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SURPASS-2: A Study of Tirzepatide (LY3298176) Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes

Sponsor
Eli Lilly and Company (Industry)
Overall Status
Completed
CT.gov ID
NCT03987919
Collaborator
(none)
1,879
Enrollment
127
Locations
4
Arms
18.6
Actual Duration (Months)
14.8
Patients Per Site
0.8
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The reason for this study is to compare the effect of the study drug tirzepatide to semaglutide on blood sugar levels in participants with type 2 diabetes. The study will last approximately 47 weeks and may include about 12 visits.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
1879 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 3, Randomized, Open-Label Trial Comparing Efficacy and Safety of Tirzepatide Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Patients With Type 2 Diabetes
Actual Study Start Date :
Jul 30, 2019
Actual Primary Completion Date :
Jan 28, 2021
Actual Study Completion Date :
Feb 15, 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
Other Names:
  • LY3298176

    		•
    Experimental: 10 mg Tirzepatide

    10 mg tirzepatide administered SC once a week.

    Drug: Tirzepatide
    Administered SC
    Other Names:
  • LY3298176

    		•
    Experimental: 15 mg Tirzepatide

    15 mg tirzepatide administered SC once a week.

    Drug: Tirzepatide
    Administered SC
    Other Names:
  • LY3298176

    		•
    Active Comparator: 1 mg Semaglutide

    1 mg semaglutide administered SC once a week.

    Drug: Semaglutide
    Administered SC

    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 + 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 + 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 + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + 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 (FSG) [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%) + Treatment + Time + Treatment*Time (Type III sum of squares).

    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%) + 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. Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score [Baseline, Week 40]

      DTSQc, an 8-item questionnaire, assesses relative change in treatment satisfaction perceived frequency of hyperglycemia, and perceived frequency of hypoglycemia from baseline to week 40 or early termination. The questionnaire consists of 8 items, 6 of which (1 and 4 through 8) assess treatment satisfaction. Each item is rated on a 7-point Likert scale. The scores from the 6 treatment satisfaction items are summed to a Total Treatment Satisfaction Score, which ranges from -18 to 18 where the higher the score the greater the improvement in satisfaction with treatment. The lower the score the greater the deterioration in satisfaction with treatment. The hyperglycemia and hypoglycemia scores range from -3 to 3 where negative scores indicate fewer problems with blood glucose levels and positive scores indicate more problems than before. LS Mean was determined by ANCOVA with Baseline DTSQs + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Treatment (Type III sum of squares).

    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 HbA1c Group (<=8.5%, >8.5%) + Treatment.

    9. Percentage of Participants Achieving an HbA1c Target Value of <5.7% [Week 40]

      Percentage of Participants Achieving an HbA1c Target Value of <5.7%.

    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)

    • Have HbA1c between ≥7.0% and ≤10.5%

    • Be on stable treatment with unchanged dose of metformin >1500 mg/day for at least 3 months prior to screening

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

    • Have a body mass index (BMI) ≥25 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 acute or chronic hepatitis, signs and symptoms of any other liver disease, or blood alanine transaminase (ALT) enzyme level >3.0 times the upper limit of normal (ULN) for the reference range, as determined by the central laboratory. Participants with nonalcoholic fatty liver disease (NAFLD) are eligible for participation in this trial only if there ALT level is ≤3.0 the ULN for the reference range

    • Have an estimated glomerular filtration rate <45 milliliters/minute/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 any other diabetes medicines other than metformin during the last 3 months

