Obesity
Conditions
Keywords
Metabolism and Nutrition Disorder, Obesity Related Health Problems, Obesity Disease
Brief summary
The main purpose of this study is to learn more about tirzepatide in participants with obesity disease. The study will also measure how Tirzepatide affects body weight with a low-calorie diet and increased physical activity. The study will last around 72 Weeks.
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
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have a BMI of greater than or equal to ≥27 kg/m² and \<less than 35 kg/m² with at least 2 obesity-related health problems or ≥35 kg/m² with at least 1 obesity-related health problems. Health problems are IGT, hyperlipidemia, or NAFLD. * Have a history of at least 1 self-reported unsuccessful dietary effort to lose body weight.
Exclusion criteria
* Have diabetes. * Acute or chronic liver disease other than NAFLD. * Have a self-reported change in body weight \>5 kg within 3 months prior to screening. * Have or plan to have endoscopic and/or device-based therapy for obesity or have had device removal within the last 6 months. * Have renal impairment measured as estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73 m2, calculated by Japanese Society of Nephrology coefficient-modified Chronic Kidney Disease-Epidemiology equation during screening. * Have a known clinically significant gastric emptying abnormality. * Have had a history of chronic or acute pancreatitis. * Have thyroid-stimulating hormone outside of the range of 0.4 to 6.0 micro units per milliliter (μIU/mL) at screening. * Have obesity induced by other endocrinologic disorders or diagnosed monogenetic or syndromic forms of obesity. * Have a history of significant active or unstable major depressive disorder or other severe psychiatric disorder within the last 2 years. * Have a cardiovascular condition within 3 months prior to randomization * Have a family or personal history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia Syndrome type 2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Change in Body Weight | Baseline, 72 Weeks | Mean percent change in body weight was measured. Least squares (LS) mean was determined using mixed model repeated measures (MMRM) model with Baseline + impaired glucose tolerance (IGT) at Screening + Hyperlipidemia at Screening + non-alcoholic fatty liver disease (NAFLD) at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables. |
| Percentage of Participants Who Achieve ≥5% Body Weight Reduction | Week 72 | Percentage of Participants Who Achieve ≥5% Body Weight Reduction |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Oral Glucose Tolerance (OGTT) 2-hr Glucose for Participants With Impaired Glucose Tolerance (IGT) at Baseline | Baseline, Week 72 | Change from Baseline in OGTT 2-hr Glucose for Participants with IGT at Baseline. LS mean was determined by MMRM model with Baseline + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables. |
| Percent Change From Baseline in Fasting Lipids [Triglycerides (TG)] for Participants With Hyperlipidemia at Baseline | Baseline, Week 72 | Percent Change from Baseline in Fasting Lipids TG for Participants with Hyperlipidemia at Baseline. LS mean was determined by MMRM model with log (Baseline) + NAFLD at Screening + IGT at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables. |
| Percent Change From Baseline in Hepatic Fat Fraction (HFF) for Participants With Non-alcoholic Fatty Liver Disease [NAFLD] | Baseline, Week 72 | Percent Change from Baseline in HFF for participants diagnosed as NAFLD by MRI at Baseline. LS mean was determined by ANCOVA model with Baseline + Hyperlipidemia at Screening + IGT at Screening + Sex + Treatment (Type III sum of squares) as variables. Percent Change from Baseline in HFF for participants with NAFLD is reported. NAFLD was diagnosed by Magnetic Resonance Imaging (MRI) at Baseline. This was evaluated only for participants who were diagnosed with NAFLD at baseline by MRI. |
| Percentage of Participants Who Achieved Improvements of IGT | Week 72 | Percentage of Participants Who Achieved Improvements of IGT. This was evaluated only for participants with IGT at baseline. |
| Percentage of Participants Who Achieved Improvements of Hyperlipidemia | Week 72 | Percentage of Participants Who Achieved Improvements of Hyperlipidemia. This was evaluated only for participants with hyperlipidemia at baseline. |
| Percentage of Participants Who Achieved Improvements of NAFLD | Week 72 | Percentage of Participants Who Achieved Improvements of NAFLD. This was evaluated only for participants who were diagnosed as NAFLD by MRI at Baseline. |
| Percentage of Participants Who Achieve ≥10% Body Weight Reduction | Week 72 | Percentage of Participants Who Achieve ≥10% body weight reduction. |
| Percentage of Participants Who Achieve ≥15% Body Weight Reduction | Week 72 | Percentage of Participants Who Achieve ≥15% body weight reduction. |
| Change From Baseline in Absolute Body Weight | Baseline, Week 72 | Change from Baseline in Absolute Body Weight. LS mean was determined by MMRM model with Baseline + IGT at Screening + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables. |
