Type 2 Diabetes Mellitus
Conditions
Brief summary
This is a trial of continuing sitagliptin versus withdrawing sitagliptin in participants with Type 2 diabetes mellitus (T2DM) and inadequate glycemic control who initiate and titrate insulin glargine (LANTUS®) based on a treat-to-target algorithm to achieve fasting glucose levels of 72-100 mg/dL (4-5.6 mmol/L). A primary hypothesis of this trial is that after 30 weeks, continuing sitagliptin results in a greater reduction of hemoglobin A1C (A1C) relative to withdrawing sitagliptin.
Interventions
DRUGSitagliptin
Sitagliptin 100 mg, oral, once daily for 30 weeks
Placebo to sitagliptin, 100 mg, oral, once daily for 30 weeks
DRUGMetformin
At least 1500 mg/day, oral, twice daily for participants entering the study on immediate-release metformin + sitagliptin or a fixed dose combination (FDC).
DRUGMetformin XR
At least 1500 mg/day, oral, once daily for participants entering the study on extended-release metformin + sitagliptin or a FDC.
DRUGInsulin glargine
Insulin glargine (LANTUS®) initiated at 10 units and titrated based on a treat-to-target algorithm to achieve fasting glucose levels of 72-100 mg/dL (4-5.6 mmol/L); administered once daily subcutaneously.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have T2DM based on American Diabetes Association guidelines * Be on one of the following treatment regimens: 1. Stable dose of sitagliptin (100 mg/day) and metformin IR or XR (metformin) (≥1500 mg/day) either co-administered or as a fixed dose combination (FDC) for ≥12 weeks with A1C between 7.5% and 11.0%, inclusive. OR 2. Stable dose of metformin (≥1500 mg/day) and another dipeptidyl peptidase-4 (DPP-4) inhibitor (at maximum labeled dose, other than sitagliptin, either co-administered or as a FDC, for ≥12 weeks with A1C between 7.5% and 11.0%, inclusive. OR 3. Stable dose of sitagliptin (100 mg/day) and metformin (≥1500 mg/day) either co administered or as a FDC, and a sulfonylurea for ≥12 weeks OR stable dose of metformin (≥1500 mg/day) and a sulfonylurea administered as a FDC and sitagliptin (100 mg/day) with A1C between 7.0% and 10.0%, inclusive. OR 4. Stable dose of metformin (≥1500 mg/day) and another DPP-4 inhibitor (at maximum labeled dose), other than sitagliptin, either co-administered or as a FDC, and a sulfonylurea for ≥12 weeks OR stable dose of metformin (≥1500 mg/day) and a sulfonylurea administered as a FDC and another DPP-4 inhibitor other than sitagliptin with A1C between 7.0% and 10.0%, inclusive OR 5. Stable dose of metformin (≥1500 mg/day) and a sulfonylurea either co-administered or as a FDC for ≥12 weeks with A1C between 7.5% and 11.0%, inclusive. * Meet one of the following categories: 1. The participant is a male 2. The participant is a female who is not of reproductive potential 3. The participant is a female who is of reproductive potential and agrees to avoid becoming pregnant while receiving study drug and for 14 days after the last dose of study drug by practicing abstinence from heterosexual activity OR use (or have her partner use) acceptable contraception during heterosexual activity
Exclusion criteria
* Has been treated with any anti-hyperglycemic agent (AHA) other than protocol-specified agents (i.e., other than metformin, DPP-4 inhibitor, or sulfonylurea agent) within the prior 12 weeks. * Has a history of 2 or more episodes of hypoglycemia resulting in seizure, coma, or loss of consciousness, OR has had recurrent (≥3 times per week) episodes of hypoglycemia over the past 8 weeks. * Has a history of type 1 diabetes mellitus (T1DM) or ketoacidosis, or has a history of latent autoimmune diabetes of adults (LADA), is assessed by the investigator as possibly having T1DM or LADA confirmed with a C-peptide \<0.7 ng/mL (\<0.23 nmol/L), or has a history of other specific types of diabetes (e.g., genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical-induced, or post-organ transplant). * Is assessed by the investigator to be not appropriate for, or does not agree to target, a fasting glucose of 72-100 mg/dL (4.0-5.6 mmol/L).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in A1C at Week 30 | Baseline and Week 30 | A1C is blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Thus, this change from baseline reflects the Week 30 A1C minus the Week 0 A1C. |
