SURPASS-1: A Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03954834
• Collaborator: (none)
• Enrollment: 478
• Locations: 53
• Arms: 4
• Actual Duration (Months): 16.9
• Patients Per Site: 9
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The goal for this study is to evaluate the efficacy and safety of tirzepatide versus placebo in participants with type 2 diabetes not under control with diet and exercise alone. The study will last approximately 47 weeks and may include about 15 visits.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: Tirzepatide; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 478 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-Controlled Trial Comparing the Efficacy and Safety of Three Tirzepatide Doses Versus Placebo in Patients With Type 2 Diabetes, Inadequately Controlled With Diet and Exercise Alone
• Actual Study Start Date: Jun 3, 2019
• Actual Primary Completion Date: Oct 5, 2020
• Actual Study Completion Date: Oct 28, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 5 mg Tirzepatide Participants received 5 milligrams (mg) of tirzepatide as subcutaneous injection once a week.	Drug: Tirzepatide; Administered SC; Other Names: LY3298176
Experimental: 10 mg Tirzepatide Participants received 10mg of tirzepatide as subcutaneous injection once a week.	Drug: Tirzepatide; Administered SC; Other Names: LY3298176
Experimental: 15 mg Tirzepatide Participants received 15mg of tirzepatide as subcutaneous injection once a week.	Drug: Tirzepatide; Administered SC; Other Names: LY3298176
Placebo Comparator: Placebo Participants received placebo as subcutaneous injection once a week.	Drug: Placebo; Administered SC

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Hemoglobin A1c (HbA1c) [Baseline, Week 40]

   HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Pooled Country + Prior Use of oral antihyperglycemic medication (OAM) (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).

Secondary Outcome Measures

1. Change From Baseline in Body Weight [Baseline, Week 40]

   Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Prior Use of OAM (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).

2. Percentage of Participants With HbA1c Target Value of <7% [Week 40]

   Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.

3. Change From Baseline in Fasting Serum Glucose [Baseline, Week 40]

   Fasting serum glucose (FSG) is a test to determine sugar levels in serum sample after an overnight fast. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Prior Use of OAM (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).

4. Percentage of Participants With HbA1c Target Value of <5.7% [Week 40]

   Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.

5. Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values [Baseline, Week 40]

   The self-monitored plasma glucose (SMBG) data were collected at the following 7 time points: Morning Premeal - Fasting, Morning 2-hour Postmeal, Midday Premeal, Midday 2-hour Postmeal, Evening Premeal, Evening 2-hour Postmeal and Bedtime. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Prior Use of OAM (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).

6. Percentage of Participants Who Achieved Weight Loss ≥5% [Week 40]

   Percentage of Participants who Achieved Weight Loss ≥5%.

7. Rate of Hypoglycemia With Blood Glucose <54 Milligram/Deciliter (mg/dL) [<3.0 Millimole/Liter (mmol/L)] or Severe Hypoglycemia [Baseline through end of safety follow-up (up to week 44)]

   The hypoglycemia events were defined by participant reported events with blood glucose <54mg/dL) (<3.0 mmol/L] or severe hypoglycemia. Severe hypoglycemia is defined as an episode with severe cognitive impairment requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. The rate of postbaseline hypoglycemia was estimated by negative binomial model: number of episodes = Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Prior Use of OAM (Yes, No) + Treatment, with log (exposure in days/365.25) as an offset variable.

8. Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve (AUC) of Tirzepatide [Week 7, 15 and 23]

   Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve (AUC) of Tirzepatide. AUC is a combined measure obtained from Week 7, 15 and 23, and a single averaged measure of AUC was reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Have been diagnosed with type 2 diabetes mellitus (T2DM).

• Are naïve to diabetes injectable therapies and have not used any oral antihyperglycemic medications (OAMs) during the 3 months preceding screening.

• Have HbA1c between ≥7.0% and ≤9.5%.

• Be of stable weight (± 5%) for at least 3 months before screening.

