Trial Outcomes & Findings for A Study of Tirzepatide (LY3298176) in Participants With Obesity or Overweight (NCT NCT04184622)

Last Updated: 2025-07-24

Results Overview

Least Squares (LS) Mean was calculated using mixed-model repeated measures (MMRM) with baseline, analysis country, sex, prediabetes status at randomization, treatment, time, treatment\*time (Type III sum of squares) in the model.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

2539 participants

Primary outcome timeframe

Baseline, Week 72

Results posted on

2025-07-24

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo * Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received once weekly (QW) subcutaneous (SC) doses of a matching placebo, administered over a period of 72 weeks. * Additional Treatment Period (Week 72-Week 176): At week 72, only participants who had prediabetes at the time of randomization and had completed the primary treatment period continued receiving the placebo dose SC QW until week 176. * Safety Follow-up Period: Participants who had completed or discontinued the primary treatment period were followed for safety for 4 weeks (weeks 72 - week 76), and those who had completed or discontinued the additional treatment period (prediabetes at randomization) were followed for 17 weeks (week 176 - week 193). No treatment was administered during this period.	5 mg Tirzepatide * Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 milligrams (mg) and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72. * Additional Treatment Period (Week 72-Week 176): At week 72, only participants who had prediabetes at the time of randomization and had completed the primary treatment period continued receiving the 5 mg tirzepatide dose SC QW until week 176. * Safety Follow-up Period: Participants who had completed or discontinued the primary treatment period were followed for safety for 4 weeks (weeks 72 - week 76), and those who had completed or discontinued the additional treatment period (prediabetes at randomization) were followed for 17 weeks (week 176 - week 193). No treatment was administered during this period.	10 mg Tirzepatide * Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72. * Additional Treatment Period (Week 72-Week 176): At week 72, only participants who had prediabetes at the time of randomization and had completed the primary treatment period continued receiving the 10 mg tirzepatide dose SC QW until week 176. * Safety Follow-up Period: Participants who had completed or discontinued the primary treatment period were followed for safety for 4 weeks (weeks 72 - week 76), and those who had completed or discontinued the additional treatment period (prediabetes at randomization) were followed for 17 weeks (week 176 - week 193). No treatment was administered during this period.	15 mg Tirzepatide * Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72. * Additional Treatment Period (Week 72-Week 176): At week 72, only participants who had prediabetes at the time of randomization and had completed the primary treatment period continued receiving the 15 mg tirzepatide dose SC QW until week 176. * Safety Follow-up Period: Participants who had completed or discontinued the primary treatment period were followed for safety for 4 weeks (weeks 72 - week 76), and those who had completed or discontinued the additional treatment period (prediabetes at randomization) were followed for 17 weeks (week 176 - week 193). No treatment was administered during this period.
Primary Treatment Period STARTED	643	630	636	630
Primary Treatment Period Received at Least One Dose of Study Drug	643	630	636	630
Primary Treatment Period Participants With Normoglycemia at Randomization	373	383	374	377
Primary Treatment Period Participants With Prediabetes at Randomization	270	247	262	253
Primary Treatment Period COMPLETED	509	569	566	575
Primary Treatment Period NOT COMPLETED	134	61	70	55
Additional Treatment Period STARTED	213	227	229	232
Additional Treatment Period COMPLETED	182	201	211	217
Additional Treatment Period NOT COMPLETED	31	26	18	15
Safety Follow-up Period STARTED	478	543	548	560
Safety Follow-up Period Entered From Primary Treatment Period	328	362	355	367
Safety Follow-up Period Entered From Additional Treatment Period	150	181	193	193
Safety Follow-up Period COMPLETED	421	508	514	518
Safety Follow-up Period NOT COMPLETED	57	35	34	42

