SURPASS-5: A Study of Tirzepatide (LY3298176) Versus Placebo in Participants With Type 2 Diabetes Inadequately Controlled on Insulin Glargine With or Without Metformin

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04039503
• Collaborator: (none)
• Enrollment: 475
• Locations: 48
• Arms: 4
• Actual Duration (Months): 16.5
• Patients Per Site: 9.9
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the safety and efficacy of the study drug tirzepatide to placebo in participants with type 2 diabetes that are already on insulin glargine, with or without metformin. Participants will administer tirzepatide or placebo along with their previous glucose lowering medications. The study will last approximately 47 weeks and may include about 23 visits.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 475 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Randomized, Phase 3, Double-blind Trial Comparing the Effect of the Addition of Tirzepatide Versus Placebo in Patients With Type 2 Diabetes Inadequately Controlled on Insulin Glargine With or Without Metformin
• Actual Study Start Date: Aug 30, 2019
• Actual Primary Completion Date: Dec 22, 2020
• Actual Study Completion Date: Jan 13, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 5 mg Tirzepatide 5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.	Drug: Tirzepatide; Administered SC as add-on to the pre-trial background medication.; Other Names: LY3298176
Experimental: 10 mg Tirzepatide 10 mg tirzepatide administered SC once a week.	Drug: Tirzepatide; Administered SC as add-on to the pre-trial background medication.; Other Names: LY3298176
Experimental: 15 mg Tirzepatide 15 mg tirzepatide administered SC once a week.	Drug: Tirzepatide; Administered SC as add-on to the pre-trial background medication.; Other Names: LY3298176
Placebo Comparator: Placebo Placebo administered SC once a week.	Drug: Placebo; Administered SC as add-on to the pre-trial background medication.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg) [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 + Baseline Metformin Use (Yes, No) + Pooled Country + Treatment + Time + Treatment*Time (Type III sum of squares).

Secondary Outcome Measures

1. Change From Baseline in HbA1c (5 mg) [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 + Baseline Metformin Use (Yes, No) + Pooled Country + Treatment + Time + Treatment*Time (Type III sum of squares).

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

   Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Baseline HbA1c Group (<= 8.0%, >8.0%) + Baseline Metformin Use (Yes, No) + Pooled Country + Treatment + Time + Treatment*Time (Type III sum of squares).

3. Percentage of Participants Achieving an 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.

4. 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. LS Mean was determined by MMRM model with Baseline + Pooled Country + Baseline Metformin Use (Yes, No) + Baseline HbA1c Group (<= 8.0%, >8.0%) + Treatment + Time + Treatment*Time (Type III sum of squares) as variables.

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 + Baseline HbA1c Group (<= 8.0%, >8.0%) + Baseline Metformin Use (Yes, No) + Pooled Country + Treatment (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. Percentage Change From Baseline in Daily Mean Insulin Glargine Dose [Baseline, Week 40]

   LS mean was calculated using MMRM model with log (Baseline) + Baseline Metformin Use (Yes, No) + Pooled Country + Baseline HbA1c Group (<= 8.0%, >8.0%) + Treatment + Time + Treatment*Time (Type III sum of squares) as variables.

8. Rate of Hypoglycemia With Blood Glucose <54 Milligram/Deciliter (mg/dL) [<3.0 Millimole/Liter (mmol/L)] or Severe Hypoglycemia [Baseline through 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 Metformin Use (Yes, No) + Baseline HbA1c Group (<= 8.0%, >8.0%) + Treatment, with log (exposure in days/365.25) as an offset variable.

9. Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve (AUC) of Tirzepatide [Week 7, 15, 23 and 39 post dose]

   AUC is a combined measure obtained from Week 7, 15, 23 and 39 and a single averaged measure of AUC was reported.

10. Percentage of Participants Achieving an 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.

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) and have been treated with insulin glargine (U100), once daily with or without metformin ≥3 months prior to screening visit.

• Have HbA1c between ≥7.0% and ≤10.5%.