| Event Rate of Documented Symptomatic Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) | Up to 30 weeks | Documented symptomatic hypoglycemia is defined as an event during which typical symptoms of hypoglycemia are accompanied by a measured (e.g., by fingerstick) plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L). The event rate was the total number of events divided by follow-up time (participant-years), including multiple events from the same participant. |
| Percentage of Participants Who Discontinued Study Drug Due to an AE | Up to 30 weeks | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. |
| Percentage of Participants Who Experienced One or More Adverse Events (AEs) | Up to 32 weeks | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Documented Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L) | Up to 30 weeks | Documented hypoglycemia is defined by a measured (e.g., by fingerstick) plasma glucose concentration \<56 mg/dL (≤3.1 mmol/L). |
| Percentage of Participants With A1C Goal <7.0% (<53 mmol/Mol) at Week 30 | Week 30 | A1C is blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 30 | Baseline and Week 30 | Blood glucose was measured on a fasting basis. Blood was drawn at predose on Day 1 and after 30 weeks of treatment to determine change in plasma glucose levels (i.e., FPG at Week 30 minus FPG at Week 0). |
| Percentage of Participants With Events of Documented Symptomatic Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) | Up to 30 weeks | Documented symptomatic hypoglycemia is defined as an event during which typical symptoms of hypoglycemia are accompanied by a measured (e.g., by fingerstick) plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L). The incidence (number of participants with ≥1 event divided by number of participants) of documented symptomatic hypoglycemia was determined. |
| Percentage of Participants With Documented Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) | Up to 30 weeks | Documented hypoglycemia is defined by a measured (e.g., by fingerstick) plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L). |
| Percentage of Participants With Documented Symptomatic Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L) | Up to 30 weeks | Documented symptomatic hypoglycemia is defined as an event during which typical symptoms of hypoglycemia are accompanied by a measured (e.g., by fingerstick) plasma glucose concentration \<56 mg/dL (≤3.1 mmol/L). |
| Percentage of Participants With A1C Goal <7.0% (<53 mmol/Mol at Week 30 and No Documented Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) up to Week 30 | Week 30 | A1C is blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. |
| Event Rate of Documented Symptomatic Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L) | Up to 30 weeks | Documented symptomatic hypoglycemia is defined as an event during which typical symptoms of hypoglycemia are accompanied by a measured (e.g., by fingerstick) plasma glucose concentration \<56 mg/dL (≤3.1 mmol/L). The event rate was the total number of events divided by follow-up time (participant-years), including multiple events from the same participant. |
| Change From Baseline in Total Daily Insulin Dose (Units) at Week 30 | Baseline and Week 30 | Change from baseline reflects the Week 30 total daily insulin dose minus the Week 0 total daily insulin dose. The Week 0 total daily insulin dose was 0, by definition, because insulin was not administered at baseline. |
| Event Rate of Documented Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) | Up to 30 weeks | Documented hypoglycemia is defined by a measured (e.g., by fingerstick) plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L). The event rate was the total number of events divided by follow-up time (participant-years), including multiple events from the same participant. |
| Event Rate of Documented Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L) | Up to 30 weeks | Documented hypoglycemia is defined by a measured (e.g., by fingerstick) plasma glucose concentration \<56 mg/dL (≤3.1 mmol/L). The event rate was the total number of events divided by follow-up time (participant-years), including multiple events from the same participant. |
Participant flow
Recruitment details
A total of 746 participants were randomized across 149 study sites in 22 countries.
Pre-assignment details
Male and female participants with Type 2 diabetes mellitus (T2DM) ≥18 years of age were enrolled in this trial.