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo * Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received once weekly (QW) subcutaneous (SC) doses of a matching placebo, administered over a period of 72 weeks. * Additional Treatment Period (Week 72-Week 176): At week 72, only participants who had prediabetes at the time of randomization and had completed the primary treatment period continued receiving the placebo dose SC QW until week 176. * Safety Follow-up Period: Participants who had completed or discontinued the primary treatment period were followed for safety for 4 weeks (weeks 72 - week 76), and those who had completed or discontinued the additional treatment period (prediabetes at randomization) were followed for 17 weeks (week 176 - week 193). No treatment was administered during this period.	5 mg Tirzepatide * Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 milligrams (mg) and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72. * Additional Treatment Period (Week 72-Week 176): At week 72, only participants who had prediabetes at the time of randomization and had completed the primary treatment period continued receiving the 5 mg tirzepatide dose SC QW until week 176. * Safety Follow-up Period: Participants who had completed or discontinued the primary treatment period were followed for safety for 4 weeks (weeks 72 - week 76), and those who had completed or discontinued the additional treatment period (prediabetes at randomization) were followed for 17 weeks (week 176 - week 193). No treatment was administered during this period.	10 mg Tirzepatide * Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72. * Additional Treatment Period (Week 72-Week 176): At week 72, only participants who had prediabetes at the time of randomization and had completed the primary treatment period continued receiving the 10 mg tirzepatide dose SC QW until week 176. * Safety Follow-up Period: Participants who had completed or discontinued the primary treatment period were followed for safety for 4 weeks (weeks 72 - week 76), and those who had completed or discontinued the additional treatment period (prediabetes at randomization) were followed for 17 weeks (week 176 - week 193). No treatment was administered during this period.	15 mg Tirzepatide * Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72. * Additional Treatment Period (Week 72-Week 176): At week 72, only participants who had prediabetes at the time of randomization and had completed the primary treatment period continued receiving the 15 mg tirzepatide dose SC QW until week 176. * Safety Follow-up Period: Participants who had completed or discontinued the primary treatment period were followed for safety for 4 weeks (weeks 72 - week 76), and those who had completed or discontinued the additional treatment period (prediabetes at randomization) were followed for 17 weeks (week 176 - week 193). No treatment was administered during this period.
Primary Treatment Period Adverse Event	6	4	8	6
Primary Treatment Period Death	4	4	2	1
Primary Treatment Period Lost to Follow-up	41	17	15	13
Primary Treatment Period Other - as reported by the investigator	21	7	6	12
Primary Treatment Period Physician Decision	0	0	3	1
Primary Treatment Period Pregnancy	4	3	4	1
Primary Treatment Period Withdrawal by Subject	58	26	32	21
Additional Treatment Period Adverse Event	1	2	1	0
Additional Treatment Period Death	0	0	1	1
Additional Treatment Period Lost to Follow-up	6	4	8	6
Additional Treatment Period Other - as reported by the investigator	2	5	2	0
Additional Treatment Period Physician Decision	0	0	1	0
Additional Treatment Period Pregnancy	0	0	0	1
Additional Treatment Period Protocol deviation	0	0	1	0
Additional Treatment Period Site closed	1	0	1	0
Additional Treatment Period Withdrawal by Subject	21	15	3	7
Safety Follow-up Period Adverse Event	6	8	9	16
Safety Follow-up Period Lost to Follow-up	4	4	10	3
Safety Follow-up Period Missing Weight at Week 176	3	2	2	2
Safety Follow-up Period Other - as reported by the investigator	10	5	6	5
Safety Follow-up Period Physician Decision	1	0	0	1
Safety Follow-up Period Pregnancy	1	3	0	6
Safety Follow-up Period Protocol deviation	1	0	0	0
Safety Follow-up Period Withdrawal by Subject	31	13	7	9

