Obesity, Overweight, Type 2 Diabetes
Conditions
Keywords
Metabolism and Nutrition Disorder
Brief summary
This is a study of tirzepatide in participants with type 2 diabetes who have obesity or are overweight. The main purpose is to learn more about how tirzepatide affects body weight. The study will last 79 weeks (22 visits).
Interventions
DRUGTirzepatide
Administered SC
OTHERPlacebo
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Have Type 2 Diabetes (T2DM) with HbA1c ≥7% to ≤10% at screening, on stable therapy for the last 3 months prior to screening. T2DM may be treated with diet/exercise alone or any oral glycemic-lowering agent (as per local labeling) EXCEPT dipeptidyl peptidase 4 (DPP-4) inhibitors or glucagon like peptide-1 receptor agonists (GLP-1 RAs) * Have a BMI of ≥27 kg/m² * Are overweight or have obesity * Have a history of at least 1 self-reported unsuccessful dietary effort to lose body weight * Are at least 18 years of age and age of majority per local laws and regulations
Exclusion criteria
* Have Type 1 diabetes mellitus, history of ketoacidosis or hyperosmolar state/coma or any other types of diabetes except T2DM * Have at least 2 confirmed fasting self-monitoring blood glucose (SMBG) values \>270 mg/dL(on 2 nonconsecutive days) prior to Visit 3 * Have proliferative diabetic retinopathy OR diabetic macular edema OR non-proliferative diabetic retinopathy that requires acute treatment * Have self-reported change in body weight \>5kg within 3 months prior to screening * Have had a history of chronic or acute pancreatitis * Change in body weight greater than 5 kg within 3 months prior to starting study * Obesity induced by other endocrinologic disorders or monogenetic or syndromic forms of obesity * Family or personal history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN-2) * History of significant active or unstable major depressive disorder (MDD) or other severe psychiatric disorder within the last 2 years * Any lifetime history of a suicide attempt
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Body Weight | Baseline, Week 72 | Least Squares Mean (LSMean) calculated using Mixed Model Repeated Measures (MMRM) model for post-baseline measures: Variable = Baseline + Analysis Country + Sex + Type of Antihyperglycemic Medication (AHM) Used at Randomization + Treatment + Time + Treatment\*Time (Type III sum of squares). |
| Percentage of Participants Who Achieve ≥5% Body Weight Reduction From Baseline | Week 72 | Percentage of participants who achieve ≥5% body weight reduction from baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieve ≥20% Body Weight Reduction From Baseline | Week 72 | Percentage of participants who achieve ≥20% body weight reduction from baseline |
| Change From Baseline in Absolute Body Weight | Baseline, Week 72 | LSMean calculated using MMRM model for post-baseline measures: Variable = Baseline + Analysis Country + Sex + Type of AHM Used at Randomization + Treatment + Time + Treatment\*Time (Type III sum of squares). |
| Change From Baseline in Body Mass Index (BMI) | Baseline, Week 72 | LSMean calculated using MMRM model for post-baseline measures: Variable = Baseline + Analysis Country + Sex + Type of AHM Used at Randomization + Treatment + Time + Treatment\*Time (Type III sum of squares). |
| Change From Baseline in Hemoglobin A1c (HbA1c) | Baseline, Week 72 | LSMean calculated using MMRM model for post-baseline measures: Variable = Baseline + Analysis Country + Sex + Type of AHM Used at Randomization + Treatment + Time + Treatment\*Time (Type III sum of squares). |
| Percentage of Participants Who Achieve HbA1c <7% | Week 72 | Percentage of participants who achieve HbA1c \<7% |
| Percentage of Participants Who Achieve HbA1c ≤6.5% | Week 72 | Percentage of participants who achieve HbA1c ≤6.5% |
| Percentage of Participants Who Achieve HbA1c <5.7% | Week 72 | Percentage of participants who achieve HbA1c \<5.7% |
| Change From Baseline in Fasting Glucose | Baseline, Week 72 | LSMean calculated using MMRM model for post-baseline measures: Variable = Baseline + Analysis Country + Sex + Type of AHM Used at Randomization + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Treatment + Time + Treatment\*Time (Type III sum of squares). |
