Obesity, Overweight, Overweight or Obesity
Conditions
Brief summary
This study will investigate the efficacy and safety of once daily oral orforglipron in adult participants with obesity or overweight with weight-related comorbidities. The study has two phases: a main phase and an extension phase. The main phase of the study lasted 72 weeks. Participants with prediabetes will continue in the extension for another 2 years.
Interventions
DRUGOrforglipron
Administered orally.
DRUGPlacebo
Administered orally.
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 a BMI * ≥30.0 kilogram/square meter (kg/m²), * ≥27.0 kg/m² and presence of at least 1 of the following weight-related comorbidities (treated or untreated) at screening: * Hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease (for example, ischemic cardiovascular disease, New York Heart Association Functional Class I-III heart failure). * Have a history of at least 1 self-reported unsuccessful dietary effort to lose body weight.
Exclusion criteria
* Have Type 1 diabetes, Type 2 diabetes, or any other types of diabetes, history of ketoacidosis, or hyperosmolar state/coma * Have a self-reported change in body weight \>5 kg (11 pounds) within 90 days prior to screening. * Have family (first-degree relative) or personal history of medullary thyroid cancer (MTC) or multiple endocrine neoplasia (MEN)2 syndrome. * Have had a history of chronic or acute pancreatitis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Body Weight (Primary Treatment Period) | Baseline, Week 72 | Values represented under "Least Squares (LS) Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE was calculated using a mixed-model repeated measures (MMRM) for post-baseline measures with geographic region, baseline by time by treatment, and strata by time by treatment in the model. Strata was defined by joint levels of Sex (female, male) and prediabetes status (yes, no). Variance-covariance structure for change from baseline was unstructured. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Waist Circumference (Primary Treatment Period) | Baseline, Week 72 | Values represented under "LS Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE was calculated using a mixed-model repeated measures (MMRM) for post-baseline measures with geographic region, baseline by time by treatment, and strata by time by treatment in the model. Strata was defined by joint levels of Sex (female, male) and prediabetes status (yes, no). Variance-covariance structure for change from baseline was unstructured. |
| Change From Baseline in Systolic Blood Pressure (SBP) (Pooled Doses of Orforglipron 6 mg, 12 mg and 36 mg) - Primary Treatment Period | Baseline, Week 72 | Values represented under "LS Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE was calculated using a mixed-model repeated measures (MMRM) for post-baseline measures with geographic region, baseline by time by treatment, and strata by time by treatment in the model. Strata was defined by joint levels of Sex (female, male) and prediabetes status (yes, no). Variance-covariance structure for change from baseline was unstructured. |
| Percent Change From Baseline in Non-High Density Lipoprotein (Non-HDL) Cholesterol (Pooled Doses of Orforglipron 6 mg, 12 mg and 36 mg) - Primary Treatment Period | Baseline, Week 72 | Values represented under "Geometric LS Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE was calculated using a mixed-model repeated measures (MMRM) for post-baseline measures with log (Actual Measurement/Baseline) = geographic region, log(baseline) by time by treatment, and strata by time by treatment in the model. Strata was defined by joint levels of Sex (female, male) and prediabetes status (yes, no). Variance-covariance structure for change from baseline was unstructured. |
| Percent Change From Baseline in Triglycerides (Pooled Doses of Orforglipron 6 mg, 12 mg and 36 mg) - Primary Treatment Period | Baseline, Week 72 | Values represented under "Geometric LS Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE was calculated using a mixed-model repeated measures (MMRM) for post-baseline measures with log (Actual Measurement/Baseline) = geographic region, log(baseline) by time by treatment, and strata by time by treatment in the model. Strata was defined by joint levels of Sex (female, male) and prediabetes status (yes, no). Variance-covariance structure for change from baseline was unstructured. |
| Change From Baseline in HbA1c (Primary Treatment Period) | Baseline, Week 72 | * Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A, measured to reflect average plasma glucose concentration over prolonged periods of time. * Values represented under "LS Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE was calculated using a mixed-model repeated measures (MMRM) for post-baseline measures with geographic region, baseline by time by treatment, and strata by time by treatment in the model. Strata was defined by joint levels of Sex (female, male) and prediabetes status (yes, no). Variance-covariance structure for change from baseline was unstructured. |