Baseline Characteristics

A Study of Tirzepatide (LY3298176) in Participants With Obesity or Overweight

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=643 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=630 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide n=636 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide n=630 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.	Total n=2539 Participants Total of all reporting groups
Age, Continuous	44.4 years STANDARD_DEVIATION 12.5 • n=39 Participants	45.6 years STANDARD_DEVIATION 12.7 • n=41 Participants	44.7 years STANDARD_DEVIATION 12.4 • n=35 Participants	44.9 years STANDARD_DEVIATION 12.3 • n=31 Participants	44.9 years STANDARD_DEVIATION 12.5 • n=146 Participants
Sex: Female, Male Female	436 Participants n=39 Participants	426 Participants n=41 Participants	427 Participants n=35 Participants	425 Participants n=31 Participants	1714 Participants n=146 Participants
Sex: Female, Male Male	207 Participants n=39 Participants	204 Participants n=41 Participants	209 Participants n=35 Participants	205 Participants n=31 Participants	825 Participants n=146 Participants
Race (NIH/OMB) American Indian or Alaska Native	58 Participants n=39 Participants	56 Participants n=41 Participants	58 Participants n=35 Participants	59 Participants n=31 Participants	231 Participants n=146 Participants
Race (NIH/OMB) Asian	71 Participants n=39 Participants	68 Participants n=41 Participants	71 Participants n=35 Participants	66 Participants n=31 Participants	276 Participants n=146 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	2 Participants n=39 Participants	2 Participants n=41 Participants	2 Participants n=35 Participants	3 Participants n=31 Participants	9 Participants n=146 Participants
Race (NIH/OMB) Black or African American	55 Participants n=39 Participants	48 Participants n=41 Participants	47 Participants n=35 Participants	51 Participants n=31 Participants	201 Participants n=146 Participants
Race (NIH/OMB) White	450 Participants n=39 Participants	447 Participants n=41 Participants	452 Participants n=35 Participants	443 Participants n=31 Participants	1792 Participants n=146 Participants
Race (NIH/OMB) More than one race	7 Participants n=39 Participants	9 Participants n=41 Participants	6 Participants n=35 Participants	8 Participants n=31 Participants	30 Participants n=146 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=39 Participants	0 Participants n=41 Participants	0 Participants n=35 Participants	0 Participants n=31 Participants	0 Participants n=146 Participants
Region of Enrollment Argentina	93 Participants n=39 Participants	90 Participants n=41 Participants	90 Participants n=35 Participants	91 Participants n=31 Participants	364 Participants n=146 Participants
Region of Enrollment United States	288 Participants n=39 Participants	282 Participants n=41 Participants	287 Participants n=35 Participants	284 Participants n=31 Participants	1141 Participants n=146 Participants
Region of Enrollment Japan	33 Participants n=39 Participants	30 Participants n=41 Participants	30 Participants n=35 Participants	31 Participants n=31 Participants	124 Participants n=146 Participants
Region of Enrollment China	7 Participants n=39 Participants	9 Participants n=41 Participants	7 Participants n=35 Participants	7 Participants n=31 Participants	30 Participants n=146 Participants
Region of Enrollment Taiwan	15 Participants n=39 Participants	12 Participants n=41 Participants	15 Participants n=35 Participants	16 Participants n=31 Participants	58 Participants n=146 Participants
Region of Enrollment Brazil	59 Participants n=39 Participants	59 Participants n=41 Participants	61 Participants n=35 Participants	60 Participants n=31 Participants	239 Participants n=146 Participants
Region of Enrollment Mexico	108 Participants n=39 Participants	110 Participants n=41 Participants	107 Participants n=35 Participants	108 Participants n=31 Participants	433 Participants n=146 Participants
Region of Enrollment Russia	32 Participants n=39 Participants	29 Participants n=41 Participants	30 Participants n=35 Participants	27 Participants n=31 Participants	118 Participants n=146 Participants
Region of Enrollment India	8 Participants n=39 Participants	9 Participants n=41 Participants	9 Participants n=35 Participants	6 Participants n=31 Participants	32 Participants n=146 Participants
Baseline Body Weight	104.9 kilograms (kg) STANDARD_DEVIATION 21.37 • n=39 Participants	102.88 kilograms (kg) STANDARD_DEVIATION 20.71 • n=41 Participants	105.84 kilograms (kg) STANDARD_DEVIATION 23.32 • n=35 Participants	105.59 kilograms (kg) STANDARD_DEVIATION 22.92 • n=31 Participants	104.78 kilograms (kg) STANDARD_DEVIATION 22.12 • n=146 Participants

PRIMARY outcome

Timeframe: Baseline, Week 72

Population: All participants who received at least one dose of study drug and had baseline and at least one post-baseline body weight value, excluding data after prematurely stopping study drug.