| Change From Baseline in Waist Circumference | Baseline, Week 72 | LSMean calculated using MMRM model for post-baseline measures: Variable = Baseline + Analysis Country + Sex + Type of AHM Used at Randomization + Treatment + Time + Treatment\*Time (Type III sum of squares). |
| Percent Change From Baseline in Total Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg) | Baseline, Week 72 | Results are reported as model-based estimates and standard error (SE) from MMRM analysis using log transformation. |
| Percent Change From Baseline in Low Density Lipoprotein (LDL) Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg) | Baseline, Week 72 | Results are reported as model-based estimates and SE from MMRM analysis using log transformation. |
| Percentage of Participants Who Achieve ≥10% Body Weight Reduction From Baseline | Week 72 | Percentage of participants who achieve ≥10% body weight reduction from baseline |
| Percent Change From Baseline in Very Low Density Lipoprotein (VLDL) Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg) | Baseline, Week 72 | Results are reported as model-based estimates and SE from MMRM analysis using log transformation. |
| Percent Change From Baseline in Triglycerides (Pooled Doses of Tirzepatide 10 mg and 15 mg) | Baseline, Week 72 | Results are reported as model-based estimates and SE from MMRM analysis using log transformation. |
| Percent Change From Baseline in Non-High Density Lipoprotein (Non-HDL) Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg) | Baseline, Week 72 | Results are reported as model-based estimates and SE from MMRM analysis using log transformation. |
| Percent Change From Baseline in Free Fatty Acids (Pooled Doses of 10 mg and 15 mg Tirzepatide) | Baseline, Week 72 | Results are reported as model-based estimates and SE from MMRM analysis using log transformation. |
| Change From Baseline in Systolic Blood Pressure (SBP) (Pooled Doses of 10 mg and 15 mg Tirzepatide) | Baseline, Week 72 | LSMean was calculated using MMRM model for post-baseline measures: Variable = Baseline + Analysis Country + Sex + Type of AHM Used at Randomization + Treatment + Time + Treatment\*Time (Type III sum of squares). |
| Change From Baseline in Diastolic Blood Pressure (DBP) (Pooled Doses of 10 mg and 15 mg Tirzepatide) | Baseline, Week 72 | LSMean was calculated using MMRM model for post-baseline measures: Variable = Baseline + Analysis Country + Sex + Type of AHM Used at Randomization + Treatment + Time + Treatment\*Time (Type III sum of squares). |
| Percent Change From Baseline in Fasting Insulin | Baseline, Week 72 | Results are reported as model-based estimates and SE from MMRM analysis using log transformation. |
| Change From Baseline in Short Form 36 Health Survey Version 2 (SF-36v2) Acute Form Physical Functioning Domain Score | Baseline, Week 72 | The SF-36v2 acute, 1-week recall version is a 36-item, generic, patient-administered measure designed to assess the following 8 domains: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. The Physical-Functioning domain assesses limitations due to health now while the remaining domains assess functioning in the past week. Each domain is scored individually and information from these 8 domains are further aggregated into 2 health-component summary scores: Physical-Component Summary and Mental-Component Summary. Items are answered on Likert scales of varying lengths (3-, 5-, or 6- point scales).The summary scores range from 0 to 100, with higher scores indicating better levels of function and/or better health. |
| Change From Baseline in Impact of Weight on Quality of Life-Lite-Clinical Trials Version (IWQOL Lite-CT) Physical Function Composite Score | Baseline, Week 72 | The IWQOL-Lite-CT is a 20-item, obesity-specific patient reported outcome (PRO) instrument developed for use in obesity clinical trials. It assesses 2 primary domains of obesity-related health-related quality of life (HRQoL): physical (7 items), and psychosocial (13 items). A 5-item subset of the physical domain, the physical-function composite is also supported. Items in the physical-function composite describe physical impacts related to general and specific physical activities. All items in the physical domain are rated on either a 5-point frequency (never to always) scale or a 5-point truth (not at all true to completely true) scale. Total score of IWQOL-Lite-CT composite ranges from 0 to 100, with higher scores reflecting better quality of life. |
