skin injection of exenatide (Byetta) or identically looking placebo for 10 days, separated by 14-day period. On the next day after each treatemnt period (day 11), they get just one injection and eat a fat-enriched breakfast. A fatty lunch of similar caloric content will be given 4 hours following the breakfast. Endothelial function will be measured just prior to the injection and every 2 hours for total 8 hours. In Substudy 2, patients on 3 different days will get infusion of exenatide withg or without a blocking drug exendin-9, and a control test with placebo without exendin-9. Endothelial function will be measured before the infusion and 2 hours later during the final 15 minutes of the infusion cocktails. Patients will not eat any meal during the test visits.
Interventions
DRUGPlacebo SC
Placebo sc BID/10days
DRUGExenatide SC
Exenatide 5-10 ug sc BID/10 days
DRUGExenatide IV
50 ng/min intravenously for 45 minutes on 2 out of 3 study visits separated by 5-10 days
DRUGExendin-9
Primed (6,000 pM/kg), continuous (600 pM/kg) intravenous infusion for 75 minutes on 1 out of 3 study visits.
DRUGPlacebo IV
Intravenous infusion for 45 minutes on 1 out of 3 visits
Sponsors
American Diabetes Association
Amylin Pharmaceuticals, LLC.
Carl T. Hayden VA Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
35 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* US Veterans * type 2 diabetes mellitus (T2D) diagnosed within 3 years with good glycemic control on diet, metformin, or sulfonylurea agents or combinations of these agents (HbA1c ≤8.0%) * T2D diagnosed ≥ 5 years prior to study enrollment * Impaired glucose tolerance
Exclusion criteria
* T2D not meeting inclusion above criteria for duration of diabetes or HbA1c values * known or suspected T1D (early onset age, low body mass index, lack of family history) * TZD use in the prior 3 months * prior regular use of insulin * Creatinine \>2.0 mg/dl or other laboratory or clinical evidence of kidney disease * anemia * known active liver disease or hepatic enzyme elevation two-and-a half times above normal * acute bacterial or viral illness or evidence of other active infection in the past 4 weeks * stable or unstable angina or other major illness in the past 6 months * Raynaud's disease or any rheumatic disease affecting fingers * current regular use of anti-inflammatory medications or antioxidants, including over the counter medications and high dose salicylates (\>1 g/day); * subjects receiving lipid lowering or anti-hypertension medications must be on stable doses for at least 2 months prior to participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Reactive Hyperemia Index (RHI) | 0, 2, 4, 6 and 8 hours on Day 11 (Sub-study 1); 0 and 120 minutes on test Days 1, 2 & 3 (Sub-study 2) | Greater RHI reflects greater endothelial function. It is calculated as average post-ischemia pulse magnitude divided by average pre-ischemia pulse magnitude. Results are expressed as least-square means of ANCOVA models. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Triglycerides | 0, 2, 4, 6 and 8 hours post-study drug on day 11 | Triglycerides concentrations were measured before and 2, 4, 6 and 8 hours following study drug. Results are expressed as least-square means of ANCOVA models adjusted for sampling time and intervention sequence. |
| Plasma Glucose | 0, 2, 4, 6, and 8 hours post-study drug on day 11 | Plasma glucose was measured before and 2, 4, 6 and 8 hours following study drug administration. Results are expressed as least-square means of ANCOVA models adjusted for sampling time and intervention sequence. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sub-study 1: Exenatide SC Exenatide 5-10 ug or placebo sc BID/10 days, day 11 AM dose and meal test - crossover study | 42 |
| Sub-study 2: Exenatide IV Intravenous infusion of (1) Saline+Exenatide, (2) Saline+Placebo or (3) Exendin-9+Exenatide on 3 seperate days, crossover study | 34 |