• Have a BMI ≥23 kilograms per meter squared (kg/m²) at screening.

Exclusion Criteria:

• Have type 1 diabetes mellitus.

• Have had chronic or acute pancreatitis any time prior to study entry.

• Have proliferative diabetic retinopathy or diabetic maculopathy or nonproliferative diabetic retinopathy requiring acute treatment.

• Have disorders associated with slowed emptying of the stomach, or have had any stomach surgeries for the purpose of weight loss.

• Have an estimated glomerular filtration rate <30 mL/minute/1.73 m².

• Have had a heart attack, stroke, or hospitalization for congestive heart failure in the past 2 months.

• Have a personal or family history of medullary thyroid carcinoma or personal history of multiple endocrine neoplasia syndrome type 2.

• Have been taking weight loss drugs, including over-the-counter medications during the last 3 months.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Research Institute	Huntington Park	California	United States	90255
2	National Research Institute	Los Angeles	California	United States	90057
3	Catalina Research Institute, LLC	Montclair	California	United States	91763
4	Valley Clinical Trials, Inc.	Northridge	California	United States	91325
5	National Research Institute	Panorama City	California	United States	91402
6	Southern California Dermatology	Santa Ana	California	United States	92701
7	Clinical Research of South Florida	Coral Gables	Florida	United States	33134
8	Encore Medical Research, LLC	Hollywood	Florida	United States	33021
9	Axcess Medical Research	Loxahatchee Groves	Florida	United States	33470
10	South Florida Wellness & Clinical Research Institute	Margate	Florida	United States	33063
11	Suncoast Research Group, LLC	Miami	Florida	United States	33135
12	Agile Clinical Research Trials	Atlanta	Georgia	United States	30328
13	Sky Clinical Research Network	Atlanta	Georgia	United States	30331
14	Cotton O'Neil Clinic	Topeka	Kansas	United States	66606
15	Clinical Research Professionals	Chesterfield	Missouri	United States	63005
16	StudyMetrix Research, LLC	Saint Peters	Missouri	United States	63303
17	Aventiv Research	Columbus	Ohio	United States	43213
18	Intend Research	Norman	Oklahoma	United States	73069
19	The Corvallis Clinic P.C.	Corvallis	Oregon	United States	97330
20	Heritage Valley Medical Group, Inc.	Beaver	Pennsylvania	United States	15009
21	Family Medical Associates	Levittown	Pennsylvania	United States	19056
22	Preferred Primary Care Physicians	Pittsburgh	Pennsylvania	United States	15236
23	Preferred Primary Care Physicians	Uniontown	Pennsylvania	United States	15401
24	Dallas Diabetes Endocrine Center	Dallas	Texas	United States	75230
25	Clinical Trials of Texas, Inc.	San Antonio	Texas	United States	78229
26	Consano Clinical Research	Shavano Park	Texas	United States	78231
27	Capital Clinical Research Center	Olympia	Washington	United States	98502
28	Rockwood Clinic Research Center	Spokane	Washington	United States	99220
29	Dr. Jivraj Mehta Smarak Health Foundation	Ahmedabad	Gujarat	India	380007
30	Bangalore Medical College and Research Institute	Bangalore	Karnataka	India	560 002
31	M S Ramaiah Medical College Hospital	Bangalore	Karnataka	India	560054
32	BSES Municipal General Hsptl	Mumbai	Maharashtra	India	400058
33	Ruby Hall Clinic and Grant Medical Foundation	Pune	Maharashtra	India	411001
34	Vijay Vallabh Hospital	Virar	Maharashtra	India	401303
35	Lifepoint Multispecialty Hsptl	Wakad	Pune	India	411057
36	Ramdevrao Hospital	Hyderabad	Telangana	India	500072
37	Gandhi Hospital	Telangana		India	500003
38	Minamiakatsuka Clinic	Mito	Ibaraki	Japan	311-4153
39	Takai Naika Clinic	Kamakura	Kanagawa	Japan	247-0056
40	Tsuruma Kaneshiro Diabetes Clinic	Yamato	Kanagawa	Japan	242-0004
41	Yokohama Minoru Clinic	Yokohama	Kanagawa	Japan	232-0064
42	Takatsuki Red Cross Hospital	Takatsuki	Osaka	Japan	569-1096
43	Meiwa Hospital	Chiyodaku	Tokyo	Japan	101 0041
44	Tokyo-Eki Center-building Clinic	Chuo-ku	Tokyo	Japan	103-0027
45	Tokyo Center Clinic	Chuo-ku	Tokyo	Japan	103-0028
46	IHL Shinagawa East One Medical Clinic	Minato-ku	Tokyo	Japan	108 0075
47	Sato Naika Clinic	Ota-ku	Tokyo	Japan	143-0015
48	Hospital Universitario UANL	Monterrey	Nuevo León	Mexico	64460
49	Unidad Medica para la Salud Integral (UMSI)	Monterrey	Nuevo León	Mexico	66465
50	Centro de Estudios de Investigacion Metabolicos y Cardiovasc	Madero	Tamaulipas	Mexico	89440
51	Investigacion en Salud y Metabolismo S.C	Chihuahua		Mexico	31217
52	Clinical Research Puerto Rico, Inc.	San Juan		Puerto Rico	00909
53	GCM Medical Group PSC	San Juan		Puerto Rico	00917