| Population Pharmacokinetics (PopPK): Steady State Area Under the Concentration Curve (AUC) of Tirzepatide | Week 8, 16, 36: 1 to 24 hours, 24 to 96 hours, or 120 to 168 hours postdose | Each participant was assigned via the Interactive Web Response System (IWRS) to one of the sampling PK time windows of 1 to 24 hours, 24 to 96 hours, or 120 to 168 hours postdose. The steady state AUC was evaluated using Population PK modeling. |
| Percent Change From Baseline in High Density Lipoprotein (HDL) Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg) | Baseline, Week 72 | Results are reported as model-based estimates and SE from MMRM analysis using log transformation. |
| Percentage of Participants Who Achieve ≥15% Body Weight Reduction From Baseline | Week 72 | Percentage of participants who achieve ≥15% body weight reduction from baseline |
Countries
Argentina, Brazil, India, Japan, Puerto Rico, Russia, Taiwan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received Placebo administered SC QW. | 315 |
| 10 mg Tirzepatide Participants received 10 mg Tirzepatide administered SC QW. | 312 |
| 15 mg Tirzepatide Participants received 15 mg Tirzepatide administered SC QW. | 311 |
| Total | 938 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 1 | 5 |
| Overall Study | Death | 0 | 2 | 0 |
| Overall Study | Lost to Follow-up | 8 | 4 | 10 |
| Overall Study | Other - As Reported by Investigator | 3 | 2 | 2 |
| Overall Study | Pregnancy | 2 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 16 | 7 | 10 |
Baseline characteristics
| Characteristic | 10 mg Tirzepatide | 15 mg Tirzepatide | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 54.3 years STANDARD_DEVIATION 10.7 | 53.6 years STANDARD_DEVIATION 10.6 | 54.7 years STANDARD_DEVIATION 10.5 | 54.2 years STANDARD_DEVIATION 10.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 184 Participants | 189 Participants | 188 Participants | 561 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 124 Participants | 112 Participants | 122 Participants | 358 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 10 Participants | 5 Participants | 19 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 44 Participants | 42 Participants | 39 Participants | 125 Participants |
| Race (NIH/OMB) Black or African American | 33 Participants | 22 Participants | 22 Participants | 77 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 12 Participants | 5 Participants | 23 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 228 Participants | 234 Participants | 248 Participants | 710 Participants |
| Region of Enrollment Argentina | 115 Participants | 115 Participants | 116 Participants | 346 Participants |
| Region of Enrollment Brazil | 29 Participants | 30 Participants | 30 Participants | 89 Participants |
| Region of Enrollment India | 8 Participants | 9 Participants | 9 Participants | 26 Participants |
| Region of Enrollment Japan | 24 Participants | 22 Participants | 21 Participants | 67 Participants |
| Region of Enrollment Russia | 13 Participants | 13 Participants | 17 Participants | 43 Participants |
| Region of Enrollment Taiwan | 9 Participants | 8 Participants | 8 Participants | 25 Participants |
| Region of Enrollment United States | 114 Participants | 114 Participants | 114 Participants | 342 Participants |
| Sex: Female, Male Female | 158 Participants | 159 Participants | 159 Participants | 476 Participants |
| Sex: Female, Male Male | 154 Participants | 152 Participants | 156 Participants | 462 Participants |
| Weight | 100.86 kilograms (kg) STANDARD_DEVIATION 20.93 | 99.60 kilograms (kg) STANDARD_DEVIATION 20.05 | 101.65 kilograms (kg) STANDARD_DEVIATION 22.26 | 100.71 kilograms (kg) STANDARD_DEVIATION 21.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 315 | 2 / 312 | 0 / 311 |
