Number of Participants Experiencing Adverse Events (AEs) in Part 1
An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. AEs are presented by individual dose received by participants during titration in an assigned study treatment sequence.
Number of Participants Experiencing Adverse Events (AEs) in Part 2
An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. AEs are presented by individual dose received by participants during titration in an assigned study treatment sequence.
Number of Participants Discontinuing Study Drug Due to Adverse Events (AEs) in Part 1
An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. Discontinuations are presented by individual dose received by participants during titration in an assigned study treatment sequence.
Number of Participants Discontinuing Study Drug Due to Adverse Events (AEs) in Part 2
An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. Discontinuations are presented by individual dose received by participants during titration in an assigned study treatment sequence.
Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 7 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
Semi-recumbent heart rate was assessed at baseline on Day 1; Day 7 at predose, 2, 4, 6, 8, 12, 13, 14, 15, 16, 22 hours postdose; and prior to dosing on Day 8. Heart rate was measured in triplicate with at least a 1-2-minute interval between measurements. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr was calculated as the area under the measurement-time curve (AUC) divided by the time period of over which the measurements were made (i.e. 24 hrs.). Change from baseline TWA0-24hr HR was calculated as the TWA0-24hr HR at Day 7 minus baseline where baseline was defined as predose on Day 1.
Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 7 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
Semi-recumbent HR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 7: predose, 2, 4, 6, 8, 12, and 16 hours postdose; and prior to dosing on Day 8. The repeated measurements were averaged before conducting the analysis. TWA0-24hr was calculated as the AUC divided by the time period of over which the measurements were made (i.e. 24 hrs.). Change from baseline TWA0-24hr HR was calculated as the TWA0-24hr HR at Day 7 minus baseline where baseline was defined as predose on Day 1.
Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 14 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
Semi-recumbent HR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 14: predose, 2, 4, 6, 8, 12, 13, 14, 15, 16, 22 hours postdose and prior to dosing on Day 15. The repeated measurements were averaged before conducting the analysis. TWA0-24hr was calculated as the AUC divided by the time period of over which the measurements were made (i.e. 24 hrs.). Change from baseline TWA0-24hr HR was calculated as the TWA0-24hr HR at Day 14 minus baseline where baseline was defined as predose on Day 1.
Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 14 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
Semi-recumbent HR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 14: predose, 2, 4, 6, 8, 12, 16, hours postdose; and prior to dosing on Day 15. The repeated measurements were averaged before conducting the analysis. TWA0-24hr was calculated as the AUC divided by the time period of over which the measurements were made (i.e. 24 hrs.). Change from baseline TWA0-24hr HR was calculated as the TWA0-24hr HR at Day 14 minus baseline where baseline was defined as predose on Day 1.
Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 19 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
Semi-recumbent HR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 19: predose, 2, 4, 6, 8, 12, 16, hours post dose; and prior to dosing on Day 20. The repeated measurements were averaged before conducting the analysis. TWA0-24hr was calculated as the AUC divided by the time period of over which the measurements were made (i.e. 24 hrs.). Change from baseline TWA0-24hr HR was calculated as the TWA0-24hr HR at Day 19 minus baseline where baseline was defined as predose on Day 1.
Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 24 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
Semi-recumbent HR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 24: predose, 2, 4, 6, 8, 12, 16, hours postdose; and prior to dosing on Day 25. The repeated measurements were averaged before conducting the analysis. TWA0-24hr was calculated as the AUC divided by the time period of over which the measurements were made (i.e. 24 hrs.). Change from baseline TWA0-24hr HR was calculated as the TWA0-24hr HR at Day 24 minus baseline where baseline was defined as predose on Day 1.
Change From Baseline in Time-weighted Average From 0 to 24 Hours (TWA0-24hr) of Heart Rate (HR) After 29 Days of Treatment in Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
Semi-recumbent HR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; and Day 29: predose, 2, 4, 6, 8, 12, 16 and 24 hours postdose. The repeated measurements were averaged before conducting the analysis. TWA0-24hr was calculated as the AUC divided by the time period of over which the measurements were made (i.e. 24 hrs.). Change from baseline TWA0-24hr HR was calculated as the TWA0-24hr HR at Day 29 minus baseline where baseline was defined as predose on Day 1.
