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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.