| other Total, other adverse events | 158 / 315 | 169 / 312 | 159 / 311 |
| serious Total, serious adverse events | 23 / 315 | 18 / 312 | 27 / 311 |
Outcome results
Primary
Percentage of Participants Who Achieve ≥5% Body Weight Reduction From Baseline
Percentage of participants who achieve ≥5% body weight reduction from baseline
Time frame: Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Achieve ≥5% Body Weight Reduction From Baseline | 30.55 percentage of participants |
| 10 mg Tirzepatide | Percentage of Participants Who Achieve ≥5% Body Weight Reduction From Baseline | 81.55 percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants Who Achieve ≥5% Body Weight Reduction From Baseline | 86.41 percentage of participants |
p-value: <0.00195% CI: [7.3, 15.84]Regression, Logistic
p-value: <0.00195% CI: [10.08, 23.14]Regression, Logistic
Primary
Percent Change From Baseline in Body Weight
Least Squares Mean (LSMean) calculated using Mixed Model Repeated Measures (MMRM) model for post-baseline measures: Variable = Baseline + Analysis Country + Sex + Type of Antihyperglycemic Medication (AHM) Used at Randomization + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Baseline, Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Body Weight | -3.3 percent change | Standard Error 0.49 |
| 10 mg Tirzepatide | Percent Change From Baseline in Body Weight | -13.4 percent change | Standard Error 0.48 |
| 15 mg Tirzepatide | Percent Change From Baseline in Body Weight | -15.7 percent change | Standard Error 0.49 |
p-value: <0.00195% CI: [-11.5, -8.8]Mixed Models Analysis
p-value: <0.00195% CI: [-13.7, -11]Mixed Models Analysis
Secondary
Change From Baseline in Absolute Body Weight
LSMean calculated using MMRM model for post-baseline measures: Variable = Baseline + Analysis Country + Sex + Type of AHM Used at Randomization + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Baseline, Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Absolute Body Weight | -3.2 kilograms (kg) | Standard Error 0.51 |
| 10 mg Tirzepatide | Change From Baseline in Absolute Body Weight | -13.5 kilograms (kg) | Standard Error 0.51 |
| 15 mg Tirzepatide | Change From Baseline in Absolute Body Weight | -15.6 kilograms (kg) | Standard Error 0.51 |
p-value: <0.00195% CI: [-11.7, -8.8]Mixed Models Analysis
p-value: <0.00195% CI: [-13.8, -11]Mixed Models Analysis
Secondary
Change From Baseline in Body Mass Index (BMI)
LSMean calculated using MMRM model for post-baseline measures: Variable = Baseline + Analysis Country + Sex + Type of AHM Used at Randomization + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Baseline, Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Body Mass Index (BMI) | -1.2 kilograms per meter squared (kg/m^2) | Standard Error 0.19 |
| 10 mg Tirzepatide | Change From Baseline in Body Mass Index (BMI) | -4.9 kilograms per meter squared (kg/m^2) | Standard Error 0.18 |
| 15 mg Tirzepatide | Change From Baseline in Body Mass Index (BMI) | -5.7 kilograms per meter squared (kg/m^2) | Standard Error 0.19 |
p-value: <0.00195% CI: [-4.2, -3.2]Mixed Models Analysis
p-value: <0.00195% CI: [-5, -4]Mixed Models Analysis
Secondary
Change From Baseline in Diastolic Blood Pressure (DBP) (Pooled Doses of 10 mg and 15 mg Tirzepatide)
LSMean was calculated using MMRM model for post-baseline measures: Variable = Baseline + Analysis Country + Sex + Type of AHM Used at Randomization + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Baseline, Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis. This analysis was planned to measure the outcome data under a single arm (pooled 10 mg and 15 mg Tirzepatide).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Diastolic Blood Pressure (DBP) (Pooled Doses of 10 mg and 15 mg Tirzepatide) | -0.2 millimeters of mercury (mmHg) | Standard Error 0.45 |
| 10 mg Tirzepatide | Change From Baseline in Diastolic Blood Pressure (DBP) (Pooled Doses of 10 mg and 15 mg Tirzepatide) | -2.6 millimeters of mercury (mmHg) | Standard Error 0.31 |
p-value: <0.00195% CI: [-3.5, -1.3]Mixed Models Analysis
