Type 2 Diabetes Mellitus
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy of the study drug tirzepatide in participants with type 2 diabetes mellitus.
Interventions
DRUGtirzepatide
Administered SC
DRUGDulaglutide
Administered SC
DRUGPlacebo
Administered SC
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Have had type 2 diabetes (T2D) for ≥6 months according to the World Health Organization (WHO) classification. * Have HbA1c of 7.0% to 10.5%, inclusive, as assessed by the central laboratory. * If on metformin, have been treated with stable doses of metformin for at least 3 months. * Have a body mass index (BMI) ≥23 and \<50 kilograms per square meter.
Exclusion criteria
* Have type 1 diabetes (T1D). * Have used any glucose-lowering medication other than metformin within 3 months prior to study entry or during screening/lead-in period or have used any glucagon-like peptide-1 receptor agonists (GLP-1 RAs) at any time in the past. * Have had any of the following cardiovascular conditions: acute myocardial infarction (MI), New York Heart Association Class III or Class IV heart failure, or cerebrovascular accident (stroke). * Have acute or chronic hepatitis, signs and symptoms of any other liver disease other than nonalcoholic fatty liver disease (NAFLD), or alanine aminotransferase (ALT) level \>2.5 times the upper limit of the reference range, as determined by the central laboratory at study entry; participants with NAFLD are eligible for participation in this trial. * Have had chronic or acute pancreatitis any time prior to study entry. * Have an estimated glomerular filtration rate (eGFR) \<45 milliliters/minute/1.73 square meter, calculated by the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation. * Have serum calcitonin ≥20 picograms per milliliter, as determined by the central laboratory at study entry. * Have any condition that is a contraindication for use of the GLP-1 RA class (per country-specific labels) at study entry or develop such condition between study entry and randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 26 in Hemoglobin A1c (HbA1c) Bayesian Dose Response | Baseline, Week 26 | HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.This was a Bayesian dose response analysis of HbA1c (%) change from baseline. At baseline: Mean (SD = Standard Deviation) of baseline HbA1c (%). After baseline: Posterior Mean (SD = Posterior Standard Deviation) of HbA1c (%) change from baseline. The Least Squares Mean is Posterior mean. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 26 in HbA1c | Baseline, Week 26 | HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. The Least Squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included the independent variables: Baseline + Baseline BMI Group + Baseline Metformin Flag + Treatment + Time + Treatment\*Time. |
| Change From Baseline to Week 12 in HbA1c | Baseline, Week 12 | HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. The Least Squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included the independent variables: Baseline + Baseline BMI Group + Baseline Metformin Flag + Treatment + Time + Treatment\*Time. |
| Change From Baseline in Body Weight | Baseline, Week 26 | Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with independent variables: Baseline + Baseline HbA1C Group + Baseline BMI Group + Baseline Metformin Flag + Treatment + Time + Treatment\*Time. |
| Percentage of Participants With 5% or Greater Body Weight Loss From Baseline | Week 26 | Percentage of participants with 5% or greater body weight loss from baseline last observation carried forward (LOCF) analyses using Logistic regression model with Baseline value + Baseline HbA1C Group + Baseline BMI Group + Baseline Metformin + Treatment as factors. |
| Percentage of Participants With 10% or Greater Body Weight Loss From Baseline | Week 26 | Percentage of participants with 10% or greater body weight loss from baseline LOCF analyses using Logistic regression model with Baseline value + Baseline HbA1C Group + Baseline BMI Group + Baseline Metformin + Treatment as factors. |
| Percentage of Participants Reaching the HbA1c Target of ≤6.5% | Week 26 | Percentage of participants with HbA1c ≤6.5% at Week 26 using a logistic regression model for endpoint used last observation carried forward (LOCF) method including baseline value, baseline BMI Group, baseline Metformin and treatment as factors. |