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin Sitagliptin 100 mg, oral, once daily for 30 weeks | 374 |
| Placebo Placebo to sitagliptin 100 mg, oral, once daily for 30 weeks | 372 |
| Total | 746 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Death | 0 | 2 |
| Overall Study | Lost to Follow-up | 1 | 5 |
| Overall Study | Physician Decision | 3 | 4 |
| Overall Study | Pregnancy | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 3 |
| Overall Study | Screen Failure | 1 | 2 |
| Overall Study | Site Discontinued Study Participation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 7 |
Baseline characteristics
| Characteristic | Sitagliptin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 58.5 years STANDARD_DEVIATION 9.5 | 58.1 years STANDARD_DEVIATION 9.7 | 58.3 years STANDARD_DEVIATION 9.6 |
| Age, Customized 85 years and over | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adolescents (12-17 years) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adults (18-64 years) | 275 Participants | 272 Participants | 547 Participants |
| Age, Customized Children (2-11 years) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized From 65-84 years | 99 Participants | 100 Participants | 199 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized In utero | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Newborns (0-27 days) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Preterm newborn infants (gestational age < 37 wks) | 0 Participants | 0 Participants | 0 Participants |
| Anti-Hyperglycemic Agent Met + DPP-4i | 184 Participants | 184 Participants | 368 Participants |
| Anti-Hyperglycemic Agent Met + DPP-4i + sulfonylurea (SU) | 87 Participants | 86 Participants | 173 Participants |
| Anti-Hyperglycemic Agent Met + SU | 103 Participants | 102 Participants | 205 Participants |
| Body Weight | 84.8 Kilograms STANDARD_DEVIATION 19.8 | 85.6 Kilograms STANDARD_DEVIATION 18.9 | 85.2 Kilograms STANDARD_DEVIATION 19.4 |
| Estimated Glomerular Filtration Rate | 103.7 mL/min/1.73 m^2 STANDARD_DEVIATION 30.3 | 106.4 mL/min/1.73 m^2 STANDARD_DEVIATION 28.1 | 105.1 mL/min/1.73 m^2 STANDARD_DEVIATION 29.2 |
| Fasting Plasma Glucose (FPG) | 199.0 mg/dL STANDARD_DEVIATION 50.8 | 201.2 mg/dL STANDARD_DEVIATION 51.8 | 200.1 mg/dL STANDARD_DEVIATION 51.3 |
| Geographic Region Asia | 36 Participants | 26 Participants | 62 Participants |
| Geographic Region Europe | 158 Participants | 172 Participants | 330 Participants |
| Geographic Region Latin America | 85 Participants | 83 Participants | 168 Participants |
| Geographic Region North America | 80 Participants | 78 Participants | 158 Participants |
| Geographic Region Other | 15 Participants | 13 Participants | 28 Participants |
| Hemoglobin A1C (A1C) | 8.8 Percent A1C STANDARD_DEVIATION 0.9 | 8.8 Percent A1C STANDARD_DEVIATION 1 | 8.8 Percent A1C STANDARD_DEVIATION 0.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 19 Participants | 18 Participants | 37 Participants |
| Race (NIH/OMB) Asian | 42 Participants | 37 Participants | 79 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 12 Participants | 24 Participants |
| Race (NIH/OMB) More than one race | 34 Participants | 34 Participants | 68 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 6 Participants | 1 Participants | 7 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 259 Participants | 270 Participants | 529 Participants |
| Sex: Female, Male Female | 204 Participants | 181 Participants | 385 Participants |
| Sex: Female, Male Male | 170 Participants | 191 Participants | 361 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 373 | 2 / 370 |
| other Total, other adverse events | 79 / 373 | 72 / 370 |
| serious Total, serious adverse events | 14 / 373 | 18 / 370 |
Outcome results
Primary
Change From Baseline in A1C at Week 30
A1C is blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Thus, this change from baseline reflects the Week 30 A1C minus the Week 0 A1C.