| Change From Baseline in Fasting Serum Glucose (FSG) (Primary Treatment Period) | Baseline, Week 72 | Values represented under "LS Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE was calculated using a mixed-model repeated measures (MMRM) for post-baseline measures with geographic region, baseline by time by treatment, and strata by time by treatment in the model. Strata was defined by joint levels of Sex (female, male) and prediabetes status (yes, no). Variance-covariance structure for change from baseline was unstructured. |
| Percent Change From Baseline in Fasting Insulin (Primary Treatment Period) | Baseline, Week 72 | * Fasting insulin is a blood test that measures the level of insulin in the blood after fasting. * Values represented under "Geometric LS Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE was calculated using a mixed-model repeated measures (MMRM) for post-baseline measures with log (Actual Measurement/Baseline) = geographic region, log(baseline) by time by treatment, and strata by time by treatment in the model. Strata was defined by joint levels of Sex (female, male) and prediabetes status (yes, no). Variance-covariance structure for change from baseline was unstructured. |
| Change From Baseline in Diastolic Blood Pressure (DBP) (Pooled Doses of Orforglipron 6 mg, 12 mg and 36 mg) - Primary Treatment Period | Baseline, Week 72 | Values represented under "LS Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE was calculated using a mixed-model repeated measures (MMRM) for post-baseline measures with geographic region, baseline by time by treatment, and strata by time by treatment in the model. Strata was defined by joint levels of Sex (female, male) and prediabetes status (yes, no). Variance-covariance structure for change from baseline was unstructured. |
| Change From Baseline in Short Form-36 Health Survey Version 2 (SF-36v2) Acute Form (Physical Component and Mental Component) Scores - (Pooled Doses of Orforglipron 6 mg, 12 mg and 36 mg) - Primary Treatment Period | Baseline, Week 72 | The SF-36v2 is a participant-reported measure designed to assess health status using 36 items across 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," whereas the remaining domains assess functioning "in the past week." Each domain is scored individually, and information from these 8 domains is aggregated into 2 health component summary scores, the Physical Component Summary and Mental Component Summary. Items are answered on Likert scales of varying lengths (3-point, 5-point, or 6-point scales). 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 a standard deviation of 10. Higher scores indicate better levels of function and/or better health. Range cannot be specified in norm-based scores. |
| Percent Change From Baseline in Body Weight (Primary and Additional Treatment Periods: Participants With Prediabetes at Randomization) | Baseline, Week 176 | — |
| Time to Onset of Type 2 Diabetes (Primary and Additional Treatment Periods: Participants With Prediabetes at Randomization) | Baseline through Week 176, Baseline through Week 190 | — |
Countries
Brazil, China, India, Japan, Puerto Rico, Slovakia, South Korea, Spain, Taiwan, United States
Contacts
STUDY_DIRECTORCall 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 8 AM - 8 PM Eastern time (UTC/GMT - 5 hours, EST)
Eli Lilly and Company
Participant flow
Recruitment details
Results reported here are based on a data cutoff of 30 July 2025, corresponding to completion of the Primary Treatment Period. Final results, including the Additional Treatment Period, will be reported at the time of study completion results posting, no later than October 2028.
Pre-assignment details
This study was designed with two treatment periods. The Primary Treatment Period (Week 0 to Week 72) enrolled participants with normoglycemia or prediabetes at randomization. The Additional Treatment Period (Week 72 to Week 176) is limited to the subset of participants who had prediabetes at randomization and completed the Primary Treatment Period.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 45.1 years STANDARD_DEVIATION 12.1 |
| Baseline Body Weight | 103.92 kilograms (kg) STANDARD_DEVIATION 22.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 258 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 443 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants |
| Race (NIH/OMB) Asian | 884 Participants |
| Race (NIH/OMB) Black or African American | 72 Participants |
| Race (NIH/OMB) More than one race | 47 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 35 Participants |
| Race (NIH/OMB) White | 1746 Participants |
| Region of Enrollment Brazil | 203 Participants |
| Region of Enrollment China | 69 Participants |
| Region of Enrollment India | 62 Participants |
| Region of Enrollment Japan | 322 Participants |
| Region of Enrollment Slovakia | 56 Participants |
| Region of Enrollment South Korea | 18 Participants |
| Region of Enrollment Spain | 305 Participants |
| Region of Enrollment Taiwan | 20 Participants |
| Region of Enrollment United States | 200 Participants |
| Sex: Female, Male Female | 2009 Participants |
| Sex: Female, Male Male | 1118 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 948 | 1 / 723 | 1 / 724 | 0 / 728 |
| other Total, other adverse events | 557 / 948 | 520 / 723 | 544 / 724 | 550 / 728 |
| serious Total, serious adverse events | 46 / 948 | 40 / 723 | 39 / 724 | 28 / 728 |
Outcome results
None listed