Secondary
Change From Baseline in Fasting Glucose
LSMean calculated using MMRM model for post-baseline measures: Variable = Baseline + Analysis Country + Sex + Type of AHM Used at Randomization + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Baseline, Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Glucose | -2.42 milligrams per deciliter (mg/dL) | Standard Error 2.281 |
| 10 mg Tirzepatide | Change From Baseline in Fasting Glucose | -49.20 milligrams per deciliter (mg/dL) | Standard Error 1.94 |
| 15 mg Tirzepatide | Change From Baseline in Fasting Glucose | -51.67 milligrams per deciliter (mg/dL) | Standard Error 1.97 |
p-value: <0.00195% CI: [-52.67, -40.91]Mixed Models Analysis
p-value: <0.00195% CI: [-55.18, -43.33]Mixed Models Analysis
Secondary
Change From Baseline in Hemoglobin A1c (HbA1c)
LSMean calculated using MMRM model for post-baseline measures: Variable = Baseline + Analysis Country + Sex + Type of AHM Used at Randomization + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Baseline, Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Hemoglobin A1c (HbA1c) | -0.16 percentage of HbA1c | Standard Error 0.067 |
| 10 mg Tirzepatide | Change From Baseline in Hemoglobin A1c (HbA1c) | -2.14 percentage of HbA1c | Standard Error 0.06 |
| 15 mg Tirzepatide | Change From Baseline in Hemoglobin A1c (HbA1c) | -2.22 percentage of HbA1c | Standard Error 0.06 |
p-value: <0.00195% CI: [-2.15, -1.8]Mixed Models Analysis
p-value: <0.00195% CI: [-2.24, -1.88]Mixed Models Analysis
Secondary
Change From Baseline in Impact of Weight on Quality of Life-Lite-Clinical Trials Version (IWQOL Lite-CT) Physical Function Composite Score
The IWQOL-Lite-CT is a 20-item, obesity-specific patient reported outcome (PRO) instrument developed for use in obesity clinical trials. It assesses 2 primary domains of obesity-related health-related quality of life (HRQoL): physical (7 items), and psychosocial (13 items). A 5-item subset of the physical domain, the physical-function composite is also supported. Items in the physical-function composite describe physical impacts related to general and specific physical activities. All items in the physical domain are rated on either a 5-point frequency (never to always) scale or a 5-point truth (not at all true to completely true) scale. Total score of IWQOL-Lite-CT composite ranges from 0 to 100, with higher scores reflecting better quality of life.
Time frame: Baseline, Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis. Missing data was imputed using Last Observation Carried Forward (LOCF) method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Impact of Weight on Quality of Life-Lite-Clinical Trials Version (IWQOL Lite-CT) Physical Function Composite Score | 7.4 score on a scale | Standard Error 1.03 |
| 10 mg Tirzepatide | Change From Baseline in Impact of Weight on Quality of Life-Lite-Clinical Trials Version (IWQOL Lite-CT) Physical Function Composite Score | 14.3 score on a scale | Standard Error 1 |
| 15 mg Tirzepatide | Change From Baseline in Impact of Weight on Quality of Life-Lite-Clinical Trials Version (IWQOL Lite-CT) Physical Function Composite Score | 15.2 score on a scale | Standard Error 1.03 |
p-value: <0.00195% CI: [4.1, 9.7]ANCOVA
p-value: <0.00195% CI: [5, 10.7]ANCOVA
Secondary
Change From Baseline in Short Form 36 Health Survey Version 2 (SF-36v2) Acute Form Physical Functioning Domain Score
The SF-36v2 acute, 1-week recall version is a 36-item, generic, patient-administered measure designed to assess the following 8 domains: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. The Physical-Functioning domain assesses limitations due to health now while the remaining domains assess functioning in the past week. Each domain is scored individually and information from these 8 domains are further aggregated into 2 health-component summary scores: Physical-Component Summary and Mental-Component Summary. Items are answered on Likert scales of varying lengths (3-, 5-, or 6- point scales).The summary scores range from 0 to 100, with higher scores indicating better levels of function and/or better health.