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

• Study Protocol - Apr 15, 2020
• Statistical Analysis Plan - Nov 20, 2020

More Information

Additional Information:

• A Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone (SURPASS-1)

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT03954834
• Other Study ID Numbers: 17000; I8F-MC-GPGK
• First Posted: May 17, 2019
• Last Update Posted: Oct 20, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Eli Lilly and Company: glucose-dependent insulinotropic polypeptide (GIP); glucagon-like peptide-1 (GLP-1); GIP/GLP-1 dual receptor agonist; T2DM
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Tirzepatide

Study Results

Participant Flow

Arm/Group Title	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Placebo
Arm/Group Description	Participants received 5 mg of tirzepatide as subcutaneous injection once a week.	Participants received 10mg of tirzepatide as subcutaneous injection once a week.	Participants received 15mg of tirzepatide as subcutaneous injection once a week.	Participants received placebo as subcutaneous injection once a week.
Period Title: Overall Study
STARTED	121	121	121	115
Received at Least One Dose of Study Drug	121	121	121	115
COMPLETED	114	112	103	99
NOT COMPLETED	7	9	18	16

Baseline Characteristics

Arm/Group Title	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Placebo	Total
Arm/Group Description	Participants received 5 mg of tirzepatide as subcutaneous injection once a week.	Participants received 10mg of tirzepatide as subcutaneous injection once a week.	Participants received 15mg of tirzepatide as subcutaneous injection once a week.	Participants received placebo as subcutaneous injection once a week.	Total of all reporting groups
Overall Participants	121	121	121	115	478
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.10 (11.88)	55.80 (10.35)	52.90 (12.34)	53.60 (12.79)	54.10 (11.88)
Sex: Female, Male (Count of Participants)
Female	65 53.7%	49 40.5%	58 47.9%	59 51.3%	231 48.3%
Male	56 46.3%	72 59.5%	63 52.1%	56 48.7%	247 51.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	50 41.3%	54 44.6%	55 45.5%	48 41.7%	207 43.3%
Not Hispanic or Latino	48 39.7%	49 40.5%	42 34.7%	45 39.1%	184 38.5%
Unknown or Not Reported	23 19%	18 14.9%	24 19.8%	22 19.1%	87 18.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	31 25.6%	31 25.6%	30 24.8%	26 22.6%	118 24.7%
Asian	45 37.2%	43 35.5%	42 34.7%	38 33%	168 35.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	7 5.8%	4 3.3%	6 5%	5 4.3%	22 4.6%
White	38 31.4%	43 35.5%	43 35.5%	46 40%	170 35.6%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
India	18 14.9%	20 16.5%	18 14.9%	17 14.8%	73 15.3%
Japan	23 19%	22 18.2%	23 19%	21 18.3%	89 18.6%
Mexico	42 34.7%	40 33.1%	42 34.7%	40 34.8%	164 34.3%
Puerto Rico	2 1.7%	4 3.3%	5 4.1%	1 0.9%	12 2.5%
United States	36 29.8%	35 28.9%	33 27.3%	36 31.3%	140 29.3%
Hemoglobin A1c (Percentage of HbA1c) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of HbA1c]	7.97 (0.841)	7.90 (0.78)	7.85 (1.02)	8.05 (0.80)	7.94 (0.87)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Hemoglobin A1c (HbA1c)
Description	HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Pooled Country + Prior Use of oral antihyperglycemic medication (OAM) (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).
Time Frame	Baseline, Week 40

