Type 2 Diabetes Mellitus
Conditions
Keywords
Diabetes Mellitus, Drug Therapy, Hyperinsulinism, Hyperglycemia, Glucose Intolerance
Brief summary
The purpose of this study is to determine the safety and effectiveness of adding alogliptin, once daily (QD), compared to glipizide with metformin in diabetic patients.
Detailed description
For patients diagnosed with type 2 diabetes mellitus, metformin is the usual first-line therapy in addition to diet control and exercise. For those patients with inadequate glycemic control with metformin monotherapy or experiencing serious side effects of metformin, sulfonylurea is a popular choice as a second-line oral antidiabetic treatment. Alogliptin is a dipeptidyl peptidase-4 inhibitor currently being developed by Takeda for use in patients with type 2 diabetes mellitus. This study is designed to further explore the durability of efficacy and safety of alogliptin compared to glipizide in type 2 diabetes mellitus patients whose blood sugar level is inadequately controlled with metformin therapy. The duration of this study will be approximately 2 years.
Interventions
DRUGAlogliptin
Alogliptin tablets
DRUGMetformin
Metformin tablets
DRUGGlipizide
Glipizide tablets
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Has a diagnosis of type 2 diabetes mellitus. * Must meet one of the following: * Has been inadequately controlled on a stable daily dose of ≥1500 mg (or documented maximum tolerated dose) of metformin for at least 2 months prior to Screening. * Has been inadequately controlled (as defined by a glycosylated hemoglobin 7.5 - 10%, inclusive) on metformin \<1500 mg without documented maximum tolerated dose. * No treatment with antidiabetic agents other than metformin within 2 months prior to Screening (for Schedule A)/Pre-Screening (for Schedule B). * Has body mass index within 23 kg/m\^2 and 45 kg/m\^2 unless the patient is Asian or of Asian descent, for whom the allowable body mass index will be ≥ 20 kg/m\^2 and ≤ 35 kg/m\^2, inclusive. * Has fasting C-peptide concentration at least 0.8 ng. * If regularly using non-excluded medications, must be on a stable dose at least 4 weeks prior to Screening/Pre-screening. * Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant, lactating or intends to donate ova from Screening throughout the duration of the study. * Must be able and willing to monitor their blood glucose concentrations with a home monitor, and comply with protocol requirements including scheduled clinic appointments.
Exclusion criteria
* Systolic blood pressure greater than or equal to 150 mmHg and/or diastolic pressure greater than or equal to 90. * Hemoglobin less than or equal to 12 g/dL for males and less than or equal to 10 g/dL for females at Screening Visit. * Alanine aminotransferase greater than or equal to 2.5 times the upper limit of normal at Screening Visit. * Serum creatinine greater than or equal to 1.5 mg/dL for males and 1.4 for females, or calculated creatinine clearance less than 60 L/min. * Males intending to impregnate others or donate sperm before, during or within 1 month after participating in the study. * A history of cancer other than squamous or basal cell carcinoma of the skin that has not been in full remission for at least 5 years. * A history of laser treatment for diabetic retinopathy within 6 months of screening. * Treated for diabetic gastric paresis, gastric banding, or gastric bypass. * New York Heart Association Class III or IV heart failure. * History of coronary angioplasty, coronary stent placement, coronary bypass surgery, myocardial infarction, stroke or transient ischemic attack within 3 months prior to screening. * Known history of human immunodeficiency virus, hepatitis B or C. * Alcohol or substance abuse within 2 years prior to screening. * Is required to take or intends