Change From Baseline in Peak Heart Rate (PHR) at Day 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
PHR was defined as the maximum time matched baseline adjusted heart rate over 24 hours. Semi-recumbent PHR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 7: predose, 2, 4, 6, 8, 12, and 16 hours postdose; and prior to dosing on Day 8. The repeated measurements were averaged before conducting the analysis. Change from baseline PHR was calculated as the peak heart rate at Day 7 minus baseline where baseline was defined as predose on Day 1.
Change From Baseline in Peak Heart Rate (PHR) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
PHR was defined as the maximum time matched baseline adjusted heart rate over 24 hours. Semi-recumbent PHR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 14: predose, 2, 4, 6, 8, 12, and 16 hours postdose; and prior to dosing on Day 15. The repeated measurements were averaged before conducting the analysis. Change from baseline PHR was calculated as the peak heart rate at Day 14 minus baseline where baseline was defined as predose on Day 1.
Change From Baseline in Peak Heart Rate (PHR) at Day 19 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
PHR was defined as the maximum time matched baseline adjusted heart rate over 24 hours. Semi-recumbent PHR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 19: predose, 2, 4, 6, 8, 12, and 16 hours postdose; and prior to dosing on Day 20. The repeated measurements were averaged before conducting the analysis. Change from baseline PHR was calculated as the peak heart rate at Day 19 minus baseline where baseline was defined as predose on Day 1.
Change From Baseline in Peak Heart Rate (PHR) at Day 24 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
PHR was defined as the maximum time matched baseline adjusted heart rate over 24 hours. Semi-recumbent PHR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; Day 24: predose, 2, 4, 6, 8, 12, and 16 hours postdose; and prior to dosing on Day 25. The repeated measurements were averaged before conducting the analysis. Change from baseline PHR was calculated as the peak heart rate at Day 24 minus baseline where baseline was defined as predose on Day 1.
Change From Baseline in Peak Heart Rate (PHR) at Day 29 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
PHR was defined as the maximum time matched baseline adjusted heart rate over 24 hours. Semi-recumbent PHR was measured in triplicate with at least a 1-2-minute interval between measurements at the following time points: baseline on Day 1; and Day 29: predose 2, 4, 6, 8, 12, 16, and 24 hours post dose. The repeated measurements were averaged before conducting the analysis. Change from baseline PHR was calculated as the peak heart rate at Day 29 minus baseline where baseline was defined as predose on Day 1.
Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 7 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
Semi-recumbent RMHR was measured in triplicate with at least a 1-2-minute interval between measurements. The repeated measurements were averaged for each time point. Change from baseline RMHR was calculated as the RMHR 24 hours after the Day 7 dose (predose Day 8) minus baseline. Baseline was an average of 2 readings prior to dosing on Day 1.
Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 14 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
Semi-recumbent RMHR was measured in triplicate with at least a 1-2-minute interval between measurements. The repeated measurements were averaged for each time point. Change from baseline RMHR was calculated as the RMHR 24 hours after the Day 14 dose (predose Day 15) minus baseline. Baseline was an average of 2 readings prior to dosing on Day 1.
Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 19 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
Semi-recumbent RMHR was measured in triplicate with at least a 1-2-minute interval between measurements. The repeated measurements were averaged for each time point. Change from baseline RMHR was calculated as the RMHR 24 hours after the Day 19 dose (predose Day 20) minus baseline. Baseline was an average of 2 readings prior to dosing on Day 1.
Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 24 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
Semi-recumbent RMHR was measured in triplicate with at least a 1-2-minute interval between measurements. The repeated measurements were averaged for each time point. Change from baseline RMHR was calculated as the RMHR 24 hours after the Day 24 dose (predose Day 25) minus baseline. Baseline was an average of 2 readings prior to dosing on Day 1.
Change From Baseline in Resting Morning Heart Rate (RMHR) After the Day 29 Dose for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
Semi-recumbent RMHR was measured in triplicate with at least a 1-2-minute interval between measurements. The repeated measurements were averaged for each time point. Change from baseline RMHR was calculated as the RMHR 24 hours after the Day 29 dose minus baseline. Baseline was an average of 2 readings prior to dosing on Day 1.