    • 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 Cahaba Research Birmingham Alabama United States 35242
    2 Syed Research Consultants Llc Sheffield Alabama United States 35660
    3 National Research Institute - Huntington Park Huntington Park California United States 90255
    4 Catalina Research Institute, LLC Montclair California United States 91763
    5 Valley Clinical Trials, Inc. Northridge California United States 91325
    6 National Research Institute - Huntington Park Panorama City California United States 91402
    7 Artemis Institute for Clinical Research Riverside California United States 92503
    8 Artemis Institute for Clinical Research San Diego California United States 92103
    9 Artemis Institute for Clinical Research San Marcos California United States 92078
    10 University Clinical Investigators, Inc. Tustin California United States 92780
    11 CMR of Greater New Haven Hamden Connecticut United States 06517
    12 Clinical Research of South Florida Coral Gables Florida United States 33134
    13 East Coast Institute for Research at The Jones Center Lake City Florida United States 32055
    14 South Florida Clinical Research Institute Margate Florida United States 33063
    15 Suncoast Research Group Miami Florida United States 33135
    16 New Horizon Research Center Miami Florida United States 33165 3338
    17 Oviedo Medical Research Oviedo Florida United States 32765
    18 South Broward Research Pembroke Pines Florida United States 33027
    19 United Osteoporosis Center Gainesville Georgia United States 30501
    20 Sky Clinical Research Network Union City Georgia United States 30291
    21 Elite Clinical Trials Blackfoot Idaho United States 83221
    22 University of Iowa Hospital & Clinic Iowa City Iowa United States 52242
    23 Cotton O'Neil Clinic Topeka Kansas United States 66606
    24 Cotton O'Neil Diabetes and Endocrinology Center Topeka Kansas United States 66606
    25 NECCR PrimaCare Research Fall River Massachusetts United States 02721
    26 ActivMed Practices and Research Methuen Massachusetts United States 01844
    27 Olive Branch Family Medical Center Olive Branch Mississippi United States 38654
    28 Clinvest Research LLC Springfield Missouri United States 65810
    29 Premier Research Trenton New Jersey United States 08611
    30 Albany Medical College, Division of Community Endocrinology Albany New York United States 12206
    31 PharmQuest Greensboro North Carolina United States 27408
    32 Diabetes & Endocrinology Consultants, PC Morehead City North Carolina United States 28557
    33 PMG Research of Wilmington Wilmington North Carolina United States 28401
    34 Lillestol Research LLC Fargo North Dakota United States 58104
    35 Aventiv Research Inc Columbus Ohio United States 43213
    36 Intend Research, LLC Norman Oklahoma United States 73069
    37 Heritage Valley Medical Group, Inc. Beaver Pennsylvania United States 15009
    38 Capital Area Research, LLC Camp Hill Pennsylvania United States 17011
    39 Detweiler Family Medicine & Associates Lansdale Pennsylvania United States 19446
    40 Green & Seidner Family Practice Associates Lansdale Pennsylvania United States 19446
    41 Thomas Jefferson University Philadelphia Pennsylvania United States 19107
    42 Preferred Primary Care Physicians, Preferred Clinical Research-St. Clair Pittsburgh Pennsylvania United States 15243
    43 Holston Medical Group Bristol Tennessee United States 37620
    44 Dallas Diabetes Research Center Dallas Texas United States 75230
    45 Biopharma Informatic, Inc. Houston Texas United States 77043
    46 Consano Clinical Research, LLC Shavano Park Texas United States 78231
    47 Carl R. Meisner Medical Clinic, PLLC Sugar Land Texas United States 77478
    48 Martin Diagnostic Clinic Tomball Texas United States 77375
    49 Burke Internal Medicine and Research Burke Virginia United States 22015
    50 Capital Clinical Research Center Olympia Washington United States 98502
    51 The Vancouver Clinic Vancouver Washington United States 98664
    52 CEDIC Caba Ar-b Argentina C1425DES
    53 CIPREC Ciudad Autonoma de Buenos Aire Ar-b Argentina C1119ACN
    54 Investigaciones Medicas Imoba Srl Buenos Aires Ar-c Argentina C1179AAB
    55 CEMEDIAB C.a.b.a. Ar-c Argentina C1205AAO
    56 Sanatorio Norte Santiago del Estero Ar-g Argentina 4200
    57 Centro de Investigaciones Metabólicas (CINME) Caba Buenos Aires Argentina C1056ABJ
    58 Centro Médico Viamonte Caba Buenos Aires Argentina C1120AAC
    59 Centro Medico Dr Laura Maffei Investigacion Clinica Aplicada Caba Buenos Aires Argentina C1425AGC
    60 Mautalen Salud e Investigacion-Centro de Osteopatías Médicas Ciudad Autonoma De Buenos Air Buenos Aires Argentina C1128AAF
    61 CIPADI Godoy Cruz Mendoza Argentina M5501ARP
    62 Instituto de Investigaciones Clínicas Mar del Plata Mar del Plata Provincia De Buenos Aires Argentina (B7600FZN)