| Percentage of Participants Reaching the HbA1c Target of <7.0% | Week 26 | Percentage of participants with HbA1c \<7.0% at Week 26 using a logistic regression model for endpoint used last observation carried forward (LOCF) method including baseline value, baseline BMI Group, baseline Metformin and treatment as factors. |
| Change From Baseline to Week 12 in Hemoglobin A1c (HbA1c) Bayesian Dose Response | Baseline, Week 12 | HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. This was a Bayesian dose response analysis of HbA1c (%) change from baseline. At baseline: Mean (SD = Standard Deviation) of baseline HbA1c (%). After baseline: Posterior Mean (SD = Posterior Standard Deviation) of HbA1c (%) change from baseline. The Least Squares Mean is Posterior mean. |
| Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) | Baseline, Week 26 | LS means were calculated using MMRM model with independent variables: Baseline, Baseline HbA1C Group, Baseline BMI Group, Baseline Metformin Flag,Treatment, time, treatment\*time. |
| Change From Baseline in Total Cholesterol | Baseline, Week 26 | LS means were calculated using MMRM model with independent variables: Baseline, Baseline HbA1C Group, Baseline BMI Group, Baseline Metformin Flag, Treatment, Time, Treatment\*Time. |
| Change From Baseline in Triglycerides | Baseline, Week 26 | LS means were calculated using MMRM model with independent variables: Baseline, Baseline HbA1C Group, Baseline BMI Group, Baseline Metformin Flag, Treatment, Time, Treatment\*Time. |
| Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) | Baseline, Week 26 | LS means were calculated using MMRM model with independent variables: Baseline, Baseline HbA1C Group, Baseline BMI Group, Baseline Metformin Flag, Treatment, Time, Treatment\*Time. |
| Change From Baseline in Waist Circumference | Baseline, Week 26 | LS means were calculated using MMRM model with independent variables: Baseline, Baseline HbA1C Group, Baseline BMI Group, Baseline Metformin Flag, Treatment, Time, Treatment\*Time. |
| Number of Participants With Anti-Drug Antibodies | Baseline through Week 30 | Number of Participants With Anti-Drug Antibodies. |
| Pharmacokinetics (PK): Model Predicted Concentration at Steady State (Css) of Tirzepatide | Predose: Week 1,8,12 and 26; Postdose: Week 1,2,4 and 12 | Pharmacokinetics (PK): Model Predicted Concentration at Steady State (Css) of Tirzepatide |
| Change From Baseline in Fasting Blood Glucose | Baseline, Week 26 | Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with covariates: Baseline + Baseline HbA1C Group + Baseline BMI Group + Baseline Metformin Flag + Treatment + Time + Treatment\*Time. |
Countries
Poland, Puerto Rico, Slovakia, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Tirzepatide placebo and dulaglutide placebo administered subcutaneously (SC) once weekly. | 51 |
| 1 mg Tirzepatide 1 mg tirzepatide administered SC once weekly. Dulaglutide placebo administered SC once weekly. | 52 |
| 5 mg Tirzepatide 5 mg tirzepatide administered SC once weekly. Dulaglutide placebo administered SC once weekly. | 55 |
| 10 mg Tirzepatide 10 mg tirzepatide administered SC once weekly. Dulaglutide placebo administered SC once weekly. | 51 |
| 15 mg Tirzepatide 15 mg tirzepatide administered SC once weekly. Dulaglutide placebo administered SC once weekly. | 53 |
| 1.5 mg Dulaglutide 1.5 mg Dulaglutide administered SC once weekly. Tirzepatide placebo administered SC once weekly. | 54 |
| Total | 316 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 1 | 2 | 2 |
| Overall Study | Death | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Inadvertent Enrollment | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 4 | 0 | 1 | 4 | 2 |
| Overall Study | Participant Started New Diabetic Drug | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Principle Investigator Decision | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 3 | 3 | 1 | 2 | 1 |
Baseline characteristics
| Characteristic | 1 mg Tirzepatide | Placebo | Total | 1.5 mg Dulaglutide | 15 mg Tirzepatide | 10 mg Tirzepatide | 5 mg Tirzepatide |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 57.4 years STANDARD_DEVIATION 8.85 | 56.6 years STANDARD_DEVIATION 8.85 | 57.2 years STANDARD_DEVIATION 8.54 | 58.7 years STANDARD_DEVIATION 7.81 | 56.0 years STANDARD_DEVIATION 7.58 | 56.5 years STANDARD_DEVIATION 9.92 | 57.9 years STANDARD_DEVIATION 8.22 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 25 Participants | 27 Participants | 142 Participants | 19 Participants | 23 Participants | 26 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 19 Participants | 139 Participants | 27 Participants | 27 Participants | 20 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 5 Participants | 35 Participants | 8 Participants | 3 Participants | 5 Participants | 10 Participants |
