Diabetes
Conditions
Keywords
Diabetes
Brief summary
In patients with type 2 diabetes with inadequate glycemic control on diet and exercise after 6 weeks of treatment: Objective: To assess the effects of co-administration of sitagliptin and metformin compared to placebo on hepatic glucose production (HGP). Hypothesis: After 6 weeks of treatment, the co-administration of sitagliptin and metformin provides greater reduction in hepatic glucose production (HGP) compared to placebo.
Detailed description
PRIMARY: In patients with type 2 diabetes with inadequate glycemic control on diet and exercise after 6 weeks of treatment: Objective: To assess the effects of co-administration of sitagliptin and metformin compared to placebo on hepatic glucose production (HGP). Hypothesis: After 6 weeks of treatment, the co-administration of sitagliptin and metformin provides greater reduction in hepatic glucose production (HGP) compared to placebo. SECONDARY: In patients with type 2 diabetes with inadequate glycemic control on diet and exercise after 6 weeks of treatment: 1. Objective: To assess the effects of co-administration of sitagliptin and metformin compared to placebo on post-meal glucose during meal tolerance test (MTT). Hypothesis: After 6 weeks of treatment the co-administration of sitagliptin and metformin provides greater reduction in the total glucose AUC (0-6 hr) during MTT compared to placebo. 2. Objective: To assess the effects of co-administration of sitagliptin and metformin compared to placebo on fasting plasma glucose (FPG). Hypothesis: After 6 weeks of treatment the co-administration of sitagliptin and metformin provides greater reduction in FPG compared to placebo. 3. Objective: To assess the effects sitagliptin alone compared to placebo on HGP. Hypothesis: After 6 weeks of treatment, sitagliptin alone provides greater reduction in HGP compared to placebo EXPLORATORY OBJECTIVES: (i) Objective: after 6 weeks of treatment, to assess the effects co-administration of sitagliptin and metformin compared to placebo on: 1. active and inactive incretin concentrations (fasting and post-meal GLP-1 and fasting and post-meal GIP). 2. glucagon concentration (fasting and post-meal). 3. parameters of insulin secretion and insulin sensitivity. 4. splanchnic glucose uptake. (ii) Objective: after 6 weeks of treatment, to assess the effects co-administration of sitagliptin and metformin compared to treatment with sitagliptin alone and metformin alone on: 5. glucose concentration (fasting and total glucose AUC \[0-6 hr\]). 6. active and inactive incretin concentrations (fasting and post-meal GLP-1 and fasting and post-meal GIP). 7. glucagon concentration (fasting and post-meal). 8. parameters of insulin secretion and insulin sensitivity. 9. HGP. 10. splanchnic glucose uptake. (iii) Objective: after 6 weeks of treatment, to assess the effects of sitagliptin alone and metformin alone compared to placebo on: 11. glucose concentration (fasting and total glucose AUC \[0-6 hr\]). 12. active and inactive incretin concentrations (fasting and post-meal GLP-1 and fasting and post-meal GIP). 13. glucagon concentration (fasting and post-meal). 14. parameters of insulin secretion and insulin sensitivity. 15. HGP. 16. splanchnic glucose uptake.
Interventions
tablet, Sitagliptin (100mg/day) + tablet, Metformin (1000 mg/bid), 6 weeks
DRUGSitagliptin
tablet, 100 mg/day, 6 weeks
DRUGMetformin
tablet, 1000 mg/ bid, 6 weeks
DRUGPlacebo
Placebo 6 weeks
Sponsors
The University of Texas Health Science Center at San Antonio
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Patients must meet all of the following inclusion criteria to participate in the study. * Patients with screening values/findings outside ranges described in the protocol may have one repeat determination performed and if the repeat value satisfies the criterion, they may continue in the screening process. * If the repeat value does not satisfy the criterion, the principal investigator will review the abnormal laboratory value and decide whether the subject may continue in the screening process. * All screening laboratory measurements are to be performed after an overnight fast ≥10 hours in duration. * Patients must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent. * Patients can be either male or female. * Patients are ≥18 and ≤70 years of age on the day of signing informed consent. * Patients must meet the current American Diabetes Association criteria for the diagnosis of type 2 diabetes mellitus * Patients must be on diet or diet plus exercise therapy. * Patients must have a HbA1c ≥ 7.5% and ≤ 9.5% * Patients must have a BMI of 23-40 kg/m2 * Patients must have the following laboratory values: * Hematocrit Males ≥ 34 vol% * Females ≥ 33vol% * Serum creatinine ≤ 1.5 mg/dL in males and ≤ 1.4 mg/dL in females * AST (SGOT): ≤ 2.5 times upper limit of normal * ALT (SGPT): ≤ 2.5 times upper limit of normal * Alkaline phosphatase ≤ 2.5 times upper limit of normal * If serum creatinine is \> 1.5 mg/dl in males and \> 1.4 mg/dl in females, the Principal Investigator can include the patient if the measured GFR is \>70 ml/min (24 hour creatinine clearance) * Patients must have been on a stable dose of allowed chronic medications for ≥30 days prior to entering the study. * Only patients whose body weight has been stable (±4 pounds) over the three months prior to the study will be included.