to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including: * Any investigational drug within 30 days * Any investigational diabetic drug within 3 months * Any antidiabetic drug in the dipeptidyl peptidase-4 inhibitors or glucagon-like peptide-1 mimetics classes within 90 days prior to Screening other than metformin * Prior treatment with alogliptin. * Weight-loss drugs * Oral or systemically injected glucocorticoids * A hypersensitivity allergy or anaphylactic reaction to any dipeptidyl peptidase-4 drug, metformin or glipizide. * Has a documented history or concurrent signs of significant thyroid disease (eg, autoimmune thyroid diseases such as Graves disease and Hashimoto thyroiditis or active thyroid nodules).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 52 | Baseline and Week 52 | The change from Baseline to Week 52 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound). The least squares (LS) means are from an analysis of covariance (ANCOVA) model with treatment, study schedule, and geographic region as class variables, and Baseline metformin dose and Baseline HbA1c as covariates. |
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 104 | Baseline and Week 104 | The change from Baseline to Week 104 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound). The least squares (LS) means are from an analysis of covariance (ANCOVA) model with treatment, study schedule, and geographic region as class variables, and Baseline metformin dose and Baseline HbA1c as covariates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5% | Weeks 26, 52, 78, and 104. | The percentage of participants with HbA1c less than or equal to 6.5% at Weeks 26, 52, 78, and 104. Participants who did not complete the scheduled Week 104 visit were assessed based on their response at the time of discontinuation. |
| Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Baseline and Weeks 4, 8, 12, 16, 20, 26, 39, 65, 78, and 91. | The change from Baseline over time in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound). LS means are from an ANCOVA model with treatment, study schedule, and geographic region as class variables, and Baseline metformin dose and Baseline HbA1c as covariates. |
| Change From Baseline in Body Weight Over Time | Baseline and Weeks 12, 26, 39, 52, 65, 78, 91, and 104. | LS Means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and Baseline weight and Baseline metformin dose as covariates. |
| Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0% | Weeks 26, 52, 78, and 104. | Percentage of participants with HbA1c ≤ 7.0% at Weeks 26, 52, 78, and 104. Participants who did not complete the scheduled Week 104 visit were assessed based on their response at the time of discontinuation. |
| Change From Baseline in Fasting Plasma Glucose Over Time | Baseline and Weeks 2, 4, 8, 12, 16, 20, 26, 39, 52, 65, 78, 91, and 104. | The change from Baseline in fasting plasma glucose (FPG) was assessed at Weeks 2, 4, 8, 12, 16, 20, 26, 39, 52, 65, 78, 91, and 104. LS means are from an ANCOVA model with treatment, study schedule, and geographic region as class variables, and Baseline FPG and Baseline metformin dose as covariates. |
Countries
Argentina, Australia, Austria, Brazil, Canada, Chile, Germany, Guatemala, Hong Kong, Hungary, India, Israel, Italy, Latvia, Lithuania, Malaysia, Mexico, New Zealand, Peru, Philippines, Poland, Puerto Rico, Romania, Russia, Singapore, South Africa, South Korea, Spain, Thailand, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 310 study sites worldwide from 05 March 2009 to 17 October 2012.
Pre-assignment details
Participants with type 2 diabetes mellitus experiencing inadequate glycemic control while on metformin therapy were enrolled equally in 1 of 3 treatment groups: alogliptin 12.5 mg once daily (QD), alogliptin 25 mg QD, and glipizide 5 mg QD.