Time frame: Baseline, Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis. Missing data was imputed using Last Observation Carried Forward (LOCF) method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Short Form 36 Health Survey Version 2 (SF-36v2) Acute Form Physical Functioning Domain Score | 1.6 score on a scale | Standard Error 0.4 |
| 10 mg Tirzepatide | Change From Baseline in Short Form 36 Health Survey Version 2 (SF-36v2) Acute Form Physical Functioning Domain Score | 3.4 score on a scale | Standard Error 0.39 |
| 15 mg Tirzepatide | Change From Baseline in Short Form 36 Health Survey Version 2 (SF-36v2) Acute Form Physical Functioning Domain Score | 3.8 score on a scale | Standard Error 0.4 |
p-value: 0.00195% CI: [0.7, 2.9]ANCOVA
p-value: <0.00195% CI: [1.1, 3.4]ANCOVA
Secondary
Change From Baseline in Systolic Blood Pressure (SBP) (Pooled Doses of 10 mg and 15 mg Tirzepatide)
LSMean was calculated using MMRM model for post-baseline measures: Variable = Baseline + Analysis Country + Sex + Type of AHM Used at Randomization + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Baseline, Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis. This analysis was planned to measure the outcome data under a single arm (pooled 10 mg and 15 mg Tirzepatide).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) (Pooled Doses of 10 mg and 15 mg Tirzepatide) | -1.0 millimeters of mercury (mmHg) | Standard Error 0.74 |
| 10 mg Tirzepatide | Change From Baseline in Systolic Blood Pressure (SBP) (Pooled Doses of 10 mg and 15 mg Tirzepatide) | -7.2 millimeters of mercury (mmHg) | Standard Error 0.52 |
p-value: <0.00195% CI: [-8, -4.4]Mixed Models Analysis
Secondary
Change From Baseline in Waist Circumference
LSMean calculated using MMRM model for post-baseline measures: Variable = Baseline + Analysis Country + Sex + Type of AHM Used at Randomization + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Baseline, Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Waist Circumference | -3.4 centimeters (cm) | Standard Error 0.51 |
| 10 mg Tirzepatide | Change From Baseline in Waist Circumference | -11.2 centimeters (cm) | Standard Error 0.5 |
| 15 mg Tirzepatide | Change From Baseline in Waist Circumference | -13.8 centimeters (cm) | Standard Error 0.51 |
p-value: <0.00195% CI: [-9.2, -6.4]Mixed Models Analysis
p-value: <0.00195% CI: [-11.8, -8.9]Mixed Models Analysis
Secondary
Percentage of Participants Who Achieve ≥10% Body Weight Reduction From Baseline
Percentage of participants who achieve ≥10% body weight reduction from baseline
Time frame: Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Achieve ≥10% Body Weight Reduction From Baseline | 8.68 percentage of participants |
| 10 mg Tirzepatide | Percentage of Participants Who Achieve ≥10% Body Weight Reduction From Baseline | 63.43 percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants Who Achieve ≥10% Body Weight Reduction From Baseline | 69.58 percentage of participants |
p-value: <0.00195% CI: [13.06, 33.58]Regression, Logistic
p-value: <0.00195% CI: [17.04, 44.39]Regression, Logistic
Secondary
Percentage of Participants Who Achieve ≥15% Body Weight Reduction From Baseline
Percentage of participants who achieve ≥15% body weight reduction from baseline
Time frame: Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Achieve ≥15% Body Weight Reduction From Baseline | 2.57 percentage of participants |
| 10 mg Tirzepatide | Percentage of Participants Who Achieve ≥15% Body Weight Reduction From Baseline | 41.42 percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants Who Achieve ≥15% Body Weight Reduction From Baseline | 51.78 percentage of participants |
p-value: <0.00195% CI: [13.81, 58.31]Regression, Logistic
p-value: <0.00195% CI: [21.2, 89.67]Regression, Logistic
Secondary
Percentage of Participants Who Achieve ≥20% Body Weight Reduction From Baseline
Percentage of participants who achieve ≥20% body weight reduction from baseline
Time frame: Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Achieve ≥20% Body Weight Reduction From Baseline | 0.96 percentage of participants |
| 10 mg Tirzepatide | Percentage of Participants Who Achieve ≥20% Body Weight Reduction From Baseline | 22.98 percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants Who Achieve ≥20% Body Weight Reduction From Baseline | 33.98 percentage of participants |