    63 Instituto Centenario Ciudad Autonoma de Buenos Aire Argentina C1204AAD
    64 Cent Priva Especiali Médicas Ambulatorias Inve Clin CEMAIC Cordoba Argentina X5008HHW
    65 Paratus Clinical Research Western Sydney Blacktown Au-nsw Australia 2148
    66 Campbelltown Medical & Dental Centre Campbelltown Au-nsw Australia 2560
    67 Paratus Clinical Research Central Coast Kanwal Au-nsw Australia 2259
    68 Holdsworth House Medical Practice Sydney New South Wales Australia 2010
    69 GenesisCare - Bundaberg Bundaberg Queensland Australia 4670
    70 Royal Brisbane and Womens Hospital Herston Queensland Australia 4029
    71 Core Research Group Milton Queensland Australia 4064
    72 AusTrials Taringa Queensland Australia 4068
    73 Eastern Clinical Research Unit Box Hill Victoria Australia 3128
    74 Barwon Health - The Geelong Hospital Geelong Victoria Australia 3220
    75 GenesisCare - Wexford Medical Centre WA Joondalup Western Australia Australia 6027
    76 GenesisCare - Wexford Medical Centre WA Murdoch Western Australia Australia 6150
    77 Adelaide Medical Solutions Woodville South Australia 5011
    78 CEDOES Vitória Br-es Brazil 29055450
    79 ISPEM - Instituto São José dos Campos em Pesquisas Médicas São José dos Campos Br-sp Brazil 12243-280
    80 CPQuali Pesquisa Clínica São Paulo Br-sp Brazil 01228-000
    81 CEPIC - Centro Paulista de Investigação Clínica São Paulo Br-sp Brazil 04266-010
    82 Centro de Pesquisas em Diabetes Porto Alegre Rio Grande Do Sul Brazil 90430-001
    83 CPCLIN São Paulo SP Brazil 01228-200
    84 Dr. Consulta Clínica Médica LTDA São Paulo Brazil 05016-090
    85 Milestone Research Inc. London Ca-on Canada N5W 6A2
    86 Bluewater Clinical Research Group Inc. Sarnia Ca-on Canada N7T 4X3
    87 Dr. Anil K. Gupta Medicine Professional Corporation Toronto Ca-on Canada M9V 4B4
    88 Manna Research Lévis Ca-qc Canada G6W 0M5
    89 Manna Research - Burlington North Burlington Ontario Canada L7M 4Y1
    90 Manna Research - Burlington North Nepean Ontario Canada K2J 4A7
    91 Manna Research - Burlington North Stoney Creek Ontario Canada L8J 3W2
    92 Manna Research - Burlington North Toronto Ontario Canada M9W 4L6
    93 Meir Medical Center Kfar Saba HaMerkaz Israel 4428164
    94 Clalit Health Services - Shuali Clinic Raanana HaMerkaz Israel 43405
    95 Sheba Medical Center Ramat Gan HaMerkaz Israel 5262100
    96 Diabetes Medical Center Tel Aviv Il-ta Israel 51549
    97 Hadassah Medical Center Jerusalem Yerushalayim Israel 9112001
    98 Clalit Health Services - Sakhnin Community Clinic Sakhnin Israel 3081000
    99 Tel Aviv Sourasky Medical Center Tel Aviv Jaffa Israel 6423906
    100 Rambam Health Care Campus Haifa Ḥeifā Israel 3109601
    101 Linn Medical Center Haifa Ḥeifā Israel 3515209
    102 Centro Especializado en Diabetes Obesidad y Enfermedades Mexico D.f. Mexico 11650
    103 Diseno y Planeacion en Investigacion Medica Guadalajara Jalisco Mexico 44130
    104 Instituto Jalisciense de Investigacion en Diabetes y Obesida Guadalajara Jalisco Mexico 44600
    105 Unidad de Investigaci�n Cl�nica Cardiometabolica de Occidente Guadalajara Mx-jal Mexico 44150
    106 Hospital Universitario Dr. Jose Eleuterio Gonzalez Monterrey N.l. Mexico 64460
    107 Unidad Médica para la Salud Integral San Nicolás de los Garza Nuevo León Mexico 66465
    108 Centro de Estudios de Investigacion Metabolicos y Cardiovasculares Ciudad Madero Tamaulipas Mexico 89440
    109 Investigacion en Salud y Metabolismo S.C Chihuahua Mexico 31238
    110 Paola Mansilla-Letelier, MD Guaynabo Puerto Rico 00970
    111 Research and Cardiovascular Corp. Ponce Puerto Rico 00717
    112 Clinical Research Puerto Rico San Juan Puerto Rico 00909
    113 Martha Gomez Cuellar M.D. San Juan Puerto Rico 00921
    114 Oldfield Surgery Bath Avon United Kingdom BA2 3HT
    115 Staploe Medical Centre Ely Gb-cam United Kingdom CB7 5JD
    116 Fowey River Practice Fowey Gb-con United Kingdom PL23 1DT
    117 Oak Tree Surgery Liskeard Gb-con United Kingdom PL14 3XA
    118 Rame Medical Ltd Torpoint Gb-con United Kingdom PL11 2TB
    119 Royal Primary Care Chesterfield North west Chesterfield Gb-dby United Kingdom S40 4AA
    120 Knowle House Surgery Plymouth Gb-dev United Kingdom PL5 3JB
    121 Queen Alexandra Hospital Portsmouth Gb-ham United Kingdom PO6 3LY
    122 Lister Hospital Stevenage Gb-hrt United Kingdom SG1 4AB
    123 Oakenhurst Medical Practice Blackburn Gb-lan United Kingdom BB2 1AX
    124 Rowden Surgery cHIPPENHAM Gb-wil United Kingdom SN15 2SB
    125 Leicester General Hospital Leicester Leicestershire United Kingdom LE5 4PW
    126 University Hospital Coventry & Warwickshire Coventry Warwickshire United Kingdom CV2 2DX
    127 Wickersley Health Centre - Clifton Medical Centre Rotherham United Kingdom S65 1DA

