Oral administration of PF-04991532; 75 mg given twice a day (BID) for 14 days

Oral administration of PF-04991532; 150 mg given twice a day (BID) for 14 days

Oral administration of PF-04991532; 300 mg given twice a day (BID) for 14 days

Oral administration of PF-04991532 Matching Placebo; given twice a day (BID) for 14 days

Time was computed as post morning dose.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

Area under the curve from time zero to 10 hours postdose of PF-04991532 (AUC10) of Day 14 divided by AUC10 of Day 1

Maximum observed plasma concentration of PF-04991532 after morning dose administration (Cmax(AM)) of Day 14 divided by Cmax(AM) of Day 1

Area under the curve from time zero to 24 Hours Postdose (AUC24) divided by total daily dose

Maximum Observed Plasma Concentration of PF-04991532 after Morning Dose Administration (Cmax(AM)) divided by dose

Mean daily glucose (MDG) was calculated based on the mean of 8 glucose measurements at pre-specified time points throughout the day.

Area under the curve of glucose from time 2 to 6 hours post morning dose (Glucose AUC(2-6)) was calculated based on 8 glucose measurements at prespecified time points using the linear trapezoidal method. Nominal times were used in the calculation. Liquid meal was administered 2 hours post morning dose of PF-04991532 for mixed meal tolerance test (MMTT).

The average of the Day -1 (hour -48), Day 0 (hour -24) and Day 1 pre-dose (hour 0) measurements was the baseline for fasting plasma glucose (FPG) analyses.

Area Under the Curve of Insulin from Time 2 to 6 Hours Post Morning Dose (Insulin AUC(2-6)) was calculated based on 8 insulin measurements at prespecified time points using the linear trapezoidal method. Nominal times were used in the calculation. Liquid meal was administered 2 hours post morning dose of PF-04991532 for mixed meal tolerance test (MMTT).

Area Under the Curve of C-peptide from Time 2 to 6 Hours Post Morning Dose (C-peptide AUC(2-6)) was calculated based on 8 C-peptide measurements at prespecified timepoints using the linear trapezoidal method. Nominal times were used in the calculation. Liquid meal was administered 2 hours post morning dose of PF-04991532 for mixed meal tolerance test (MMTT).

Baseline for fasting triglycerides (TG) was defined as the average of the Day -1 (hour -48), Day 0 (hour -24), and Day 1 pre-dose (hour 0) measurements. Baseline for fasting total cholesterol (TC), cholesterol (high-density lipoprotein (HDL)), and cholesterol (low-density lipoprotein (LDL)) was defined as the Day 1 pre-dose (hour 0) measurement.

PF-04991532 75 mg tablet orally twice daily for 2 weeks.

PF-04991532 150 mg tablet orally twice daily for 2 weeks.

PF-04991532 300 mg tablet orally twice daily for 2 weeks.

Total of all reporting groups

PF-04991532 75 mg tablet orally twice daily for 2 weeks.

PF-04991532 150 mg tablet orally twice daily for 2 weeks.

PF-04991532 300 mg tablet orally twice daily for 2 weeks.

Area under the plasma concentration versus time curve (AUC) from time zero to 24 hours post morning dose

The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest; "n" is the number of participants analyzed for each day.

Area under the plasma concentration versus time curve (AUC) from time zero to 10 hours post morning dose.

The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest; "n" is the number of participants analyzed for each day.

The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest; "n" is the number of participants analyzed for each day.

The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest.

The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest; "n" is the number of participants analyzed for each day.

Time was computed as post morning dose.

The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest; "n" is the number of participants analyzed for each day.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest; "n" is the number of participants analyzed for each day.

Area under the curve from time zero to 10 hours postdose of PF-04991532 (AUC10) of Day 14 divided by AUC10 of Day 1

The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest.

Maximum observed plasma concentration of PF-04991532 after morning dose administration (Cmax(AM)) of Day 14 divided by Cmax(AM) of Day 1

The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest.