Area Under the Concentration-time Curve From 0 to 24 Hours (AUC0-24hr) of MK-8521 on Days 1, 7, and 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
AUC0-24hr was the area under the concentration-time curve of MK-8521 from time zero to 24 hours after administration. Plasma samples were collected from predose to 24 hours postdose for determination of AUC0-24hr. Individual values were natural log-transformed and evaluated with a linear-mixed effects model containing fixed effects for treatment, day, and treatment by day interaction, and a random effect for participant. Kenward and Roger's method was used to calculate the degree of freedom for the fixed effects. AUC0-24hr is presented as geometric mean and percent coefficient of variation of geometric mean.
Maximum Concentration (Cmax) of MK-8521 on Days 1 and 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
Cmax was the maximum observed concentration of MK-8521 in plasma after administration. Plasma samples were collected from predose to 24 hours postdose for determination of Cmax. Individual values were natural log-transformed and evaluated with a linear-mixed effects model containing fixed effects for treatment, day, and treatment by day interaction, and a random effect for participant. Kenward and Roger's method was used to calculate the degree of freedom for the fixed effects. Cmax is presented as geometric mean and percent coefficient of variation of geometric mean.
Maximum Concentration (Cmax) of MK-8521 on Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
Cmax was the maximum observed concentration of MK-8521 in plasma after administration on Day 14. Plasma samples were collected from predose to 120 hours postdose for determination of Cmax. Individual values were natural log-transformed and evaluated with a linear-mixed effects model containing fixed effects for treatment, day, and treatment by day interaction, and a random effect for participant. Kenward and Roger's method was used to calculate the degree of freedom for the fixed effects. Cmax is presented as geometric mean and percent coefficient of variation of geometric mean.
Trough Concentration (Ctrough) of MK-8521 on Days 1, 7, and 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
Ctrough was the lowest observed concentration of MK-8521 in plasma. Plasma samples were collected predose on Day 2 (sampled after the Day 1 dose and prior to Day 2 dose), 7, and 14 for determination of Ctrough. Individual values were natural log-transformed and evaluated with a linear-mixed effects model containing fixed effects for treatment, day, and treatment by day interaction, and a random effect for participant. Kenward and Roger's method was used to calculate the degree of freedom for the fixed effects. Ctrough is presented as geometric mean and percent coefficient of variation of geometric mean.
Time to Maximum Concentration (Tmax) of MK-8521 on Days 1 and 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
Tmax was the time required to reach the maximum concentration of MK-8521 in plasma. Plasma samples were collected from predose to 24 hours postdose for determination of Tmax. Tmax is presented as median with a full range.
Time to Maximum Concentration (Tmax) of MK-8521 on Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
Tmax was the time required to reach the maximum concentration of MK-8521 in plasma. Plasma samples were collected from predose to 120 hours postdose for determination of Tmax. Tmax is presented as median with a full range.
Apparent Terminal Half Life (t1/2) of MK-8521 on Days 1 and 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
t1/2 was the time required to divide the MK-8521 concentration by half after reaching pseudo-equilibrium. Plasma samples were collected from predose to 24 hours postdose for determination of t1/2. t1/2 is presented as geometric mean and percent coefficient of variation of geometric mean.
Apparent Terminal Half Life (t1/2) of MK-8521 on Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
t1/2 was the time required to divide the MK-8521 concentration by half after reaching pseudo-equilibrium. Plasma samples were collected from predose to 120 hours postdose for determination of t1/2. t1/2 was measured on Day 14 which is the longest time point for sampling for T2DM participants in Part 1. t1/2 is presented as geometric mean and percent coefficient of variation of geometric mean.
Accumulation Ratio of the Area Under the Concentration-time Curve From 0 to 24 Hours (AUC0-24hr) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
Plasma samples were collected from predose to 24 hours postdose for determination of the accumulation ratio of AUC0-24hr. The geometric mean accumulation ratio was calculated as Day 7 AUC0-24hr/Day 1 AUC0-24hr and presented as geometric mean ratio with a full range.
Accumulation Ratio of the Maximum Concentration (Cmax) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
Plasma samples were collected from predose to 24 hours postdose for determination of the accumulation ratio of Cmax. The geometric mean accumulation ratio was calculated as Day 7 Cmax/Day 1 Cmax and presented as geometric mean ratio with a full range.