| Change From Baseline in Body Mass Index (BMI) | Baseline, Week 72 | Change from Baseline in BMI. LS mean was determined using MMRM model with Baseline + IGT at Screening + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables. |
| Percent Change From Baseline in Visceral Adipose Tissue (VAT) | Baseline, Week 72 | Percent Change from Baseline in VAT. LS mean was determined by MMRM model with Baseline + IGT at Screening + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables. |
| Percentage of Participants Who Had Improvement in Obesity-related Health Problems | Week 72 | Percentage of participants who had improvement in obesity-related health problems |
| Change From Baseline in VAT/SAT Ratio | Baseline, Week 72 | Change from Baseline in VAT/SAT Ratio. LS mean was determined by MMRM model with Baseline + IGT at Screening + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables. |
| Percentage of Participants Who Achieved VAT <100 Square Centimeter (cm²) From Baseline for Participants With VAT≥100 cm² at Baseline | Week 72 | Percentage of Participants Who Achieve VAT \<100 cm² from Baseline for participants with VAT≥100 cm² at Baseline. |
| Change From Baseline in Waist Circumference | Baseline, Week 72 | Change from Baseline in Waist Circumference. LS mean was determined using MMRM model with = Baseline + IGT at Screening + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables. |
| Change From Baseline in Hemoglobin A1c (HbA1c) | Baseline, Week 72 | Change from Baseline in HbA1c was assessed only for Participants with IGT at Baseline. LS mean was determined using MMRM model with = Baseline + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables. |
| Change From Baseline in Fasting Insulin for Participants With IGT at Baseline | Baseline, Week 72 | Change from Baseline in Fasting Insulin for Participants with IGT at Baseline. LS mean was determined using MMRM model log(Baseline) + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables. |
| Change From Baseline in Systolic Blood Pressure | Baseline, Week 72 | Change from Baseline in Systolic Blood Pressure. LS mean was determined using MMRM model with Baseline + Hyperlipidemia at Screening + NAFLD at Screening + IGT at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables. |
| Change From Baseline in Diastolic Blood Pressure | Baseline, Week 72 | Change from Baseline in Diastolic Blood Pressure. LS mean was determined using MMRM model with Baseline + Hyperlipidemia at Screening + NAFLD at Screening + IGT at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables. |
| Change From Baseline in Short Form 36 Version 2 Health Survey (SF-36v2) Acute Form Physical Functioning Domain Score | Baseline, Week 72 | The SF-36v2 acute form, 1-week recall assesses participants' health-related quality of life (HRQoL) on 8 domains: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. Information from these 8 domains is further aggregated into 2 health component summary scores: Physical Component Summary and Mental Component Summary. Items are answered on Likert scales of varying lengths. Scoring of each domain and both summary scores are norm based and presented in the form of T scores, with a mean of 50 and standard deviation of 10; higher scores indicate better levels of function and/or better health. Range cannot be specified in norm-based scores. LS mean was determined using ANCOVA model with Week 0 (Visit 3) + IGT at Screening + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment (Type III sum of squares) as variables. |
| 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 consists of 20 items, assessing 2 primary domains of obesity related 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. LS mean was determined using ANCOVA model with Week 0 (Visit 3) + IGT at Screening + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment (Type III sum of squares) as variables. |
| Change From Baseline in Euro Quality of Life Five Dimensions (EQ-5D-5L) | Baseline, Week 72 | The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the participants. It comprises of 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, unable to perform/extreme problems). In addition to the health profile, a single health state index value can be derived based on a formula that attaches weights to each of the levels in each dimension. This index value ranges between ˂0 (where 0 is a health state equivalent to death; negative values are valued as worse than dead) to 1 (perfect health). LS mean was determined using ANCOVA model with Week 0 (Visit 3) + IGT at Screening + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment (Type III sum of squares) as variables. |
| Percent Change From Baseline in Subcutaneous Adipose Tissue (SAT) | Baseline, Week 72 | Percent Change from Baseline in SAT. LS mean was determined by MMRM model with Baseline + IGT at Screening + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables. |