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug and had a baseline and at least 1 post-baseline value, excluding patients discontinuing study drug due to inadvertent enrollment and data after initiating rescue antihyperglycemic medication or prematurely stopping study drug.

Arm/Group Title	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Placebo
Arm/Group Description	Participants received 5 mg of tirzepatide as subcutaneous injection once a week.	Participants received 10mg of tirzepatide as subcutaneous injection once a week.	Participants received 15mg of tirzepatide as subcutaneous injection once a week.	Participants received placebo as subcutaneous injection once a week.
Measure Participants	121	118	116	112
Least Squares Mean (Standard Error) [Percentage of HbA1c]	-1.87 (0.094)	-1.89 (0.096)	-2.07 (0.098)	0.04 (0.105)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	5 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.91
	Confidence Interval	(2-Sided) 95%; -2.18 to -1.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	10 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.93
	Confidence Interval	(2-Sided) 95%; -2.21 to -1.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	15 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.11
	Confidence Interval	(2-Sided) 95%; -2.39 to -1.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Body Weight
Description	Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Prior Use of OAM (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).
Time Frame	Baseline, Week 40

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug and had a baseline and at least 1 post-baseline value, excluding patients discontinuing study drug due to inadvertent enrollment and data after initiating rescue antihyperglycemic medication or prematurely stopping study drug.

Arm/Group Title	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Placebo
Arm/Group Description	Participants received 5 mg of tirzepatide as subcutaneous injection once a week.	Participants received 10mg of tirzepatide as subcutaneous injection once a week.	Participants received 15mg of tirzepatide as subcutaneous injection once a week.	Participants received placebo as subcutaneous injection once a week.
Measure Participants	121	118	116	112
Least Squares Mean (Standard Error) [Kilograms (kg)]	-7.0 (0.52)	-7.8 (0.53)	-9.5 (0.54)	-0.7 (0.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	5 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-6.3
	Confidence Interval	(2-Sided) 95%; -7.8 to -4.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	10 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-7.1
	Confidence Interval	(2-Sided) 95%; -8.6 to -5.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	15 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-8.8
	Confidence Interval	(2-Sided) 95%; -10.3 to -7.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants With HbA1c Target Value of <7%
Description	Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.
Time Frame	Week 40

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug and had a baseline and at least 1 post-baseline value, excluding patients discontinuing study drug due to inadvertent enrollment and data after initiating rescue antihyperglycemic medication or prematurely stopping study drug.

Arm/Group Title	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Placebo
Arm/Group Description	Participants received 5 mg of tirzepatide as subcutaneous injection once a week.	Participants received 10mg of tirzepatide as subcutaneous injection once a week.	Participants received 15mg of tirzepatide as subcutaneous injection once a week.	Participants received placebo as subcutaneous injection once a week.
Measure Participants	121	118	116	112
Number [Percentage of participants]	86.78 71.7%	91.53 75.6%	87.93 72.7%	19.64 17.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	5 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	49.00
	Confidence Interval	(2-Sided) 95%; 21.12 to 113.67
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	10 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	80.39
	Confidence Interval	(2-Sided) 95%; 31.80 to 203.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	15 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	52.95
	Confidence Interval	(2-Sided) 95%; 22.30 to 125.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Fasting Serum Glucose
Description	Fasting serum glucose (FSG) is a test to determine sugar levels in serum sample after an overnight fast. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Prior Use of OAM (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).
Time Frame	Baseline, Week 40

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug and had a baseline and at least 1 post-baseline value, excluding patients discontinuing study drug due to inadvertent enrollment and data after initiating rescue antihyperglycemic medication or prematurely stopping study drug.