    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)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT03987919
    Other Study ID Numbers:
    • 17001
    • I8F-MC-GPGL
    • 2018-004422-29
    First Posted:
    Jun 17, 2019
    Last Update Posted:
    Feb 14, 2022
    Last Verified:
    Jul 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
    T2DM
    GLP-1 RA
    Glucose-dependent insulinotropic polypeptide (GIP)
    glucagon-like peptide-1 (GLP-1)
    GIP/GLP-1 dual receptor agonist
    Additional relevant MeSH terms:
    Diabetes Mellitus
    Diabetes Mellitus, Type 2
    Tirzepatide

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title 5 mg Tirzepatide 10 mg Tirzepatide 15 mg Tirzepatide 1 mg Semaglutide
    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. 1 mg semaglutide administered SC once a week.
    Period Title: Overall Study
    STARTED 471 469 470 469
    Received at Least One Dose of Study Drug 470 469 470 469
    COMPLETED 452 442 446 443
    NOT COMPLETED 19 27 24 26

    Baseline Characteristics

    Arm/Group Title 5 mg Tirzepatide 10 mg Tirzepatide 15 mg Tirzepatide 1 mg Semaglutide Total
    Arm/Group Description 5 mg tirzepatide administered SC once a week. 10 mg tirzepatide administered SC once a week. 15 mg tirzepatide administered SC once a week. 1 mg semaglutide administered SC once a week. Total of all reporting groups
    Overall Participants 470 469 470 469 1878
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    56.3
    (10.0)
    57.2
    (10.5)
    55.9
    (10.4)
    56.9
    (10.8)
    56.6
    (10.4)
    Sex: Female, Male (Count of Participants)
    Female
    265
    56.4%
    231
    49.3%
    256
    54.5%
    244
    52%
    996
    53%
    Male
    205
    43.6%
    238
    50.7%
    214
    45.5%
    225
    48%
    882
    47%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    325
    69.1%
    322
    68.7%
    334
    71.1%
    336
    71.6%
    1317
    70.1%
    Not Hispanic or Latino
    145
    30.9%
    147
    31.3%
    136
    28.9%
    133
    28.4%
    561
    29.9%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    53
    11.3%
    53
    11.3%
    57
    12.1%
    45
    9.6%
    208
    11.1%
    Asian
    6
    1.3%
    11
    2.3%
    5
    1.1%
    3
    0.6%
    25
    1.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    1
    0.2%
    2
    0.4%
    3
    0.2%
    Black or African American
    28
    6%
    21
    4.5%
    15
    3.2%
    15
    3.2%
    79
    4.2%
    White
    382
    81.3%
    376
    80.2%
    392
    83.4%
    401
    85.5%
    1551
    82.6%
    More than one race
    1
    0.2%
    8
    1.7%
    0
    0%
    3
    0.6%
    12
    0.6%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (Count of Participants)
    Argentina
    158
    33.6%
    160
    34.1%
    161
    34.3%
    161
    34.3%
    640
    34.1%
    Australia
    12
    2.6%
    11
    2.3%
    12
    2.6%
    11
    2.3%
    46
    2.4%
    Brazil
    37
    7.9%
    37
    7.9%
    36
    7.7%
    37
    7.9%
    147
    7.8%
    Canada
    15
    3.2%
    15
    3.2%
    14
    3%
    15
    3.2%
    59
    3.1%
    Israel
    22
    4.7%
    22
    4.7%
    22
    4.7%
    21
    4.5%
    87
    4.6%
    Mexico
    89
    18.9%
    87
    18.6%
    88
    18.7%
    88
    18.8%
    352
    18.7%
    Puerto Rico
    6
    1.3%
    4
    0.9%
    6
    1.3%
    3
    0.6%
    19
    1%
    United Kingdom
    18
    3.8%
    18
    3.8%
    18
    3.8%
    18
    3.8%
    72
    3.8%
    United States
    113
    24%
    115
    24.5%
    113
    24%
    115
    24.5%
    456
    24.3%
    Hemoglobin A1c (Percentage of HbA1c) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Percentage of HbA1c]
    8.32
    (1.08)
    8.30
    (1.02)
    8.26
    (1.00)
    8.25
    (1.01)
    8.28
    (1.03)