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

• Have a body mass index (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 [for participants on metformin, estimated glomerular filtration rate <45 mL/min/1.73 m2 (or lower than the country-specific threshold for using the protocol-required dose of metformin per local label)]

• 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	Valley Endocrine, Fresno	Fresno	California	United States	93720
2	Sun Coast Clinical Research, Inc	New Port Richey	Florida	United States	34652
3	Southern New Hampshire Diabetes and Endocrinology	Nashua	New Hampshire	United States	03063
4	Manhattan Medical Research	New York	New York	United States	10016
5	Intend Research	Norman	Oklahoma	United States	73069
6	Milan Kvapil s.r.o.	Pribram	Středočeský Kraj	Czechia	26201
7	Diacentrum Brandys n.L. s.r.o.	Brandys Nad Labem-Stara Bolesl		Czechia	25001
8	Diabetologicka ordinace pro dospele	Krnov		Czechia	79401
9	Diahelp s.r.o., Interni a diabetologicka ambulance	Pardubice		Czechia	53002
10	Lekarna Dr. Max	Praha 1		Czechia	11000
11	Milan Kvapil s.r.o.	Praha 4		Czechia	149 00
12	RESTRIAL s.r.o.	Praha 8		Czechia	181 00
13	Praxis Dr. Jörg Lüdemann	Falkensee	Brandenburg	Germany	14612
14	Arztpraxis Dr. Cornelia Marck	Pohlheim	Hessen	Germany	35415
15	InnoDiab Forschung GmbH	Essen	Nordrhein-Westfalen	Germany	45136
16	Institut für Diabetesforschung Münster GmbH	Münster	Nordrhein-Westfalen	Germany	48145
17	Praxis Dr. Kempe - Dr. Stemler	Ludwigshafen am Rhein	Rheinland-Pfalz	Germany	67059
18	Schwerpunktpraxis Diabetes	Saint Ingbert-Oberwürzbach	Saarland	Germany	66386
19	SMO.MD GmbH	Magdeburg	Sachsen-Anhalt	Germany	39112
20	RED-Institut GmbH	Oldenburg in Holstein	Schleswig Holstein	Germany	23758
21	Diabetologische Schwerpunktpraxis B. Scholz/Dr. B. Paschen	Hamburg		Germany	21073
22	Gemeinschaftspraxis für innere Medizin und Diabetologie	Hamburg		Germany	22607
23	Kashiwa hospital	Kashiwa	Chiba	Japan	277-0825
24	Manda Hospital	Sapporo	Hokkaido	Japan	060-0062
25	Takai Naika Clinic	Kamakura	Kanagawa	Japan	247-0056
26	Takatsuki Red Cross Hospital	Takatsuki	Osaka	Japan	569-1096
27	Tokyo-Eki Center-building Clinic	Chuo-ku	Tokyo	Japan	103-0027
28	Tokyo Center Clinic	Chuo-ku	Tokyo	Japan	103-0028
29	Tokyo Clinical Trial Centre Fukuwa Clinic	Chuo-ku	Tokyo	Japan	104-0031
30	The Institute for Adult Diseases, Asahi Life Foundation	Chuou-ku	Tokyo	Japan	1030002
31	Sato Naika Clinic	Ota-ku	Tokyo	Japan	143-0015
32	Jinnouchi Hospital	Kumamoto		Japan	862-0976
33	Centrum Medyczne AMED	Warszawa	Mazowieckie	Poland	01-518
34	NZOZ ZDROWIE Osteo-Medic	Bialystok	Podlaskie	Poland	15-351
35	Centrum Badan Klinicznych, PI House	Gdansk	Pomorskie	Poland	80-546
36	NZOZ Przychodnia Specjalistyczna MEDICA	Lublin		Poland	20-538
37	Centro de Endocrinologia y Nutricion del Turabo	Caguas		Puerto Rico	00725
38	Manati Center for Clinical Research Inc	Manati		Puerto Rico	00674
39	Ambulancia vnútorného lekárstva Hnúša (Diabetes care)	Hnusta		Slovakia	98101
40	Sin Azucar	Malacky		Slovakia	901 01
41	Dia-Clarus.s.r.o.	Prievidza		Slovakia	971 01
42	JAL	Trnava		Slovakia	917 01
43	Medivasa, s.r.o.	Zilina		Slovakia	01001
44	Hospital Clinico Universitario Virgen de la Victoria	Malaga	Andalucia	Spain	29010
45	Hospital de la Ribera	Alcira	Valencia	Spain	46600
46	Hospital Universitario Virgen Macarena	Sevilla		Spain	41009
47	Hospital Infanta Luisa	Sevilla		Spain	41010
48	Hospital Universitari i Politecnic La Fe-ENDO	València		Spain	46026

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 - Jun 26, 2020
• Statistical Analysis Plan - Feb 1, 2021

