Trial Outcomes & Findings for A Study of Once-Daily Oral Orforglipron (LY3502970) in Japanese Adult Participants With Obesity Disease (NCT NCT05931380)

Last Updated: 2026-07-20

Results Overview

Values reported as "LS Mean" are model-based estimates (MBE) of the adjusted (unconditional) treatment effect. MBEs was calculated using an analysis of covariance (ANCOVA) model with the following variables: treatment group, baseline value, baseline Body Mass Index (BMI) category (\<35 kilogram per meter square \[kg/m²\] or ≥35 kg/m²), and stratification factors (sex and baseline type 2 diabetes status). Strata were defined by joint levels of sex (female, male) and baseline type 2 diabetes status (yes, no).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

238 participants

Primary outcome timeframe

Baseline, Week 72

Results posted on

2026-07-20

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo QD Participants received matching placebo capsule orally once daily (QD). Treatment was initiated with placebo corresponding to 1 mg equivalent to Orforglipron, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	12 mg Orforglipron QD Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 12 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Overall Study STARTED	60	61	57	60
Overall Study Received At Least One Dose of Study Drug	60	61	57	60
Overall Study COMPLETED	54	54	52	54
Overall Study NOT COMPLETED	6	7	5	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo QD Participants received matching placebo capsule orally once daily (QD). Treatment was initiated with placebo corresponding to 1 mg equivalent to Orforglipron, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	12 mg Orforglipron QD Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 12 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Overall Study Adverse Event	0	1	2	2
Overall Study Death	0	0	0	1
Overall Study Lost to Follow-up	2	0	0	1
Overall Study Physician Decision	1	0	0	0
Overall Study Protocol Deviation	1	1	2	0
Overall Study Withdrawal by Subject	2	5	1	2

Baseline Characteristics

A Study of Once-Daily Oral Orforglipron (LY3502970) in Japanese Adult Participants With Obesity Disease

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo QD n=60 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=61 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	12 mg Orforglipron QD n=57 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 12 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=60 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Total n=238 Participants Total of all reporting groups
Body Weight	87.78 Kilogram (Kg) STANDARD_DEVIATION 14.58 • n=20 Participants	88.64 Kilogram (Kg) STANDARD_DEVIATION 13.95 • n=20 Participants	88.40 Kilogram (Kg) STANDARD_DEVIATION 15.18 • n=40 Participants	86.69 Kilogram (Kg) STANDARD_DEVIATION 14.69 • n=6 Participants	87.87 Kilogram (Kg) STANDARD_DEVIATION 14.53 • n=7 Participants
Age, Continuous	53.2 years STANDARD_DEVIATION 11.44 • n=20 Participants	53.5 years STANDARD_DEVIATION 10.34 • n=20 Participants	53.5 years STANDARD_DEVIATION 11.20 • n=40 Participants	56.3 years STANDARD_DEVIATION 11.65 • n=6 Participants	54.1 years STANDARD_DEVIATION 11.17 • n=7 Participants
Sex: Female, Male Female	23 Participants n=20 Participants	25 Participants n=20 Participants	22 Participants n=40 Participants	24 Participants n=6 Participants	94 Participants n=7 Participants
Sex: Female, Male Male	37 Participants n=20 Participants	36 Participants n=20 Participants	35 Participants n=40 Participants	36 Participants n=6 Participants	144 Participants n=7 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=20 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants	0 Participants n=6 Participants	0 Participants n=7 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	0 Participants n=20 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants	0 Participants n=6 Participants	0 Participants n=7 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	60 Participants n=20 Participants	61 Participants n=20 Participants	57 Participants n=40 Participants	60 Participants n=6 Participants	238 Participants n=7 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=20 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants	0 Participants n=6 Participants	0 Participants n=7 Participants
Race (NIH/OMB) Asian	60 Participants n=20 Participants	61 Participants n=20 Participants	57 Participants n=40 Participants	60 Participants n=6 Participants	238 Participants n=7 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=20 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants	0 Participants n=6 Participants	0 Participants n=7 Participants
Race (NIH/OMB) Black or African American	0 Participants n=20 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants	0 Participants n=6 Participants	0 Participants n=7 Participants
Race (NIH/OMB) White	0 Participants n=20 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants	0 Participants n=6 Participants	0 Participants n=7 Participants
Race (NIH/OMB) More than one race	0 Participants n=20 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants	0 Participants n=6 Participants	0 Participants n=7 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=20 Participants	0 Participants n=20 Participants	0 Participants n=40 Participants	0 Participants n=6 Participants	0 Participants n=7 Participants
Region of Enrollment Japan	60 Participants n=20 Participants	61 Participants n=20 Participants	57 Participants n=40 Participants	60 Participants n=6 Participants	238 Participants n=7 Participants