| Change From Baseline in Fasting Glucose for Participants With IGT at Baseline | Baseline, Week 72 | Change from Baseline in Fasting Glucose for Participants with IGT at Baseline. LS mean was determined by MMRM model with = Baseline + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables. |
Countries
Japan
Participant flow
Recruitment details
267 participants were randomized in the study. However, due to good clinical practice (GCP) compliance issues identified at one of the investigative sites, all 42 participants from that site were excluded from the study analyses
Participants by arm
| Arm | Count |
|---|---|
| 10 mg Tirzepatide Participants received maintenance dose 10 mg with dose escalation starting from 2.5 mg, 5 mg, 7.5 mg and then 10 mg tirzepatide administered SC QW. | 73 |
| 15 mg Tirzepatide Participants received maintenance dose 15 mg with dose escalation starting from 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg and then 15 mg tirzepatide administered SC QW. | 77 |
| Placebo Participants received matching placebo administered SC QW. | 75 |
| Total | 225 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 8 | 5 |
| Overall Study | Participants Excluded Due to GCP Compliance Issue | 15 | 13 | 14 |
| Overall Study | Physician Decision | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 3 | 3 |
Baseline characteristics
| Characteristic | 10 mg Tirzepatide | Total | Placebo | 15 mg Tirzepatide |
|---|---|---|---|---|
| Age, Continuous | 49.00 years STANDARD_DEVIATION 10.87 | 50.80 years STANDARD_DEVIATION 10.74 | 52.30 years STANDARD_DEVIATION 10.93 | 51.10 years STANDARD_DEVIATION 10.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 73 Participants | 225 Participants | 75 Participants | 77 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 73 Participants | 225 Participants | 75 Participants | 77 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Japan | 73 Participants | 225 Participants | 75 Participants | 77 Participants |
| Sex: Female, Male Female | 30 Participants | 92 Participants | 30 Participants | 32 Participants |
| Sex: Female, Male Male | 43 Participants | 133 Participants | 45 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 73 | 0 / 77 | 0 / 75 |
| other Total, other adverse events | 59 / 73 | 65 / 77 | 51 / 75 |
| serious Total, serious adverse events | 8 / 73 | 5 / 77 | 5 / 75 |
Outcome results
Primary
Mean Percent Change in Body Weight
Mean percent change in body weight was measured. Least squares (LS) mean was determined using mixed model repeated measures (MMRM) model with Baseline + impaired glucose tolerance (IGT) at Screening + Hyperlipidemia at Screening + non-alcoholic fatty liver disease (NAFLD) at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables.
Time frame: Baseline, 72 Weeks
Population: All participants, excluding the GCP compliance investigative site, who received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Mean Percent Change in Body Weight | -17.8 Percent change | Standard Error 0.94 |
| 15 mg Tirzepatide | Mean Percent Change in Body Weight | -22.7 Percent change | Standard Error 0.9 |
| Placebo | Mean Percent Change in Body Weight | -1.7 Percent change | Standard Error 0.9 |
p-value: <0.00195% CI: [-18.7, -13.5]Mixed Models Analysis
p-value: <0.00195% CI: [-23.6, -18.5]Mixed Models Analysis
Primary
Percentage of Participants Who Achieve ≥5% Body Weight Reduction
Percentage of Participants Who Achieve ≥5% Body Weight Reduction
Time frame: Week 72
Population: All participants, excluding the GCP compliance investigative site, who received at least one dose of study drug, had a baseline and at least one post-baseline value for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg Tirzepatide | Percentage of Participants Who Achieve ≥5% Body Weight Reduction | 94.37 Percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants Who Achieve ≥5% Body Weight Reduction | 96.05 Percentage of participants |
| Placebo | Percentage of Participants Who Achieve ≥5% Body Weight Reduction | 20 Percentage of participants |
p-value: <0.00195% CI: [29.06, 492.67]Mixed Models Analysis
p-value: <0.00195% CI: [36.03, 654.53]Mixed Models Analysis
Secondary
Change From Baseline in Absolute Body Weight
Change from Baseline in Absolute Body Weight. LS mean was determined by MMRM model with Baseline + IGT at Screening + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables.
Time frame: Baseline, Week 72
Population: All participants, excluding the GCP compliance investigative site, who received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Change From Baseline in Absolute Body Weight | -16.0 kilograms (kg) | Standard Error 0.86 |
| 15 mg Tirzepatide | Change From Baseline in Absolute Body Weight | -20.8 kilograms (kg) | Standard Error 0.82 |
| Placebo | Change From Baseline in Absolute Body Weight | -1.5 kilograms (kg) | Standard Error 0.82 |
p-value: <0.00195% CI: [-16.8, -12.2]Mixed Models Analysis
p-value: <0.00195% CI: [-21.6, -17]Mixed Models Analysis
Secondary
Change From Baseline in Body Mass Index (BMI)
Change from Baseline in BMI. LS mean was determined using MMRM model with Baseline + IGT at Screening + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables.