More Information

Additional Information:

• A Study of Tirzepatide (LY3298176) Versus Placebo in Participants With Type 2 Diabetes Inadequately Controlled on Insulin Glargine With or Without Metformin

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT04039503
• Other Study ID Numbers: 16998; I8F-MC-GPGI; 2019-000860-99
• First Posted: Jul 31, 2019
• Last Update Posted: Jan 12, 2022
• Last Verified: Dec 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	5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.	10 mg tirzepatide administered SC once a week.	15 mg tirzepatide administered SC once a week.	Placebo administered SC once a week.
Period Title: Overall Study
STARTED	116	119	120	120
Received at Least One Dose of Study Drug	116	119	120	120
COMPLETED	109	115	110	117
NOT COMPLETED	7	4	10	3

Baseline Characteristics

Arm/Group Title	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Placebo	Total
Arm/Group Description	5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.	10 mg tirzepatide administered SC once a week.	15 mg tirzepatide administered SC once a week.	Placebo administered SC once a week.	Total of all reporting groups
Overall Participants	116	119	120	120	475
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.50 (9.81)	60.40 (10.24)	60.50 (9.92)	60.00 (9.63)	60.60 (9.88)
Sex: Female, Male (Count of Participants)
Female	55 47.4%	47 39.5%	55 45.8%	54 45%	211 44.4%
Male	61 52.6%	72 60.5%	65 54.2%	66 55%	264 55.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 3.4%	8 6.7%	5 4.2%	5 4.2%	22 4.6%
Not Hispanic or Latino	94 81%	95 79.8%	93 77.5%	98 81.7%	380 80%
Unknown or Not Reported	18 15.5%	16 13.4%	22 18.3%	17 14.2%	73 15.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 0.8%	1 0.8%	0 0%	2 0.4%
Asian	20 17.2%	21 17.6%	22 18.3%	22 18.3%	85 17.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 0.9%	2 1.7%	3 2.5%	0 0%	6 1.3%
White	95 81.9%	94 79%	94 78.3%	97 80.8%	380 80%
More than one race	0 0%	1 0.8%	0 0%	1 0.8%	2 0.4%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
Czechia	24 20.7%	24 20.2%	23 19.2%	23 19.2%	94 19.8%
Germany	32 27.6%	32 26.9%	33 27.5%	32 26.7%	129 27.2%
Japan	19 16.4%	21 17.6%	20 16.7%	22 18.3%	82 17.3%
Poland	8 6.9%	9 7.6%	10 8.3%	9 7.5%	36 7.6%
Puerto Rico	2 1.7%	6 5%	1 0.8%	3 2.5%	12 2.5%
Slovakia	8 6.9%	7 5.9%	8 6.7%	8 6.7%	31 6.5%
Spain	13 11.2%	15 12.6%	15 12.5%	14 11.7%	57 12%
United States	10 8.6%	5 4.2%	10 8.3%	9 7.5%	34 7.2%
Hemoglobin A1c (Percentage of HbA1c) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of HbA1c]	8.30 (0.88)	8.36 (0.83)	8.23 (0.86)	8.37 (0.84)	8.31 (0.85)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg)
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 + Baseline Metformin Use (Yes, No) + Pooled Country + Treatment + Time + Treatment*Time (Type III sum of squares).
Time Frame	Baseline, Week 40

Outcome Measure Data

Analysis Population Description

All randomized participants from who received at least 1 dose 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	10 mg Tirzepatide	15 mg Tirzepatide	Placebo
Arm/Group Description	10 mg tirzepatide administered SC once a week.	15 mg tirzepatide administered SC once a week.	Placebo administered SC once a week.
Measure Participants	113	117	118
Least Squares Mean (Standard Error) [Percentage of HbA1c]	-2.59 (0.081)	-2.59 (0.083)	-0.93 (0.079)

Statistical Analysis 1

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	-1.66
	Confidence Interval	(2-Sided) 95%; -1.88 to -1.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

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	-1.65
	Confidence Interval	(2-Sided) 95%; -1.88 to -1.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in HbA1c (5 mg)
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 + Baseline Metformin Use (Yes, No) + Pooled Country + 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 one dose of 5 mg tirzepatide, placebo 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.