| Total | 76 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Phase 1 | Adverse Event | 0 | 0 | 1 |
| Phase 1 | Lost to Follow-up | 0 | 1 | 1 |
| Phase 1 | Protocol Violation | 1 | 0 | 0 |
| Phase 2 | Adverse Event | 0 | 3 | 0 |
| Phase 2 | Medical condition | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Sub-study 2: Exenatide IV | Sub-study 1: Exenatide SC | Total |
|---|---|---|---|
| Age, Continuous | 60 years STANDARD_DEVIATION 6 | 62 years STANDARD_DEVIATION 6 | 61 years STANDARD_DEVIATION 6 |
| Body mass index | 33 kg/m^2 STANDARD_DEVIATION 12 | 33 kg/m^2 STANDARD_DEVIATION 6 | 33 kg/m^2 STANDARD_DEVIATION 9 |
| Diabetes duration (years) | 0 years | 6 years | 6 years |
| Diastolic BP (mmHg) | 80 mmHg STANDARD_DEVIATION 8 | 78 mmHg STANDARD_DEVIATION 8 | 79 mmHg STANDARD_DEVIATION 8 |
| Glycated hemoglobin | 6.1 % STANDARD_DEVIATION 0.5 | 6.6 % STANDARD_DEVIATION 0.9 | 6.4 % STANDARD_DEVIATION 0.8 |
| History of hypertension No | 18 participants | 9 participants | 27 participants |
| History of hypertension Yes | 16 participants | 33 participants | 49 participants |
| Lipid-lowering therapy No | 19 participants | 37 participants | 56 participants |
| Lipid-lowering therapy Yes | 15 participants | 5 participants | 20 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 6 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 29 Participants | 36 Participants | 65 Participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 32 Participants | 42 Participants | 74 Participants |
| Systolic BP | 125 mmHg STANDARD_DEVIATION 12 | 128 mmHg STANDARD_DEVIATION 8 | 127 mmHg STANDARD_DEVIATION 14 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 16 / 41 | 3 / 41 | 0 / 32 | 0 / 33 | 0 / 33 |
| serious Total, serious adverse events | 0 / 41 | 0 / 41 | 0 / 32 | 1 / 33 | 0 / 33 |
Outcome results
Primary
Reactive Hyperemia Index (RHI)
Greater RHI reflects greater endothelial function. It is calculated as average post-ischemia pulse magnitude divided by average pre-ischemia pulse magnitude. Results are expressed as least-square means of ANCOVA models.
Time frame: 0, 2, 4, 6 and 8 hours on Day 11 (Sub-study 1); 0 and 120 minutes on test Days 1, 2 & 3 (Sub-study 2)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide (Subs-study 1) | Reactive Hyperemia Index (RHI) | 1.90 ratio | Standard Error 0.005 |
| Placebo (Sub-study 1) | Reactive Hyperemia Index (RHI) | 1.79 ratio | Standard Error 0.05 |
| Saline+Exenatide (Sub-study 2) | Reactive Hyperemia Index (RHI) | 2.24 ratio | Standard Error 0.07 |
| Saline+Placebo (Sub-study 2) | Reactive Hyperemia Index (RHI) | 1.95 ratio | Standard Error 0.07 |
| Exendin-9+Exenatide (Sub-study 2) | Reactive Hyperemia Index (RHI) | 1.99 ratio | Standard Error 0.07 |
p-value: <0.0001ANCOVA
p-value: 0.006ANCOVA
p-value: 0.003ANCOVA
Secondary
Plasma Glucose
Plasma glucose was measured before and 2, 4, 6 and 8 hours following study drug administration. Results are expressed as least-square means of ANCOVA models adjusted for sampling time and intervention sequence.
Time frame: 0, 2, 4, 6, and 8 hours post-study drug on day 11
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide (Subs-study 1) | Plasma Glucose | 115 mg/dl | Standard Error 5 |
| Placebo (Sub-study 1) | Plasma Glucose | 136 mg/dl | Standard Error 5 |
p-value: <0.0001ANCOVA
Secondary
Plasma Triglycerides
Triglycerides concentrations were measured before and 2, 4, 6 and 8 hours following study drug. Results are expressed as least-square means of ANCOVA models adjusted for sampling time and intervention sequence.
Time frame: 0, 2, 4, 6 and 8 hours post-study drug on day 11
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide (Subs-study 1) | Plasma Triglycerides | 175 mg/dl | Standard Error 14 |
| Placebo (Sub-study 1) | Plasma Triglycerides | 230 mg/dl | Standard Error 14 |
p-value: <0.0001ANCOVA