| Hemoglobin A1C (HbA1c) at Baseline | 8.21 Percentage of HbA1c STANDARD_DEVIATION 0.905 | 8.04 Percentage of HbA1c STANDARD_DEVIATION 0.861 | 8.14 Percentage of HbA1c STANDARD_DEVIATION 0.966 | 8.13 Percentage of HbA1c STANDARD_DEVIATION 0.954 | 8.13 Percentage of HbA1c STANDARD_DEVIATION 1.061 | 8.15 Percentage of HbA1c STANDARD_DEVIATION 1.072 | 8.17 Percentage of HbA1c STANDARD_DEVIATION 0.961 |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 5 Participants | 15 Participants | 1 Participants | 2 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 5 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 2 Participants | 30 Participants | 4 Participants | 6 Participants | 7 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 9 Participants | 2 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 42 Participants | 41 Participants | 253 Participants | 44 Participants | 43 Participants | 37 Participants | 46 Participants |
| Region of Enrollment Poland | 7 Participants | 6 Participants | 31 Participants | 2 Participants | 6 Participants | 6 Participants | 4 Participants |
| Region of Enrollment Puerto Rico | 4 Participants | 4 Participants | 16 Participants | 1 Participants | 1 Participants | 3 Participants | 3 Participants |
| Region of Enrollment Slovakia | 4 Participants | 5 Participants | 35 Participants | 8 Participants | 3 Participants | 5 Participants | 10 Participants |
| Region of Enrollment United States | 37 Participants | 36 Participants | 234 Participants | 43 Participants | 43 Participants | 37 Participants | 38 Participants |
| Sex: Female, Male Female | 23 Participants | 22 Participants | 148 Participants | 30 Participants | 31 Participants | 21 Participants | 21 Participants |
| Sex: Female, Male Male | 29 Participants | 29 Participants | 168 Participants | 24 Participants | 22 Participants | 30 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 51 | 1 / 52 | 0 / 55 | 0 / 51 | 0 / 53 | 0 / 54 |
| other Total, other adverse events | 17 / 51 | 17 / 52 | 29 / 55 | 32 / 51 | 39 / 53 | 31 / 54 |
| serious Total, serious adverse events | 2 / 51 | 2 / 52 | 1 / 55 | 3 / 51 | 2 / 53 | 3 / 54 |
Outcome results
Primary
Change From Baseline to Week 26 in Hemoglobin A1c (HbA1c) Bayesian Dose Response
HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.This was a Bayesian dose response analysis of HbA1c (%) change from baseline. At baseline: Mean (SD = Standard Deviation) of baseline HbA1c (%). After baseline: Posterior Mean (SD = Posterior Standard Deviation) of HbA1c (%) change from baseline. The Least Squares Mean is Posterior mean.
Time frame: Baseline, Week 26
Population: All randomized participants who received at least one dose of study drug and had a baseline and postbaseline excluding data after rescue drug initiation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 26 in Hemoglobin A1c (HbA1c) Bayesian Dose Response | -0.06 Percentage of HbA1c | Standard Deviation 0.14 |
| 1 mg Tirzepatide | Change From Baseline to Week 26 in Hemoglobin A1c (HbA1c) Bayesian Dose Response | -1.06 Percentage of HbA1c | Standard Deviation 0.11 |
| 5 mg Tirzepatide | Change From Baseline to Week 26 in Hemoglobin A1c (HbA1c) Bayesian Dose Response | -1.73 Percentage of HbA1c | Standard Deviation 0.08 |
| 10 mg Tirzepatide | Change From Baseline to Week 26 in Hemoglobin A1c (HbA1c) Bayesian Dose Response | -1.89 Percentage of HbA1c | Standard Deviation 0.08 |
| 15 mg Tirzepatide | Change From Baseline to Week 26 in Hemoglobin A1c (HbA1c) Bayesian Dose Response | -1.94 Percentage of HbA1c | Standard Deviation 0.09 |
| 1.5 mg Dulaglutide | Change From Baseline to Week 26 in Hemoglobin A1c (HbA1c) Bayesian Dose Response | -1.21 Percentage of HbA1c | Standard Deviation 0.14 |
Secondary
Change From Baseline in Body Weight
Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with independent variables: Baseline + Baseline HbA1C Group + Baseline BMI Group + Baseline Metformin Flag + Treatment + Time + Treatment\*Time.