Participants by arm
| Arm | Count |
|---|---|
| Metformin + Alogliptin 12.5 mg Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. | 880 |
| Metformin + Alogliptin 25 mg Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. | 885 |
| Metformin + Glipizide Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks. After at least 2 weeks of treatment but prior to Week 20, participants with persistent hyperglycemia (fasting plasma glucose ≥250 mg/dL) underwent a dose titration of glipizide up to 20 mg in 5-mg increments in 4-week intervals. | 874 |
| Total | 2,639 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 60 | 74 | 82 |
| Overall Study | Hyperglycemic rescue | 231 | 201 | 235 |
| Overall Study | Investigator discretion | 9 | 8 | 10 |
| Overall Study | Lost to Follow-up | 20 | 22 | 28 |
| Overall Study | Major protocol deviation | 24 | 16 | 15 |
| Overall Study | Other | 15 | 17 | 14 |
| Overall Study | Pregnancy | 1 | 2 | 0 |
| Overall Study | Randomized in error | 0 | 0 | 1 |
| Overall Study | Voluntary withdrawal | 48 | 52 | 62 |
Baseline characteristics
| Characteristic | Metformin + Alogliptin 12.5 mg | Metformin + Alogliptin 25 mg | Metformin + Glipizide | Total |
|---|---|---|---|---|
| Age Continuous | 55.2 years STANDARD_DEVIATION 9.6 | 55.5 years STANDARD_DEVIATION 9.81 | 55.4 years STANDARD_DEVIATION 9.6 | 55.4 years STANDARD_DEVIATION 9.67 |
| Age, Customized <65 years | 734 participants | 710 participants | 723 participants | 2167 participants |
| Age, Customized ≥65 years | 146 participants | 175 participants | 151 participants | 472 participants |
| Age, Customized ≥75 years | 13 participants | 17 participants | 15 participants | 45 participants |
| Baseline HbA1c Category <8.0% | 615 participants | 620 participants | 613 participants | 1848 participants |
| Baseline HbA1c Category ≥8.0% | 265 participants | 265 participants | 261 participants | 791 participants |
| Body Mass Index (BMI) | 31.27 kg/m^2 STANDARD_DEVIATION 5.417 | 31.27 kg/m^2 STANDARD_DEVIATION 5.341 | 31.11 kg/m^2 STANDARD_DEVIATION 5.32 | 31.22 kg/m^2 STANDARD_DEVIATION 5.358 |
| Diabetes duration | 5.65 years STANDARD_DEVIATION 5.324 | 5.42 years STANDARD_DEVIATION 4.73 | 5.48 years STANDARD_DEVIATION 4.884 | 5.52 years STANDARD_DEVIATION 4.985 |
| Glomerular filtration rate Cockcroft-Gault | 109.3 mL/min/1.73m^2 STANDARD_DEVIATION 33.4 | 109.3 mL/min/1.73m^2 STANDARD_DEVIATION 32.85 | 108.0 mL/min/1.73m^2 STANDARD_DEVIATION 32.64 | 108.9 mL/min/1.73m^2 STANDARD_DEVIATION 32.96 |
| Glomerular filtration rate MDRD | 83.04 mL/min/1.73m^2 STANDARD_DEVIATION 16.586 | 82.35 mL/min/1.73m^2 STANDARD_DEVIATION 16.199 | 82.28 mL/min/1.73m^2 STANDARD_DEVIATION 16.994 | 82.56 mL/min/1.73m^2 STANDARD_DEVIATION 16.591 |
| Glycosylated hemoglobin (HbA1c) | 7.59 percentage STANDARD_DEVIATION 0.599 | 7.61 percentage STANDARD_DEVIATION 0.606 | 7.60 percentage STANDARD_DEVIATION 0.617 | 7.60 percentage STANDARD_DEVIATION 0.607 |
| Metformin dose | 1825.2 mg STANDARD_DEVIATION 405.59 | 1837.2 mg STANDARD_DEVIATION 373.06 | 1823.4 mg STANDARD_DEVIATION 390.63 | 1828.6 mg STANDARD_DEVIATION 389.85 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 40 participants | 42 participants | 36 participants | 118 participants |
| Race/Ethnicity, Customized Asian | 191 participants | 207 participants | 203 participants | 601 participants |
| Race/Ethnicity, Customized Black or African American | 74 participants | 66 participants | 81 participants | 221 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 192 participants | 204 participants | 192 participants | 588 participants |
| Race/Ethnicity, Customized Multiracial | 11 participants | 14 participants | 17 participants | 42 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 7 participants | 1 participants | 4 participants | 12 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 688 participants | 681 participants | 682 participants | 2051 participants |
| Race/Ethnicity, Customized White | 557 participants | 555 participants | 533 participants | 1645 participants |
| Sex: Female, Male Female | 461 Participants | 433 Participants | 433 Participants | 1327 Participants |
| Sex: Female, Male Male | 419 Participants | 452 Participants | 441 Participants | 1312 Participants |
| Smoking history Current smoker | 135 participants | 122 participants | 111 participants | 368 participants |
| Smoking history Ex-smoker | 202 participants | 177 participants | 185 participants | 564 participants |
| Smoking history Never smoked | 543 participants | 586 participants | 578 participants | 1707 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 | 688 / 873 | 687 / 878 | 668 / 869 |
| serious Total, serious adverse events | 86 / 873 | 97 / 878 | 81 / 869 |
Outcome results
Primary
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 104
The change from Baseline to Week 104 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound). The least squares (LS) means are from an analysis of covariance (ANCOVA) model with treatment, study schedule, and geographic region as class variables, and Baseline metformin dose and Baseline HbA1c as covariates.