Area under the curve from time zero to 24 Hours Postdose (AUC24) divided by total daily dose

The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest; "n" is the number of participants analyzed for each day.

Maximum Observed Plasma Concentration of PF-04991532 after Morning Dose Administration (Cmax(AM)) divided by dose

The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest; "n" is the number of participants analyzed for each day.

Mean daily glucose (MDG) was calculated based on the mean of 8 glucose measurements at pre-specified time points throughout the day.

The pharmacodynamic analysis population was defined as all randomized participants who received at least 1 dose of study medication (PF-04991532 or placebo) and had at least 1 of the pharmacodynamic parameters of interest.

Area under the curve of glucose from time 2 to 6 hours post morning dose (Glucose AUC(2-6)) was calculated based on 8 glucose measurements at prespecified time points using the linear trapezoidal method. Nominal times were used in the calculation. Liquid meal was administered 2 hours post morning dose of PF-04991532 for mixed meal tolerance test (MMTT).

The pharmacodynamic analysis population was defined as all randomized participants who received at least 1 dose of study medication (PF-04991532 or placebo) and had at least 1 of the pharmacodynamic parameters of interest.

The average of the Day -1 (hour -48), Day 0 (hour -24) and Day 1 pre-dose (hour 0) measurements was the baseline for fasting plasma glucose (FPG) analyses.

The pharmacodynamic analysis population was defined as all randomized participants who received at least 1 dose of study medication (PF-04991532 or placebo) and had at least 1 of the pharmacodynamic parameters of interest; "n" is the number of participants analyzed for each day.

Area Under the Curve of Insulin from Time 2 to 6 Hours Post Morning Dose (Insulin AUC(2-6)) was calculated based on 8 insulin measurements at prespecified time points using the linear trapezoidal method. Nominal times were used in the calculation. Liquid meal was administered 2 hours post morning dose of PF-04991532 for mixed meal tolerance test (MMTT).

The pharmacodynamic analysis population was defined as all randomized participants who received at least 1 dose of study medication (PF-04991532 or placebo) and had at least 1 of the pharmacodynamic parameters of interest.

Area Under the Curve of C-peptide from Time 2 to 6 Hours Post Morning Dose (C-peptide AUC(2-6)) was calculated based on 8 C-peptide measurements at prespecified timepoints using the linear trapezoidal method. Nominal times were used in the calculation. Liquid meal was administered 2 hours post morning dose of PF-04991532 for mixed meal tolerance test (MMTT).

The pharmacodynamic analysis population was defined as all randomized participants who received at least 1 dose of study medication (PF-04991532 or placebo) and had at least 1 of the pharmacodynamic parameters of interest.

Baseline for fasting triglycerides (TG) was defined as the average of the Day -1 (hour -48), Day 0 (hour -24), and Day 1 pre-dose (hour 0) measurements. Baseline for fasting total cholesterol (TC), cholesterol (high-density lipoprotein (HDL)), and cholesterol (low-density lipoprotein (LDL)) was defined as the Day 1 pre-dose (hour 0) measurement.

The pharmacodynamic analysis population was defined as all randomized participants who received at least 1 dose of study medication (PF-04991532 or placebo) and had at least 1 of the pharmacodynamic parameters of interest; "n" is the number of participants analyzed for each day.

PF-04991532 25 milligram (mg) tablet orally twice daily for 2 weeks.

PF-04991532 75 mg tablet orally twice daily for 2 weeks.

PF-04991532 150 mg tablet orally twice daily for 2 weeks.

PF-04991532 300 mg tablet orally twice daily for 2 weeks.

Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in MDG (Day 13) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.

Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in MDG (Day 13) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.

Treatment difference and 90% confidence interval (CI) were based on adjusted geometric mean.

Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in Glucose AUC(2-6) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.

Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in Glucose AUC(2-6) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.

Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 2 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.

Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 2 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.

Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 2 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.

Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 3 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.

Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 3 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.