Time frame: Baseline, Week 26
Population: All randomized participants who received at least one dose of study drug and had a baseline and postbaseline value excluding data after study drug discontinuation or rescue drug initiation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Body Weight | -0.4 Kilograms (Kg) | Standard Error 0.81 |
| 1 mg Tirzepatide | Change From Baseline in Body Weight | -0.9 Kilograms (Kg) | Standard Error 0.8 |
| 5 mg Tirzepatide | Change From Baseline in Body Weight | -4.8 Kilograms (Kg) | Standard Error 0.77 |
| 10 mg Tirzepatide | Change From Baseline in Body Weight | -8.7 Kilograms (Kg) | Standard Error 0.8 |
| 15 mg Tirzepatide | Change From Baseline in Body Weight | -11.3 Kilograms (Kg) | Standard Error 0.88 |
| 1.5 mg Dulaglutide | Change From Baseline in Body Weight | -2.7 Kilograms (Kg) | Standard Error 0.78 |
p-value: 0.65595% CI: [-2.7, 1.7]Mixed Models Analysis
p-value: <0.00195% CI: [-6.6, -2.3]Mixed Models Analysis
p-value: <0.00195% CI: [-10.5, -6]Mixed Models Analysis
p-value: <0.00195% CI: [-13.3, -8.6]Mixed Models Analysis
Secondary
Change From Baseline in Fasting Blood Glucose
Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with covariates: Baseline + Baseline HbA1C Group + Baseline BMI Group + Baseline Metformin Flag + Treatment + Time + Treatment\*Time.
Time frame: Baseline, Week 26
Population: All randomized participants who received at least one dose of study drug who had a baseline and postbaseline value excluding data after study drug discontinuation or rescue drug initiation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Blood Glucose | 15.5 milligrams per deciliter (mg/dL) | Standard Error 6.66 |
| 1 mg Tirzepatide | Change From Baseline in Fasting Blood Glucose | -6.8 milligrams per deciliter (mg/dL) | Standard Error 6.43 |
| 5 mg Tirzepatide | Change From Baseline in Fasting Blood Glucose | -40.7 milligrams per deciliter (mg/dL) | Standard Error 6.23 |
| 10 mg Tirzepatide | Change From Baseline in Fasting Blood Glucose | -60.7 milligrams per deciliter (mg/dL) | Standard Error 6.36 |
| 15 mg Tirzepatide | Change From Baseline in Fasting Blood Glucose | -57.5 milligrams per deciliter (mg/dL) | Standard Error 7.1 |
| 1.5 mg Dulaglutide | Change From Baseline in Fasting Blood Glucose | -21.2 milligrams per deciliter (mg/dL) | Standard Error 6.4 |
p-value: 0.0195% CI: [-39.4, -5.3]Mixed Models Analysis
p-value: <0.00195% CI: [-72.9, -39.5]Mixed Models Analysis
p-value: <0.00195% CI: [-93.3, -59.2]Mixed Models Analysis
p-value: <0.00195% CI: [-90.9, -55.2]Mixed Models Analysis
Secondary
Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C)
LS means were calculated using MMRM model with independent variables: Baseline, Baseline HbA1C Group, Baseline BMI Group, Baseline Metformin Flag,Treatment, time, treatment\*time.
Time frame: Baseline, Week 26
Population: All randomized participants who received at least one dose of study drug and had a baseline and postbaseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) | 0.0 Millimoles Per Litre (mmol/L) | Standard Error 0.03 |
| 1 mg Tirzepatide | Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) | -0.0 Millimoles Per Litre (mmol/L) | Standard Error 0.03 |
| 5 mg Tirzepatide | Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) | 0.0 Millimoles Per Litre (mmol/L) | Standard Error 0.03 |
| 10 mg Tirzepatide | Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) | 0.0 Millimoles Per Litre (mmol/L) | Standard Error 0.03 |
| 15 mg Tirzepatide | Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) | 0.1 Millimoles Per Litre (mmol/L) | Standard Error 0.03 |
| 1.5 mg Dulaglutide | Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) | 0.0 Millimoles Per Litre (mmol/L) | Standard Error 0.03 |
p-value: 0.39695% CI: [-0.1, 0]Mixed Models Analysis
p-value: 0.90395% CI: [-0.1, 0.1]Mixed Models Analysis
p-value: 0.53695% CI: [-0.1, 0.1]Mixed Models Analysis
p-value: 0.32595% CI: [0, 0.1]Mixed Models Analysis
Secondary
Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C)
LS means were calculated using MMRM model with independent variables: Baseline, Baseline HbA1C Group, Baseline BMI Group, Baseline Metformin Flag, Treatment, Time, Treatment\*Time.