PRIMARY outcome

Timeframe: Baseline, Week 72

Population: All randomized participants who received at least one dose of study drug. As pre-specified in Statistical Analysis Plan, Missing endpoint values were imputed using primary multiple imputation and combined using Rubin's rules. All data points obtained during the treatment period defined as at or after baseline and up to the last visit within the treatment period, regardless of study intervention discontinuation or initiation of prohibited weight management treatments.

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=57 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=60 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=61 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=60 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Percent Change From Baseline in Body Weight at Week 72	-8.69 percent change Standard Error 1.136	-0.63 percent change Standard Error 0.732	-5.90 percent change Standard Error 0.866	-7.93 percent change Standard Error 1.063

PRIMARY outcome

Timeframe: Baseline to Week 72

Population: All randomized participants who received at least one dose of study drug. Missing values were imputed using primary multiple imputation and combined using Rubin's rules. All data points obtained during the treatment period defined as at or after baseline and up to the last visit within the treatment period, regardless of study intervention discontinuation or initiation of prohibited weight management treatments.

Percentage of participants with ≥5% body weight reduction was analysed by Logistic regression with the following variables: treatment group, baseline value, baseline BMI category (\<35 kg/m² or ≥35 kg/m²), and stratification factors (sex and baseline type 2 diabetes status). Stratification factors were defined by the combination of sex (female, male) and baseline type 2 diabetes status (yes, no). The model also allowed the treatment effect to vary across baseline values and stratification factors.

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=57 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=60 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=61 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=60 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Percentage of Participants Who Achieved With Greater Than or Equal to (≥) 5% Body Weight Reduction From Baseline	61.40 Percentage of Participants	15.00 Percentage of Participants	45.90 Percentage of Participants	58.33 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline to Week 72

Percentage of participants with ≥10% body weight reduction was analysed by Logistic regression with the following variables: treatment group, baseline value, baseline BMI category (\<35 kg/m² or ≥35 kg/m²), and stratification factors (sex and baseline type 2 diabetes status). Stratification factors were defined by the combination of sex (female, male) and baseline type 2 diabetes status (yes, no). The model also allowed the treatment effect to vary across baseline values and stratification factors.

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=57 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=60 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=61 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=60 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Percentage of Participants Who Achieved ≥10% Body Weight Reduction From Baseline	35.09 Percentage of Participants	3.33 Percentage of Participants	18.03 Percentage of Participants	38.33 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline to Week 72

Percentage of participants with ≥15% body weight reduction was analysed by Logistic regression with the following variables: treatment group, baseline value, baseline BMI category (\<35 kg/m² or ≥35 kg/m²), and stratification factors (sex and baseline type 2 diabetes status). Stratification factors were defined by the combination of sex (female, male) and baseline type 2 diabetes status (yes, no). The model also allowed the treatment effect to vary across baseline values and stratification factors.