Outcome measures

Outcome measures
Measure	Placebo n=635 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=623 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide n=629 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide n=625 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Percent Change From Baseline in Body Weight (Primary Treatment Period)	-2.4 percent change Standard Error 0.40	-16.0 percent change Standard Error 0.39	-21.4 percent change Standard Error 0.39	-22.5 percent change Standard Error 0.39

PRIMARY outcome

Timeframe: Week 72

Population: All participants who received at least one dose of study drug and had baseline and at least one post-baseline value for ≥5% Body Weight Reduction, excluding data after prematurely stopping study drug.

Percentage of participants who achieve greater than or equal to( ≥) 5% body weight reduction.

Outcome measures

Outcome measures
Measure	Placebo n=635 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=623 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide n=629 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide n=625 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Percentage of Participants Who Achieve ≥5% Body Weight Reduction (Primary Treatment Period)	27.87 Percentage of Participants	89.41 Percentage of Participants	96.18 Percentage of Participants	96.32 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline, Week 20

Population: All participants who received at least one dose of study drug and had baseline and at least one post-baseline body weight value, excluding data after prematurely stopping study drug. This analysis was planned to measure the outcome for pooled 10 mg and 15 mg tirzepatide.

LS Mean was calculated using MMRM with baseline, analysis country, sex, prediabetes status at randomization, treatment, time, treatment\*time (Type III sum of squares) in the model.

Outcome measures

Outcome measures
Measure	Placebo n=635 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=1254 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Change From Baseline in Body Weight (Pooled Doses of Tirzepatide 10 mg and 15 mg) - Primary Treatment Period	-2.5 kilograms Standard Error 0.22	-13.2 kilograms Standard Error 0.16	—	—

SECONDARY outcome

Timeframe: Week 72

Population: All participants who received at least one dose of study drug and had baseline and at least one post-baseline value for ≥10% Body Weight Reduction, excluding data after prematurely stopping study drug.

Percentage of Participants who Achieve ≥10% Body Weight Reduction

Outcome measures

Outcome measures
Measure	Placebo n=635 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=623 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide n=629 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide n=625 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Percentage of Participants Who Achieve ≥10% Body Weight Reduction (Primary Treatment Period)	13.54 Percentage of Participants	73.35 Percentage of Participants	85.85 Percentage of Participants	90.08 Percentage of Participants

SECONDARY outcome

Timeframe: Week 72

Population: All participants who received at least one dose of study drug and had baseline and at least one post-baseline value for ≥15% body weight reduction, excluding data after prematurely stopping study drug.

Percentage of participants who achieve ≥15% body weight reduction.

Outcome measures

Outcome measures
Measure	Placebo n=635 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=623 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide n=629 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide n=625 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Percentage of Participants Who Achieve ≥15% Body Weight Reduction (Primary Treatment Period)	5.98 Percentage of Participants	50.24 Percentage of Participants	73.61 Percentage of Participants	78.24 Percentage of Participants

SECONDARY outcome

Timeframe: Week 72

Population: All participants who received at least one dose of study drug and had baseline and at least one post-baseline value for ≥20% Body Weight Reduction, excluding data after prematurely stopping study drug.

Percentage of participants who achieve ≥20% body weight reduction.

Outcome measures

Outcome measures
Measure	Placebo n=635 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=623 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide n=629 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide n=625 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Percentage of Participants Who Achieve ≥20% Body Weight Reduction (Primary Treatment Period)	1.26 Percentage of Participants	31.62 Percentage of Participants	55.48 Percentage of Participants	62.88 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline, Week 72

Population: All participants who received at least one dose of study drug and had baseline and at least one post-baseline weight circumference value, excluding data after prematurely stopping study drug.

LS Mean was calculated using MMRM with baseline, analysis country, sex, prediabetes status at randomization, treatment, time, treatment\*time (Type III sum of squares) in the model.

Outcome measures

Outcome measures
Measure	Placebo n=634 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=622 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide n=629 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide n=625 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Change From Baseline in Waist Circumference (Primary Treatment Period)	-3.4 centimeters Standard Error 0.42	-14.6 centimeters Standard Error 0.41	-19.4 centimeters Standard Error 0.41	-19.9 centimeters Standard Error 0.41

SECONDARY outcome

Timeframe: Baseline, Week 72

Population: All participants who received at least one dose of study drug and had baseline and at least one post-baseline SF-36v2 value, excluding data after prematurely stopping study drug. This analysis was planned to measure the outcome for pooled 10 mg and 15 mg tirzepatide.