p-value: <0.00195% CI: [9.73, 83.73]Regression, Logistic
p-value: <0.00195% CI: [17.03, 144.94]Regression, Logistic
Secondary
Percentage of Participants Who Achieve HbA1c <5.7%
Percentage of participants who achieve HbA1c \<5.7%
Time frame: Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Achieve HbA1c <5.7% | 2.76 percentage of participants |
| 10 mg Tirzepatide | Percentage of Participants Who Achieve HbA1c <5.7% | 50.17 percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants Who Achieve HbA1c <5.7% | 55.33 percentage of participants |
p-value: <0.00195% CI: [20.46, 88.5]Regression, Logistic
p-value: <0.00195% CI: [26, 113.38]Regression, Logistic
Secondary
Percentage of Participants Who Achieve HbA1c ≤6.5%
Percentage of participants who achieve HbA1c ≤6.5%
Time frame: Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Achieve HbA1c ≤6.5% | 15.52 percentage of participants |
| 10 mg Tirzepatide | Percentage of Participants Who Achieve HbA1c ≤6.5% | 84.05 percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants Who Achieve HbA1c ≤6.5% | 86.67 percentage of participants |
p-value: <0.00195% CI: [25.61, 69.26]Regression, Logistic
p-value: <0.00195% CI: [34.29, 100.37]Regression, Logistic
Secondary
Percentage of Participants Who Achieve HbA1c <7%
Percentage of participants who achieve HbA1c \<7%
Time frame: Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Achieve HbA1c <7% | 29.31 percentage of participants |
| 10 mg Tirzepatide | Percentage of Participants Who Achieve HbA1c <7% | 90.03 percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants Who Achieve HbA1c <7% | 90.67 percentage of participants |
p-value: <0.00195% CI: [17.21, 45.59]Regression, Logistic
p-value: <0.00195% CI: [20.27, 57.67]Regression, Logistic
Secondary
Percent Change From Baseline in Fasting Insulin
Results are reported as model-based estimates and SE from MMRM analysis using log transformation.
Time frame: Baseline, Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Fasting Insulin | -14.5 percent change | Standard Error 3.39 |
| 10 mg Tirzepatide | Percent Change From Baseline in Fasting Insulin | -29.6 percent change | Standard Error 2.28 |
| 15 mg Tirzepatide | Percent Change From Baseline in Fasting Insulin | -40.3 percent change | Standard Error 1.99 |
p-value: <0.00195% CI: [-25.5, -8.9]Mixed Models Analysis
p-value: <0.00195% CI: [-37, -22.7]Mixed Models Analysis
Secondary
Percent Change From Baseline in Free Fatty Acids (Pooled Doses of 10 mg and 15 mg Tirzepatide)
Results are reported as model-based estimates and SE from MMRM analysis using log transformation.
Time frame: Baseline, Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis. This analysis was planned to measure the outcome data under a single arm (pooled 10 mg and 15 mg Tirzepatide).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Free Fatty Acids (Pooled Doses of 10 mg and 15 mg Tirzepatide) | 0.03 percent change | Standard Error 2.838 |
| 10 mg Tirzepatide | Percent Change From Baseline in Free Fatty Acids (Pooled Doses of 10 mg and 15 mg Tirzepatide) | -23.58 percent change | Standard Error 1.502 |
p-value: <0.00195% CI: [-28.62, -18.24]Mixed Models Analysis
Secondary
Percent Change From Baseline in High Density Lipoprotein (HDL) Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg)
Results are reported as model-based estimates and SE from MMRM analysis using log transformation.
Time frame: Baseline, Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis. This analysis was planned to measure the outcome data under a single arm (pooled 10 mg and 15 mg Tirzepatide).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in High Density Lipoprotein (HDL) Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg) | 1.10 percent change | Standard Error 1.048 |
| 10 mg Tirzepatide | Percent Change From Baseline in High Density Lipoprotein (HDL) Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg) | 8.19 percent change | Standard Error 0.782 |
p-value: <0.00195% CI: [4.4, 9.71]Mixed Models Analysis
Secondary
Percent Change From Baseline in Low Density Lipoprotein (LDL) Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg)
Results are reported as model-based estimates and SE from MMRM analysis using log transformation.