Arm/Group Title	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Placebo
Arm/Group Description	Participants received 5 mg of tirzepatide as subcutaneous injection once a week.	Participants received 10mg of tirzepatide as subcutaneous injection once a week.	Participants received 15mg of tirzepatide as subcutaneous injection once a week.	Participants received placebo as subcutaneous injection once a week.
Measure Participants	121	118	116	112
Least Squares Mean (Standard Error) [milligram per Deciliter (mg/dL)]	-43.6 (3.40)	-45.9 (3.45)	-49.3 (3.62)	12.9 (4.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	5 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.776
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 95%; -11.9 to 8.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	10 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.622
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.6
	Confidence Interval	(2-Sided) 95%; -13.0 to 7.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	15 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.908
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -11.1 to 9.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Percentage of Participants With HbA1c Target Value of <5.7%
Description	Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.
Time Frame	Week 40

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug and had a baseline and at least 1 post-baseline value, excluding patients discontinuing study drug due to inadvertent enrollment and data after initiating rescue antihyperglycemic medication or prematurely stopping study drug.

Arm/Group Title	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Placebo
Arm/Group Description	Participants received 5 mg of tirzepatide as subcutaneous injection once a week.	Participants received 10mg of tirzepatide as subcutaneous injection once a week.	Participants received 15mg of tirzepatide as subcutaneous injection once a week.	Participants received placebo as subcutaneous injection once a week.
Measure Participants	121	118	116	112
Number [Percentage of participants]	33.88 28%	30.51 25.2%	51.72 42.7%	0.89 0.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	5 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	40.28
	Confidence Interval	(2-Sided) 95%; 7.74 to 209.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	10 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	34.12
	Confidence Interval	(2-Sided) 95%; 6.53 to 178.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	15 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	85.13
	Confidence Interval	(2-Sided) 95%; 16.36 to 443.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values
Description	The self-monitored plasma glucose (SMBG) data were collected at the following 7 time points: Morning Premeal - Fasting, Morning 2-hour Postmeal, Midday Premeal, Midday 2-hour Postmeal, Evening Premeal, Evening 2-hour Postmeal and Bedtime. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Prior Use of OAM (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).
Time Frame	Baseline, Week 40

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug and had a baseline and at least 1 post-baseline value, excluding patients discontinuing study drug due to inadvertent enrollment and data after initiating rescue antihyperglycemic medication or prematurely stopping study drug.

