Type 2 Diabetes Mellitus
Conditions
Brief summary
This study will assess the effects of sitagliptin and metformin alone and after co-administration on incretin hormone concentrations in patients with Type 2 diabetes.
Interventions
DRUGsitagliptin phosphate
Sitagliptin 100 mg tablet on Day 1 and Day 2 in the morning. There will be a 7-day washout between treatment periods.
DRUGmetformin hydrochloride
Metformin 500 mg tablet in the morning and evening on Day 1 and two 500 mg tablets of metformin (total dose 1000 mg) on Day 2 in the morning. There will be a 7-day washout between treatment periods.
DRUGComparator: placebo sitagliptin
Placebo to sitagliptin 100 mg in the morning on Days 1 and 2. There will be a 7-day washout between treatment periods.
DRUGComparator: placebo metformin
Placebo to metformin 500 mg tablet in the morning and evening on Day 1 and two placebo to metformin 500 mg tablets (1000 mg total dose) in the morning of Day 2. There will be a 7-day wash out between treatment periods.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Female subjects must have a negative pregnancy test * Subject has type 2 diabetes and is not currently receiving treatment with an oral AHA agent, has not received such treatment for 3 months prior to study, and/or has not received more than 4 total weeks treatment with an oral AHA agent for 12 to 18 months prior to the study * Subject is a nonsmoker or has not smoked and/or used nicotine for at least 6 months
Exclusion criteria
* Subject has a history of stroke, seizures, or major neurological disorders * Female subject is breastfeeding * Subject cannot refrain from use of any prescription or non-prescription drugs beginning 2 weeks prior to first dose of study drug * Subject consumes more than 3 alcoholic beverages per day * Subject consumes more than 6 caffeinated beverages per day * Subject has had major surgery, or has donated or lost 1 unit of blood within 4 weeks of screening * Subject has a history of cancer, except certain skin or cervical cancer or other cancers treated more than 10 years prior to screening * Subject has a history of multiple and/or severe allergies or intolerance to drugs or food
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incremental Post-prandial 4-hour Weighted Mean Active Glucagon-like Peptide-1 (GLP-1) Plasma Concentrations | 6 hours postdose (4 hours postmeal) on Day 2 | Meal was given 2 hours postdose. Blood samples for determination of active GLP-1 concentration were collected (4 hours postmeal) on Day 2 in each treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| β-cell Sensitivity | 6 hour post-dose (4 hour postmeal) on Day 2 | β-cell sensitivity was defined as the incremental post-prandial 4-hour area under the curve (AUC) for insulin secretion rate (ISR) normalized by the incremental post-prandial 4-hour plasma glucose AUC. |
| Incremental Post-prandial 4-hour Weighted Mean Plasma Glucose Concentrations | 6 hours postdose (4 hours postmeal) on Day 2 | Meal was given 2 hours postdose. Blood samples for determination of glucose concentration were collected (4 hours postmeal) on Day 2 in each treatment period. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants Participants received four 2-day treatment regimens (sitagliptin + placebo metformin for 2 days, metformin + placebo sitagliptin for 2 days, co-administration of sitagliptin + metformin for 2 days, and placebo sitagliptin + placebo metformin for 2 days) with a 7-day washout between each treatment period. | 18 |
| Total | 18 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants |
| Region of Enrollment United States | 18 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 13 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 | 4 / 18 | 3 / 18 | 3 / 18 | 4 / 18 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 | 0 / 18 | 0 / 18 |
Outcome results
Primary
Incremental Post-prandial 4-hour Weighted Mean Active Glucagon-like Peptide-1 (GLP-1) Plasma Concentrations
Meal was given 2 hours postdose. Blood samples for determination of active GLP-1 concentration were collected (4 hours postmeal) on Day 2 in each treatment period.
Time frame: 6 hours postdose (4 hours postmeal) on Day 2
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| All Participants | Incremental Post-prandial 4-hour Weighted Mean Active Glucagon-like Peptide-1 (GLP-1) Plasma Concentrations | Sitagliptin + placebo metformin | 6.00 picomolar |
| All Participants | Incremental Post-prandial 4-hour Weighted Mean Active Glucagon-like Peptide-1 (GLP-1) Plasma Concentrations | Metformin + placebo sitagliptin | 4.09 picomolar |
| All Participants | Incremental Post-prandial 4-hour Weighted Mean Active Glucagon-like Peptide-1 (GLP-1) Plasma Concentrations | Sitagliptin + metformin | 7.22 picomolar |
| All Participants | Incremental Post-prandial 4-hour Weighted Mean Active Glucagon-like Peptide-1 (GLP-1) Plasma Concentrations | Placebo sitagliptin + placebo metformin | 1.55 picomolar |
Secondary
Incremental Post-prandial 4-hour Weighted Mean Plasma Glucose Concentrations
Meal was given 2 hours postdose. Blood samples for determination of glucose concentration were collected (4 hours postmeal) on Day 2 in each treatment period.
Time frame: 6 hours postdose (4 hours postmeal) on Day 2
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| All Participants | Incremental Post-prandial 4-hour Weighted Mean Plasma Glucose Concentrations | Sitagliptin + metformin | 20.02 mg/dL |
| All Participants | Incremental Post-prandial 4-hour Weighted Mean Plasma Glucose Concentrations | Sitagliptin + placebo metformin | 42.30 mg/dL |
| All Participants | Incremental Post-prandial 4-hour Weighted Mean Plasma Glucose Concentrations | Metformin + placebo sitagliptin | 29.33 mg/dL |
| All Participants | Incremental Post-prandial 4-hour Weighted Mean Plasma Glucose Concentrations | Placebo sitagliptin + placebo metformin | 51.02 mg/dL |
Secondary
β-cell Sensitivity
β-cell sensitivity was defined as the incremental post-prandial 4-hour area under the curve (AUC) for insulin secretion rate (ISR) normalized by the incremental post-prandial 4-hour plasma glucose AUC.
Time frame: 6 hour post-dose (4 hour postmeal) on Day 2
Population: Beta-cell sensitivity was not calculated for 1 participant following the administration of sitagliptin alone and metformin alone due to missing insulin data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| All Participants | β-cell Sensitivity | Sitagliptin + placebo metformin, n=17 | 19.50 (ng/min)/(mg/dL)*10^ -3 |
| All Participants | β-cell Sensitivity | Metformin + placebo sitagliptin, n=17 | 25.71 (ng/min)/(mg/dL)*10^ -3 |
| All Participants | β-cell Sensitivity | Sitagliptin + metformin, n=18 | 26.39 (ng/min)/(mg/dL)*10^ -3 |
| All Participants | β-cell Sensitivity | Placebo sitagliptin + placebo metformin, n=18 | 15.44 (ng/min)/(mg/dL)*10^ -3 |