Arm/Group Title	5 mg Tirzepatide	Placebo
Arm/Group Description	5 mg tirzepatide administered subcutaneously (SC) once a week.	Placebo administered SC once a week.
Measure Participants	115	118
Least Squares Mean (Standard Error) [Percentage of HbA1c]	-2.23 (0.081)	-0.93 (0.079)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	10 mg Tirzepatide, 15 mg Tirzepatide
	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	-1.30
	Confidence Interval	(2-Sided) 95%; -1.52 to -1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. 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 + Baseline HbA1c Group (<= 8.0%, >8.0%) + Baseline Metformin Use (Yes, No) + Pooled Country + Treatment + Time + Treatment*Time (Type III sum of squares).
Time Frame	Baseline, Week 40

Outcome Measure Data

Analysis Population Description

All randomly assigned participants who took 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	5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.	10 mg tirzepatide administered SC once a week.	15 mg tirzepatide administered SC once a week.	Placebo administered SC once a week.
Measure Participants	115	113	117	118
Least Squares Mean (Standard Error) [Kilograms (kg)]	-6.2 (0.58)	-8.2 (0.58)	-10.9 (0.59)	1.7 (0.57)

Statistical Analysis 1

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	-7.8
	Confidence Interval	(2-Sided) 95%; -9.4 to -6.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

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	-9.9
	Confidence Interval	(2-Sided) 95%; -11.5 to -8.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, 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	-12.6
	Confidence Interval	(2-Sided) 95%; -14.2 to -11.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Participants Achieving an 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 randomly assigned participants who took 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	5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.	10 mg tirzepatide administered SC once a week.	15 mg tirzepatide administered SC once a week.	Placebo administered SC once a week.
Measure Participants	115	113	117	118
Number [Percentage of Participants]	93.04 80.2%	97.35 81.8%	94.02 78.4%	33.90 28.3%

Statistical Analysis 1

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	37.77
	Confidence Interval	(2-Sided) 95%; 15.23 to 93.70
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

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	100.07
	Confidence Interval	(2-Sided) 95%; 30.02 to 333.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, 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	43.31
	Confidence Interval	(2-Sided) 95%; 16.92 to 110.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. 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. LS Mean was determined by MMRM model with Baseline + Pooled Country + Baseline Metformin Use (Yes, No) + Baseline HbA1c Group (<= 8.0%, >8.0%) + Treatment + Time + Treatment*Time (Type III sum of squares) as variables.
Time Frame	Baseline, Week 40

Outcome Measure Data

Analysis Population Description

All randomly assigned participants who took 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	5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.	10 mg tirzepatide administered SC once a week.	15 mg tirzepatide administered SC once a week.	Placebo administered SC once a week.
Measure Participants	115	116	118	118
Least Squares Mean (Standard Error) [milligram per Deciliter (mg/dL)]	-61.4 (2.55)	-67.9 (2.55)	-67.7 (2.64)	-38.9 (2.49)

Statistical Analysis 1

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	-22.5
	Confidence Interval	(2-Sided) 95%; -29.5 to -15.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

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	-29.0
	Confidence Interval	(2-Sided) 95%; -36.0 to -22.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, 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	-28.8
	Confidence Interval	(2-Sided) 95%; -35.9 to -21.6
	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 + Baseline HbA1c Group (<= 8.0%, >8.0%) + Baseline Metformin Use (Yes, No) + Pooled Country + Treatment (Type III sum of squares).
Time Frame	Baseline, Week 40

Outcome Measure Data

Analysis Population Description

All randomly assigned participants who took 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	5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.	10 mg tirzepatide administered SC once a week.	15 mg tirzepatide administered SC once a week.	Placebo administered SC once a week.
Measure Participants	100	99	94	97
Least Squares Mean (Standard Error) [mg/dL]	-67.1 (2.05)	-71.7 (2.04)	-73.7 (2.10)	-39.4 (2.07)

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 randomly assigned participants who took 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	5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.	10 mg tirzepatide administered SC once a week.	15 mg tirzepatide administered SC once a week.	Placebo administered SC once a week.
Measure Participants	115	113	117	118
Number [Percentage of Participants]	53.91 46.5%	64.60 54.3%	84.62 70.5%	5.93 4.9%

Statistical Analysis 1

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	17.15
	Confidence Interval	(2-Sided) 95%; 7.55 to 38.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