Time frame: Baseline, Week 26
Population: All randomized participants who received at least one dose of study drug and had a baseline and postbaseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) | 0.2 Millimoles Per Litre (mmol/L) | Standard Error 0.12 |
| 1 mg Tirzepatide | Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) | 0.2 Millimoles Per Litre (mmol/L) | Standard Error 0.11 |
| 5 mg Tirzepatide | Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) | 0.0 Millimoles Per Litre (mmol/L) | Standard Error 0.11 |
| 10 mg Tirzepatide | Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) | -0.0 Millimoles Per Litre (mmol/L) | Standard Error 0.11 |
| 15 mg Tirzepatide | Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) | -0.1 Millimoles Per Litre (mmol/L) | Standard Error 0.12 |
| 1.5 mg Dulaglutide | Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) | -0.1 Millimoles Per Litre (mmol/L) | Standard Error 0.11 |
p-value: 0.91995% CI: [-0.3, 0.3]Mixed Models Analysis
p-value: 0.19495% CI: [-0.5, 0.1]Mixed Models Analysis
p-value: 0.14595% CI: [-0.5, 0.1]Mixed Models Analysis
p-value: 0.06795% CI: [-0.6, 0]Mixed Models Analysis
Secondary
Change From Baseline in Total Cholesterol
LS means were calculated using MMRM model with independent variables: Baseline, Baseline HbA1C Group, Baseline BMI Group, Baseline Metformin Flag, Treatment, Time, Treatment\*Time.
Time frame: Baseline, Week 26
Population: All randomized participants who received at least one dose of study drug and had a baseline and postbaseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Total Cholesterol | 0.3 Millimoles Per Litre (mmol/L) | Standard Error 0.13 |
| 1 mg Tirzepatide | Change From Baseline in Total Cholesterol | 0.2 Millimoles Per Litre (mmol/L) | Standard Error 0.13 |
| 5 mg Tirzepatide | Change From Baseline in Total Cholesterol | -0.1 Millimoles Per Litre (mmol/L) | Standard Error 0.12 |
| 10 mg Tirzepatide | Change From Baseline in Total Cholesterol | -0.3 Millimoles Per Litre (mmol/L) | Standard Error 0.12 |
| 15 mg Tirzepatide | Change From Baseline in Total Cholesterol | -0.3 Millimoles Per Litre (mmol/L) | Standard Error 0.13 |
| 1.5 mg Dulaglutide | Change From Baseline in Total Cholesterol | -0.2 Millimoles Per Litre (mmol/L) | Standard Error 0.12 |
p-value: 0.56595% CI: [-0.4, 0.2]Mixed Models Analysis
p-value: 0.0195% CI: [-0.7, -0.1]Mixed Models Analysis
p-value: 0.00195% CI: [-0.9, -0.2]Mixed Models Analysis
p-value: <0.00195% CI: [-0.9, -0.3]Mixed Models Analysis
Secondary
Change From Baseline in Triglycerides
LS means were calculated using MMRM model with independent variables: Baseline, Baseline HbA1C Group, Baseline BMI Group, Baseline Metformin Flag, Treatment, Time, Treatment\*Time.
Time frame: Baseline, Week 26
Population: All randomized participants who received at least one dose of study drug and had a baseline and postbaseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Triglycerides | 0.3 Millimoles Per Litre (mmol/L) | Standard Error 0.16 |
| 1 mg Tirzepatide | Change From Baseline in Triglycerides | -0.0 Millimoles Per Litre (mmol/L) | Standard Error 0.16 |
| 5 mg Tirzepatide | Change From Baseline in Triglycerides | -0.5 Millimoles Per Litre (mmol/L) | Standard Error 0.15 |
| 10 mg Tirzepatide | Change From Baseline in Triglycerides | -0.7 Millimoles Per Litre (mmol/L) | Standard Error 0.15 |
| 15 mg Tirzepatide | Change From Baseline in Triglycerides | -0.8 Millimoles Per Litre (mmol/L) | Standard Error 0.16 |
| 1.5 mg Dulaglutide | Change From Baseline in Triglycerides | -0.3 Millimoles Per Litre (mmol/L) | Standard Error 0.15 |
p-value: 0.16495% CI: [-0.7, 0.1]Mixed Models Analysis
p-value: <0.00195% CI: [-1.1, -0.4]Mixed Models Analysis
p-value: <0.00195% CI: [-1.4, -0.6]Mixed Models Analysis
p-value: <0.00195% CI: [-1.5, -0.7]Mixed Models Analysis
Secondary
Change From Baseline in Waist Circumference
LS means were calculated using MMRM model with independent variables: Baseline, Baseline HbA1C Group, Baseline BMI Group, Baseline Metformin Flag, Treatment, Time, Treatment\*Time.