The SF-36v2 acute, 1-week recall version is a 36-item, generic, patient-administered measure designed to assess the following 8 domains: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. The Physical-Functioning domain assesses limitations due to health "now" while the remaining domains assess functioning "in the past week." Each domain is scored individually and information from these 8 domains are further aggregated into 2 health-component summary scores: Physical-Component Summary and Mental-Component Summary. Items are answered on Likert scales of varying lengths (3-, 5-, or 6- point scales).The summary scores range from 0 to 100, with higher scores indicating better levels of function and/or better health.

Outcome measures

Outcome measures
Measure	Placebo n=482 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=1080 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Change From Baseline in Short Form Survey-36 Version 2 (SF-36v2) Acute Form Physical Functioning Domain Score at Week 72 (Pooled Doses of Tirzepatide 10 mg and 15 mg) - Primary Treatment Period	1.7 score on a scale Standard Error 0.27	4.0 score on a scale Standard Error 0.18	—	—

SECONDARY outcome

Timeframe: Baseline, Week 72

Population: All participants who received at least one dose of study drug and had a baseline and at least one post-baseline triglyceride value, excluding data after prematurely stopping study drug. This analysis was planned to measure the outcome for pooled 5 mg, 10 mg and 15 mg tirzepatide.

Percent change from baseline in triglycerides are reported as model-based estimate and Standard Error (SE) from MMRM analysis using log transformation.

Outcome measures

Outcome measures
Measure	Placebo n=612 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=1822 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Percent Change From Baseline in Triglycerides (Pooled Doses of Tirzepatide 5 mg, 10 mg and 15 mg) - Primary Treatment Period	-6.3 percent change Standard Error 1.55	-27.6 percent change Standard Error 0.66	—	—

SECONDARY outcome

Timeframe: Baseline, Week 72

Population: All participants who received at least one dose of study drug and had baseline and at least one post-baseline total cholesterol value, excluding data after prematurely stopping study drug. This analysis was planned to measure the outcome for pooled 5 mg, 10 mg and 15 mg tirzepatide.

Results are reported as model-based estimate and SE from MMRM analysis using log transformation.

Outcome measures

Outcome measures
Measure	Placebo n=612 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=1822 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Percent Change From Baseline in Total Cholesterol (Pooled Doses of Tirzepatide 5 mg, 10 mg and 15 mg) - Primary Treatment Period	-1.11 percent change Standard Error 0.695	-5.97 percent change Standard Error 0.364	—	—

SECONDARY outcome

Timeframe: Baseline, Week 72

Population: All participants who received at least one dose of study drug and had baseline and at least one post-baseline total cholesterol HDL value, excluding data after prematurely stopping study drug. This analysis was planned to measure the outcome for pooled 5 mg, 10 mg and 15 mg tirzepatide.

Results are reported as model-based estimate and SE from MMRM analysis using log transformation.

Outcome measures

Outcome measures
Measure	Placebo n=581 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=1764 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Percent Change From Baseline in High-Density Lipoprotein (HDL) Cholesterol at Week 72 (Pooled Doses of Tirzepatide 5 mg, 10 mg and 15 mg) - Primary Treatment Period	0.25 percent change Standard Error 0.757	7.92 percent change Standard Error 0.447	—	—

SECONDARY outcome

Timeframe: Baseline, Week 72

Population: All participants who received at least one dose of study drug and had baseline and at least one post-baseline SBP value, excluding data after prematurely stopping study drug. This analysis was planned to measure the outcome for pooled 5 mg, 10 mg and 15 mg tirzepatide.

LS Mean was calculated using MMRM with baseline, analysis country, sex, prediabetes status at randomization, treatment, time, treatment\*time (Type III sum of squares) in the model.