Exclusion criteria
* Patients are excluded from participation in the study if they meet any of the following criteria: * Patient has type 1 diabetes. * Patient has received insulin for more than one week within the previous year prior to entry. * Patient has been treated with exenatide or a non-TZD, oral antihyperglycemic agent within the last 2 months or with a TZD (pioglitazone or rosiglitazone) within the last 4 months. * Patient is receiving any medications with known adverse effects on glucose tolerance (e.g., systemic glucocorticoids, psychotropic drugs like clozapine, olanzapine, haloperidol, risperidone). Note: Patients may be taking stable doses of estrogens, other hormonal replacement therapy, or lipid and blood pressure lowering agents if the patient has been on these agents for the prior three months. * Patient has evidence of a significant cardiovascular disorder within 6 months of signing informed consent (e.g. acute coronary syndrome, coronary artery intervention, stroke or transient ischemic neurological disorder) or has New York Heart Association Classification greater than Class 2; or has significant findings on ECG (other than non-specific ST-T wave changes); or peripheral vascular disease (history of claudication); or has dyspnea on exertion of one flight or less, or abnormal breath sounds on auscultation. * Patient has a history of intolerance or hypersensitivity to a DPP-4 inhibitor or to metformin. * Patient is pregnant or plans to become pregnant within the projected duration of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective: Comparisons of the Effects of Co-administration of Sitagliptin and Metformin Alone or in Combination Versus Placebo on Baseline Endogenous Glucose Production (EGP). | 6 weeks | Baseline endogenous glucose production prior to a mixed meal tolerance test (placebo) and following 6 weeks of either sitagliptin, metformin or sitagliptin plus metformin combination therapy in all 16 participants |
| Average of Plasma Glucose During Mixed Meal Tolerance Test (MTT) Compared to Baseline Plasma Glucose to Post Therapy (6-weeks). | 6 weeks | The degree of suppression of baseline endogenous glucose production was measured in absolute values and as a percent of basal values at the end of each 6-week therapeutic period. The absolute values obtained in each sequence study group (both basal and post-meal) were compared amongst all groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Plasma Glucose 6 Weeks After Therapy | 6 weeks | Basal pasma glucose was determined with the glucose oxidase method after each specific 6 week treatment. The absolute values obtained of basal plasma glucose at the end of each 6-week therapeutic period in each sequence study group (both basal and post-meal) were compared amongst all groups. |
| Changes in Plasma Glucose Post-MTT After Each Six Weeks of Therapy Compared to Baseline | 360 min | The absolute values of mean plasma glucose post-meal (360 minutes)were determined after each specific 6 week treatment and these absolute values after each specific sequence therapy were compared amongst all groups. |
Countries
United States
Participant flow
Recruitment details
Texas Diabetes Institute from March 2010 July 2011
Pre-assignment details
A 4 week washout period for those subjects on oral anti-diabetic therapy with sulfonylureas was used in 7 subjects
Participants by arm
| Arm | Count |
|---|---|
| Placebo all subjects after 6 weeks of placebo therapy | 4 |
| Metformin all subjects after receiving 6 weeks of metformin therapy | 4 |
| Sitagliptin all subjects after receiving 6 weeks of sitagliptin therapy | 4 |
| Metformin Plus Sitagliptin all subjects after receiving 6 weeks of combined sitagliptin plus metformin therpay | 4 |
| Total | 16 |
Baseline characteristics
| Characteristic | Placebo | Metformin | Sitagliptin | Metformin Plus Sitagliptin | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 16 Participants |
| Region of Enrollment United States | 4 participants | 4 participants | 4 participants | 4 participants | 16 participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 3 Participants | 2 Participants | 10 Participants |
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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 16 |
Outcome results
Primary
Average of Plasma Glucose During Mixed Meal Tolerance Test (MTT) Compared to Baseline Plasma Glucose to Post Therapy (6-weeks).
The degree of suppression of baseline endogenous glucose production was measured in absolute values and as a percent of basal values at the end of each 6-week therapeutic period. The absolute values obtained in each sequence study group (both basal and post-meal) were compared amongst all groups.