Time frame: Baseline, Week 26
Population: All randomized participants who received at least one dose of study drug and had a baseline and postbaseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Waist Circumference | -1.3 centimeters (cm) | Standard Error 0.91 |
| 1 mg Tirzepatide | Change From Baseline in Waist Circumference | -2.1 centimeters (cm) | Standard Error 0.89 |
| 5 mg Tirzepatide | Change From Baseline in Waist Circumference | -5.1 centimeters (cm) | Standard Error 0.86 |
| 10 mg Tirzepatide | Change From Baseline in Waist Circumference | -7.4 centimeters (cm) | Standard Error 0.88 |
| 15 mg Tirzepatide | Change From Baseline in Waist Circumference | -10.2 centimeters (cm) | Standard Error 1 |
| 1.5 mg Dulaglutide | Change From Baseline in Waist Circumference | -2.5 centimeters (cm) | Standard Error 0.87 |
p-value: 0.53995% CI: [-3.1, 1.6]Mixed Models Analysis
p-value: 0.00195% CI: [-6.1, -1.5]Mixed Models Analysis
p-value: <0.00195% CI: [-8.4, -3.7]Mixed Models Analysis
p-value: <0.00195% CI: [-11.3, -6.4]Mixed Models Analysis
Secondary
Change From Baseline to Week 12 in HbA1c
HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. The Least Squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included the independent variables: Baseline + Baseline BMI Group + Baseline Metformin Flag + Treatment + Time + Treatment\*Time.
Time frame: Baseline, Week 12
Population: randomized participants who received at least one dose of study drug who had a baseline and postbaseline value excluding data after study drug discontinuation or rescue drug initiation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 12 in HbA1c | -0.1 Percentage of HbA1c | Standard Error 0.13 |
| 1 mg Tirzepatide | Change From Baseline to Week 12 in HbA1c | -0.9 Percentage of HbA1c | Standard Error 0.13 |
| 5 mg Tirzepatide | Change From Baseline to Week 12 in HbA1c | -1.7 Percentage of HbA1c | Standard Error 0.13 |
| 10 mg Tirzepatide | Change From Baseline to Week 12 in HbA1c | -2.0 Percentage of HbA1c | Standard Error 0.13 |
| 15 mg Tirzepatide | Change From Baseline to Week 12 in HbA1c | -2.1 Percentage of HbA1c | Standard Error 0.15 |
| 1.5 mg Dulaglutide | Change From Baseline to Week 12 in HbA1c | -1.2 Percentage of HbA1c | Standard Error 0.13 |
p-value: <0.00195% CI: [-1.1, -0.4]Mixed Models Analysis
p-value: <0.00195% CI: [-2, -1.3]Mixed Models Analysis
p-value: <0.00195% CI: [-2.3, -1.5]Mixed Models Analysis
p-value: <0.00195% CI: [-2.4, -1.7]Mixed Models Analysis
Secondary
Change From Baseline to Week 12 in Hemoglobin A1c (HbA1c) Bayesian Dose Response
HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. This was a Bayesian dose response analysis of HbA1c (%) change from baseline. At baseline: Mean (SD = Standard Deviation) of baseline HbA1c (%). After baseline: Posterior Mean (SD = Posterior Standard Deviation) of HbA1c (%) change from baseline. The Least Squares Mean is Posterior mean.
Time frame: Baseline, Week 12
Population: All randomized participants who received at least one dose of study drug and had a baseline and postbaseline value excluding data after rescue drug initiation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 12 in Hemoglobin A1c (HbA1c) Bayesian Dose Response | -0.05 Percentage of HbA1c | Standard Deviation 0.13 |
| 1 mg Tirzepatide | Change From Baseline to Week 12 in Hemoglobin A1c (HbA1c) Bayesian Dose Response | -0.94 Percentage of HbA1c | Standard Deviation 0.1 |
| 5 mg Tirzepatide | Change From Baseline to Week 12 in Hemoglobin A1c (HbA1c) Bayesian Dose Response | -1.54 Percentage of HbA1c | Standard Deviation 0.07 |
| 10 mg Tirzepatide | Change From Baseline to Week 12 in Hemoglobin A1c (HbA1c) Bayesian Dose Response | -1.68 Percentage of HbA1c | Standard Deviation 0.08 |
| 15 mg Tirzepatide | Change From Baseline to Week 12 in Hemoglobin A1c (HbA1c) Bayesian Dose Response | -1.72 Percentage of HbA1c | Standard Deviation 0.08 |
| 1.5 mg Dulaglutide | Change From Baseline to Week 12 in Hemoglobin A1c (HbA1c) Bayesian Dose Response | -1.08 Percentage of HbA1c | Standard Deviation 0.13 |
Secondary
Change From Baseline to Week 26 in HbA1c
HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. The Least Squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included the independent variables: Baseline + Baseline BMI Group + Baseline Metformin Flag + Treatment + Time + Treatment\*Time.