Outcome measures

Outcome measures
Measure	Placebo n=634 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=1878 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Change From Baseline in Systolic Blood Pressure (SBP) (Pooled Doses of Tirzepatide 5 mg, 10 mg and 15 mg) - Primary Treatment Period	-1.3 millimeter of mercury (mmHg) Standard Error 0.48	-8.1 millimeter of mercury (mmHg) Standard Error 0.27	—	—

SECONDARY outcome

Timeframe: Baseline, Week 72

Population: All participants who received at least one dose of study drug and had a baseline and at least one post-baseline fasting insulin value, excluding data after prematurely stopping study drug. This analysis was planned to measure the outcome for pooled 5 mg, 10 mg and 15 mg tirzepatide.

Fasting Insulin is a test used to measure the amount of insulin in the body. Results are reported as model-based estimates and SE from MMRM analysis using log transformation.

Outcome measures

Outcome measures
Measure	Placebo n=590 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=1779 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Percent Change From Baseline in Fasting Insulin (Pooled Doses of Tirzepatide 5 mg, 10 mg and 15 mg) - Primary Treatment Period	-9.7 percent change Standard Error 2.60	-46.9 percent change Standard Error 0.83	—	—

SECONDARY outcome

Timeframe: Baseline, Week 176

Population: Participants with prediabetes at randomization who received at least one dose of study drug and had baseline and at least one post-baseline body weight value, excluding data after prematurely stopping study drug.

LS Mean was calculated using mixed-model repeated measures (MMRM) with baseline, analysis country, sex, treatment, time, treatment\*time (Type III sum of squares) in the model.

Outcome measures

Outcome measures
Measure	Placebo n=264 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=245 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide n=260 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide n=249 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Percent Change From Baseline in Body Weight (Primary and Additional Treatment Periods : Participants With Prediabetes at Randomization)	-2.1 percent change Standard Error 0.78	-15.4 percent change Standard Error 0.74	-19.9 percent change Standard Error 0.72	-22.9 percent change Standard Error 0.73

SECONDARY outcome

Timeframe: Baseline through Week 176

Population: Participants with prediabetes at randomization who received at least one dose of study drug (including the censored participants). Number of participants censored in Placebo = 236, Pooled 5 mg/10 mg/15 mg Tirzepatide = 753.

The percentage of participants with onset of Type 2 diabetes mellitus (T2DM), evaluated as time to onset of T2DM among those who had pre-diabetes at randomization, was reported. Time to onset of Type 2 diabetes mellitus was defined as the duration from the date of randomization to the adjudication committee-confirmed date of incident diabetes. Participants who did not experience the event were censored.

Outcome measures

Outcome measures
Measure	Placebo n=270 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=762 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Percentage of Participants With Onset of Type 2 Diabetes From Baseline to Week 176 (Primary and Additional Treatment Periods: Participants With Prediabetes at Randomization)	12.6 Percentage of Participants	1.2 Percentage of Participants	—	—

SECONDARY outcome

Timeframe: Baseline through Week 193

Outcome measures

Outcome measures
Measure	Placebo n=270 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=762 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Percentage of Participants With Onset of Type 2 Diabetes From Baseline to Week 193 (Primary and Additional Treatment Periods + Safety Follow-up Period: Participants With Prediabetes at Randomization)	13.7 Percentage of Participants	2.4 Percentage of Participants	—	—

SECONDARY outcome

Timeframe: Baseline, Week 72

Population: All participants who received at least one dose of study drug and had baseline and at least one post-baseline BMI value, excluding data after prematurely stopping study drug.

LS Mean was calculated using MMRM with baseline, analysis country, sex, prediabetes status at randomization, treatment, time, treatment\*time (Type III sum of squares) in the model.

Outcome measures

Outcome measures
Measure	Placebo n=635 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=623 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide n=629 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide n=625 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Change From Baseline in Body Mass Index (BMI) - Primary Treatment Period	-0.9 kilograms per meter squared (kg/m^2) Standard Error 0.16	-5.9 kilograms per meter squared (kg/m^2) Standard Error 0.16	-8.1 kilograms per meter squared (kg/m^2) Standard Error 0.16	-8.6 kilograms per meter squared (kg/m^2) Standard Error 0.16

SECONDARY outcome

Timeframe: Baseline, Week 72

Population: All participants who received at least one dose of study drug and had baseline and at least one post-baseline HbA1c value, excluding data after prematurely stopping study drug.

HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. LS Mean was calculated using MMRM with baseline, analysis country, sex, prediabetes status at randomization, treatment, time, treatment\*time (Type III sum of squares) in the model.

Outcome measures

Outcome measures
Measure	Placebo n=612 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=607 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide n=607 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide n=608 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Change From Baseline in Hemoglobin A1c (HbA1c) - Primary Treatment Period	-0.07 Percentage of HbA1c Standard Error 0.012	-0.40 Percentage of HbA1c Standard Error 0.012	-0.49 Percentage of HbA1c Standard Error 0.012	-0.51 Percentage of HbA1c Standard Error 0.012

SECONDARY outcome

Timeframe: Baseline, Week 72

Population: All participants who received at least one dose of study drug and had baseline and at least one post-baseline fasting glucose value, excluding data after prematurely stopping study drug.

LS Mean was calculated using MMRM with baseline, analysis country, sex, prediabetes status at randomization, treatment, time, treatment\*time (Type III sum of squares) in the model.

Outcome measures

Outcome measures
Measure	Placebo n=612 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=608 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide n=606 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide n=608 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Change From Baseline in Fasting Glucose (Primary Treatment Period)	0.86 milligram per deciliter (mg/dL) Standard Error 0.514	-7.73 milligram per deciliter (mg/dL) Standard Error 0.484	-9.73 milligram per deciliter (mg/dL) Standard Error 0.486	-10.55 milligram per deciliter (mg/dL) Standard Error 0.486

SECONDARY outcome

Timeframe: Baseline, Week 72

Population: All participants who received at least one dose of study drug and had a baseline and at least one post-baseline LDL value, excluding data after prematurely stopping study drug. This analysis was planned to measure the outcome for pooled 5 mg, 10 mg and 15 mg tirzepatide.

Results are reported as model-based estimate and SE from MMRM analysis using log transformation.

Outcome measures

Outcome measures
Measure	Placebo n=578 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=1754 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Percent Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol (Pooled Doses of Tirzepatide 5 mg, 10 mg and 15 mg) - Primary Treatment Period	-0.85 percent change Standard Error 1.076	-6.86 percent change Standard Error 0.555	—	—

SECONDARY outcome

Timeframe: Baseline, Week 72

Population: All participants who received at least one dose of study drug and had baseline and at least one post-baseline VLDL value, excluding data after prematurely stopping study drug. This analysis was planned to measure the outcome for pooled 5 mg, 10 mg and 15 mg tirzepatide.

Results are reported as model-based estimate and SE from MMRM analysis using log transformation.

Outcome measures

Outcome measures
Measure	Placebo n=577 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=1754 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Percent Change From Baseline in Very Low-Density Lipoprotein (VLDL) Cholesterol (Pooled Doses of Tirzepatide 5 mg, 10 mg and 15 mg) - Primary Treatment Period	-5.6 percent change Standard Error 1.55	-27.6 percent change Standard Error 0.65	—	—

SECONDARY outcome

Timeframe: Baseline, Week 72

Population: All participants who received at least one dose of study drug and had baseline and at least one post-baseline free fatty acids value, excluding data after prematurely stopping study drug. This analysis was planned to measure the outcome for pooled 5 mg, 10 mg and 15 mg tirzepatide.

Results are reported as model-based estimate and SE from MMRM analysis using log transformation.

Outcome measures

Outcome measures
Measure	Placebo n=576 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=1756 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Percent Change From Baseline in Free Fatty Acids (Pooled Doses of Tirzepatide 5 mg, 10 mg and 15 mg) - Primary Treatment Period	6.1 percent change Standard Error 2.65	-5.9 percent change Standard Error 1.28	—	—

SECONDARY outcome

Timeframe: Baseline, Week 72

Population: All participants who received at least one dose of study drug and had baseline and at least one post-baseline DBP value, excluding data after prematurely stopping study drug. This analysis was planned to measure the outcome for pooled 5 mg, 10 mg and 15 mg tirzepatide.

LS Mean was calculated using MMRM with baseline, analysis country, sex, prediabetes status at randomization, treatment, time, treatment\*time (Type III sum of squares) in the model.