Arm/Group Title	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Placebo
Arm/Group Description	Participants received 5 mg of tirzepatide as subcutaneous injection once a week.	Participants received 10mg of tirzepatide as subcutaneous injection once a week.	Participants received 15mg of tirzepatide as subcutaneous injection once a week.	Participants received placebo as subcutaneous injection once a week.
Measure Participants	115	111	108	101
Morning Premeal - Fasting	-46.9 (2.09)	-47.9 (2.11)	-45.7 (2.23)	-9.2 (2.53)
Morning 2-hour Postmeal	-69.5 (3.41)	-61.4 (3.44)	-68.9 (3.66)	-11.6 (4.12)
Midday Premeal	-43.5 (2.80)	-42.5 (2.82)	-42.7 (3.00)	-2.6 (3.42)
Midday 2-hour Postmeal	-64.2 (3.60)	-60.0 (3.63)	-63.4 (3.84)	-12.7 (4.33)
Evening Premeal	-44.8 (2.80)	-45.1 (2.82)	-42.3 (3.02)	-5.8 (3.38)
Evening 2-hour Postmeal	-61.9 (3.76)	-62.8 (3.81)	-63.5 (4.03)	-10.3 (4.52)
Bedtime	-57.0 (3.49)	-59.8 (3.52)	-60.8 (3.66)	-9.1 (4.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	5 mg Tirzepatide, Placebo
	Comments	Morning Premeal - Fasting
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-37.7
	Confidence Interval	(2-Sided) 95%; -44.1 to -31.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	10 mg Tirzepatide, Placebo
	Comments	Morning Premeal - Fasting
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-38.6
	Confidence Interval	(2-Sided) 95%; -45.1 to -32.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	15 mg Tirzepatide, Placebo
	Comments	Morning Premeal - Fasting
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-36.5
	Confidence Interval	(2-Sided) 95%; -43.1 to -29.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	5 mg Tirzepatide, Placebo
	Comments	Morning 2-hour Postmeal
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-57.9
	Confidence Interval	(2-Sided) 95%; -68.4 to -47.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	10 mg Tirzepatide, Placebo
	Comments	Morning 2-hour Postmeal
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-49.7
	Confidence Interval	(2-Sided) 95%; -60.3 to -39.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	15 mg Tirzepatide, Placebo
	Comments	Morning 2-hour Postmeal
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-57.3
	Confidence Interval	(2-Sided) 95%; -68.1 to -46.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	5 mg Tirzepatide, Placebo
	Comments	Midday Premeal
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-40.9
	Confidence Interval	(2-Sided) 95%; -49.6 to -32.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	10 mg Tirzepatide, Placebo
	Comments	Midday Premeal
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-39.9
	Confidence Interval	(2-Sided) 95%; -48.6 to -31.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	15 mg Tirzepatide, Placebo
	Comments	Midday Premeal
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-40.0
	Confidence Interval	(2-Sided) 95%; -49.0 to -31.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	5 mg Tirzepatide, Placebo
	Comments	Midday 2-hour Postmeal
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-51.4
	Confidence Interval	(2-Sided) 95%; -62.5 to -40.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	10 mg Tirzepatide, Placebo
	Comments	Midday 2-hour Postmeal
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-47.3
	Confidence Interval	(2-Sided) 95%; -58.4 to -36.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	15 mg Tirzepatide, Placebo
	Comments	Midday 2-hour Postmeal
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-50.7
	Confidence Interval	(2-Sided) 95%; -62.1 to -39.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	5 mg Tirzepatide, Placebo
	Comments	Evening Premeal
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-39.0
	Confidence Interval	(2-Sided) 95%; -47.6 to -30.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	10 mg Tirzepatide, Placebo
	Comments	Evening Premeal
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-39.2
	Confidence Interval	(2-Sided) 95%; -47.9 to -30.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	15 mg Tirzepatide, Placebo
	Comments	Evening Premeal
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-36.4
	Confidence Interval	(2-Sided) 95%; -45.3 to -27.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	5 mg Tirzepatide, Placebo
	Comments	Evening 2-hour Postmeal
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-51.7
	Confidence Interval	(2-Sided) 95%; -63.2 to -40.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	10 mg Tirzepatide, Placebo
	Comments	Evening 2-hour Postmeal
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-52.5
	Confidence Interval	(2-Sided) 95%; -64.1 to -40.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	15 mg Tirzepatide, Placebo
	Comments	Evening 2-hour Postmeal
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-53.2
	Confidence Interval	(2-Sided) 95%; -65.1 to -41.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	5 mg Tirzepatide, Placebo
	Comments	Bedtime
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-48.0
	Confidence Interval	(2-Sided) 95%; -58.6 to -37.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	10 mg Tirzepatide, Placebo
	Comments	Bedtime
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-50.7
	Confidence Interval	(2-Sided) 95%; -61.3 to -40.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	15 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-51.7
	Confidence Interval	(2-Sided) 95%; -62.6 to -40.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Percentage of Participants Who Achieved Weight Loss ≥5%
Description	Percentage of Participants who Achieved Weight Loss ≥5%.
Time Frame	Week 40

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug and had a baseline and at least 1 post-baseline value, excluding patients discontinuing study drug due to inadvertent enrollment and data after initiating rescue antihyperglycemic medication or prematurely stopping study drug.