Time frame: 6 weeks
Population: power calculations with data from previous similar studies
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Average of Plasma Glucose During Mixed Meal Tolerance Test (MTT) Compared to Baseline Plasma Glucose to Post Therapy (6-weeks). | 1.8 mg/kg.min | Standard Error 0.2 |
| Metformin | Average of Plasma Glucose During Mixed Meal Tolerance Test (MTT) Compared to Baseline Plasma Glucose to Post Therapy (6-weeks). | 1.6 mg/kg.min | Standard Error 0.2 |
| Sitagliptin | Average of Plasma Glucose During Mixed Meal Tolerance Test (MTT) Compared to Baseline Plasma Glucose to Post Therapy (6-weeks). | 1.7 mg/kg.min | Standard Error 0.2 |
| Sitagliptin Plus Metformin | Average of Plasma Glucose During Mixed Meal Tolerance Test (MTT) Compared to Baseline Plasma Glucose to Post Therapy (6-weeks). | 1.5 mg/kg.min | Standard Error 0.2 |
Comparison: ANOVAp-value: 0.05ANOVA
Primary
Objective: Comparisons of the Effects of Co-administration of Sitagliptin and Metformin Alone or in Combination Versus Placebo on Baseline Endogenous Glucose Production (EGP).
Baseline endogenous glucose production prior to a mixed meal tolerance test (placebo) and following 6 weeks of either sitagliptin, metformin or sitagliptin plus metformin combination therapy in all 16 participants
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Objective: Comparisons of the Effects of Co-administration of Sitagliptin and Metformin Alone or in Combination Versus Placebo on Baseline Endogenous Glucose Production (EGP). | 2.0 mg/kg.min | Standard Error 0.2 |
| Metformin | Objective: Comparisons of the Effects of Co-administration of Sitagliptin and Metformin Alone or in Combination Versus Placebo on Baseline Endogenous Glucose Production (EGP). | 1.8 mg/kg.min | Standard Error 0.2 |
| Sitagliptin | Objective: Comparisons of the Effects of Co-administration of Sitagliptin and Metformin Alone or in Combination Versus Placebo on Baseline Endogenous Glucose Production (EGP). | 1.7 mg/kg.min | Standard Error 0.2 |
| Sitagliptin Plus Metformin | Objective: Comparisons of the Effects of Co-administration of Sitagliptin and Metformin Alone or in Combination Versus Placebo on Baseline Endogenous Glucose Production (EGP). | 1.5 mg/kg.min | Standard Error 0.1 |
Comparison: A general unstructured variance-covariance matrix (ANOVA) was applied for measurements at different periods. Between-group comparisons after 6 wks of treatment were assessed using the ANOVA model at alpha=0.05 (two-sided).~16 subjects provide \~90% power to detect difference in EGP of 0.28 mg/kg.min (95% CI = 0.17 mg/kg.min).p-value: <0.05ANOVA
Secondary
Changes in Plasma Glucose Post-MTT After Each Six Weeks of Therapy Compared to Baseline
The absolute values of mean plasma glucose post-meal (360 minutes)were determined after each specific 6 week treatment and these absolute values after each specific sequence therapy were compared amongst all groups.
Time frame: 360 min
Population: power calculation based on previous data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Changes in Plasma Glucose Post-MTT After Each Six Weeks of Therapy Compared to Baseline | 205 mg/dl | Standard Error 5 |
| Metformin | Changes in Plasma Glucose Post-MTT After Each Six Weeks of Therapy Compared to Baseline | 191 mg/dl | Standard Error 4 |
| Sitagliptin | Changes in Plasma Glucose Post-MTT After Each Six Weeks of Therapy Compared to Baseline | 195 mg/dl | Standard Error 4 |
| Sitagliptin Plus Metformin | Changes in Plasma Glucose Post-MTT After Each Six Weeks of Therapy Compared to Baseline | 161 mg/dl | Standard Error 3 |
p-value: 0.05ANOVA
Secondary
Fasting Plasma Glucose 6 Weeks After Therapy
Basal pasma glucose was determined with the glucose oxidase method after each specific 6 week treatment. The absolute values obtained of basal plasma glucose at the end of each 6-week therapeutic period in each sequence study group (both basal and post-meal) were compared amongst all groups.
Time frame: 6 weeks
Population: All 16 participants were analyzed using ANOVA to compare results after each 6 week period of exposure to therapeutic agent(s)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Fasting Plasma Glucose 6 Weeks After Therapy | 160 mg/dl | Standard Error 4 |
| Metformin | Fasting Plasma Glucose 6 Weeks After Therapy | 145 mg/dl | Standard Error 5 |
| Sitagliptin | Fasting Plasma Glucose 6 Weeks After Therapy | 150 mg/dl | Standard Error 4 |
| Sitagliptin Plus Metformin | Fasting Plasma Glucose 6 Weeks After Therapy | 120 mg/dl | Standard Error 6 |
Comparison: multivariate analysis was performed to compare results amongst all four groupsp-value: <0.05ANOVA