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=57 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=60 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=61 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=60 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Percentage of Participants Who Achieved ≥15% Body Weight Reduction From Baseline	22.81 Percentage of Participants	0 Percentage of Participants	9.84 Percentage of Participants	18.33 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline to Week 72

Percentage of participants with ≥20% body weight reduction was analysed by Logistic regression with the following variables: treatment group, baseline value, baseline BMI category (\<35 kg/m² or ≥35 kg/m²), and stratification factors (sex and baseline type 2 diabetes status). Stratification factors were defined by the combination of sex (female, male) and baseline type 2 diabetes status (yes, no). The model also allowed the treatment effect to vary across baseline values and stratification factors.

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=57 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=60 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=61 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=60 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Percentage of Participants Who Achieved ≥20% Body Weight Reduction From Baseline	12.28 Percentage of Participants	0 Percentage of Participants	3.28 Percentage of Participants	8.33 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline, Week 72

Values reported as "LS Mean" are model-based estimates (MBE) of the adjusted (unconditional) treatment effect. MBE was calculated using an ANCOVA model with the following variables: baseline, treatment, baseline BMI group, and strata in the model, including treatment-by-baseline and treatment-by-strata interaction terms. Strata were defined by joint levels of sex (female, male) and baseline type 2 diabetes status (yes, no). The model also allowed the treatment effect to vary across baseline values and stratification factors.

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=57 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=60 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=61 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=60 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Change From Baseline in Body Mass Index (BMI) at Week 72	-2.83 kilograms per meter square (kg/m^2) Standard Error 0.354	-0.21 kilograms per meter square (kg/m^2) Standard Error 0.230	-1.94 kilograms per meter square (kg/m^2) Standard Error 0.271	-2.63 kilograms per meter square (kg/m^2) Standard Error 0.355

SECONDARY outcome

Timeframe: Baseline to Week 72

Population: All randomized participants with hypertension at baseline who received at least one dose of study drug who had evaluable data for this outcome measure. All data points obtained during the treatment period defined as at or after baseline and up to the last visit within the treatment period, regardless of study intervention discontinuation or initiation of prohibited weight management treatments.

Percentage of participants achieving hypertension improvement ((Systolic blood pressure \<130 mmHg and diastolic blood pressure \<80 mmHg) was analysed using logistic regression with the following variables: treatment, baseline BMI group, and strata in the model. Strata were defined by joint levels of sex (female, male) and baseline type 2 diabetes status (yes, no). The estimates (odds ratio and corresponding confidence intervals) were derived using observed data.

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=50 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=47 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=49 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=51 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Percentage of Participants Who Had Improvements in Hypertension	30.0 Percentage of Participants	14.9 Percentage of Participants	34.7 Percentage of Participants	23.5 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline to Week 72

Population: All randomized participants with dyslipidemia at baseline who received at least one dose of study drug who had evaluable data for this outcome measure. All data points obtained during the treatment period defined as at or after baseline and up to the last visit within the treatment period, regardless of study intervention discontinuation or initiation of prohibited weight management treatments.

Percentage of participants achieving dyslipidemia improvement (Low-density lipoprotein cholesterol \<140 milligrams per deciliter (mg/dL), triglycerides \<150 mg/dL, and high-density lipoprotein cholesterol ≥40 mg/dL) was analysed using logistic regression with the following variables: treatment, baseline BMI group, and strata in the model. Strata were defined by joint levels of sex (female, male) and baseline type 2 diabetes status (yes, no). The estimates (odds ratio and corresponding confidence intervals) were derived using observed data.

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=44 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=46 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=47 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=46 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Percentage of Participants Who Had Improvements in Dyslipidemia	63.6 Percentage of Participants	60.9 Percentage of Participants	57.4 Percentage of Participants	65.2 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline to Week 72

Population: All randomized participants with type 2 diabetes at baseline who received at least one dose of study drug. As pre-specified in SAP, Missing endpoint values were imputed using primary multiple imputation and combined using Rubin's rules. All data points obtained during the treatment period defined as at or after baseline and up to the last visit within the treatment period, regardless of study intervention discontinuation or initiation of prohibited weight management treatments.