Time frame: Baseline and Week 104
Population: The Per-protocol set included all randomized patients who took at least 1 dose of double-blind study drug, with a Baseline assessment and at least 1 post-baseline assessment for that variable and who had no major protocol violations. Last observation carried forward was used (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 104 | -0.68 percentage glycosylated hemoglobin | Standard Error 0.037 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 104 | -0.72 percentage glycosylated hemoglobin | Standard Error 0.037 |
| Metformin + Glipizide | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 104 | -0.59 percentage glycosylated hemoglobin | Standard Error 0.039 |
Comparison: The null hypotheses were tested in a fixed order at the 1-sided 0.0125 significance level at Weeks 52 and 104, independently: H01: Alogliptin 25 mg was inferior in HbA1c change from Baseline vs glipizide. H02: Alogliptin 12.5 mg was inferior vs glipizide. H03: Alogliptin 25 mg was not superior vs glipizide. H04: Alogliptin 12.5 mg was not superior vs glipizide. Each subsequent null hypothesis was tested only if all previously tested null hypotheses were rejected with respect to Weeks 52 and 104.
Primary
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 52
The change from Baseline to Week 52 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound). The least squares (LS) means are from an analysis of covariance (ANCOVA) model with treatment, study schedule, and geographic region as class variables, and Baseline metformin dose and Baseline HbA1c as covariates.
Time frame: Baseline and Week 52
Population: The Per-protocol set included all randomized patients who took at least 1 dose of double-blind study drug, with a Baseline assessment and at least 1 post-baseline assessment for that variable and who had no major protocol violations. Last observation carried forward (LOCF) was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 52 | -0.81 percentage glycosylated hemoglobin | Standard Error 0.027 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 52 | -0.76 percentage glycosylated hemoglobin | Standard Error 0.027 |
| Metformin + Glipizide | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 52 | -0.73 percentage glycosylated hemoglobin | Standard Error 0.029 |
Comparison: The null hypotheses were tested in a fixed order at the 1-sided 0.0125 significance level at Weeks 52 and 104, independently: H01: Alogliptin 25 mg was inferior in HbA1c change from Baseline vs glipizide. H02: Alogliptin 12.5 mg was inferior vs glipizide. H03: Alogliptin 25 mg was not superior vs glipizide. H04: Alogliptin 12.5 mg was not superior vs glipizide. Each subsequent null hypothesis was tested only if all previously tested null hypotheses were rejected with respect to Weeks 52 and 104.
Secondary
Change From Baseline in Body Weight Over Time
LS Means are from an ANCOVA model with treatment, study schedule and geographic region as class variables, and Baseline weight and Baseline metformin dose as covariates.
Time frame: Baseline and Weeks 12, 26, 39, 52, 65, 78, 91, and 104.