Accumulation Ratio of the Trough Concentration (Ctrough) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
Plasma samples were collected predose on Days 2 (sampled after the Day 1 dose and prior to Day 2 dose) and 7 for determination of the accumulation ratio of Ctrough. The geometric mean accumulation ratio was calculated as Day 7 Ctrough/Day 1 Ctrough (sampled after the Day 1 dose and prior to Day 2 dose) and presented as geometric mean ratio with a full range.
Area Under the Concentration-time Curve From 0 to 24 Hours (AUC0-24hr) of MK-8521 on Days 1, 7, and 14 for Type 2 Diabetes Mellitus (T2DM) and Non-Diabetic Overweight/Obese Participants in Part 2
AUC0-24hr was the area under the concentration-time curve of MK-8521 from time zero to 24 hours after administration. Plasma samples were collected from predose to 24 hours postdose for determination of AUC0-24hr. Individual values were natural log-transformed and evaluated with a linear-mixed effects model containing fixed effects for treatment, day, and treatment by day interaction, and a random effect for participant. Kenward and Roger's method was used to calculate the degree of freedom for the fixed effects. AUC0-24hr is presented as geometric mean and percent coefficient of variation of geometric mean.
Accumulation Ratio of the Area Under the Concentration-time Curve From 0 to 24 Hours (AUC0-24hr) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) and Non-Diabetic Overweight/Obese Participants in Part 2
Plasma samples were collected from predose to 24 hours postdose for determination of the accumulation ratio of AUC0-24hr. The geometric mean accumulation ratio was calculated as Day 7 AUC0-24hr/Day 1 AUC0-24hr and presented as geometric mean ratio and percent geometric coefficient of variation.
Change From Baseline in Fasting Plasma Glucose (FPG) at Day 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
FPG was measured predose on Days 1 and 7. The change from baseline of FPG was calculated as the difference between the predose measurement on Day 1 (baseline) and the measurement obtained predose on Day 7. FPG is presented as mean change from baseline with a standard error.
Change From Baseline in Fasting Plasma Glucose (FPG) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
FPG was measured predose on Days 1 and 14. The change from baseline of FPG was calculated as the difference between the predose measurement on Day 1 (baseline) and the measurement obtained predose on Day 14. FPG is presented as mean change from baseline with a standard error.
Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 7 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
The 24-hour WMG was calculated as the area under the 24-hour glucose curve (AUC0-24hr) divided by 24 hours. Blood samples for glucose were collected immediately prior to, and after each meal. The change from baseline value for 24-hour WMG was calculated where baseline was the WMG before food and prior to treatment on Day 1. Blood for plasma glucose concentrations was obtained at predose Day 1 at pre meal (breakfast), 0.5, 1, 2, 3, 4 (pre lunch), 4.5, 5, 6, 7, 10 (pre dinner), 10.5, 11, 12, 13, 15 and 23 hours post breakfast meal; and on Day 7 at 1 (pre breakfast), 1.5, 2, 3, 4, 5 (pre lunch), 5.5, 6, 7, 8, 11 (pre dinner), 11.5, 12, 13, 14, 16, 24 hours post dose. Individual change from baseline 24-hour WMG was analyzed in a linear mixed effects model with fixed effects for treatment, day and treatment by day interaction, a random effect for participant, and baseline 24-hour WMG as a covariate. WMG is presented as least squares mean with a 95% confidence interval.
Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 1
The 24-hour WMG was calculated as the area under the 24-hour glucose curve (AUC0-24hr) divided by 24 hours. Blood samples for glucose were collected immediately prior to and after each meal. The change from baseline value for 24-hour WMG was calculated where baseline was the WMG before food and prior to treatment on Day 1. Blood for plasma glucose concentrations was obtained on Day -1 at pre meal (breakfast), 0.5, 1, 2, 3, 4 (pre lunch), 4.5, 5, 6, 7, 10 (pre dinner), 10.5, 11, 12, 13, 15 and 23 hours post breakfast meal; and on Day 14 at 1 (pre breakfast), 1.5, 2, 3, 4, 5 (pre lunch), 5.5, 6, 7, 8, 11(pre dinner), 11.5, 12, 13, 14, 16, 24 hours post dose. Individual change from baseline 24-hour WMG was analyzed in a linear mixed effects model with fixed effects for treatment, day and treatment by day interaction, a random effect for participant, and baseline 24-hour WMG as a covariate. WMG is presented as least squares mean with a 95% confidence interval.