Percentage of participants achieving HbA1c \<6.5% was analysed using logistic regression with the following variables: baseline, treatment, baseline BMI group, and sex in the model, including treatment-by-baseline and treatment-by-sex interaction terms.

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=11 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=14 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=16 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=14 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Percentage of Participants Who Achieve Hemoglobin A1c (HbA1c) Target Value (<6.5% [48 mmol/Mol])	45.45 Percentage of Participants	0 Percentage of Participants	31.25 Percentage of Participants	78.57 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline, Week 72

Population: All randomized participants who had computer tomography measurements and received at least one dose of study drug. As pre-specified in SAP, Missing endpoint values were imputed using primary multiple imputation and combined using Rubin's rules. All data points obtained during the treatment period defined as at or after baseline and up to the last visit within the treatment period, regardless of study intervention discontinuation or initiation of prohibited weight management treatments.

Values represented under "LS Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE was calculated using an ANCOVA model with the following variables: baseline, treatment, baseline BMI group, and strata in the model, including treatment-by-baseline and treatment-by-strata interaction terms. Strata were defined by joint levels of sex (female, male) and baseline type 2 diabetes status (yes, no).

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=25 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=30 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=22 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=25 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Mean Change From Baseline in Visceral Adipose Tissue (VAT) at Week 72	-52.3 Square Centimeter (cm^2) Standard Error 8.043	-7.20 Square Centimeter (cm^2) Standard Error 5.220	-47.5 Square Centimeter (cm^2) Standard Error 5.519	-49.3 Square Centimeter (cm^2) Standard Error 6.526

SECONDARY outcome

Timeframe: Baseline, Week 72

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=57 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=60 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=61 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=60 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Mean Change From Baseline in Waist Circumference at Umbilical Level at Week 72	-5.87 Centimeter Standard Error 0.851	-0.063 Centimeter Standard Error 0.592	-3.67 Centimeter Standard Error 0.845	-5.67 Centimeter Standard Error 0.909

SECONDARY outcome

Timeframe: Baseline, Week 72

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=57 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=60 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=61 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=60 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Mean Change From Baseline in Systolic Blood Pressure (SBP) at Week 72	-3.84 millimeters of mercury (mmHg) Standard Error 1.636	-0.055 millimeters of mercury (mmHg) Standard Error 1.415	-5.08 millimeters of mercury (mmHg) Standard Error 1.673	-4.36 millimeters of mercury (mmHg) Standard Error 1.342

SECONDARY outcome

Timeframe: Baseline, Week 72

Values represented as LS means are model-based estimates (MBE) of the unconditional average treatment effect on the log-transformed scale. MBE was calculated using an ANCOVA model for log(Actual Value/Baseline), including log-transformed baseline, treatment, baseline BMI group, and strata (defined by joint levels of sex \[female, male\] and baseline type 2 diabetes status \[yes, no\]) as covariates, with treatment-by-log(baseline) and treatment-by-strata interaction terms included in the model.

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=57 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=60 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=61 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=60 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Percent Change From Baseline in Non-High Density Lipoprotein (Non-HDL) at Week 72	-10.20 percent change Standard Error 2.395	0.05 percent change Standard Error 1.711	-6.91 percent change Standard Error 2.270	-10.75 percent change Standard Error 2.352

SECONDARY outcome

Timeframe: Baseline, Week 72

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=57 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=60 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=61 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=60 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Percent Change From Baseline in High Density Lipoprotein (HDL) at Week 72	8.62 percent change Standard Error 2.628	7.37 percent change Standard Error 2.079	5.75 percent change Standard Error 2.314	5.17 percent change Standard Error 2.199

SECONDARY outcome

Timeframe: Baseline, Week 72

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=57 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=60 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=61 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=60 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Percent Change From Baseline in Triglycerides at Week 72	-24.85 percent change Standard Error 3.976	-9.61 percent change Standard Error 3.015	-16.85 percent change Standard Error 4.014	-15.64 percent change Standard Error 3.772

