Diabetes Mellitus, Type 2
Conditions
Brief summary
This study is being done to compare the effectiveness and safety of two treatment paradigms (oral sitagliptin with or without glimepiride versus liraglutide with or without increased dosing) for the treatment of participants with Type 2 Diabetes that is not adequately controlled with metformin alone. The primary hypothesis postulated that the mean change from baseline in hemoglobin A1c (A1C) in participants treated with a sitagliptin-based treatment is non-inferior to that of participants treated with a liraglutide-based treatment.
Interventions
DRUGsitagliptin
100 mg tablet, orally, once daily.
DRUGliraglutide
0.6 mg by subcutaneous (pen) injection, once daily, on Days 1-7; up-titrated on Day 8 to 1.2 mg daily. At Week 12, dose may be increased to 1.8 mg once daily for participants who did not meet protocol-specified glycemic goals.
DRUGglimepiride
starting dose of 1 mg tablet (up-titrated as needed), once daily, as needed, after Week 12.
DRUGmetformin
metformin tablets at a dose of ≥1500 mg per day
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes mellitus. * On stable dose of metformin monotherapy at a dose of at least 1500 mg per day for at least 12 weeks and a hemoglobin A1C ≥7.0% and ≤11.0%. * Capable of using a liraglutide pen device.
Exclusion criteria
* History of Type 1 Diabetes mellitus. * Use of any oral antihyperglycemic agent (AHA) besides metformin, within the prior 12 weeks of screening. * Cardiovascular disorders within the past 3 months including acute coronary syndrome or new or worsening symptoms of coronary heart disease, coronary artery intervention, stroke, or transient ischemic neurological disorder. * Impaired liver function. * Impaired kidney function. * History of malignancy or clinically important hematological disorder that requires disease-specific treatment (chemotherapy, radiation therapy, surgery) or, in the opinion of the investigator, is likely to recur during the duration of the study. * History of leukemia, lymphoma, aplastic anemia, myeloproliferative or myelodysplastic diseases, thrombocytopenia, or malignant melanoma, regardless of the time since treatment. * Pregnancy or breastfeeding, or intention to become pregnant or donate eggs within the projected duration of the study. * Participation in another study with an investigational drug or device within 12 weeks prior to screening. * History of hypersensitivity or any contraindication to sitagliptin, liraglutide, glimepiride, or metformin based upon the labels of the country of the investigational site. * Participation in a weight loss program and not yet in maintenance phase, or starting of a weight loss medication (such as orlistat or phentermine) within the prior 8 weeks. * Surgery within the prior 4 weeks or major surgery planned during the study. * Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2). * User of recreational or illicit drugs or recent history (within the last year) of drug abuse or increased alcohol consumption.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1c (A1C) | Baseline and Week 26 | A1C is measured as percent. Thus, this change from baseline reflects the Week 26 A1C percent minus the Week 0 A1C percent. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Plasma Glucose (FPG) | Baseline and Week 26 | Change from baseline at Week 26 is defined as Week 26 minus Week 0. |
| Percentage of Participants Reaching A1C Goal of <7.0% | Week 26 | — |
| Percentage of Participants Reaching A1C Goal of <6.5% | Week 26 | — |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin +/- Glimepiride Sitagliptin 100 mg tablet once daily for 26 weeks. Participants continued their stable dose of metformin \>=1500 mg orally daily. Participants may have received glimepiride for glycemic control. | 326 |
| Liraglutide Liraglutide subcutaneous injection once daily for 26 weeks (starting dose 0.6 mg daily up-titrated to 1.2 mg daily on Day 8). Participants continued their stable dose of metformin \>=1500 mg orally daily. Participants may have had their liraglutide dose uptitrated to 1.8 mg daily for glycemic control. | 327 |