Change From Baseline in Fasting Plasma Glucose (FPG) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
FPG was measured predose on Days 1 and 14. The change from baseline of FPG was calculated as the difference between the predose measurement on Day 1 (baseline) and the measurement obtained predose on Day 14. FPG is presented as least squares mean change from baseline with a 95% confidence interval.
Change From Baseline in Fasting Plasma Glucose (FPG) at Day 19 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
FPG was measured predose on Days 1 and 19. The change from baseline of FPG was calculated as the difference between the predose measurement on Day 1 (baseline) and the measurement obtained predose on Day 19. FPG is presented as least squares mean change from baseline with a 95% confidence interval.
Change From Baseline in Fasting Plasma Glucose (FPG) at Day 24 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
FPG was measured predose on Days 1 and 24. The change from baseline of FPG was calculated as the difference between the predose measurement on Day 1 (baseline) and the measurement obtained predose on Day 24. FPG is presented as least squares mean change from baseline with a 95% confidence interval.
Change From Baseline in Fasting Plasma Glucose (FPG) at Day 29 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
FPG was measured predose on Days 1 and 29. The change from baseline of FPG was calculated as the difference between the predose measurement on Day 1 (baseline) and the measurement obtained predose on Day 29. FPG is presented as least squares mean change from baseline with a 95% confidence interval.
Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 14 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
The 24-hour WMG was calculated as the area under the 24-hour glucose curve (AUC0-24hr) divided by 24 hours. Plasma glucose concentrations were obtained on Day -1 at pre meal (breakfast), 1, 3, 4 (pre lunch), 5, 7, 10 (pre dinner), 11, 13, 15 and 23 hours post breakfast meal and Day 14 at 1 (pre breakfast), 2, 4, 5 (pre lunch), 6, 8, 11 (pre dinner), 12, 14, 16, 24 hours post dose. The timing of samples on Day -1 are relative to the breakfast meal. Day 14 samples are relative to dosing. The change from baseline value for 24-hour WMG was calculated where baseline was the WMG before food and prior to treatment on Day 1. Individual change from baseline 24-hour WMG was analyzed in a linear mixed effects model with group, day and group by day interaction as fixed effects, baseline 24-hour WMG as a covariate, and participant as a random effect. WMG is presented as least squares mean with a 95% confidence interval.
Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 19 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
The 24-hour WMG was calculated as the area under the 24-hour glucose curve (AUC0-24hr) divided by 24 hours. Plasma glucose concentrations were obtained on Day -1 at pre meal (breakfast), 1, 3, 4 (pre lunch), 5, 7, 10 (pre dinner), 11, 13, 15 and 23 hours post breakfast meal and Day 19 at 1 (pre breakfast), 2, 4, 5 (pre lunch), 6, 8, 11 (pre dinner), 12, 14, 16, 24 hours post dose. The timing of samples on Day -1 are relative to the breakfast meal. Day 19 samples are relative to dosing. The change from baseline value for 24-hour WMG was calculated where baseline was the WMG before food and prior to treatment on Day 1. Individual change from baseline 24-hour WMG was analyzed in a linear mixed effects model with group, day and group by day interaction as fixed effects, baseline 24-hour WMG as a covariate, and participant as a random effect. WMG is presented as least squares mean with a 95% confidence interval.
Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 24 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
The 24-hour WMG was calculated as the area under the 24-hour glucose curve (AUC0-24hr) divided by 24 hours. Plasma glucose concentrations were obtained on Day -1 at pre meal (breakfast), 1, 3, 4 (pre lunch), 5, 7, 10 (pre dinner), 11, 13, 15 and 23 hours post breakfast meal and Day 24 at 1 (pre breakfast), 2, 4, 5 (pre lunch), 6, 8, 11 (pre dinner), 12, 14, 16, 24 hours post dose. The timing of samples on Day -1 are relative to the breakfast meal. Day 24 samples are relative to dosing. The change from baseline value for 24-hour WMG was calculated where baseline was the WMG before food and prior to treatment on Day 1. Individual change from baseline 24-hour WMG was analyzed in a linear mixed effects model with group, day and group by day interaction as fixed effects, baseline 24-hour WMG as a covariate, and participant as a random effect. WMG is presented as least squares mean with a 95% confidence interval.