Time frame: Baseline, Week 72
Population: All participants, excluding the GCP compliance investigative site, who received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Change From Baseline in Body Mass Index (BMI) | -5.8 kilograms per metres squared (kg/m^2) | Standard Error 0.32 |
| 15 mg Tirzepatide | Change From Baseline in Body Mass Index (BMI) | -7.7 kilograms per metres squared (kg/m^2) | Standard Error 0.3 |
| Placebo | Change From Baseline in Body Mass Index (BMI) | -0.6 kilograms per metres squared (kg/m^2) | Standard Error 0.3 |
p-value: <0.00195% CI: [-6.1, -4.4]Mixed Models Analysis
p-value: <0.00195% CI: [-8, -6.3]Mixed Models Analysis
Secondary
Change From Baseline in Diastolic Blood Pressure
Change from Baseline in Diastolic Blood Pressure. LS mean was determined using MMRM model with Baseline + Hyperlipidemia at Screening + NAFLD at Screening + IGT at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables.
Time frame: Baseline, Week 72
Population: All participants, excluding the GCP compliance investigative site, who received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Change From Baseline in Diastolic Blood Pressure | -5.9 millimeters of Mercury (mmHg) | Standard Error 1.09 |
| 15 mg Tirzepatide | Change From Baseline in Diastolic Blood Pressure | -6.3 millimeters of Mercury (mmHg) | Standard Error 1.04 |
| Placebo | Change From Baseline in Diastolic Blood Pressure | 0.5 millimeters of Mercury (mmHg) | Standard Error 1.04 |
p-value: <0.00195% CI: [-9.3, -3.4]Mixed Models Analysis
p-value: <0.00195% CI: [-9.7, -3.9]Mixed Models Analysis
Secondary
Change From Baseline in Euro Quality of Life Five Dimensions (EQ-5D-5L)
The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the participants. It comprises of 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, unable to perform/extreme problems). In addition to the health profile, a single health state index value can be derived based on a formula that attaches weights to each of the levels in each dimension. This index value ranges between ˂0 (where 0 is a health state equivalent to death; negative values are valued as worse than dead) to 1 (perfect health). LS mean was determined using ANCOVA model with Week 0 (Visit 3) + IGT at Screening + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment (Type III sum of squares) as variables.
Time frame: Baseline, Week 72
Population: All participants, excluding the GCP compliance investigative site, who received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Change From Baseline in Euro Quality of Life Five Dimensions (EQ-5D-5L) | 0.01 Score on a scale | Standard Error 0.011 |
| 15 mg Tirzepatide | Change From Baseline in Euro Quality of Life Five Dimensions (EQ-5D-5L) | 0.01 Score on a scale | Standard Error 0.011 |
| Placebo | Change From Baseline in Euro Quality of Life Five Dimensions (EQ-5D-5L) | -0.01 Score on a scale | Standard Error 0.011 |
p-value: 0.09995% CI: [0, 0.06]ANCOVA
p-value: 0.23695% CI: [-0.01, 0.05]ANCOVA
Secondary
Change From Baseline in Fasting Glucose for Participants With IGT at Baseline
Change from Baseline in Fasting Glucose for Participants with IGT at Baseline. LS mean was determined by MMRM model with = Baseline + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables.
Time frame: Baseline, Week 72
Population: All participants, excluding the GCP compliance investigative site, who had IGT at baseline, received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Change From Baseline in Fasting Glucose for Participants With IGT at Baseline | -12.81 milligrams per deciliter (mg/dL) | Standard Error 1.49 |
| 15 mg Tirzepatide | Change From Baseline in Fasting Glucose for Participants With IGT at Baseline | -10.61 milligrams per deciliter (mg/dL) | Standard Error 1.391 |
| Placebo | Change From Baseline in Fasting Glucose for Participants With IGT at Baseline | 2.19 milligrams per deciliter (mg/dL) | Standard Error 1.291 |
p-value: <0.00195% CI: [-18.91, -11.09]Mixed Models Analysis
p-value: <0.00195% CI: [-16.56, -9.05]Mixed Models Analysis
Secondary
Change From Baseline in Fasting Insulin for Participants With IGT at Baseline
Change from Baseline in Fasting Insulin for Participants with IGT at Baseline. LS mean was determined using MMRM model log(Baseline) + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables.