Arm/Group Title	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Placebo
Arm/Group Description	Participants received 5 mg of tirzepatide as subcutaneous injection once a week.	Participants received 10mg of tirzepatide as subcutaneous injection once a week.	Participants received 15mg of tirzepatide as subcutaneous injection once a week.	Participants received placebo as subcutaneous injection once a week.
Measure Participants	121	118	116	112
Number [Percentage of participants]	66.94 55.3%	77.97 64.4%	76.72 63.4%	14.29 12.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	5 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	12.40
	Confidence Interval	(2-Sided) 95%; 6.43 to 23.94
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	10 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	21.13
	Confidence Interval	(2-Sided) 95%; 10.59 to 42.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	15 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	20.10
	Confidence Interval	(2-Sided) 95%; 10.09 to 40.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Rate of Hypoglycemia With Blood Glucose <54 Milligram/Deciliter (mg/dL) [<3.0 Millimole/Liter (mmol/L)] or Severe Hypoglycemia
Description	The hypoglycemia events were defined by participant reported events with blood glucose <54mg/dL) (<3.0 mmol/L] or severe hypoglycemia. Severe hypoglycemia is defined as an episode with severe cognitive impairment requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. The rate of postbaseline hypoglycemia was estimated by negative binomial model: number of episodes = Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Prior Use of OAM (Yes, No) + Treatment, with log (exposure in days/365.25) as an offset variable.
Time Frame	Baseline through end of safety follow-up (up to week 44)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug and had a baseline and at least 1 post-baseline value.

Arm/Group Title	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Placebo
Arm/Group Description	Participants received 5 mg of tirzepatide as subcutaneous injection once a week.	Participants received 10mg of tirzepatide as subcutaneous injection once a week.	Participants received 15mg of tirzepatide as subcutaneous injection once a week.	Participants received placebo as subcutaneous injection once a week.
Measure Participants	121	119	120	115
Mean (Standard Error) [Episodes/participant/365.25 days]	0.02 (0.002)	0.02 (0.002)	0.02 (0.002)	0.04 (0.028)

9. Secondary Outcome

Title	Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve (AUC) of Tirzepatide
Description	Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve (AUC) of Tirzepatide. AUC is a combined measure obtained from Week 7, 15 and 23, and a single averaged measure of AUC was reported.
Time Frame	Week 7, 15 and 23

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide
Arm/Group Description	Participants received 5 mg of tirzepatide as subcutaneous injection once a week.	Participants received 10mg of tirzepatide as subcutaneous injection once a week.	Participants received 15mg of tirzepatide as subcutaneous injection once a week.
Measure Participants	121	118	120
Geometric Mean (Geometric Coefficient of Variation) [nanograms*hours per milliliter (h*ng/mL)]	86900 (25.4)	171000 (26.2)	252000 (23.3)