Population: Full analysis set, LOCF was used.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Body Weight Over Time | Week 104 | -0.68 kg | Standard Error 0.127 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Body Weight Over Time | Week 12 | -0.51 kg | Standard Error 0.076 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Body Weight Over Time | Week 52 | -0.63 kg | Standard Error 0.117 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Body Weight Over Time | Week 91 | -0.67 kg | Standard Error 0.127 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Body Weight Over Time | Week 26 | -0.65 kg | Standard Error 0.101 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Body Weight Over Time | Week 65 | -0.70 kg | Standard Error 0.122 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Body Weight Over Time | Week 39 | -0.60 kg | Standard Error 0.109 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Body Weight Over Time | Week 78 | -0.78 kg | Standard Error 0.124 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Body Weight Over Time | Week 26 | -0.71 kg | Standard Error 0.101 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Body Weight Over Time | Week 78 | -0.94 kg | Standard Error 0.124 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Body Weight Over Time | Week 91 | -0.88 kg | Standard Error 0.127 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Body Weight Over Time | Week 12 | -0.53 kg | Standard Error 0.076 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Body Weight Over Time | Week 104 | -0.89 kg | Standard Error 0.127 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Body Weight Over Time | Week 39 | -0.86 kg | Standard Error 0.109 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Body Weight Over Time | Week 52 | -0.90 kg | Standard Error 0.117 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Body Weight Over Time | Week 65 | -0.92 kg | Standard Error 0.122 |
| Metformin + Glipizide | Change From Baseline in Body Weight Over Time | Week 104 | 0.95 kg | Standard Error 0.127 |
| Metformin + Glipizide | Change From Baseline in Body Weight Over Time | Week 12 | 0.71 kg | Standard Error 0.077 |
| Metformin + Glipizide | Change From Baseline in Body Weight Over Time | Week 26 | 0.86 kg | Standard Error 0.101 |
| Metformin + Glipizide | Change From Baseline in Body Weight Over Time | Week 39 | 0.97 kg | Standard Error 0.11 |
| Metformin + Glipizide | Change From Baseline in Body Weight Over Time | Week 52 | 0.89 kg | Standard Error 0.117 |
| Metformin + Glipizide | Change From Baseline in Body Weight Over Time | Week 65 | 0.87 kg | Standard Error 0.123 |
| Metformin + Glipizide | Change From Baseline in Body Weight Over Time | Week 91 | 0.89 kg | Standard Error 0.127 |
| Metformin + Glipizide | Change From Baseline in Body Weight Over Time | Week 78 | 0.88 kg | Standard Error 0.125 |
Secondary
Change From Baseline in Fasting Plasma Glucose Over Time
The change from Baseline in fasting plasma glucose (FPG) was assessed at Weeks 2, 4, 8, 12, 16, 20, 26, 39, 52, 65, 78, 91, and 104. LS means are from an ANCOVA model with treatment, study schedule, and geographic region as class variables, and Baseline FPG and Baseline metformin dose as covariates.
Time frame: Baseline and Weeks 2, 4, 8, 12, 16, 20, 26, 39, 52, 65, 78, 91, and 104.