Time frame: Baseline, Week 72
Population: All participants, excluding the GCP compliance investigative site, who had IGT at baseline, received at least one dose of study drug, and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Change From Baseline in Fasting Insulin for Participants With IGT at Baseline | -6.04 milli-international units/liter (mIU/L) | Standard Error 0.517 |
| 15 mg Tirzepatide | Change From Baseline in Fasting Insulin for Participants With IGT at Baseline | -6.69 milli-international units/liter (mIU/L) | Standard Error 0.433 |
| Placebo | Change From Baseline in Fasting Insulin for Participants With IGT at Baseline | -2.13 milli-international units/liter (mIU/L) | Standard Error 0.776 |
95% CI: [-5.74, -2.08]
95% CI: [-6.29, -2.81]
Secondary
Change From Baseline in Hemoglobin A1c (HbA1c)
Change from Baseline in HbA1c was assessed only for Participants with IGT at Baseline. LS mean was determined using MMRM model with = Baseline + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables.
Time frame: Baseline, Week 72
Population: All participants, excluding the GCP compliance investigative site, who had IGT at baseline, received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Change From Baseline in Hemoglobin A1c (HbA1c) | -0.67 Percentage of HbA1c | Standard Error 0.045 |
| 15 mg Tirzepatide | Change From Baseline in Hemoglobin A1c (HbA1c) | -0.68 Percentage of HbA1c | Standard Error 0.042 |
| Placebo | Change From Baseline in Hemoglobin A1c (HbA1c) | -0.02 Percentage of HbA1c | Standard Error 0.039 |
p-value: <0.00195% CI: [-0.77, -0.53]Mixed Models Analysis
p-value: <0.00195% CI: [-0.77, -0.55]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 consists of 20 items, assessing 2 primary domains of obesity related 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. LS mean was determined using ANCOVA model with Week 0 (Visit 3) + IGT at Screening + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment (Type III sum of squares) as variables.
Time frame: Baseline, Week 72
Population: All participants, excluding the GCP compliance investigative site, who received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 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 | 15.2 Score on a scale | Standard Error 2.05 |
| 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 | 13.0 Score on a scale | Standard Error 1.95 |
| Placebo | Change From Baseline in Impact of Weight on Quality-of-Life Lite Clinical Trials Version (IWQOL-Lite-CT) Physical Function Composite Score | 2.2 Score on a scale | Standard Error 1.96 |
p-value: <0.00195% CI: [7.4, 18.7]ANCOVA
p-value: <0.00195% CI: [5.4, 16.3]ANCOVA
Secondary
Change From Baseline in Oral Glucose Tolerance (OGTT) 2-hr Glucose for Participants With Impaired Glucose Tolerance (IGT) at Baseline
Change from Baseline in OGTT 2-hr Glucose for Participants with IGT at Baseline. LS mean was determined by MMRM model with Baseline + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables.
Time frame: Baseline, Week 72
Population: All participants, excluding the GCP compliance investigative site, who had IGT at baseline, received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Change From Baseline in Oral Glucose Tolerance (OGTT) 2-hr Glucose for Participants With Impaired Glucose Tolerance (IGT) at Baseline | -61.50 milligrams per deciliter (mg/dL) | Standard Error 5.33 |
| 15 mg Tirzepatide | Change From Baseline in Oral Glucose Tolerance (OGTT) 2-hr Glucose for Participants With Impaired Glucose Tolerance (IGT) at Baseline | -70.56 milligrams per deciliter (mg/dL) | Standard Error 4.951 |
| Placebo | Change From Baseline in Oral Glucose Tolerance (OGTT) 2-hr Glucose for Participants With Impaired Glucose Tolerance (IGT) at Baseline | -5.74 milligrams per deciliter (mg/dL) | Standard Error 4.612 |
p-value: <0.00195% CI: [-69.74, -41.77]Mixed Models Analysis
p-value: <0.00195% CI: [-78.2, -51.43]Mixed Models Analysis
Secondary
Change From Baseline in Short Form 36 Version 2 Health Survey (SF-36v2) Acute Form Physical Functioning Domain Score
The SF-36v2 acute form, 1-week recall assesses participants' health-related quality of life (HRQoL) on 8 domains: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. Information from these 8 domains is further aggregated into 2 health component summary scores: Physical Component Summary and Mental Component Summary. Items are answered on Likert scales of varying lengths. Scoring of each domain and both summary scores are norm based and presented in the form of T scores, with a mean of 50 and standard deviation of 10; higher scores indicate better levels of function and/or better health. Range cannot be specified in norm-based scores. LS mean was determined using ANCOVA model with Week 0 (Visit 3) + IGT at Screening + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment (Type III sum of squares) as variables.
