Pre-diabetes, Type 2 Diabetes
Conditions
Keywords
Exenatide, Sitagliptin, Glimepiride, Glucagon-Like Peptide-1, Impaired Fasting Glucose, Type 2 Diabetes, Beta-cell Function, Beta-cell Secretory Capacity, Glucose-potentiated arginine
Brief summary
This study evaluates exenatide, sitagliptin, and glimepiride for the treatment of high blood sugar in patients with impaired fasting glucose or early type 2 diabetes. The purpose of this study is to determine if exenatide and sitagliptin increase the amount of insulin made by the pancreas compared to glimepiride. It is hypothesized that exenatide or sitagliptin will sustain or increase the amount of insulin made by the pancreas in comparison to glimepiride.
Detailed description
The incidence of type 2 diabetes (T2D) has reached epidemic proportions throughout the world. In the United States more than 1.5 million new cases of diabetes were diagnosed in 2005, and the estimated prevalence of the disease was over 20 million. Another 54 million Americans are believed to have impaired fasting glucose, which represents a pre-diabetic state at increased risk for progression to overt diabetes. T2D ultimately results from an inadequate mass of functional beta-cells, where insufficient beta-cell compensation for insulin resistance leads to the development of impaired glucose tolerance and eventually diabetes. Autopsy studies have demonstrated a decreased beta-cell mass occurring with fasting glucose \> 110 mg/dl, consistent with functional studies that demonstrate decreased beta-cell (insulin) secretory capacity beginning in the range of impaired fasting glucose. Strategies that might preserve or expand functional beta-cell mass in vivo would be expected to reverse the progressive deterioration in blood glucose control seen with diabetes. One such strategy involves the incretin hormone glucagon-like peptide-1 (GLP-1), which is trophic for islet beta-cells, having both pro-proliferative and anti-apoptotic effects. However, it is not known whether increasing GLP-1 effects can preserve or enhance functional beta-cell mass in humans. This proposal will determine the effect of increasing GLP-1 levels on functional beta-cell mass in human subjects with impaired fasting glucose (fasting glucose 110 - 126 mg/dl) or early T2D (fasting glucose 127 - 149 mg/dl) where a critical window exists for reversing further beta-cell deterioration. GLP-1 effects will be promoted by administration of either the GLP-1 analog, exenatide, or by increasing endogenous GLP-1 levels through administration of the oral dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin for a 6-month period. To control for the effect of exenatide and sitagliptin on normalization of blood glucose, subjects will be randomized to receive exenatide, sitagliptin or the sulfonylurea glimepiride, the latter being a first-line anti-diabetogenic agent that will serve as an active comparator.
Interventions
DRUGExenatide
Exenatide (Byetta®)-5 µg injected subcutaneously twice daily and increased after 1 month to 10 µg twice daily as tolerated by gastrointestinal effects
DRUGSitagliptin
Sitagliptin (Januvia®)100 mg by mouth every morning
DRUGGlimepiride
Glimepiride (Amaryl®)-0.5 mg by mouth every morning and then increased by 0.5 - 1.0 mg at each monthly visit to achieve an average fasting glucose \< 110mg/dl
Sponsors
Pennsylvania Department of Health
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Male and female patients age 18 to 70 years. 2. Ability to provide written informed consent 3. Mentally stable and able to comply with the procedures of the study protocol 4. Clinical history compatible with impaired fasting glucose or early T2D as defined by a plasma glucose concentration between 110-159 mg/dl following a 12 hour overnight fast performed off any anti-diabetogenic agent for at least 2 weeks (6 weeks for thiazolidinediones) 5. Stable body weight (+ 5%) for at least 2 weeks 6. Female Patients: Agree to use adequate contraception if reproductively capable. Adequate contraception includes either a hormonal or barrier method, or surgical sterilization.