SECONDARY outcome

Timeframe: Baseline, Week 72

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=57 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=60 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=61 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=60 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Mean Change From Baseline in Fasting Glucose at Week 72	-15.50 milligrams per deciliter (mg/dL) Standard Error 2.163	-0.31 milligrams per deciliter (mg/dL) Standard Error 1.564	-13.98 milligrams per deciliter (mg/dL) Standard Error 1.879	-17.79 milligrams per deciliter (mg/dL) Standard Error 1.713

SECONDARY outcome

Timeframe: 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 an ANCOVA model with the following variables: baseline, treatment, baseline BMI group, and strata in the model, including treatment-by-baseline and treatment-by-strata interaction terms. Strata were defined by joint levels of sex (female, male) and baseline type 2 diabetes status (yes, no).

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=57 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=60 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=61 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=60 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Mean Change From Baseline in Hemoglobin A1c (HbA1c) at Week 72	-0.61 Percentage of HbA1c Standard Error 0.0976	0.041 Percentage of HbA1c Standard Error 0.0589	-0.53 Percentage of HbA1c Standard Error 0.0646	-0.62 Percentage of HbA1c Standard Error 0.0776

SECONDARY outcome

Timeframe: Baseline, Week 72

Population: All randomized participants who received at least one dose of study drug. All data points obtained during the treatment period defined as at or after baseline and up to the earliest date of study intervention discontinuation or initiation of prohibited weight management treatments.

Values represented under "LS Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE was calculated using a mixed model for repeated measures (MMRM) with the following variables: baseline BMI group, baseline-by-time-by-treatment, and strata-by-time-by-treatment interaction terms in the model. Strata were defined by joint levels of sex (female, male) and baseline type 2 diabetes status (yes, no). An unstructured variance-covariance matrix was used.

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=57 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=60 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=61 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=60 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Mean Change From Baseline in High-sensitivity C-reactive Protein at Week 72	-0.61 milligrams per liter (mg/L) Standard Error 0.070	-0.41 milligrams per liter (mg/L) Standard Error 0.095	-0.34 milligrams per liter (mg/L) Standard Error 0.146	-0.61 milligrams per liter (mg/L) Standard Error 0.135

SECONDARY outcome

Timeframe: Up to Week 72

Population: All randomized participants who received at least one dose of study drug. Participants without type 2 diabetes at baseline were included in this analysis. As pre-specified in SAP, this analysis was planned to measure the outcome for pooled 6 mg, 12 mg and 36 mg Orforglipron capsules.

Time to event was defined as the duration from randomization to adjudication committee-confirmed diagnosis of type 2 diabetes mellitus (T2D). Descriptive statistics are presented as Kaplan-Meier estimates of time to onset of T2D (in weeks). Time to onset of T2D was also analyzed using a Cox proportional hazards model, with treatment (pooled orforglipron dose groups) and sex as factors and baseline fasting serum glucose as a covariate. Hazard ratios with corresponding confidence intervals were estimated and reported in statistical analysis. Statistical significance between treatment groups was assessed using a two-sided log-rank test.

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=46 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=137 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Time to Onset of Type 2 Diabetes (T2D)	—	2.27 Weeks Interval 0.38 to 13.74	0.78 Weeks Interval 0.16 to 3.89	—

SECONDARY outcome

Timeframe: Baseline, Week 72

The SF-36v2 acute form, 1-week recall assesses participants' health-related quality of life on 8 domains: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. Each domain is scored individually and information from these 8 domains is further aggregated into 2 health component summary scores, a Physical Component Summary, and a 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 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.