Time frame: Baseline, Week 72
Population: All participants, excluding the GCP compliance investigative site, who received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Change From Baseline in Short Form 36 Version 2 Health Survey (SF-36v2) Acute Form Physical Functioning Domain Score | 1.1 Score on a scale | Standard Error 0.39 |
| 15 mg Tirzepatide | Change From Baseline in Short Form 36 Version 2 Health Survey (SF-36v2) Acute Form Physical Functioning Domain Score | 2.0 Score on a scale | Standard Error 0.37 |
| Placebo | Change From Baseline in Short Form 36 Version 2 Health Survey (SF-36v2) Acute Form Physical Functioning Domain Score | -0.1 Score on a scale | Standard Error 0.37 |
p-value: 0.02295% CI: [0.2, 2.3]ANCOVA
p-value: <0.00195% CI: [1.1, 3.2]ANCOVA
Secondary
Change From Baseline in Systolic Blood Pressure
Change from Baseline in Systolic Blood Pressure. LS mean was determined using MMRM model with Baseline + Hyperlipidemia at Screening + NAFLD at Screening + IGT at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables.
Time frame: Baseline, Week 72
Population: All participants, excluding the GCP compliance investigative site, who received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Change From Baseline in Systolic Blood Pressure | -11.2 millimeters of Mercury (mmHg) | Standard Error 1.42 |
| 15 mg Tirzepatide | Change From Baseline in Systolic Blood Pressure | -12.0 millimeters of Mercury (mmHg) | Standard Error 1.35 |
| Placebo | Change From Baseline in Systolic Blood Pressure | 1.9 millimeters of Mercury (mmHg) | Standard Error 1.35 |
p-value: <0.00195% CI: [-17, -9.3]Mixed Models Analysis
p-value: <0.00195% CI: [-17.7, -10.1]Mixed Models Analysis
Secondary
Change From Baseline in VAT/SAT Ratio
Change from Baseline in VAT/SAT Ratio. LS mean was determined by MMRM model with Baseline + IGT at Screening + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables.
Time frame: Baseline, Week 72
Population: All participants, excluding the GCP compliance investigative site, who received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Change From Baseline in VAT/SAT Ratio | -0.09 ratio | Standard Error 0.023 |
| 15 mg Tirzepatide | Change From Baseline in VAT/SAT Ratio | -0.08 ratio | Standard Error 0.023 |
| Placebo | Change From Baseline in VAT/SAT Ratio | 0.01 ratio | Standard Error 0.023 |
p-value: 0.00495% CI: [-0.16, -0.03]Mixed Models Analysis
p-value: 0.00695% CI: [-0.15, -0.03]Mixed Models Analysis
Secondary
Change From Baseline in Waist Circumference
Change from Baseline in Waist Circumference. LS mean was determined using MMRM model with = Baseline + IGT at Screening + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables.
Time frame: Baseline, Week 72
Population: All participants, excluding the GCP compliance investigative site, who received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Change From Baseline in Waist Circumference | -12.7 centimeters (cm) | Standard Error 0.88 |
| 15 mg Tirzepatide | Change From Baseline in Waist Circumference | -16.6 centimeters (cm) | Standard Error 0.83 |
| Placebo | Change From Baseline in Waist Circumference | -1.3 centimeters (cm) | Standard Error 0.84 |
p-value: <0.00195% CI: [-13.8, -9]Mixed Models Analysis
p-value: <0.00195% CI: [-17.7, -13]Mixed Models Analysis
Secondary
Percentage of Participants Who Achieve ≥10% Body Weight Reduction
Percentage of Participants Who Achieve ≥10% body weight reduction.
Time frame: Week 72
Population: All participants, excluding the GCP compliance investigative site, who received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg Tirzepatide | Percentage of Participants Who Achieve ≥10% Body Weight Reduction | 85.92 Percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants Who Achieve ≥10% Body Weight Reduction | 92.11 Percentage of participants |
| Placebo | Percentage of Participants Who Achieve ≥10% Body Weight Reduction | 4 Percentage of participants |
p-value: <0.00195% CI: [46.39, 745.16]Regression, Logistic
p-value: <0.00195% CI: [74.49, 1357.79]Regression, Logistic
Secondary
Percentage of Participants Who Achieve ≥15% Body Weight Reduction
Percentage of Participants Who Achieve ≥15% body weight reduction.
Time frame: Week 72
Population: All participants, excluding the GCP compliance investigative site, who received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg Tirzepatide | Percentage of Participants Who Achieve ≥15% Body Weight Reduction | 63.38 Percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants Who Achieve ≥15% Body Weight Reduction | 82.89 Percentage of participants |
| Placebo | Percentage of Participants Who Achieve ≥15% Body Weight Reduction | 1.33 Percentage of participants |
p-value: <0.00195% CI: [18.64, 538.74]Regression, Logistic
p-value: <0.00195% CI: [50.68, 1622.06]Regression, Logistic
Secondary
Percentage of Participants Who Achieved Improvements of Hyperlipidemia
Percentage of Participants Who Achieved Improvements of Hyperlipidemia. This was evaluated only for participants with hyperlipidemia at baseline.