Exclusion criteria
1. Diagnosis of type 1 diabetes 2. Receiving insulin, exenatide (Byetta®), or sitagliptin (Januvia®) treatment or taking \> 2 oral anti-diabetogenic agents for the treatment of diabetes 3. BMI \> 44 kg/m2 4. Allergy to any sulfa-containing compounds 5. Uncontrolled hypertension (Systolic Blood Pressure \>160 or Diastolic Blood Pressure \> 100 mmHg) 6. Uncontrolled hyperlipidemia (triglycerides \> 500 or LDL \> 160 mg/dl) 7. Elevation of liver function tests \> 2 times the upper limit of normal 8. Estimated Glomerular Filtration Rate (GFR) \< 55 ml/min/1.73m2 (46) 9. Hyperkalemia (serum potassium \> 5.5 mmol/L) 10. Moderate anemia (hemoglobin concentration \< 12 g/dl in men and \< 11 g/dl in women) 11. Female patients: pregnant or lactating 12. Hepatic cirrhosis 13. Known active alcohol or substance abuse 14. Active cardiovascular disease 15. Use of any investigational agent within 6 weeks of the baseline visit 16. Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (μU/ml) | Baseline and 6 months | The acute insulin response to arginine (AIRarg) performed during the 340mg/dl glucose clamp allows for estimation of the the beta-cell secretory capacity (AIRmax) or functional beta-cell mass. Changes from baseline to 6 months of AIRmax were compared across groups |
| Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (pg/mL) | Baseline and 6 months | AGRmin is performed during the 340mg/dl glucose clamp allows for estimation of the minimum alpha-cell glucagon secretion. Changes from baseline to 6 months of AGRmin were compared across groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Acute Insulin Response to Arginine. (AIRarg) | Baseline and 6 months | The changes in B-cell insulin secretion, Acute Insulin Response to arginine (AIRarg) after 6 months were compared to baseline AIRarg for each group. Listed below are AIRarg at baseline and 6 months for each group. |
| Insulin Sensitivity at Baseline and 6 Months | Baseline and 6 months | Insulin sensitivity (M/I) was determined by dividing the mean glucose infusion rate required during the 230 mg/dL glucose clamp (M) by the mean prestimulus insulin level (I) between 40 and 45 min of the glucose infusion The mean difference after 6 months in insulin sensitivity (M/I) were compared |
| PG 50 (the Plasma Glucose Level at Which Half-maximal Insulin Secretion is Achieved During the Glucose-potentiated Arginine Test) at Baseline and 6 Months | Baseline and 6 months | Between ∼60 and 250 mg/dL, the magnitude of AIRarg is a linear function of the plasma glucose level, so the difference in AIRarg at fasting and 230 mg/dL glucose levels divided by the difference in plasma glucose (ΔAIRarg/ΔPG) gives the glucose-potentiation slope (GPS) (8,24-26). Using the y-intercept (b) from the line created by these two points, the plasma glucose level at which half-maximal insulin secretion is achieved (PG50) is derived from solving the equation 1/2 (AIRmax) = (GPS · PG50) + b, and provides a measure of β-cell sensitivity to glucose The mean difference after 6 months in PG 50 were compared. Listed below are the PG50 values at baseline and 6 months. |
Countries
United States
Participant flow
Recruitment details
Recruitment is now closed for this study. All subject follow-up was completed in the spring of 2012. The purpose of the study was to evaluate three medications for the treatment of high blood sugar.
Participants by arm
| Arm | Count |
|---|---|
| Exenatide Exenatide (Byetta®)-5 µg injected subcutaneously twice daily and increased after 1 month to 10 µg twice daily as tolerated by gastrointestinal effects
Exenatide: Exenatide (Byetta®)-5 µg injected subcutaneously twice daily and increased after 1 month to 10 µg twice daily as tolerated by gastrointestinal effects | 17 |
| Sitagliptin Sitagliptin (Januvia®)-100 mg by mouth every morning
Sitagliptin: Sitagliptin (Januvia®)100 mg by mouth every morning | 13 |
| Glimepiride Glimepiride (Amaryl®)-0.5 mg by mouth every morning and then increased by 0.5 - 1.0 mg at each monthly visit to achieve an average fasting glucose \< 110mg/dl
Glimepiride: Glimepiride (Amaryl®)-0.5 mg by mouth every morning and then increased by 0.5 - 1.0 mg at each monthly visit to achieve an average fasting glucose \< 110mg/dl | 17 |
| Total | 47 |
Baseline characteristics
| Characteristic | Exenatide | Sitagliptin | Glimepiride | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 13 Participants | 17 Participants | 47 Participants |
| Age, Continuous | 57 years STANDARD_DEVIATION 2 | 57 years STANDARD_DEVIATION 3 | 52 years STANDARD_DEVIATION 3 | 55.3 years STANDARD_DEVIATION 2.6 |
| Region of Enrollment United States | 17 participants | 13 participants | 17 participants | 47 participants |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 7 Participants | 17 Participants |
| Sex: Female, Male Male | 11 Participants | 9 Participants | 10 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 13 | 0 / 17 |
| other Total, other adverse events | 0 / 17 | 0 / 13 | 0 / 17 |
| serious Total, serious adverse events | 0 / 17 | 0 / 13 | 0 / 17 |
Outcome results
Primary
Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (pg/mL)
AGRmin is performed during the 340mg/dl glucose clamp allows for estimation of the minimum alpha-cell glucagon secretion. Changes from baseline to 6 months of AGRmin were compared across groups.