    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 + Pooled Country + Treatment + Time + Treatment*Time (Type III sum of squares).
    Time Frame Baseline, Week 40

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline HbA1c value, excluding patients who discontinued 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 1 mg Semaglutide
    Arm/Group Description 10 mg tirzepatide administered SC once a week. 15 mg tirzepatide administered SC once a week. 1 mg semaglutide administered SC once a week.
    Measure Participants 459 464 461
    Least Squares Mean (Standard Error) [Percentage of HbA1c]
    -2.37
    (0.048)
    -2.46
    (0.048)
    -1.86
    (0.048)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 10 mg Tirzepatide, 1 mg Semaglutide
    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 -0.51
    Confidence Interval (2-Sided) 95%
    -0.64 to -0.38
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 15 mg Tirzepatide, 1 mg Semaglutide
    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 -0.60
    Confidence Interval (2-Sided) 95%
    -0.73 to -0.47
    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 + Pooled Country + Treatment + Time + Treatment*Time (Type III sum of squares).
    Time Frame Baseline, Week 40

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline HbA1c value, excluding patients who discontinued study drug due to inadvertent enrollment and data after initiating rescue antihyperglycemic medication or prematurely stopping study drug.
    Arm/Group Title 5 mg Tirzepatide 1 mg Semaglutide
    Arm/Group Description 5 mg tirzepatide administered SC once a week. 1 mg semaglutide administered SC once a week.
    Measure Participants 461 461
    Least Squares Mean (Standard Error) [Percentage of HbA1c]
    -2.09
    (0.047)
    -1.86
    (0.048)
    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 -0.23
    Confidence Interval (2-Sided) 95%
    -0.36 to -0.10
    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 + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Treatment + Time + Treatment*Time (Type III sum of squares).
    Time Frame Baseline, Week 40