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=57 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=60 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=61 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=60 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Mean Change From Baseline in Short Form 36 Version 2 (SF-36v2) Acute Form For Domain and Component Scores at Week 72 Mental Component Score	-0.87 T-score Standard Error 0.819	-1.59 T-score Standard Error 1.015	-1.08 T-score Standard Error 0.776	-0.21 T-score Standard Error 0.831
Mean Change From Baseline in Short Form 36 Version 2 (SF-36v2) Acute Form For Domain and Component Scores at Week 72 Mental Health	-0.88 T-score Standard Error 0.793	-1.83 T-score Standard Error 1.003	-1.65 T-score Standard Error 0.919	-1.35 T-score Standard Error 1.050
Mean Change From Baseline in Short Form 36 Version 2 (SF-36v2) Acute Form For Domain and Component Scores at Week 72 Physical Component Score	0.84 T-score Standard Error 0.690	-0.30 T-score Standard Error 0.642	-0.092 T-score Standard Error 0.765	0.011 T-score Standard Error 0.673
Mean Change From Baseline in Short Form 36 Version 2 (SF-36v2) Acute Form For Domain and Component Scores at Week 72 Physical Functioning	1.44 T-score Standard Error 0.621	-0.56 T-score Standard Error 0.596	0.15 T-score Standard Error 0.542	0.59 T-score Standard Error 0.599
Mean Change From Baseline in Short Form 36 Version 2 (SF-36v2) Acute Form For Domain and Component Scores at Week 72 Role-Physical	-0.06 T-score Standard Error 0.584	-0.12 T-score Standard Error 0.594	-0.58 T-score Standard Error 0.710	-1.11 T-score Standard Error 0.696
Mean Change From Baseline in Short Form 36 Version 2 (SF-36v2) Acute Form For Domain and Component Scores at Week 72 Bodily Pain	-0.56 T-score Standard Error 1.035	-1.08 T-score Standard Error 1.075	-0.58 T-score Standard Error 1.210	-1.07 T-score Standard Error 1.269
Mean Change From Baseline in Short Form 36 Version 2 (SF-36v2) Acute Form For Domain and Component Scores at Week 72 General Health	1.05 T-score Standard Error 0.745	-0.80 T-score Standard Error 0.685	0.02 T-score Standard Error 0.735	0.01 T-score Standard Error 0.659
Mean Change From Baseline in Short Form 36 Version 2 (SF-36v2) Acute Form For Domain and Component Scores at Week 72 Vitality	-1.58 T-score Standard Error 0.888	-0.65 T-score Standard Error 0.883	-0.82 T-score Standard Error 0.943	-0.080 T-score Standard Error 0.979
Mean Change From Baseline in Short Form 36 Version 2 (SF-36v2) Acute Form For Domain and Component Scores at Week 72 Social Functioning	-0.61 T-score Standard Error 0.731	-1.19 T-score Standard Error 0.762	-1.22 T-score Standard Error 0.900	-0.48 T-score Standard Error 0.779
Mean Change From Baseline in Short Form 36 Version 2 (SF-36v2) Acute Form For Domain and Component Scores at Week 72 Role-Emotional	0.66 T-score Standard Error 0.851	-1.21 T-score Standard Error 1.068	-0.22 T-score Standard Error 0.809	0.25 T-score Standard Error 0.816

SECONDARY outcome

Timeframe: Baseline, Week 72

The IWQOL-Lite-CT is a 20-item, obesity-specific patient reported outcome instrument developed for use in obesity clinical trials. It assesses 2 primary domains of obesity-related health-related quality of life: 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 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. The two domain scores (Physical and Psychosocial) and composite score (Physical function) range from 0 to 100 with higher scores indicating greater functioning. Raw scores are then linearly transformed to a 0 (worst) -100 (best) scale using: 100×(average item score-1)/4. Higher scores indicate better quality of life/function; lower scores indicate greater impairment.