Time frame: Baseline and Week 30
Population: All randomized participants who received at least one dose of study treatment and had at least one measurement of the respective endpoint (baseline or post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Change From Baseline in A1C at Week 30 | -1.88 Percent A1C | 95% Confidence Interval -1.98 |
| Placebo | Change From Baseline in A1C at Week 30 | -1.42 Percent A1C | 95% Confidence Interval -1.52 |
Comparison: A longitudinal data analysis (LDA) model included terms for treatment, AHA treatment at screening (Met + DPP-4i, Met + DPP-4i + SU, Met + SU), time, and the interactions of time by treatment and of time by AHA treatment at screening. Least Squares Means = LSM95% CI: [-0.58, -0.34]LDA
Comparison: A LDA model included terms for treatment, AHA treatment at screening (Met + DPP-4i, Met + DPP-4i + SU, Met + SU), time, and the interactions of time by treatment and of time by AHA treatment at screening.p-value: <0.00195% CI: [-0.58, -0.34]LDA
Primary
Event Rate of Documented Symptomatic Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L)
Documented symptomatic hypoglycemia is defined as an event during which typical symptoms of hypoglycemia are accompanied by a measured (e.g., by fingerstick) plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L). The event rate was the total number of events divided by follow-up time (participant-years), including multiple events from the same participant.
Time frame: Up to 30 weeks
Population: All randomized participants who received at least one dose of study treatment. Two participants in the sitagliptin group were not included in the primary analysis due to a missing value of a model covariate (race).
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Sitagliptin | Event Rate of Documented Symptomatic Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) | 1.55 Events/Participant-Years | 95% Confidence Interval 1.22 |
| Placebo | Event Rate of Documented Symptomatic Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) | 2.12 Events/Participant-Years | 95% Confidence Interval 1.7 |
Comparison: Calculated via the Negative Binomial Model including terms for treatment, race (i.e., White and Other), region (i.e., Europe, North America, and Other), AHA treatment at screening, baseline A1C value and baseline body weight and an offset for follow-up time (on the natural log scale).p-value: =0.03995% CI: [0.54, 0.98]Negative Binomial Model
Primary
Percentage of Participants Who Discontinued Study Drug Due to an AE
An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Time frame: Up to 30 weeks
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Percentage of Participants Who Discontinued Study Drug Due to an AE | 1.3 Percentage of participants |
| Placebo | Percentage of Participants Who Discontinued Study Drug Due to an AE | 1.6 Percentage of participants |
95% CI: [-2.3, 1.7]Miettinen & Nurminen
Primary
Percentage of Participants Who Experienced One or More Adverse Events (AEs)
An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Time frame: Up to 32 weeks
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Percentage of Participants Who Experienced One or More Adverse Events (AEs) | 57.9 Percentage of participants |
| Placebo | Percentage of Participants Who Experienced One or More Adverse Events (AEs) | 60.0 Percentage of participants |
95% CI: [-9.1, 5]Miettinen & Nurminen
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 30
Blood glucose was measured on a fasting basis. Blood was drawn at predose on Day 1 and after 30 weeks of treatment to determine change in plasma glucose levels (i.e., FPG at Week 30 minus FPG at Week 0).
Time frame: Baseline and Week 30
Population: All randomized participants who received at least one dose of study treatment and had at least one measurement of the respective endpoint (baseline or post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 30 | -84.8 mg/dL | 95% Confidence Interval -90 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 30 | -78.3 mg/dL | 95% Confidence Interval -83.5 |
Comparison: Analysis was based on a LDA model including terms for treatment, AHA treatment at screening (Met + DPP-4i, Met + DPP-4i + SU, Met + SU), time, and the interactions of time by treatment and of time by AHA treatment at screening.p-value: =0.0295% CI: [-11.9, -1]LDA
Secondary
Change From Baseline in Total Daily Insulin Dose (Units) at Week 30
Change from baseline reflects the Week 30 total daily insulin dose minus the Week 0 total daily insulin dose. The Week 0 total daily insulin dose was 0, by definition, because insulin was not administered at baseline.
Time frame: Baseline and Week 30
Population: All randomized participants who received at least one dose of study treatment and had at least one measurement of the respective endpoint (baseline or post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Change From Baseline in Total Daily Insulin Dose (Units) at Week 30 | 53.2 Insulin Units | 95% Confidence Interval 48.5 |
| Placebo | Change From Baseline in Total Daily Insulin Dose (Units) at Week 30 | 61.3 Insulin Units | 95% Confidence Interval 56.5 |
Comparison: The analysis is based on a LDA model including terms for treatment, AHA treatment at screening (Met + DPP-4i, Met + DPP-4i + SU, Met + SU), time, and the interactions of time by treatment and of time by AHA treatment at screening.p-value: =0.01695% CI: [-14.6, -1.5]LDA model
Secondary
Event Rate of Documented Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L)
Documented hypoglycemia is defined by a measured (e.g., by fingerstick) plasma glucose concentration \<56 mg/dL (≤3.1 mmol/L). The event rate was the total number of events divided by follow-up time (participant-years), including multiple events from the same participant.