Time frame: Baseline, Week 26
Population: All randomized participants who received at least one dose of study drug who had a baseline and postbaseline value excluding data after study drug discontinuation or rescue drug initiation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 26 in HbA1c | 0.1 Percentage of HbA1c | Standard Error 0.16 |
| 1 mg Tirzepatide | Change From Baseline to Week 26 in HbA1c | -0.7 Percentage of HbA1c | Standard Error 0.16 |
| 5 mg Tirzepatide | Change From Baseline to Week 26 in HbA1c | -1.6 Percentage of HbA1c | Standard Error 0.15 |
| 10 mg Tirzepatide | Change From Baseline to Week 26 in HbA1c | -2.0 Percentage of HbA1c | Standard Error 0.16 |
| 15 mg Tirzepatide | Change From Baseline to Week 26 in HbA1c | -2.4 Percentage of HbA1c | Standard Error 0.17 |
| 1.5 mg Dulaglutide | Change From Baseline to Week 26 in HbA1c | -1.1 Percentage of HbA1c | Standard Error 0.15 |
p-value: <0.00195% CI: [-1.2, -0.4]Mixed Models Analysis
p-value: <0.00195% CI: [-2.2, -1.3]Mixed Models Analysis
p-value: <0.00195% CI: [-2.5, -1.6]Mixed Models Analysis
p-value: <0.00195% CI: [-2.9, -2]Mixed Models Analysis
Secondary
Number of Participants With Anti-Drug Antibodies
Number of Participants With Anti-Drug Antibodies.
Time frame: Baseline through Week 30
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Anti-Drug Antibodies | 0 Participants |
| 1 mg Tirzepatide | Number of Participants With Anti-Drug Antibodies | 16 Participants |
| 5 mg Tirzepatide | Number of Participants With Anti-Drug Antibodies | 19 Participants |
| 10 mg Tirzepatide | Number of Participants With Anti-Drug Antibodies | 24 Participants |
| 15 mg Tirzepatide | Number of Participants With Anti-Drug Antibodies | 26 Participants |
| 1.5 mg Dulaglutide | Number of Participants With Anti-Drug Antibodies | 0 Participants |
Secondary
Percentage of Participants Reaching the HbA1c Target of ≤6.5%
Percentage of participants with HbA1c ≤6.5% at Week 26 using a logistic regression model for endpoint used last observation carried forward (LOCF) method including baseline value, baseline BMI Group, baseline Metformin and treatment as factors.
Time frame: Week 26
Population: All randomized participants who received at least one dose of study drug excluding data after study drug discontinuation or rescue drug initiation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Reaching the HbA1c Target of ≤6.5% | 2.0 percentage of participants |
| 1 mg Tirzepatide | Percentage of Participants Reaching the HbA1c Target of ≤6.5% | 15.4 percentage of participants |
| 5 mg Tirzepatide | Percentage of Participants Reaching the HbA1c Target of ≤6.5% | 63.6 percentage of participants |
| 10 mg Tirzepatide | Percentage of Participants Reaching the HbA1c Target of ≤6.5% | 82.0 percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants Reaching the HbA1c Target of ≤6.5% | 58.5 percentage of participants |
| 1.5 mg Dulaglutide | Percentage of Participants Reaching the HbA1c Target of ≤6.5% | 38.9 percentage of participants |
p-value: 0.03Regression, Logistic
p-value: <0.001Regression, Logistic
p-value: <0.001Regression, Logistic
p-value: <0.001Regression, Logistic
Secondary
Percentage of Participants Reaching the HbA1c Target of <7.0%
Percentage of participants with HbA1c \<7.0% at Week 26 using a logistic regression model for endpoint used last observation carried forward (LOCF) method including baseline value, baseline BMI Group, baseline Metformin and treatment as factors.