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	27.24
	Confidence Interval	(2-Sided) 95%; 11.87 to 62.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, 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	79.61
	Confidence Interval	(2-Sided) 95%; 32.76 to 193.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Percentage Change From Baseline in Daily Mean Insulin Glargine Dose
Description	LS mean was calculated using MMRM model with log (Baseline) + Baseline Metformin Use (Yes, No) + Pooled Country + Baseline HbA1c Group (<= 8.0%, >8.0%) + Treatment + Time + Treatment*Time (Type III sum of squares) as variables.
Time Frame	Baseline, Week 40

Outcome Measure Data

Analysis Population Description

All randomly assigned participants who took 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	5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.	10 mg tirzepatide administered SC once a week.	15 mg tirzepatide administered SC once a week.	Placebo administered SC once a week.
Measure Participants	105	103	96	111
Least Squares Mean (Standard Error) [International Units (IU)]	13.0 (7.34)	8.1 (7.03)	-11.4 (5.85)	75.0 (11.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	10 mg Tirzepatide, 15 mg Tirzepatide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Estimate Difference
	Estimated Value	-35.4
	Confidence Interval	(2-Sided) 95%; -46.0 to -22.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	15 mg Tirzepatide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Estimate Difference
	Estimated Value	-38.2
	Confidence Interval	(2-Sided) 95%; -48.3 to -26.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Estimate Difference
	Estimated Value	-49.3
	Confidence Interval	(2-Sided) 95%; -57.7 to -39.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. 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 Metformin Use (Yes, No) + Baseline HbA1c Group (<= 8.0%, >8.0%) + Treatment, with log (exposure in days/365.25) as an offset variable.
Time Frame	Baseline through Safety Follow-Up (Up to Week 44)

Outcome Measure Data

Analysis Population Description

All randomly assigned participants who took at least 1 dose of study drug.

Arm/Group Title	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide	Placebo
Arm/Group Description	5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.	10 mg tirzepatide administered SC once a week.	15 mg tirzepatide administered SC once a week.	Placebo administered SC once a week.
Measure Participants	116	119	120	120
Mean (Standard Error) [Episodes/participant/365.25 days]	0.49 (0.141)	0.66 (0.169)	0.38 (0.099)	0.51 (0.149)

10. Secondary Outcome

Title	Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve (AUC) of Tirzepatide
Description	AUC is a combined measure obtained from Week 7, 15, 23 and 39 and a single averaged measure of AUC was reported.
Time Frame	Week 7, 15, 23 and 39 post dose

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	5 mg Tirzepatide	10 mg Tirzepatide	15 mg Tirzepatide
Arm/Group Description	5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.	10 mg tirzepatide administered SC once a week.	15 mg tirzepatide administered SC once a week.
Measure Participants	115	116	118
Geometric Mean (Geometric Coefficient of Variation) [nanogram*hour per milliliter (ng*h/mL)]	79700 (24.5)	164000 (26.7)	246000 (26.4)

11. Secondary Outcome

Title	Percentage of Participants Achieving an 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 randomly assigned participants who took 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	5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.	10 mg tirzepatide administered SC once a week.	15 mg tirzepatide administered SC once a week.	Placebo administered SC once a week.
Measure Participants	115	113	117	118
Number [Percentage of Participants]	26.09 22.5%	47.79 40.2%	62.39 52%	2.54 2.1%

Statistical Analysis 1

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	12.22
	Confidence Interval	(2-Sided) 95%; 3.93 to 38.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