Time frame: Baseline and 6 months
Population: We conducted a randomized controlled trial in 40 adult subjects with early Type 2 diabetes (T2D) who received the~glucagon-like peptide (GLP-1) analog exenatide, the dipeptidyl peptidase IV inhibitor sitagliptin or the sulfonylurea glimepiride as an active comparator insulin secretagogue for 6 months.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide | Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (pg/mL) | Acute Glucose Response (AGRmin) Baseline | 51 pg/mL | Standard Error 12 |
| Exenatide | Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (pg/mL) | Acute Glucose Response (AGRmin) 6 Months | 52 pg/mL | Standard Error 12 |
| Sitagliptin | Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (pg/mL) | Acute Glucose Response (AGRmin) Baseline | 55 pg/mL | Standard Error 8 |
| Sitagliptin | Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (pg/mL) | Acute Glucose Response (AGRmin) 6 Months | 59 pg/mL | Standard Error 19 |
| Glimepiride | Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (pg/mL) | Acute Glucose Response (AGRmin) Baseline | 37 pg/mL | Standard Error 6 |
| Glimepiride | Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (pg/mL) | Acute Glucose Response (AGRmin) 6 Months | 59 pg/mL | Standard Error 8 |
Primary
Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (μU/ml)
The acute insulin response to arginine (AIRarg) performed during the 340mg/dl glucose clamp allows for estimation of the the beta-cell secretory capacity (AIRmax) or functional beta-cell mass. Changes from baseline to 6 months of AIRmax were compared across groups
Time frame: Baseline and 6 months
Population: We conducted a randomized controlled trial in 40 adult subjects with early Type 2 diabetes (T2D) who received the~glucagon-like peptide (GLP-1) analog exenatide, the dipeptidyl peptidase IV inhibitor sitagliptin or the sulfonylurea glimepiride as an active comparator insulin secretagogue for 6 months.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide | Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (μU/ml) | Acute Insulin Response (AIRmax)Baseline | 214 μU/ml | Standard Error 60 |
| Exenatide | Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (μU/ml) | Acute Insulin Response (AIRmax) 6 Months | 188.5 μU/ml | Standard Error 34.6 |
| Sitagliptin | Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (μU/ml) | Acute Insulin Response (AIRmax)Baseline | 149 μU/ml | Standard Error 20 |
| Sitagliptin | Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (μU/ml) | Acute Insulin Response (AIRmax) 6 Months | 158.3 μU/ml | Standard Error 30.3 |
| Glimepiride | Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (μU/ml) | Acute Insulin Response (AIRmax)Baseline | 133 μU/ml | Standard Error 19 |
| Glimepiride | Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (μU/ml) | Acute Insulin Response (AIRmax) 6 Months | 202.5 μU/ml | Standard Error 35.1 |
Comparison: Student t testp-value: =0.1t-test, 2 sided
Comparison: Repeated measure (baseline and 6 months)p-value: <0.05t-test, 2 sided
Secondary
Change in Acute Insulin Response to Arginine. (AIRarg)
The changes in B-cell insulin secretion, Acute Insulin Response to arginine (AIRarg) after 6 months were compared to baseline AIRarg for each group. Listed below are AIRarg at baseline and 6 months for each group.