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline body weight value, excluding patients who discontinued 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 1 mg Semaglutide
    Arm/Group Description 5 mg tirzepatide administered SC once a week. 10 mg tirzepatide administered SC once a week. 15 mg tirzepatide administered SC once a week. 1 mg of semaglutide administered SC once a week.
    Measure Participants 461 459 464 462
    Least Squares Mean (Standard Error) [Kilograms (kg)]
    -7.8
    (0.33)
    -10.3
    (0.34)
    -12.4
    (0.34)
    -6.2
    (0.33)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 10 mg Tirzepatide, 1 mg Semaglutide
    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 -1.7
    Confidence Interval (2-Sided) 95%
    -2.6 to -0.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 15 mg Tirzepatide, 1 mg Semaglutide
    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 -4.1
    Confidence Interval (2-Sided) 95%
    -5.0 to -3.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 1 mg Semaglutide, 1 mg Semaglutide
    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 -6.2
    Confidence Interval (2-Sided) 95%
    -7.1 to -5.3
    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 participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline HbA1c value, excluding patients who discontinued 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 1 mg Semaglutide
    Arm/Group Description 5 mg tirzepatide administered SC once a week. 10 mg tirzepatide administered SC once a week. 15 mg tirzepatide administered SC once a week. 1 mg semaglutide administered SC once a week.
    Measure Participants 461 459 464 461
    Number [Percentage of Participants]
    85.47
    18.2%
    88.89
    19%
    92.24
    19.6%
    81.13
    17.3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 10 mg Tirzepatide, 1 mg Semaglutide
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.023
    Comments
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 1.54
    Confidence Interval (2-Sided) 95%
    1.06 to 2.23
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 15 mg Tirzepatide, 1 mg Semaglutide
    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 2.14
    Confidence Interval (2-Sided) 95%
    1.44 to 3.17
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 1 mg Semaglutide, 1 mg Semaglutide
    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 3.03
    Confidence Interval (2-Sided) 95%
    1.97 to 4.66
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title Change From Baseline in Fasting Serum Glucose (FSG)
    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%) + Treatment + Time + Treatment*Time (Type III sum of squares).
    Time Frame Baseline, Week 40

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline FSG value, excluding patients who discontinued 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 1 mg Semaglutide
    Arm/Group Description 5 mg tirzepatide administered SC once a week. 10 mg tirzepatide administered SC once a week. 15 mg tirzepatide administered SC once a week. 1 mg semaglutide administered SC once a week.
    Measure Participants 461 458 464 459
    Least Squares Mean (Standard Error) [milligram per Deciliter (mg/dL)]
    -56.0
    (1.57)
    -61.6
    (1.60)
    -63.4
    (1.59)
    -48.6
    (1.58)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 10 mg Tirzepatide, 1 mg Semaglutide
    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 -7.3
    Confidence Interval (2-Sided) 95%
    -11.7 to -3.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 15 mg Tirzepatide, 1 mg Semaglutide
    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 -13.0
    Confidence Interval (2-Sided) 95%
    -17.4 to -8.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 1 mg Semaglutide, 1 mg Semaglutide
    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 -14.7
    Confidence Interval (2-Sided) 95%
    -19.1 to -10.3
    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%) + Treatment + Time + Treatment*Time (Type III sum of squares).
    Time Frame Baseline, Week 40