Time frame: Up to 30 weeks
Population: All randomized participants who received at least one dose of study treatment and had at least one measurement of the respective endpoint (baseline or post-baseline). Two participants (both in the sitagliptin group) were not included in the analysis due to a missing value of a model covariate (race).
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Sitagliptin | Event Rate of Documented Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L) | 0.30 Events/Participant-Years | 95% Confidence Interval 0.2 |
| Placebo | Event Rate of Documented Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L) | 0.36 Events/Participant-Years | 95% Confidence Interval 0.25 |
Comparison: Negative Binomial Model including terms for treatment, race (i.e., White and Other), region (i.e., Europe, North America, and Other), AHA treatment at screening, baseline A1C value and baseline body weight and an offset for follow-up time (on the natural log scale).p-value: =0.47395% CI: [0.51, 1.37]Negative Binomial Model
Secondary
Event Rate of Documented Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L)
Documented hypoglycemia is defined by a measured (e.g., by fingerstick) plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L). The event rate was the total number of events divided by follow-up time (participant-years), including multiple events from the same participant.
Time frame: Up to 30 weeks
Population: All randomized participants who received at least one dose of study treatment and had at least one measurement of the respective endpoint (baseline or post-baseline). Two participants (both in the sitagliptin group) were not included in the analysis due to a missing value of a model covariate (race).
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Sitagliptin | Event Rate of Documented Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) | 5.05 Events/Participant-Years | 95% Confidence Interval 4.34 |
| Placebo | Event Rate of Documented Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) | 6.21 Events/Participant-Years | 95% Confidence Interval 5.33 |
Comparison: Negative Binomial Model including terms for treatment, race (i.e., White and Other), region (i.e., Europe, North America, and Other), AHA treatment at screening, baseline A1C value and baseline body weight and an offset for follow-up time (on the natural log scale).p-value: =0.04195% CI: [0.67, 0.99]Negative Binomial Model
Secondary
Event Rate of Documented Symptomatic Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L)
Documented symptomatic hypoglycemia is defined as an event during which typical symptoms of hypoglycemia are accompanied by a measured (e.g., by fingerstick) plasma glucose concentration \<56 mg/dL (≤3.1 mmol/L). The event rate was the total number of events divided by follow-up time (participant-years), including multiple events from the same participant.
Time frame: Up to 30 weeks
Population: All randomized participants who received at least one dose of study treatment. Two participants in the sitagliptin group were not included in the primary analysis due to a missing value of a model covariate (race).
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Sitagliptin | Event Rate of Documented Symptomatic Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L) | 0.17 Events/Participant-Years | 95% Confidence Interval 0.1 |
| Placebo | Event Rate of Documented Symptomatic Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L) | 0.22 Events/Participant-Years | 95% Confidence Interval 0.14 |
Comparison: The analysis was calculated via the Negative Binomial Model including terms for treatment, race (i.e., White and Other), region (i.e., Europe, North America, and Other), AHA treatment at screening, baseline A1C value and baseline body weight and an offset for follow-up time (on the natural log scale).p-value: =0.39495% CI: [0.4, 1.44]Negative Binomial Model
Secondary
Percentage of Participants With A1C Goal <7.0% (<53 mmol/Mol) at Week 30
A1C is blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100.
Time frame: Week 30
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Percentage of Participants With A1C Goal <7.0% (<53 mmol/Mol) at Week 30 | 54.2 Percentage of participants |
| Placebo | Percentage of Participants With A1C Goal <7.0% (<53 mmol/Mol) at Week 30 | 35.4 Percentage of participants |
p-value: <0.00195% CI: [11.6, 25.7]Miettinen and Nurminen
Secondary
Percentage of Participants With A1C Goal <7.0% (<53 mmol/Mol at Week 30 and No Documented Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) up to Week 30
A1C is blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100.