Change From Baseline in 24-hour Weighted Mean Glucose (WMG) at Day 29 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
The 24-hour WMG was calculated as the area under the 24-hour glucose curve (AUC0-24hr) divided by 24 hours. Plasma glucose concentrations were obtained on Day -1 at pre meal (breakfast), 1, 3, 4 (pre lunch), 5, 7, 10 (pre dinner), 11, 13, 15 and 23 hours post breakfast meal and Day 29 at 1 (pre breakfast), 2, 4, 5 (pre lunch), 6, 8, 11 (pre dinner), 12, 14, 16, 24 hours post dose. The timing of samples on Day -1 are relative to the breakfast meal. Day 29 samples are relative to dosing. The change from baseline value for 24-hour WMG was calculated where baseline was the WMG before food and prior to treatment on Day 1. Individual change from baseline 24-hour WMG was analyzed in a linear mixed effects model with group, day and group by day interaction as fixed effects, baseline 24-hour WMG as a covariate, and participant as a random effect. WMG is presented as least squares mean with a 95% confidence interval.
Maximum Concentration (Cmax) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) and Non-Diabetic Overweight/Obese Participants in Part 2
Cmax was the maximum observed concentration of MK-8521 in plasma after administration. Plasma samples were collected from predose to 120 hours postdose for determination of Cmax. Per protocol, Cmax in the non-diabetic overweight/obese participants was not measured on Days 19, 24, and 29 because they only received 14 days of treatment. Individual values were natural log-transformed and evaluated with a linear-mixed effects model containing fixed effects for treatment, day, and treatment by day interaction, and a random effect for participant. Kenward and Roger's method was used to calculate the degree of freedom for the fixed effects. Cmax is presented as geometric mean and percent coefficient of variation of geometric mean.
Trough Concentration (Ctrough) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) and Non-Diabetic Overweight/Obese Participants in Part 2
Ctrough was the lowest observed concentration of MK-8521 in plasma. Plasma samples were collected predose on Day 2 (sampled after the Day 1 dose and prior to Day 2 dose), 7, 14, 19, 24, and 29 for determination of Ctrough. Per protocol, Ctrough in the non-diabetic overweight/obese participants was not measured on Days 19, 24, and 29 because they only received 14 days of treatment. Individual values were natural log-transformed and evaluated with a linear-mixed effects model containing fixed effects for treatment, day, and treatment by day interaction, and a random effect for participant. Kenward and Roger's method was used to calculate the degree of freedom for the fixed effects. Ctrough is presented as geometric mean and percent coefficient of variation of geometric mean.
Time to Maximum Concentration (Tmax) of MK-8521 for Type 2 Diabetes Mellitus (T2DM) and Non-Diabetic Overweight/Obese Participants in Part 2
Tmax was the time required to reach the maximum concentration of MK-8521 in plasma. Plasma samples were collected from predose to 120 hours postdose for determination of Tmax. Per protocol, Tmax in the non-diabetic overweight/obese participants was not measured on Days 19, 24, and 29 because they only received 14 days of treatment. Tmax is presented as median with a full range.
Apparent Terminal Half Life (t1/2) of MK-8521 on Day 29 for Type 2 Diabetes Mellitus (T2DM) Participants in Part 2
t1/2 was the time required to divide the MK-8521 concentration by half after reaching pseudo-equilibrium. Plasma samples were collected from predose to 120 hours postdose for determination of t1/2. Per protocol, t1/2 was measured on Day 29 which is the longest time point for sampling for T2DM participants 1/2 is presented as geometric mean and percent coefficient of variation of geometric mean.
Apparent Terminal Half Life (t1/2) of MK-8521 on Day 14 for Non-Diabetic Overweight/Obese Participants in Part 2
t1/2 was the time required to divide the MK-8521 concentration by half after reaching pseudo-equilibrium. Plasma samples were collected from predose to 24 hours postdose for determination of t1/2. Per protocol, t1/2 was measured on Day 14 which is the longest time point for sampling for non-diabetic overweight/obese participants 1/2 is presented as geometric mean and percent coefficient of variation of geometric mean.