Healthy, Impaired Glucose Tolerance, Type 2 Diabetes
Conditions
Keywords
Type 2 diabetes pathogenesis, thiazolidinediones, impaired glucose tolerance, Incretins, Insulin secretion
Brief summary
Pioglitazone, a drug used in treatment of type 2 diabetes has been shown to improve insulin sensitivity in skeletal muscle, liver, and fat cells. Despite the beneficial effects of pioglitazone to improve insulin sensitivity and reduce cardiovascular disease in high risk type 2 diabetic patients, weight gain has been a limiting factor. Exenatide, another agent used for treatment of T2DM, improves glycemic control and promotes moderate weight loss. In this proposal we will examine the effect of combination therapy with pioglitazone plus exenatide on body weight, fat topography, beta cell function, glycemic control, and plasma lipid levels in subjects with type 2 diabetes mellitus compared to treatment with each drug separately. Assessment of beta cell function will be performed by measuring the maximal insulin secretory capacity using a maximal hyperglycemic stimulus combined with an intravenous arginine stimulus.
Detailed description
The thiazolidinedione (TZD) class of drugs has been shown to improve insulin sensitivity in skeletal muscle, liver, and adipocytes and to have anti-inflammatory and cardioprotective effects. The beta cell function, measured by the insulin secretion/insulin resistance index during the OGTT, improves significantly. In the present study, we will perform a more definitive assessment of beta cell function in TZD-treated diabetic patients by measuring the maximal insulin secretory capacity using a maximal hyperglycemic stimulus combined with an intravenous arginine stimulus. Despite the beneficial effects of pioglitazone to improve insulin sensitivity and reduce cardiovascular events in high risk type 2 diabetic patients, weight gain has been a limiting factor for primary care physicians even though pioglitazone treatment leads to a redistribution of fat out of muscle/liver/visceral area to subcutaneous fat. Exenatide (Byetta) is 39 amino acid peptide which exhibits biological actions similar to GLP-1. In clinical trials exenatide reduces HbA1c by 1-1.2% in subjects with type 2 diabetes and promotes moderate weight loss which is sustained for up to 2 years. In this proposal we will examine the effect of combination therapy with pioglitazone plus exenatide on body weight, fat topography, beta cell function, glycemic control, and plasma lipid levels in subjects with type 2 diabetes mellitus compared to monotherapy with each agent separately. We postulate that combination therapy will result in significant weight loss (in contrast to the weight gain which accompanies pioglitazone treatment) and have an additive, or even synergistic, effect to improve beta cell function and glycemic control in type 2 diabetic patients who are inadequately controlled on oral agent therapy with metformin alone, a sulfonylurea alone, or combination of metformin plus a sulfonylurea. We will also compare the insulin secretion in healthy control subjects (NGT, n=15) and subjects with impaired glucose tolerance (IGT, n=15) to evaluate the relative decline in beta cell function in T2DM compared to NGT and IGT subjects. NGT and IGT subjects will participate only in a OGTT and a Hyperglycemic clamp- they will not receive any medication.
Interventions
DRUGPioglitazone
Pioglitazone 15 mg/day for 1 month and then 45 mg/day for 5 months
DRUGExenatide
Exenatide 5mcg twice daily for 1 month, then 10mcg twice daily for 5 months
DRUGPioglitazone and Exenatide
Pioglitazone 30mg daily for 1 month and then 45mg daily for 5 months and Exenatide 5mcg twice daily for one month then 10mcg twice daily for 5 months
Sponsors
The University of Texas Health Science Center at San Antonio
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Diabetic patients must be on diet therapy alone or diet plus a sulfonylurea, or diet plus metformin, or diet plus sulfonylurea/metformin and have a HbA1c ≥ 7.0%. 2. Patients must have the following laboratory values: Hematocrit ≥ 34 vol% Serum creatinine ≤ 1.8 mg/dl AST (SGOT) ≤ 2 times upper limit of normal ALT (SGPT) ≤ 2 times upper limit of normal Alkaline phosphatase ≤ 2 times upper limit of normal 3. Patients must have been on a stable dose of allowed chronic medications for 30 days prior to entering the study. 4. Body weight must be stable (± 3-4 pounds) over the three months prior to study 5. The normal healthy control group will be age, weight (BMI), and gender matched with the diabetic group and must have a normal OGTT according to ADA criteria. 6. Subjects with IFG/IGT will have a FPG (100-125mg/dl) and/or 2-h plasma glucose (140-199mg/dl) according to ADA criteria.