Time frame: Week 72
Population: All participants, excluding the GCP compliance investigative site, with hyperlipidemia at baseline, received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg Tirzepatide | Percentage of Participants Who Achieved Improvements of Hyperlipidemia | 72.41 Percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants Who Achieved Improvements of Hyperlipidemia | 81.08 Percentage of participants |
| Placebo | Percentage of Participants Who Achieved Improvements of Hyperlipidemia | 25 Percentage of participants |
p-value: <0.00195% CI: [2.86, 30.2]Regression, Logistic
p-value: <0.00195% CI: [4.78, 51.37]Regression, Logistic
Secondary
Percentage of Participants Who Achieved Improvements of IGT
Percentage of Participants Who Achieved Improvements of IGT. This was evaluated only for participants with IGT at baseline.
Time frame: Week 72
Population: All participants, excluding the GCP compliance investigative site, who had IGT at baseline, received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg Tirzepatide | Percentage of Participants Who Achieved Improvements of IGT | 92.50 Percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants Who Achieved Improvements of IGT | 97.83 Percentage of participants |
| Placebo | Percentage of Participants Who Achieved Improvements of IGT | 28.0 Percentage of participants |
p-value: <0.00195% CI: [7.25, 89.14]Regression, Logistic
p-value: <0.00195% CI: [12.73, 392.24]Regression, Logistic
Secondary
Percentage of Participants Who Achieved Improvements of NAFLD
Percentage of Participants Who Achieved Improvements of NAFLD. This was evaluated only for participants who were diagnosed as NAFLD by MRI at Baseline.
Time frame: Week 72
Population: All participants, excluding the GCP compliance investigative site, diagnosed as NAFLD by MRI at baseline, received at least one dose of study drug, and had evaluable data for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg Tirzepatide | Percentage of Participants Who Achieved Improvements of NAFLD | 69.49 Percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants Who Achieved Improvements of NAFLD | 77.42 Percentage of participants |
| Placebo | Percentage of Participants Who Achieved Improvements of NAFLD | 9.84 Percentage of participants |
p-value: <0.00195% CI: [9.35, 80.88]Regression, Logistic
p-value: <0.00195% CI: [13.27, 120.57]Regression, Logistic
Secondary
Percentage of Participants Who Achieved VAT <100 Square Centimeter (cm²) From Baseline for Participants With VAT≥100 cm² at Baseline
Percentage of Participants Who Achieve VAT \<100 cm² from Baseline for participants with VAT≥100 cm² at Baseline.
Time frame: Week 72
Population: All participants, excluding the GCP compliance investigative site, who received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg Tirzepatide | Percentage of Participants Who Achieved VAT <100 Square Centimeter (cm²) From Baseline for Participants With VAT≥100 cm² at Baseline | 26.32 Percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants Who Achieved VAT <100 Square Centimeter (cm²) From Baseline for Participants With VAT≥100 cm² at Baseline | 37.10 Percentage of participants |
| Placebo | Percentage of Participants Who Achieved VAT <100 Square Centimeter (cm²) From Baseline for Participants With VAT≥100 cm² at Baseline | 1.64 Percentage of participants |
p-value: <0.00195% CI: [4.31, 188.55]Regression, Logistic
p-value: <0.00195% CI: [8.68, 383.88]Regression, Logistic
Secondary
Percentage of Participants Who Had Improvement in Obesity-related Health Problems
Percentage of participants who had improvement in obesity-related health problems
Time frame: Week 72
Population: All participants, excluding the GCP compliance investigative site, who received at least one dose of study drug and evaluable data for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg Tirzepatide | Percentage of Participants Who Had Improvement in Obesity-related Health Problems | 70.0 Percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants Who Had Improvement in Obesity-related Health Problems | 79.69 Percentage of participants |
| Placebo | Percentage of Participants Who Had Improvement in Obesity-related Health Problems | 11.11 Percentage of participants |
p-value: <0.00195% CI: [8.62, 68.28]Regression, Logistic
p-value: <0.00195% CI: [13.21, 110.89]Regression, Logistic
Secondary
Percent Change From Baseline in Fasting Lipids [Triglycerides (TG)] for Participants With Hyperlipidemia at Baseline
Percent Change from Baseline in Fasting Lipids TG for Participants with Hyperlipidemia at Baseline. LS mean was determined by MMRM model with log (Baseline) + NAFLD at Screening + IGT at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables.