Time frame: Week 30
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Percentage of Participants With A1C Goal <7.0% (<53 mmol/Mol at Week 30 and No Documented Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) up to Week 30 | 15.3 Percentage of participants |
| Placebo | Percentage of Participants With A1C Goal <7.0% (<53 mmol/Mol at Week 30 and No Documented Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) up to Week 30 | 10.0 Percentage of participants |
p-value: =0.0395% CI: [0.5, 10.1]Miettinen and Nurminen
Secondary
Percentage of Participants With Documented Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L)
Documented hypoglycemia is defined by a measured (e.g., by fingerstick) plasma glucose concentration \<56 mg/dL (≤3.1 mmol/L).
Time frame: Up to 30 weeks
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Sitagliptin | Percentage of Participants With Documented Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L) | 12.4 Percentage of participants | 95% Confidence Interval 8.9 |
| Placebo | Percentage of Participants With Documented Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L) | 13.6 Percentage of participants | 95% Confidence Interval 10 |
Comparison: Percentages and difference in percentages were calculated via the Miettinen and Nurminen stratified by AHA treatment at screening. Includes imputed events after participants discontinued from the study medication, using a Gamma frailty model. The bootstrap method was used to obtain the CI and p-value.p-value: =0.62495% CI: [-6.2, 3.7]Miettinen and Nurminen
Secondary
Percentage of Participants With Documented Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L)
Documented hypoglycemia is defined by a measured (e.g., by fingerstick) plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L).
Time frame: Up to 30 weeks
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Sitagliptin | Percentage of Participants With Documented Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) | 66.8 Percentage of participants | 95% Confidence Interval 61.9 |
| Placebo | Percentage of Participants With Documented Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) | 68.0 Percentage of participants | 95% Confidence Interval 63.2 |
Comparison: The analysis included imputed events after participants discontinued from the study medication, using a Gamma frailty model. Proportions and difference in proportions were calculated via the Miettinen and Nurminen stratified by AHA treatment at screening. The bootstrap method was used to obtain the CI and p-value.p-value: =0.7495% CI: [-8.2, 5.8]Miettinen and Nurminen
Secondary
Percentage of Participants With Documented Symptomatic Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L)
Documented symptomatic hypoglycemia is defined as an event during which typical symptoms of hypoglycemia are accompanied by a measured (e.g., by fingerstick) plasma glucose concentration \<56 mg/dL (≤3.1 mmol/L).
Time frame: Up to 30 weeks
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Sitagliptin | Percentage of Participants With Documented Symptomatic Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L) | 7.6 Percentage of participants | 95% Confidence Interval 4.9 |
| Placebo | Percentage of Participants With Documented Symptomatic Hypoglycemia With Blood Glucose <56 mg/dL (≤3.1 mmol/L) | 8.3 Percentage of participants | 95% Confidence Interval 5.4 |
Comparison: Percentages and difference in percentages were calculated via the Miettinen and Nurminen stratified by AHA treatment at screening. The analysis included imputed events after subjects discontinued from the study medication, using a Gamma frailty model. The bootstrap method was used to obtain the CI and p-value.p-value: =0.71295% CI: [-4.7, 3.2]Miettinen and Nurminen
Secondary
Percentage of Participants With Events of Documented Symptomatic Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L)
Documented symptomatic hypoglycemia is defined as an event during which typical symptoms of hypoglycemia are accompanied by a measured (e.g., by fingerstick) plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L). The incidence (number of participants with ≥1 event divided by number of participants) of documented symptomatic hypoglycemia was determined.
Time frame: Up to 30 weeks
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Sitagliptin | Percentage of Participants With Events of Documented Symptomatic Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) | 33.5 Percentage of participants | 95% Confidence Interval 28.5 |
| Placebo | Percentage of Participants With Events of Documented Symptomatic Hypoglycemia With Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) | 37.7 Percentage of participants | 95% Confidence Interval 32.7 |
p-value: =0.2595% CI: [-11.2, 2.9]Miettinen and Nurminen