Adverse Events

Time Frame	Baseline to end of Safety follow-up (up to 44 weeks)
Adverse Event Reporting Description	All randomized participants who received at least one dose of study drug.
Arm/Group Title	5 mg Tirzepatide		10 mg Tirzepatide		15 mg Tirzepatide		Placebo
Arm/Group Description	Participants received 5 mg of Tirzepatide as subcutaneous injection, once weekly.		Participants received 10 mg of Tirzepatide as subcutaneous injection, once weekly.		Participants received 15 mg of Tirzepatide as subcutaneous injection, once weekly.		Participants received placebo as subcutaneous injection, once weekly.
All Cause Mortality
	5 mg Tirzepatide		10 mg Tirzepatide		15 mg Tirzepatide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/121 (0%)		0/121 (0%)		0/121 (0%)		1/115 (0.9%)
Serious Adverse Events
	5 mg Tirzepatide		10 mg Tirzepatide		15 mg Tirzepatide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/121 (4.1%)		2/121 (1.7%)		1/121 (0.8%)		3/115 (2.6%)
Cardiac disorders
Acute myocardial infarction	0/121 (0%)	0	0/121 (0%)	0	0/121 (0%)	0	1/115 (0.9%)	1
Cardiac failure	0/121 (0%)	0	0/121 (0%)	0	0/121 (0%)	0	1/115 (0.9%)	1
Supraventricular tachycardia	1/121 (0.8%)	1	0/121 (0%)	0	0/121 (0%)	0	0/115 (0%)	0
Gastrointestinal disorders
Colitis ischaemic	1/121 (0.8%)	1	0/121 (0%)	0	0/121 (0%)	0	0/115 (0%)	0
Infections and infestations
Clostridium difficile infection	0/121 (0%)	0	1/121 (0.8%)	1	0/121 (0%)	0	0/115 (0%)	0
Pneumonia	0/121 (0%)	0	1/121 (0.8%)	1	0/121 (0%)	0	0/115 (0%)	0
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	0/121 (0%)	0	0/121 (0%)	0	1/121 (0.8%)	1	0/115 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma	1/121 (0.8%)	1	0/121 (0%)	0	0/121 (0%)	0	0/115 (0%)	0
Cholangiocarcinoma	0/121 (0%)	0	0/121 (0%)	0	0/121 (0%)	0	1/115 (0.9%)	1
Nervous system disorders
Syncope	1/121 (0.8%)	1	0/121 (0%)	0	0/121 (0%)	0	0/115 (0%)	0
Renal and urinary disorders
Nephrolithiasis	1/121 (0.8%)	1	0/121 (0%)	0	0/121 (0%)	0	0/115 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/121 (0.8%)	1	0/121 (0%)	0	0/121 (0%)	0	0/115 (0%)	0
Vascular disorders
Peripheral arterial occlusive disease	1/121 (0.8%)	1	0/121 (0%)	0	0/121 (0%)	0	0/115 (0%)	0
Other (Not Including Serious) Adverse Events
	5 mg Tirzepatide		10 mg Tirzepatide		15 mg Tirzepatide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	50/121 (41.3%)		55/121 (45.5%)		53/121 (43.8%)		54/115 (47%)
Gastrointestinal disorders
Constipation	7/121 (5.8%)	11	6/121 (5%)	6	8/121 (6.6%)	9	1/115 (0.9%)	1
Diarrhoea	14/121 (11.6%)	21	17/121 (14%)	19	14/121 (11.6%)	20	9/115 (7.8%)	15
Dyspepsia	11/121 (9.1%)	15	8/121 (6.6%)	12	7/121 (5.8%)	7	4/115 (3.5%)	4
Nausea	14/121 (11.6%)	31	16/121 (13.2%)	82	22/121 (18.2%)	50	7/115 (6.1%)	8
Vomiting	4/121 (3.3%)	6	3/121 (2.5%)	3	7/121 (5.8%)	9	2/115 (1.7%)	3
Infections and infestations
Influenza	7/121 (5.8%)	7	3/121 (2.5%)	3	0/121 (0%)	0	2/115 (1.7%)	2
Nasopharyngitis	7/121 (5.8%)	7	8/121 (6.6%)	13	8/121 (6.6%)	8	10/115 (8.7%)	11
Metabolism and nutrition disorders
Decreased appetite	5/121 (4.1%)	5	8/121 (6.6%)	9	10/121 (8.3%)	10	1/115 (0.9%)	1
Hyperglycaemia	4/121 (3.3%)	4	5/121 (4.1%)	7	3/121 (2.5%)	3	31/115 (27%)	31
Nervous system disorders
Headache	5/121 (4.1%)	9	4/121 (3.3%)	7	5/121 (4.1%)	8	9/115 (7.8%)	12

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.