Exclusion criteria
1. Patients must not have type 1 diabetes. 2. Patients must not have a fasting plasma glucose of greater than 270 mg/dl or HbA1c \> 10.0%. 3. Patients must not have received a thiazolidinedione or insulin for more than one week during the year prior to randomization. 4. Patients with a history of clinically significant heart disease (New York Heart Classification greater than class 2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Pioglitazone, Exenatide and Combined Pioglitazone and Exenatide on Body Weight | baseline and 6 months | Effect of Pioglitazone, Exenatide and combined Pioglitazone and Exenatide on body weight and beta cell function |
| HbA1c | baseline and 6 months | change in HbA1c was measured before and after treatment in three groups |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect Pioglitazone, Exenatide, and Pioglitazone Plus Exenatide • Insulin Sensitivity • Inflammatory Cytokines • Glucagon and Free Fatty Acids • Plasma Lipids | 6 months | Effect pioglitazone, exenatide, and pioglitazone plus exenatide on * Insulin sensitivity * Inflammatory cytokines * glucagon and free fatty acids * plasma lipids measured over a 6 month period |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pioglitazone Pioglitazone: 15 Patients will be randomized to Pioglitazone only arm | 13 |
| Exenatide Exenatide: 15 subjects will be randomized to receive Exenatide | 15 |
| Pioglitazone and Exentatide Pioglitazone and Exenatide: 15 subjects will be randomized to Pioglitazone and Exenatide | 15 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 1 |
| Overall Study | Lost to Follow-up | 3 | 3 | 4 |
| Overall Study | Physician Decision | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Exenatide | Pioglitazone and Exentatide | Pioglitazone | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 15 Participants | 13 Participants | 42 Participants |
| Age, Continuous | 54.3 years STANDARD_DEVIATION 8.5 | 53.8 years STANDARD_DEVIATION 9.8 | 54.6 years STANDARD_DEVIATION 5.7 | 54.2 years STANDARD_DEVIATION 8.02 |
| Region of Enrollment United States | 15 participants | 15 participants | 13 participants | 43 participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 4 Participants | 13 Participants |
| Sex: Female, Male Male | 11 Participants | 10 Participants | 9 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 12 | 1 / 15 | 1 / 15 |
| serious Total, serious adverse events | 0 / 12 | 0 / 15 | 0 / 15 |
Outcome results
Primary
Effect of Pioglitazone, Exenatide and Combined Pioglitazone and Exenatide on Body Weight
Effect of Pioglitazone, Exenatide and combined Pioglitazone and Exenatide on body weight and beta cell function
Time frame: baseline and 6 months
Population: we analyzed the weight at the end of study completion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PIOGLITAZONE | Effect of Pioglitazone, Exenatide and Combined Pioglitazone and Exenatide on Body Weight | 5.5 kg | Standard Deviation 7.3 |
| EXENATIDE | Effect of Pioglitazone, Exenatide and Combined Pioglitazone and Exenatide on Body Weight | 2.4 kg | Standard Deviation 2.8 |
| PIOGLITAZONE and EXNATIDE | Effect of Pioglitazone, Exenatide and Combined Pioglitazone and Exenatide on Body Weight | 2.7 kg | Standard Deviation 4.4 |
p-value: <0.05ANCOVA
p-value: <0.05ANOVA
Primary
HbA1c
change in HbA1c was measured before and after treatment in three groups
Time frame: baseline and 6 months
Population: There was a greater improvement in HbA1c from baseline after combined treatment with Pioglitazone and Exenatide when compared with either therapy alone.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PIOGLITAZONE | HbA1c | 1.37 percent point decrease from baseline | Standard Deviation 0.68 |
| EXENATIDE | HbA1c | 1.09 percent point decrease from baseline | Standard Deviation 0.68 |
| PIOGLITAZONE and EXNATIDE | HbA1c | 1.91 percent point decrease from baseline | Standard Deviation 1.2 |
Secondary
Effect Pioglitazone, Exenatide, and Pioglitazone Plus Exenatide • Insulin Sensitivity • Inflammatory Cytokines • Glucagon and Free Fatty Acids • Plasma Lipids
Effect pioglitazone, exenatide, and pioglitazone plus exenatide on * Insulin sensitivity * Inflammatory cytokines * glucagon and free fatty acids * plasma lipids measured over a 6 month period
Time frame: 6 months
Population: Data were not collected for this analysis