Population: Full analysis set, which included all randomized patients who received at least 1 dose of double-blind study drug who had a Baseline assessment and at least 1 post-baseline assessment for FPG. LOCF was used.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 104 (n=867, 867, 859) | -0.9 mg/dL | Standard Error 1.28 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 52 (n=867, 867, 859) | -5.0 mg/dL | Standard Error 1.22 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 12 (n=867, 867, 859) | -10.7 mg/dL | Standard Error 0.94 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 2 (n=781, 803, 777) | -10.2 mg/dL | Standard Error 0.89 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 26 (n=867, 867, 859) | -7.5 mg/dL | Standard Error 1.06 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 8 (n=867, 867, 859) | -9.2 mg/dL | Standard Error 0.91 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 4 (n=863, 865, 855) | -10.6 mg/dL | Standard Error 0.85 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 78 (n=867, 867, 859) | -2.8 mg/dL | Standard Error 1.47 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 39 (n=867, 867, 859) | -6.9 mg/dL | Standard Error 1.14 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 20 (n=867, 867, 859) | -7.6 mg/dL | Standard Error 1.02 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 91 (n=867, 867, 859) | -0.9 mg/dL | Standard Error 1.27 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 65 (n=867, 867, 859) | -3.4 mg/dL | Standard Error 1.21 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 16 (n=867, 867, 859) | -8.6 mg/dL | Standard Error 0.98 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 39 (n=867, 867, 859) | -8.4 mg/dL | Standard Error 1.14 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 52 (n=867, 867, 859) | -7.0 mg/dL | Standard Error 1.22 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 65 (n=867, 867, 859) | -5.9 mg/dL | Standard Error 1.21 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 78 (n=867, 867, 859) | -5.1 mg/dL | Standard Error 1.47 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 91 (n=867, 867, 859) | -3.4 mg/dL | Standard Error 1.27 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 104 (n=867, 867, 859) | -3.2 mg/dL | Standard Error 1.28 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 2 (n=781, 803, 777) | -11.4 mg/dL | Standard Error 0.87 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 4 (n=863, 865, 855) | -11.6 mg/dL | Standard Error 0.85 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 8 (n=867, 867, 859) | -11.6 mg/dL | Standard Error 0.91 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 12 (n=867, 867, 859) | -11.2 mg/dL | Standard Error 0.94 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 16 (n=867, 867, 859) | -9.9 mg/dL | Standard Error 0.98 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 20 (n=867, 867, 859) | -10.1 mg/dL | Standard Error 1.02 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Fasting Plasma Glucose Over Time | Week 26 (n=867, 867, 859) | -10.1 mg/dL | Standard Error 1.06 |
| Metformin + Glipizide | Change From Baseline in Fasting Plasma Glucose Over Time | Week 39 (n=867, 867, 859) | -0.6 mg/dL | Standard Error 1.15 |
| Metformin + Glipizide | Change From Baseline in Fasting Plasma Glucose Over Time | Week 12 (n=867, 867, 859) | -9.4 mg/dL | Standard Error 0.95 |
| Metformin + Glipizide | Change From Baseline in Fasting Plasma Glucose Over Time | Week 91 (n=867, 867, 859) | 4.9 mg/dL | Standard Error 1.28 |
| Metformin + Glipizide | Change From Baseline in Fasting Plasma Glucose Over Time | Week 26 (n=867, 867, 859) | -4.3 mg/dL | Standard Error 1.06 |
| Metformin + Glipizide | Change From Baseline in Fasting Plasma Glucose Over Time | Week 16 (n=867, 867, 859) | -7.1 mg/dL | Standard Error 0.98 |
| Metformin + Glipizide | Change From Baseline in Fasting Plasma Glucose Over Time | Week 78 (n=867, 867, 859) | 5.1 mg/dL | Standard Error 1.48 |
| Metformin + Glipizide | Change From Baseline in Fasting Plasma Glucose Over Time | Week 52 (n=867, 867, 859) | 0.9 mg/dL | Standard Error 1.23 |
| Metformin + Glipizide | Change From Baseline in Fasting Plasma Glucose Over Time | Week 20 (n=867, 867, 859) | -5.5 mg/dL | Standard Error 1.02 |
| Metformin + Glipizide | Change From Baseline in Fasting Plasma Glucose Over Time | Week 4 (n=863, 865, 855) | -10.2 mg/dL | Standard Error 0.85 |
| Metformin + Glipizide | Change From Baseline in Fasting Plasma Glucose Over Time | Week 2 (n=781, 803, 777) | -7.7 mg/dL | Standard Error 0.89 |
| Metformin + Glipizide | Change From Baseline in Fasting Plasma Glucose Over Time | Week 65 (n=867, 867, 859) | 1.4 mg/dL | Standard Error 1.21 |
| Metformin + Glipizide | Change From Baseline in Fasting Plasma Glucose Over Time | Week 8 (n=867, 867, 859) | -9.3 mg/dL | Standard Error 0.92 |
| Metformin + Glipizide | Change From Baseline in Fasting Plasma Glucose Over Time | Week 104 (n=867, 867, 859) | 5.4 mg/dL | Standard Error 1.29 |
Secondary
Change From Baseline in Glycosylated Hemoglobin at Other Time Points
The change from Baseline over time in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound). LS means are from an ANCOVA model with treatment, study schedule, and geographic region as class variables, and Baseline metformin dose and Baseline HbA1c as covariates.