Time frame: Baseline, Week 72
Population: All participants, excluding the GCP compliance investigative site, who had hyperlipidemia at baseline, received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Percent Change From Baseline in Fasting Lipids [Triglycerides (TG)] for Participants With Hyperlipidemia at Baseline | -47.3 Percent change | Standard Error 3.34 |
| 15 mg Tirzepatide | Percent Change From Baseline in Fasting Lipids [Triglycerides (TG)] for Participants With Hyperlipidemia at Baseline | -50.6 Percent change | Standard Error 2.77 |
| Placebo | Percent Change From Baseline in Fasting Lipids [Triglycerides (TG)] for Participants With Hyperlipidemia at Baseline | -11.0 Percent change | Standard Error 5.14 |
p-value: <0.00195% CI: [-50, -29.7]Mixed Models Analysis
p-value: <0.00195% CI: [-52.7, -34.9]Mixed Models Analysis
Secondary
Percent Change From Baseline in Hepatic Fat Fraction (HFF) for Participants With Non-alcoholic Fatty Liver Disease [NAFLD]
Percent Change from Baseline in HFF for participants diagnosed as NAFLD by MRI at Baseline. LS mean was determined by ANCOVA model with Baseline + Hyperlipidemia at Screening + IGT at Screening + Sex + Treatment (Type III sum of squares) as variables. Percent Change from Baseline in HFF for participants with NAFLD is reported. NAFLD was diagnosed by Magnetic Resonance Imaging (MRI) at Baseline. This was evaluated only for participants who were diagnosed with NAFLD at baseline by MRI.
Time frame: Baseline, Week 72
Population: All participants, excluding the GCP compliance investigative site, who were diagnosed as NAFLD by MRI at baseline and received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Percent Change From Baseline in Hepatic Fat Fraction (HFF) for Participants With Non-alcoholic Fatty Liver Disease [NAFLD] | -63.9 Percent change | Standard Error 3.09 |
| 15 mg Tirzepatide | Percent Change From Baseline in Hepatic Fat Fraction (HFF) for Participants With Non-alcoholic Fatty Liver Disease [NAFLD] | -69.9 Percent change | Standard Error 2.99 |
| Placebo | Percent Change From Baseline in Hepatic Fat Fraction (HFF) for Participants With Non-alcoholic Fatty Liver Disease [NAFLD] | -19.6 Percent change | Standard Error 3.05 |
p-value: <0.00195% CI: [-53, -35.7]ANCOVA
p-value: <0.00195% CI: [-58.8, -41.9]ANCOVA
Secondary
Percent Change From Baseline in Subcutaneous Adipose Tissue (SAT)
Percent Change from Baseline in SAT. LS mean was determined by MMRM model with Baseline + IGT at Screening + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables.
Time frame: Baseline, Week 72
Population: All participants, excluding the GCP compliance investigative site, who received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Percent Change From Baseline in Subcutaneous Adipose Tissue (SAT) | -32.2 Percent change | Standard Error 1.9 |
| 15 mg Tirzepatide | Percent Change From Baseline in Subcutaneous Adipose Tissue (SAT) | -36.5 Percent change | Standard Error 1.85 |
| Placebo | Percent Change From Baseline in Subcutaneous Adipose Tissue (SAT) | -5.0 Percent change | Standard Error 1.9 |
p-value: <0.00195% CI: [-32.6, -21.9]Mixed Models Analysis
p-value: <0.00195% CI: [-36.7, -26.2]Mixed Models Analysis
Secondary
Percent Change From Baseline in Visceral Adipose Tissue (VAT)
Percent Change from Baseline in VAT. LS mean was determined by MMRM model with Baseline + IGT at Screening + Hyperlipidemia at Screening + NAFLD at Screening + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables.
Time frame: Baseline, Week 72
Population: All participants, excluding the GCP compliance investigative site, who received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Percent Change From Baseline in Visceral Adipose Tissue (VAT) | -39.4 Percent change | Standard Error 2.44 |
| 15 mg Tirzepatide | Percent Change From Baseline in Visceral Adipose Tissue (VAT) | -44.5 Percent change | Standard Error 2.37 |
| Placebo | Percent Change From Baseline in Visceral Adipose Tissue (VAT) | -3.4 Percent change | Standard Error 2.42 |
p-value: <0.00195% CI: [-42.9, -29.3]Mixed Models Analysis
p-value: <0.00195% CI: [-47.8, -34.4]Mixed Models Analysis