Time frame: Baseline and 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide | Change in Acute Insulin Response to Arginine. (AIRarg) | Acute Insulin Response (AIRarg) Baseline | 52 uU/mL | Standard Error 14 |
| Exenatide | Change in Acute Insulin Response to Arginine. (AIRarg) | Acute Insulin Response (AIRarg) 6 Months | 52 uU/mL | Standard Error 11 |
| Sitagliptin | Change in Acute Insulin Response to Arginine. (AIRarg) | Acute Insulin Response (AIRarg) Baseline | 35 uU/mL | Standard Error 4 |
| Sitagliptin | Change in Acute Insulin Response to Arginine. (AIRarg) | Acute Insulin Response (AIRarg) 6 Months | 34 uU/mL | Standard Error 6 |
| Glimepiride | Change in Acute Insulin Response to Arginine. (AIRarg) | Acute Insulin Response (AIRarg) Baseline | 44 uU/mL | Standard Error 6 |
| Glimepiride | Change in Acute Insulin Response to Arginine. (AIRarg) | Acute Insulin Response (AIRarg) 6 Months | 42 uU/mL | Standard Error 4 |
Comparison: Within group changes over 6 months (delta= final - baseline) were compared.p-value: >0.1t-test, 1 sided
Secondary
Insulin Sensitivity at Baseline and 6 Months
Insulin sensitivity (M/I) was determined by dividing the mean glucose infusion rate required during the 230 mg/dL glucose clamp (M) by the mean prestimulus insulin level (I) between 40 and 45 min of the glucose infusion The mean difference after 6 months in insulin sensitivity (M/I) were compared
Time frame: Baseline and 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide | Insulin Sensitivity at Baseline and 6 Months | M/I Baseline | 0.3 ((mg/kg) /min) /uU/mL | Standard Error 0.1 |
| Exenatide | Insulin Sensitivity at Baseline and 6 Months | M/I 6 Months | 0.3 ((mg/kg) /min) /uU/mL | Standard Error 0.1 |
| Sitagliptin | Insulin Sensitivity at Baseline and 6 Months | M/I Baseline | 0.3 ((mg/kg) /min) /uU/mL | Standard Error 0 |
| Sitagliptin | Insulin Sensitivity at Baseline and 6 Months | M/I 6 Months | 0.3 ((mg/kg) /min) /uU/mL | Standard Error 0.1 |
| Glimepiride | Insulin Sensitivity at Baseline and 6 Months | M/I Baseline | 0.3 ((mg/kg) /min) /uU/mL | Standard Error 0.1 |
| Glimepiride | Insulin Sensitivity at Baseline and 6 Months | M/I 6 Months | 0.3 ((mg/kg) /min) /uU/mL | Standard Error 0.1 |
Comparison: To determine if exenatide or sitagliptin induced significant changes from baseline, the change for each measure (Δ = final - baseline) for each group was compared with the change in the glimepiride group using independent Student t testsp-value: >0.1t-test, 1 sided
Secondary
PG 50 (the Plasma Glucose Level at Which Half-maximal Insulin Secretion is Achieved During the Glucose-potentiated Arginine Test) at Baseline and 6 Months
Between ∼60 and 250 mg/dL, the magnitude of AIRarg is a linear function of the plasma glucose level, so the difference in AIRarg at fasting and 230 mg/dL glucose levels divided by the difference in plasma glucose (ΔAIRarg/ΔPG) gives the glucose-potentiation slope (GPS) (8,24-26). Using the y-intercept (b) from the line created by these two points, the plasma glucose level at which half-maximal insulin secretion is achieved (PG50) is derived from solving the equation 1/2 (AIRmax) = (GPS · PG50) + b, and provides a measure of β-cell sensitivity to glucose The mean difference after 6 months in PG 50 were compared. Listed below are the PG50 values at baseline and 6 months.
Time frame: Baseline and 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide | PG 50 (the Plasma Glucose Level at Which Half-maximal Insulin Secretion is Achieved During the Glucose-potentiated Arginine Test) at Baseline and 6 Months | PG50 Baseline | 175 mg/dL | Standard Error 13 |
| Exenatide | PG 50 (the Plasma Glucose Level at Which Half-maximal Insulin Secretion is Achieved During the Glucose-potentiated Arginine Test) at Baseline and 6 Months | PG50 6 Months | 190 mg/dL | Standard Error 14 |
| Sitagliptin | PG 50 (the Plasma Glucose Level at Which Half-maximal Insulin Secretion is Achieved During the Glucose-potentiated Arginine Test) at Baseline and 6 Months | PG50 Baseline | 226 mg/dL | Standard Error 12 |
| Sitagliptin | PG 50 (the Plasma Glucose Level at Which Half-maximal Insulin Secretion is Achieved During the Glucose-potentiated Arginine Test) at Baseline and 6 Months | PG50 6 Months | 209 mg/dL | Standard Error 16 |
| Glimepiride | PG 50 (the Plasma Glucose Level at Which Half-maximal Insulin Secretion is Achieved During the Glucose-potentiated Arginine Test) at Baseline and 6 Months | PG50 Baseline | 168 mg/dL | Standard Error 17 |
| Glimepiride | PG 50 (the Plasma Glucose Level at Which Half-maximal Insulin Secretion is Achieved During the Glucose-potentiated Arginine Test) at Baseline and 6 Months | PG50 6 Months | 182 mg/dL | Standard Error 10 |
p-value: >0.1t-test, 1 sided