Time frame: Baseline and Weeks 4, 8, 12, 16, 20, 26, 39, 65, 78, and 91.
Population: Per-protocol set; LOCF was used.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 4 (n=341, 354, 318) | -0.37 percentage of glycosylated hemoglobin | Standard Error 0.02 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 8 (n=370, 382, 336) | -0.56 percentage of glycosylated hemoglobin | Standard Error 0.024 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 12 (n=371, 382, 336) | -0.69 percentage of glycosylated hemoglobin | Standard Error 0.025 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 16 (n=371, 382, 336) | -0.74 percentage of glycosylated hemoglobin | Standard Error 0.026 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 20 (n=371, 382, 336) | -0.76 percentage of glycosylated hemoglobin | Standard Error 0.026 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 26 (n=371, 382, 336) | -0.80 percentage of glycosylated hemoglobin | Standard Error 0.027 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 39 (n=371, 382, 336) | -0.81 percentage of glycosylated hemoglobin | Standard Error 0.026 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 65 (n=371, 382, 336) | -0.81 percentage of glycosylated hemoglobin | Standard Error 0.029 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 78 (n=371, 382, 336) | -0.82 percentage of glycosylated hemoglobin | Standard Error 0.03 |
| Metformin + Alogliptin 12.5 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 91 (n=371, 382, 336) | -0.76 percentage of glycosylated hemoglobin | Standard Error 0.033 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 78 (n=371, 382, 336) | -0.80 percentage of glycosylated hemoglobin | Standard Error 0.03 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 4 (n=341, 354, 318) | -0.40 percentage of glycosylated hemoglobin | Standard Error 0.02 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 26 (n=371, 382, 336) | -0.79 percentage of glycosylated hemoglobin | Standard Error 0.026 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 20 (n=371, 382, 336) | -0.78 percentage of glycosylated hemoglobin | Standard Error 0.025 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 8 (n=370, 382, 336) | -0.60 percentage of glycosylated hemoglobin | Standard Error 0.024 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 91 (n=371, 382, 336) | -0.77 percentage of glycosylated hemoglobin | Standard Error 0.033 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 65 (n=371, 382, 336) | -0.83 percentage of glycosylated hemoglobin | Standard Error 0.028 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 12 (n=371, 382, 336) | -0.71 percentage of glycosylated hemoglobin | Standard Error 0.025 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 39 (n=371, 382, 336) | -0.81 percentage of glycosylated hemoglobin | Standard Error 0.025 |
| Metformin + Alogliptin 25 mg | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 16 (n=371, 382, 336) | -0.76 percentage of glycosylated hemoglobin | Standard Error 0.025 |
| Metformin + Glipizide | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 65 (n=371, 382, 336) | -0.76 percentage of glycosylated hemoglobin | Standard Error 0.03 |
| Metformin + Glipizide | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 16 (n=371, 382, 336) | -0.78 percentage of glycosylated hemoglobin | Standard Error 0.027 |
| Metformin + Glipizide | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 20 (n=371, 382, 336) | -0.79 percentage of glycosylated hemoglobin | Standard Error 0.027 |
| Metformin + Glipizide | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 26 (n=371, 382, 336) | -0.80 percentage of glycosylated hemoglobin | Standard Error 0.028 |
| Metformin + Glipizide | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 78 (n=371, 382, 336) | -0.73 percentage of glycosylated hemoglobin | Standard Error 0.032 |
| Metformin + Glipizide | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 39 (n=371, 382, 336) | -0.74 percentage of glycosylated hemoglobin | Standard Error 0.027 |
| Metformin + Glipizide | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 4 (n=341, 354, 318) | -0.41 percentage of glycosylated hemoglobin | Standard Error 0.021 |
| Metformin + Glipizide | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 91 (n=371, 382, 336) | -0.68 percentage of glycosylated hemoglobin | Standard Error 0.035 |
| Metformin + Glipizide | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 8 (n=370, 382, 336) | -0.66 percentage of glycosylated hemoglobin | Standard Error 0.025 |
| Metformin + Glipizide | Change From Baseline in Glycosylated Hemoglobin at Other Time Points | Week 12 (n=371, 382, 336) | -0.78 percentage of glycosylated hemoglobin | Standard Error 0.026 |
Secondary
Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5%
The percentage of participants with HbA1c less than or equal to 6.5% at Weeks 26, 52, 78, and 104. Participants who did not complete the scheduled Week 104 visit were assessed based on their response at the time of discontinuation.