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	32.36
	Confidence Interval	(2-Sided) 95%; 10.52 to 99.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, 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	56.26
	Confidence Interval	(2-Sided) 95%; 18.27 to 173.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Baseline, 17 Months
Adverse Event Reporting Description	All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Arm/Group Title	5 mg Tirzepatide		10 mg Tirzepatide		15 mg Tirzepatide		Placebo
Arm/Group Description	5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.		10 mg tirzepatide administered SC once a week.		15 mg tirzepatide administered SC once a week.		Placebo administered SC once a week.
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	0/116 (0%)		0/119 (0%)		0/120 (0%)		0/120 (0%)
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	9/116 (7.8%)		13/119 (10.9%)		9/120 (7.5%)		10/120 (8.3%)
Cardiac disorders
Acute myocardial infarction	0/116 (0%)	0	1/119 (0.8%)	1	1/120 (0.8%)	1	0/120 (0%)	0
Angina pectoris	0/116 (0%)	0	0/119 (0%)	0	1/120 (0.8%)	1	0/120 (0%)	0
Atrial fibrillation	1/116 (0.9%)	1	0/119 (0%)	0	0/120 (0%)	0	0/120 (0%)	0
Cardiac failure	3/116 (2.6%)	3	1/119 (0.8%)	1	0/120 (0%)	0	0/120 (0%)	0
Coronary artery disease	0/116 (0%)	0	0/119 (0%)	0	2/120 (1.7%)	2	0/120 (0%)	0
Myocardial infarction	0/116 (0%)	0	0/119 (0%)	0	0/120 (0%)	0	1/120 (0.8%)	1
Tachycardia	0/116 (0%)	0	0/119 (0%)	0	0/120 (0%)	0	1/120 (0.8%)	1
Ear and labyrinth disorders
Deafness unilateral	0/116 (0%)	0	0/119 (0%)	0	1/120 (0.8%)	1	0/120 (0%)	0
Gastrointestinal disorders
Abdominal hernia	0/116 (0%)	0	0/119 (0%)	0	0/120 (0%)	0	1/120 (0.8%)	1
Faecaloma	1/116 (0.9%)	1	0/119 (0%)	0	0/120 (0%)	0	0/120 (0%)	0
Pancreatic disorder	0/116 (0%)	0	0/119 (0%)	0	0/120 (0%)	0	1/120 (0.8%)	1
General disorders
Asthenia	1/116 (0.9%)	1	0/119 (0%)	0	0/120 (0%)	0	0/120 (0%)	0
Impaired healing	0/116 (0%)	0	0/119 (0%)	0	1/120 (0.8%)	1	0/120 (0%)	0
Infections and infestations
Cellulitis	0/116 (0%)	0	1/119 (0.8%)	1	0/120 (0%)	0	0/120 (0%)	0
Coronavirus infection	1/116 (0.9%)	1	0/119 (0%)	0	0/120 (0%)	0	0/120 (0%)	0
Covid-19 pneumonia	0/116 (0%)	0	0/119 (0%)	0	0/120 (0%)	0	1/120 (0.8%)	1
Gastroenteritis	1/116 (0.9%)	1	0/119 (0%)	0	0/120 (0%)	0	0/120 (0%)	0
Postoperative wound infection	0/116 (0%)	0	1/119 (0.8%)	1	0/120 (0%)	0	0/120 (0%)	0
Pyelonephritis	0/116 (0%)	0	0/119 (0%)	0	1/120 (0.8%)	1	0/120 (0%)	0
Urinary tract infection	0/116 (0%)	0	0/119 (0%)	0	1/120 (0.8%)	1	0/120 (0%)	0
Injury, poisoning and procedural complications
Hip fracture	0/116 (0%)	0	0/119 (0%)	0	1/120 (0.8%)	1	0/120 (0%)	0
Humerus fracture	0/116 (0%)	0	1/119 (0.8%)	1	0/120 (0%)	0	0/120 (0%)	0
Intestinal anastomosis complication	0/116 (0%)	0	0/119 (0%)	0	0/120 (0%)	0	1/120 (0.8%)	1
Spinal compression fracture	0/116 (0%)	0	1/119 (0.8%)	1	0/120 (0%)	0	0/120 (0%)	0
Metabolism and nutrition disorders
Hypoglycaemia	0/116 (0%)	0	1/119 (0.8%)	1	1/120 (0.8%)	1	0/120 (0%)	0
Musculoskeletal and connective tissue disorders
Spinal stenosis	0/116 (0%)	0	1/119 (0.8%)	1	0/120 (0%)	0	0/120 (0%)	0