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=57 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=60 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=61 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD n=60 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Mean Change From Baseline in Impact of Weight on Quality-of-Life Lite Clinical Trials Version (IWQOL-Lite-CT) of Physical Function, Physical, and Psychosocial Composite Score at Week 72 Physical Composite Score	2.67 score on a scale Standard Error 1.961	-2.73 score on a scale Standard Error 1.973	2.32 score on a scale Standard Error 1.968	2.00 score on a scale Standard Error 1.728
Mean Change From Baseline in Impact of Weight on Quality-of-Life Lite Clinical Trials Version (IWQOL-Lite-CT) of Physical Function, Physical, and Psychosocial Composite Score at Week 72 Physical Function Composite Scores	3.08 score on a scale Standard Error 1.995	-0.43 score on a scale Standard Error 1.903	3.71 score on a scale Standard Error 2.039	2.51 score on a scale Standard Error 1.739
Mean Change From Baseline in Impact of Weight on Quality-of-Life Lite Clinical Trials Version (IWQOL-Lite-CT) of Physical Function, Physical, and Psychosocial Composite Score at Week 72 Psychosocial Composite Scores	5.41 score on a scale Standard Error 1.597	1.74 score on a scale Standard Error 1.637	3.47 score on a scale Standard Error 1.316	4.02 score on a scale Standard Error 1.360

SECONDARY outcome

Timeframe: Pre-dose at Weeks 8, 24, and 48; post-dose at Week 16 (4 to 12 hours) and Week 36 (1 to 4 hours)

Population: All randomized participants who received at least one dose of study drug and had evaluable PK data.

Plasma concentrations of orforglipron were measured at predefined pre-dose and post-dose sampling time points.

Outcome measures

Outcome measures
Measure	36 mg Orforglipron QD n=59 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	Placebo QD n=59 Participants Participants received matching placebo capsule orally once daily. Treatment was initiated with placebo corresponding to 1 mg equivalent, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	6 mg Orforglipron QD n=57 Participants Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.	36 mg Orforglipron QD Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 36 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity.
Pharmacokinetics (PK): Mean Plasma Concentration of Orforglipron Week 36	173 nanograms per milliliter (ng/mL) Standard Deviation 126	36.7 nanograms per milliliter (ng/mL) Standard Deviation 21.9	83.9 nanograms per milliliter (ng/mL) Standard Deviation 98.1	—
Pharmacokinetics (PK): Mean Plasma Concentration of Orforglipron Week 48	146 nanograms per milliliter (ng/mL) Standard Deviation 108	29.9 nanograms per milliliter (ng/mL) Standard Deviation 15.1	55.8 nanograms per milliliter (ng/mL) Standard Deviation 37.2	—
Pharmacokinetics (PK): Mean Plasma Concentration of Orforglipron Week 16	153 nanograms per milliliter (ng/mL) Standard Deviation 111	54.3 nanograms per milliliter (ng/mL) Standard Deviation 30.5	109 nanograms per milliliter (ng/mL) Standard Deviation 51.1	—
Pharmacokinetics (PK): Mean Plasma Concentration of Orforglipron Week 24	155 nanograms per milliliter (ng/mL) Standard Deviation 144	26.4 nanograms per milliliter (ng/mL) Standard Deviation 15.3	61.6 nanograms per milliliter (ng/mL) Standard Deviation 43.6	—
Pharmacokinetics (PK): Mean Plasma Concentration of Orforglipron Week 8	15.2 nanograms per milliliter (ng/mL) Standard Deviation 10.5	14.5 nanograms per milliliter (ng/mL) Standard Deviation 8.53	13.3 nanograms per milliliter (ng/mL) Standard Deviation 8.16	—

Adverse Events

Placebo QD

Serious events: 5 serious events

Other events: 47 other events

Deaths: 0 deaths

6 mg Orforglipron QD

Serious events: 1 serious events

Other events: 51 other events

Deaths: 0 deaths

12 mg Orforglipron QD

Serious events: 3 serious events

Other events: 48 other events

Deaths: 0 deaths

36 mg Orforglipron QD

Serious events: 6 serious events

Other events: 51 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 8005455979

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60