Time frame: Week 26
Population: All randomized participants who received at least one dose of study drug excluding data after study drug discontinuation or rescue drug initiation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Reaching the HbA1c Target of <7.0% | 11.8 percentage of participants |
| 1 mg Tirzepatide | Percentage of Participants Reaching the HbA1c Target of <7.0% | 32.7 percentage of participants |
| 5 mg Tirzepatide | Percentage of Participants Reaching the HbA1c Target of <7.0% | 69.1 percentage of participants |
| 10 mg Tirzepatide | Percentage of Participants Reaching the HbA1c Target of <7.0% | 90.0 percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants Reaching the HbA1c Target of <7.0% | 77.4 percentage of participants |
| 1.5 mg Dulaglutide | Percentage of Participants Reaching the HbA1c Target of <7.0% | 51.9 percentage of participants |
p-value: 0.008Regression, Logistic
p-value: <0.001Regression, Logistic
p-value: <0.001Regression, Logistic
p-value: <0.001Regression, Logistic
Secondary
Percentage of Participants With 10% or Greater Body Weight Loss From Baseline
Percentage of participants with 10% or greater body weight loss from baseline LOCF analyses using Logistic regression model with Baseline value + Baseline HbA1C Group + Baseline BMI Group + Baseline Metformin + Treatment as factors.
Time frame: Week 26
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With 10% or Greater Body Weight Loss From Baseline | 0 percentage of participants |
| 1 mg Tirzepatide | Percentage of Participants With 10% or Greater Body Weight Loss From Baseline | 5.8 percentage of participants |
| 5 mg Tirzepatide | Percentage of Participants With 10% or Greater Body Weight Loss From Baseline | 16.4 percentage of participants |
| 10 mg Tirzepatide | Percentage of Participants With 10% or Greater Body Weight Loss From Baseline | 39.2 percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants With 10% or Greater Body Weight Loss From Baseline | 37.7 percentage of participants |
| 1.5 mg Dulaglutide | Percentage of Participants With 10% or Greater Body Weight Loss From Baseline | 9.3 percentage of participants |
p-value: 0.193Regression, Logistic
p-value: 0.036Regression, Logistic
p-value: 0.003Regression, Logistic
p-value: 0.003Regression, Logistic
Secondary
Percentage of Participants With 5% or Greater Body Weight Loss From Baseline
Percentage of participants with 5% or greater body weight loss from baseline last observation carried forward (LOCF) analyses using Logistic regression model with Baseline value + Baseline HbA1C Group + Baseline BMI Group + Baseline Metformin + Treatment as factors.
Time frame: Week 26
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With 5% or Greater Body Weight Loss From Baseline | 0 percentage of participants |
| 1 mg Tirzepatide | Percentage of Participants With 5% or Greater Body Weight Loss From Baseline | 13.5 percentage of participants |
| 5 mg Tirzepatide | Percentage of Participants With 5% or Greater Body Weight Loss From Baseline | 47.3 percentage of participants |
| 10 mg Tirzepatide | Percentage of Participants With 5% or Greater Body Weight Loss From Baseline | 70.6 percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants With 5% or Greater Body Weight Loss From Baseline | 62.3 percentage of participants |
| 1.5 mg Dulaglutide | Percentage of Participants With 5% or Greater Body Weight Loss From Baseline | 22.2 percentage of participants |
p-value: 0.053Regression, Logistic
p-value: 0.002Regression, Logistic
p-value: <0.001Regression, Logistic
p-value: <0.001Regression, Logistic
Secondary
Pharmacokinetics (PK): Model Predicted Concentration at Steady State (Css) of Tirzepatide
Pharmacokinetics (PK): Model Predicted Concentration at Steady State (Css) of Tirzepatide
Time frame: Predose: Week 1,8,12 and 26; Postdose: Week 1,2,4 and 12
Population: All randomized participants who received at least one dose of Tirzepatide study drug excluding post rescue data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Pharmacokinetics (PK): Model Predicted Concentration at Steady State (Css) of Tirzepatide | 78.6 Nanograms Per Millilitre (ng/mL) | Geometric Coefficient of Variation 29 |
| 1 mg Tirzepatide | Pharmacokinetics (PK): Model Predicted Concentration at Steady State (Css) of Tirzepatide | 394 Nanograms Per Millilitre (ng/mL) | Geometric Coefficient of Variation 29 |
| 5 mg Tirzepatide | Pharmacokinetics (PK): Model Predicted Concentration at Steady State (Css) of Tirzepatide | 787 Nanograms Per Millilitre (ng/mL) | Geometric Coefficient of Variation 29 |
| 10 mg Tirzepatide | Pharmacokinetics (PK): Model Predicted Concentration at Steady State (Css) of Tirzepatide | 1180 Nanograms Per Millilitre (ng/mL) | Geometric Coefficient of Variation 29 |