Time frame: Weeks 26, 52, 78, and 104.
Population: Full analysis set. Participants who did not complete the scheduled Week 26, Week 52, Week 78 or Week 104 visit were assessed based on their response at the time of discontinuation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Metformin + Alogliptin 12.5 mg | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5% | Week 26 | 25.6 percentage of participants |
| Metformin + Alogliptin 12.5 mg | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5% | Week 52 | 24.5 percentage of participants |
| Metformin + Alogliptin 12.5 mg | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5% | Week 78 | 24.2 percentage of participants |
| Metformin + Alogliptin 12.5 mg | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5% | Week 104 | 23.5 percentage of participants |
| Metformin + Alogliptin 25 mg | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5% | Week 104 | 24.1 percentage of participants |
| Metformin + Alogliptin 25 mg | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5% | Week 26 | 26.2 percentage of participants |
| Metformin + Alogliptin 25 mg | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5% | Week 78 | 26.4 percentage of participants |
| Metformin + Alogliptin 25 mg | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5% | Week 52 | 24.8 percentage of participants |
| Metformin + Glipizide | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5% | Week 104 | 19.0 percentage of participants |
| Metformin + Glipizide | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5% | Week 52 | 20.8 percentage of participants |
| Metformin + Glipizide | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5% | Week 78 | 21.8 percentage of participants |
| Metformin + Glipizide | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5% | Week 26 | 24.8 percentage of participants |
Secondary
Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0%
Percentage of participants with HbA1c ≤ 7.0% at Weeks 26, 52, 78, and 104. Participants who did not complete the scheduled Week 104 visit were assessed based on their response at the time of discontinuation.
Time frame: Weeks 26, 52, 78, and 104.
Population: Full analysis set. Participants who did not complete the scheduled Week 26, Week 52, Week 78 or Week 104 visit were assessed based on their response at the time of discontinuation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Metformin + Alogliptin 12.5 mg | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0% | Week 26 | 56.4 percentage of participants |
| Metformin + Alogliptin 12.5 mg | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0% | Week 52 | 51.7 percentage of participants |
| Metformin + Alogliptin 12.5 mg | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0% | Week 78 | 48.8 percentage of participants |
| Metformin + Alogliptin 12.5 mg | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0% | Week 104 | 45.6 percentage of participants |
| Metformin + Alogliptin 25 mg | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0% | Week 104 | 48.5 percentage of participants |
| Metformin + Alogliptin 25 mg | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0% | Week 26 | 59.2 percentage of participants |
| Metformin + Alogliptin 25 mg | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0% | Week 78 | 52.4 percentage of participants |
| Metformin + Alogliptin 25 mg | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0% | Week 52 | 55.5 percentage of participants |
| Metformin + Glipizide | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0% | Week 104 | 42.8 percentage of participants |
| Metformin + Glipizide | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0% | Week 52 | 47.4 percentage of participants |
| Metformin + Glipizide | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0% | Week 78 | 46.6 percentage of participants |
| Metformin + Glipizide | Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0% | Week 26 | 56.1 percentage of participants |