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline SMBG value, excluding patients who discontinued 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 1 mg Semaglutide
    Arm/Group Description 5 mg tirzepatide administered SC once a week. 10 mg tirzepatide administered SC once a week. 15 mg tirzepatide administered SC once a week. 1 mg of semaglutide administered SC once a week.
    Measure Participants 424 412 413 414
    Least Squares Mean (Standard Error) [mg/dL]
    -65.4
    (1.04)
    -70.6
    (1.05)
    -74.3
    (1.05)
    -61.4
    (1.04)
    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 participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline weight loss, excluding patients who discontinued 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 1 mg Semaglutide
    Arm/Group Description 5 mg tirzepatide administered SC once a week. 10 mg tirzepatide administered SC once a week. 15 mg tirzepatide administered SC once a week. 1 mg of semaglutide administered SC once a week.
    Measure Participants 461 459 464 462
    Number [Percentage of Participants]
    68.55
    14.6%
    82.35
    17.6%
    86.21
    18.3%
    58.44
    12.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 10 mg Tirzepatide, 1 mg Semaglutide
    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 1.58
    Confidence Interval (2-Sided) 95%
    1.20 to 2.08
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 15 mg Tirzepatide, 1 mg Semaglutide
    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 3.49
    Confidence Interval (2-Sided) 95%
    2.57 to 4.75
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 1 mg Semaglutide, 1 mg Semaglutide
    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 4.60
    Confidence Interval (2-Sided) 95%
    3.32 to 6.38
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    8. Secondary Outcome
    Title Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score
    Description DTSQc, an 8-item questionnaire, assesses relative change in treatment satisfaction perceived frequency of hyperglycemia, and perceived frequency of hypoglycemia from baseline to week 40 or early termination. The questionnaire consists of 8 items, 6 of which (1 and 4 through 8) assess treatment satisfaction. Each item is rated on a 7-point Likert scale. The scores from the 6 treatment satisfaction items are summed to a Total Treatment Satisfaction Score, which ranges from -18 to 18 where the higher the score the greater the improvement in satisfaction with treatment. The lower the score the greater the deterioration in satisfaction with treatment. The hyperglycemia and hypoglycemia scores range from -3 to 3 where negative scores indicate fewer problems with blood glucose levels and positive scores indicate more problems than before. LS Mean was determined by ANCOVA with Baseline DTSQs + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Treatment (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 study drug. Last observation carried forward (LOCF) endpoint only carries forward the last non-baseline observations before rescue therapy or stopping study drug.
    Arm/Group Title 5 mg Tirzepatide 10 mg Tirzepatide 15 mg Tirzepatide 1 mg Semaglutide
    Arm/Group Description 5 mg tirzepatide administered SC once a week. 10 mg tirzepatide administered SC once a week. 15 mg tirzepatide administered SC once a week. 1 mg of semaglutide administered SC once a week.
    Measure Participants 419 399 398 412
    Hyperglycemia
    -1.3
    (0.10)
    -1.4
    (0.10)
    -1.5
    (0.10)
    -1.1
    (0.10)
    Hypoglycemia
    -0.7
    (0.10)
    -0.7
    (0.10)
    -0.8
    (0.10)
    -0.7
    (0.10)
    Total Score
    15.7
    (0.18)
    15.6
    (0.19)
    16.1
    (0.19)
    15.8
    (0.19)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 10 mg Tirzepatide, 1 mg Semaglutide
    Comments Hyperglycemia
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.084
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.24
    Confidence Interval (2-Sided) 95%
    -0.50 to 0.03
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 15 mg Tirzepatide, 1 mg Semaglutide
    Comments Hyperglycemia
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.050
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.27
    Confidence Interval (2-Sided) 95%
    -0.54 to 0.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 1 mg Semaglutide, 1 mg Semaglutide
    Comments Hyperglycemia
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.005
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.39
    Confidence Interval (2-Sided) 95%
    -0.66 to -0.12
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection 10 mg Tirzepatide, 1 mg Semaglutide
    Comments Hypoglycemia
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.688
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.06
    Confidence Interval (2-Sided) 95%
    -0.33 to 0.22
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection 15 mg Tirzepatide, 1 mg Semaglutide
    Comments Hypoglycemia
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.909
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.02
    Confidence Interval (2-Sided) 95%
    -0.29 to 0.26
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection 1 mg Semaglutide, 1 mg Semaglutide
    Comments Hypoglycemia
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.358
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.13
    Confidence Interval (2-Sided) 95%
    -0.40 to 0.15
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection 10 mg Tirzepatide, 1 mg Semaglutide
    Comments Total Score
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.701
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.10
    Confidence Interval (2-Sided) 95%
    -0.62 to 0.41
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection 15 mg Tirzepatide, 1 mg Semaglutide
    Comments Total Score
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.341
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.25
    Confidence Interval (2-Sided) 95%
    -0.78 to 0.27
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection 1 mg Semaglutide, 1 mg Semaglutide
    Comments Total Score
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.321
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.26
    Confidence Interval (2-Sided) 95%
    -0.26 to 0.79
    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 HbA1c Group (<=8.5%, >8.5%) + Treatment.
    Time Frame Baseline through Safety Follow-Up (Up to Week 44)

    Outcome Measure Data

    Analysis Population 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 1 mg Semaglutide
    Arm/Group Description 5 mg tirzepatide administered SC once a week. 10 mg tirzepatide administered SC once a week. 15 mg tirzepatide administered SC once a week. 1 mg of semaglutide administered SC once a week.
    Measure Participants 470 469 470 469
    Mean (Standard Error) [Episodes/participant/365.25 days]
    0.0102
    (0.00423)
    0.0046
    (0.00488)
    0.0202
    (0.00840)
    0.0046
    (0.00340)
    10. Secondary Outcome
    Title Percentage of Participants Achieving an HbA1c Target Value of <5.7%
    Description Percentage of Participants Achieving an HbA1c Target Value of <5.7%.
    Time Frame Week 40