Time frame: Baseline, Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis. This analysis was planned to measure the outcome data under a single arm (pooled 10 mg and 15 mg Tirzepatide).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Low Density Lipoprotein (LDL) Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg) | 6.29 percent change | Standard Error 1.874 |
| 10 mg Tirzepatide | Percent Change From Baseline in Low Density Lipoprotein (LDL) Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg) | 2.72 percent change | Standard Error 1.264 |
p-value: 0.11295% CI: [-7.36, 0.81]Mixed Models Analysis
Secondary
Percent Change From Baseline in Non-High Density Lipoprotein (Non-HDL) Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg)
Results are reported as model-based estimates and SE from MMRM analysis using log transformation.
Time frame: Baseline, Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis. This analysis was planned to measure the outcome data under a single arm (pooled 10 mg and 15 mg Tirzepatide).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Non-High Density Lipoprotein (Non-HDL) Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg) | 2.30 percent change | Standard Error 1.573 |
| 10 mg Tirzepatide | Percent Change From Baseline in Non-High Density Lipoprotein (Non-HDL) Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg) | -6.64 percent change | Standard Error 1.001 |
p-value: <0.00195% CI: [-12.04, -5.32]Mixed Models Analysis
Secondary
Percent Change From Baseline in Total Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg)
Results are reported as model-based estimates and standard error (SE) from MMRM analysis using log transformation.
Time frame: Baseline, Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis. This analysis was planned to measure the outcome data under a single arm (pooled 10 mg and 15 mg Tirzepatide).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Total Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg) | 2.13 percent change | Standard Error 1.135 |
| 10 mg Tirzepatide | Percent Change From Baseline in Total Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg) | -2.58 percent change | Standard Error 0.755 |
p-value: <0.00195% CI: [-7.11, -2.03]Mixed Models Analysis
Secondary
Percent Change From Baseline in Triglycerides (Pooled Doses of Tirzepatide 10 mg and 15 mg)
Results are reported as model-based estimates and SE from MMRM analysis using log transformation.
Time frame: Baseline, Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis. This analysis was planned to measure the outcome data under a single arm (pooled 10 mg and 15 mg Tirzepatide).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Triglycerides (Pooled Doses of Tirzepatide 10 mg and 15 mg) | -5.8 percent change | Standard Error 2.32 |
| 10 mg Tirzepatide | Percent Change From Baseline in Triglycerides (Pooled Doses of Tirzepatide 10 mg and 15 mg) | -28.6 percent change | Standard Error 1.22 |
p-value: <0.00195% CI: [-28.6, -19.6]Mixed Models Analysis
Secondary
Percent Change From Baseline in Very Low Density Lipoprotein (VLDL) Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg)
Results are reported as model-based estimates and SE from MMRM analysis using log transformation.
Time frame: Baseline, Week 72
Population: All randomized participants who received at least one dose of study drug. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis. This analysis was planned to measure the outcome data under a single arm (pooled 10 mg and 15 mg Tirzepatide).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Very Low Density Lipoprotein (VLDL) Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg) | -6.0 percent change | Standard Error 2.18 |
| 10 mg Tirzepatide | Percent Change From Baseline in Very Low Density Lipoprotein (VLDL) Cholesterol (Pooled Doses of Tirzepatide 10 mg and 15 mg) | -27.9 percent change | Standard Error 1.16 |
p-value: <0.00195% CI: [-27.5, -18.9]Mixed Models Analysis
Secondary
Population Pharmacokinetics (PopPK): Steady State Area Under the Concentration Curve (AUC) of Tirzepatide
Each participant was assigned via the Interactive Web Response System (IWRS) to one of the sampling PK time windows of 1 to 24 hours, 24 to 96 hours, or 120 to 168 hours postdose. The steady state AUC was evaluated using Population PK modeling.
Time frame: Week 8, 16, 36: 1 to 24 hours, 24 to 96 hours, or 120 to 168 hours postdose
Population: All participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Population Pharmacokinetics (PopPK): Steady State Area Under the Concentration Curve (AUC) of Tirzepatide | 153000 nanograms*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 19.5 |
| 10 mg Tirzepatide | Population Pharmacokinetics (PopPK): Steady State Area Under the Concentration Curve (AUC) of Tirzepatide | 234000 nanograms*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 19.2 |