Outcome measures

Outcome measures
Measure	Placebo n=634 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=1878 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Change From Baseline in Diastolic Blood Pressure (DBP) (Pooled Doses of Tirzepatide 5 mg, 10 mg and 15 mg) - Primary Treatment Period	-1.0 mmHg Standard Error 0.35	-5.3 mmHg Standard Error 0.19	—	—

SECONDARY outcome

Timeframe: Week 176

Population: Participants with prediabetes at randomization who received at least one dose of study drug and had baseline and at least one post-baseline value for body weight, excluding data after prematurely stopping study drug.

Percentage of Participants Who Achieve ≥5% Body Weight Reduction.

Outcome measures

Outcome measures
Measure	Placebo n=264 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=245 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide n=260 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide n=249 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Percentage of Participants Who Achieve ≥5% Body Weight Reduction (Primary and Additional Treatment Periods : Participants With Prediabetes at Randomization)	24.62 Percentage of Participants	90.61 Percentage of Participants	91.92 Percentage of Participants	94.78 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline, Week 72

Population: All participants who received at least one dose of study drug and had baseline and at least one post-baseline IWQOL-Lite CT value, excluding data after prematurely stopping study drug.

The IWQOL-Lite-CT is a 20-item, obesity-specific patient-reported outcomes (PRO) instrument developed for use in obesity clinical trials. It assesses 2 primary domains of obesity-related health-related quality of life (HRQoL): physical (7 items), and psychosocial (13 items). A 5-item subset of the physical domain, the physical-function composite is also supported. Items in the physical-function composite describe physical impacts related to general and specific physical activities. All items in the physical domain are rated on either a 5-point frequency ("never" to "always") scale or a 5-point truth ("not at all true" to "completely true") scale. Total score of IWQOL-Lite-CT composite ranges from 0 to 100, with higher scores reflecting better quality of life.

Outcome measures

Outcome measures
Measure	Placebo n=477 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=545 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide n=539 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide n=535 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Change From Baseline in Impact of Weight on Quality of Life-Lite-Clinical Trials Version (IWQOL-Lite-CT) Physical Function Composite Score at Week 72 (Primary Treatment Period)	10.1 score on a scale Standard Error 0.78	17.8 score on a scale Standard Error 0.73	20.7 score on a scale Standard Error 0.73	21.8 score on a scale Standard Error 0.73

SECONDARY outcome

Timeframe: Week 8, 16, and 36, at 1 to 24 hours, 24 to 96 hours, or 120 to 168 hours postdose

Population: All randomly assigned participants who are exposed to at least one dose of study drug who had evaluable PK data.

PK: Steady State AUC of Tirzepatide. each participant will be assigned via the Interactive Web Response System (IWRS) to one of the sampling PK time windows of 1 to 24 hours, 24 to 96 hours, or 120 to 168 hours postdose.

Outcome measures

Outcome measures
Measure	Placebo n=626 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of a matching placebo, administered over a period of 72 weeks.	5 mg Tirzepatide n=629 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 5 mg, which was then maintained up to week 72.	10 mg Tirzepatide n=625 Participants Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 10 mg, which was then maintained up to week 72.	15 mg Tirzepatide Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received QW SC doses of tirzepatide, starting at 2.5 mg and increasing by 2.5 mg every 4 weeks until reaching a dose of 15 mg, which was then maintained up to week 72.
Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve (AUC) of Tirzepatide (Primary Treatment Period)	88900 nanogramshours per milliliter (ngh/mL) Geometric Coefficient of Variation 20.2	177000 nanogramshours per milliliter (ngh/mL) Geometric Coefficient of Variation 22.0	266000 nanogramshours per milliliter (ngh/mL) Geometric Coefficient of Variation 20.4	—

Adverse Events

Placebo

Serious events: 53 serious events

Other events: 315 other events

Deaths: 4 deaths

5 mg Tirzepatide

Serious events: 57 serious events

Other events: 443 other events

Deaths: 4 deaths

10 mg Tirzepatide

Serious events: 60 serious events

Other events: 451 other events

Deaths: 3 deaths

15 mg Tirzepatide

Serious events: 50 serious events

Other events: 429 other events

Deaths: 2 deaths

Serious adverse events

Other adverse events

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-595-5979

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60