Synovial cyst	0/116 (0%)	0	1/119 (0.8%)	1	0/120 (0%)	0	0/120 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Papillary renal cell carcinoma	1/116 (0.9%)	1	0/119 (0%)	0	0/120 (0%)	0	0/120 (0%)	0
Renal neoplasm	1/116 (0.9%)	1	0/119 (0%)	0	0/120 (0%)	0	0/120 (0%)	0
Transitional cell carcinoma	0/116 (0%)	0	0/119 (0%)	0	0/120 (0%)	0	1/120 (0.8%)	1
Uterine cancer	0/55 (0%)	0	1/47 (2.1%)	1	0/55 (0%)	0	0/54 (0%)	0
Nervous system disorders
Hypoglycaemic unconsciousness	0/116 (0%)	0	1/119 (0.8%)	1	0/120 (0%)	0	0/120 (0%)	0
Orthostatic intolerance	0/116 (0%)	0	0/119 (0%)	0	1/120 (0.8%)	1	0/120 (0%)	0
Syncope	0/116 (0%)	0	0/119 (0%)	0	0/120 (0%)	0	1/120 (0.8%)	1
Transient ischaemic attack	0/116 (0%)	0	1/119 (0.8%)	1	0/120 (0%)	0	0/120 (0%)	0
Psychiatric disorders
Anxiety	0/116 (0%)	0	1/119 (0.8%)	1	0/120 (0%)	0	0/120 (0%)	0
Renal and urinary disorders
Bladder disorder	0/116 (0%)	0	0/119 (0%)	0	0/120 (0%)	0	1/120 (0.8%)	1
Calculus urinary	0/116 (0%)	0	0/119 (0%)	0	1/120 (0.8%)	2	0/120 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/116 (0%)	0	0/119 (0%)	0	2/120 (1.7%)	2	0/120 (0%)	0
Dyspnoea	0/116 (0%)	0	1/119 (0.8%)	1	0/120 (0%)	0	0/120 (0%)	0
Pulmonary embolism	0/116 (0%)	0	0/119 (0%)	0	0/120 (0%)	0	1/120 (0.8%)	1
Respiratory failure	0/116 (0%)	0	0/119 (0%)	0	1/120 (0.8%)	1	0/120 (0%)	0
Sleep apnoea syndrome	1/116 (0.9%)	1	0/119 (0%)	0	0/120 (0%)	0	0/120 (0%)	0
Surgical and medical procedures
Cardiac ablation	0/116 (0%)	0	1/119 (0.8%)	1	0/120 (0%)	0	0/120 (0%)	0
Pancreatic lesion excision	0/116 (0%)	0	0/119 (0%)	0	0/120 (0%)	0	1/120 (0.8%)	1
Vascular disorders
Aortic stenosis	0/116 (0%)	0	0/119 (0%)	0	0/120 (0%)	0	1/120 (0.8%)	1
Peripheral arterial occlusive disease	0/116 (0%)	0	1/119 (0.8%)	1	1/120 (0.8%)	1	0/120 (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	52/116 (44.8%)		60/119 (50.4%)		67/120 (55.8%)		58/120 (48.3%)
Gastrointestinal disorders
Constipation	7/116 (6%)	7	8/119 (6.7%)	8	8/120 (6.7%)	9	2/120 (1.7%)	2
Diarrhoea	14/116 (12.1%)	22	15/119 (12.6%)	46	25/120 (20.8%)	44	12/120 (10%)	12
Dyspepsia	8/116 (6.9%)	9	10/119 (8.4%)	12	6/120 (5%)	6	2/120 (1.7%)	2
Eructation	6/116 (5.2%)	11	4/119 (3.4%)	16	7/120 (5.8%)	11	1/120 (0.8%)	1
Flatulence	3/116 (2.6%)	3	6/119 (5%)	21	7/120 (5.8%)	12	0/120 (0%)	0
Nausea	15/116 (12.9%)	26	21/119 (17.6%)	43	22/120 (18.3%)	44	3/120 (2.5%)	3
Vomiting	8/116 (6.9%)	12	9/119 (7.6%)	18	15/120 (12.5%)	26	3/120 (2.5%)	3
Infections and infestations
Nasopharyngitis	18/116 (15.5%)	23	8/119 (6.7%)	11	15/120 (12.5%)	19	23/120 (19.2%)	27
Investigations
Lipase increased	4/116 (3.4%)	4	2/119 (1.7%)	2	10/120 (8.3%)	12	2/120 (1.7%)	2
Metabolism and nutrition disorders
Decreased appetite	8/116 (6.9%)	8	15/119 (12.6%)	17	17/120 (14.2%)	21	2/120 (1.7%)	2
Hyperglycaemia	2/116 (1.7%)	2	0/119 (0%)	0	1/120 (0.8%)	1	16/120 (13.3%)	18
Musculoskeletal and connective tissue disorders
Arthralgia	6/116 (5.2%)	7	4/119 (3.4%)	4	3/120 (2.5%)	3	2/120 (1.7%)	2
Back pain	6/116 (5.2%)	8	6/119 (5%)	7	4/120 (3.3%)	6	7/120 (5.8%)	7
Vascular disorders
Hypertension	3/116 (2.6%)	3	3/119 (2.5%)	3	1/120 (0.8%)	1	7/120 (5.8%)	7

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.