| Total | 653 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 29 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost to Follow-up | 10 | 7 |
| Overall Study | Non-compliance with study drug | 1 | 2 |
| Overall Study | Other reason not specified | 20 | 15 |
| Overall Study | Physician Decision | 1 | 3 |
| Overall Study | Pregnancy | 0 | 1 |
| Overall Study | Withdrawal by Subject | 10 | 13 |
Baseline characteristics
| Characteristic | Sitagliptin +/- Glimepiride | Liraglutide | Total |
|---|---|---|---|
| Age, Continuous | 56.9 years STANDARD_DEVIATION 10 | 57.6 years STANDARD_DEVIATION 10.8 | 57.3 years STANDARD_DEVIATION 10.4 |
| Fasting Plasma Glucose | 174.1 mg/dL STANDARD_DEVIATION 43.7 | 172.9 mg/dL STANDARD_DEVIATION 40.8 | 173.5 mg/dL STANDARD_DEVIATION 42.3 |
| Hemoglobin A1c (A1C) | 8.2 Percent STANDARD_DEVIATION 1.1 | 8.1 Percent STANDARD_DEVIATION 0.9 | 8.2 Percent STANDARD_DEVIATION 1 |
| Sex: Female, Male Female | 148 Participants | 147 Participants | 295 Participants |
| Sex: Female, Male Male | 178 Participants | 180 Participants | 358 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 58 / 326 | 97 / 324 |
| serious Total, serious adverse events | 17 / 326 | 12 / 324 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1c (A1C)
A1C is measured as percent. Thus, this change from baseline reflects the Week 26 A1C percent minus the Week 0 A1C percent.
Time frame: Baseline and Week 26
Population: Per-protocol population defined as participants who had a measurement at baseline and a measurement after at least 24 weeks (i.e., 168 days) of treatment, and did not have any major protocol violations.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin +/- Glimepiride | Change From Baseline in Hemoglobin A1c (A1C) | -1.32 percent | 95% Confidence Interval 1.06 |
| Liraglutide | Change From Baseline in Hemoglobin A1c (A1C) | -1.42 percent | 95% Confidence Interval 1.04 |
95% CI: [-0.05, 0.23]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG)
Change from baseline at Week 26 is defined as Week 26 minus Week 0.
Time frame: Baseline and Week 26
Population: Per-protocol population defined as participants who had a measurement at baseline and a measurement after at least 24 weeks (i.e., 168 days) of treatment, and did not have any major protocol violations.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin +/- Glimepiride | Change From Baseline in Fasting Plasma Glucose (FPG) | -33.7 mg/dL | 95% Confidence Interval 46.2 |
| Liraglutide | Change From Baseline in Fasting Plasma Glucose (FPG) | -39.6 mg/dL | 95% Confidence Interval 40.3 |
95% CI: [0.5, 11.4]ANCOVA
Secondary
Percentage of Participants Reaching A1C Goal of <6.5%
Time frame: Week 26
Population: Per-protocol population defined as participants who had a measurement at baseline and a measurement after at least 24 weeks (i.e., 168 days) of treatment, and did not have any major protocol violations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin +/- Glimepiride | Percentage of Participants Reaching A1C Goal of <6.5% | 33.8 percentage of participants |
| Liraglutide | Percentage of Participants Reaching A1C Goal of <6.5% | 38.3 percentage of participants |
95% CI: [-12.7, 3.7]Miettinen & Nurminen
Secondary
Percentage of Participants Reaching A1C Goal of <7.0%
Time frame: Week 26
Population: Per-protocol population defined as participants who had a measurement at baseline and a measurement after at least 24 weeks (i.e., 168 days) of treatment, and did not have any major protocol violations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin +/- Glimepiride | Percentage of Participants Reaching A1C Goal of <7.0% | 62.8 percentage of participants |
| Liraglutide | Percentage of Participants Reaching A1C Goal of <7.0% | 72.3 percentage of participants |
95% CI: [-17.4, -1.5]Miettinen & Nurminen