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline HbA1c 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 1 mg Semaglutide
    Arm/Group Description 5 mg tirzepatide administered SC once a week. 10 mg tirzepatide administered SC once a week. 15 mg tirzepatide administered SC once a week. 1 mg of semaglutide administered SC once a week.
    Measure Participants 461 459 464 461
    Number [Percentage of Participants]
    29.28
    6.2%
    44.66
    9.5%
    50.86
    10.8%
    19.74
    4.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 10 mg Tirzepatide, 1 mg Semaglutide
    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 1.86
    Confidence Interval (2-Sided) 95%
    1.35 to 2.57
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 15 mg Tirzepatide, 1 mg Semaglutide
    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 3.94
    Confidence Interval (2-Sided) 95%
    2.88 to 5.39
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 1 mg Semaglutide, 1 mg Semaglutide
    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 5.10
    Confidence Interval (2-Sided) 95%
    3.73 to 6.97
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame Baseline, Safety follow-up (44 Weeks)
    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 1 mg Semaglutide
    Arm/Group Description 5 mg tirzepatide administered subcutaneously (SC) once a week. 10 mg tirzepatide administered SC once a week. 15 mg tirzepatide administered SC once a week. 1 mg of semaglutide administered SC once a week.
    All Cause Mortality
    5 mg Tirzepatide 10 mg Tirzepatide 15 mg Tirzepatide 1 mg Semaglutide
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 4/470 (0.9%) 4/469 (0.9%) 4/470 (0.9%) 1/469 (0.2%)
    Serious Adverse Events
    5 mg Tirzepatide 10 mg Tirzepatide 15 mg Tirzepatide 1 mg Semaglutide
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 33/470 (7%) 25/469 (5.3%) 27/470 (5.7%) 13/469 (2.8%)
    Blood and lymphatic system disorders
    Anaemia 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Cardiac disorders
    Acute myocardial infarction 2/470 (0.4%) 3 0/469 (0%) 0 2/470 (0.4%) 2 0/469 (0%) 0
    Angina unstable 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    Atrial fibrillation 2/470 (0.4%) 4 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Atrial flutter 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Cardiac failure 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Cardio-respiratory arrest 1/470 (0.2%) 1 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Coronary artery disease 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Ventricular tachycardia 0/470 (0%) 0 0/469 (0%) 0 0/470 (0%) 0 1/469 (0.2%) 1
    Endocrine disorders
    Acromegaly 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Eye disorders
    Retinal vein occlusion 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    Abdominal pain upper 1/470 (0.2%) 1 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Constipation 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Epiploic appendagitis 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    Gastrointestinal haemorrhage 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Inguinal hernia, obstructive 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Irritable bowel syndrome 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    Lower gastrointestinal haemorrhage 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Nausea 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    Strangulated umbilical hernia 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Vomiting 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    General disorders
    Chest pain 0/470 (0%) 0 1/469 (0.2%) 1 1/470 (0.2%) 1 0/469 (0%) 0
    Death 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Pyrexia 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Sudden death 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    Hepatobiliary disorders
    Cholecystitis acute 1/470 (0.2%) 1 2/469 (0.4%) 2 2/470 (0.4%) 2 0/469 (0%) 0
    Infections and infestations
    Appendicitis 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Bacteraemia 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 1/469 (0.2%) 1
    Cellulitis 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    Cholecystitis infective 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    Complicated appendicitis 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Covid-19 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 1/469 (0.2%) 1
    Covid-19 pneumonia 2/470 (0.4%) 2 2/469 (0.4%) 2 2/470 (0.4%) 2 4/469 (0.9%) 4
    Dengue fever 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Epididymitis 1/205 (0.5%) 1 0/238 (0%) 0 0/214 (0%) 0 0/225 (0%) 0
    Escherichia bacteraemia 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Lower respiratory tract infection 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Osteomyelitis 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Pharyngeal abscess 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    Pneumonia 1/470 (0.2%) 1 0/469 (0%) 0 1/470 (0.2%) 1 1/469 (0.2%) 1
    Pyelonephritis 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Sepsis 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Suspected covid-19 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Urinary tract infection 0/470 (0%) 0 2/469 (0.4%) 2 0/470 (0%) 0 0/469 (0%) 0
    Urosepsis 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Injury, poisoning and procedural complications
    Ankle fracture 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    Femur fracture 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Hip fracture 0/470 (0%) 0 0/469 (0%) 0 0/470 (0%) 0 1/469 (0.2%) 1
    Intentional overdose 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Ligament injury 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    Multiple injuries 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Traumatic amputation 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Upper limb fracture 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Wrist fracture 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    Investigations
    Amylase increased 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    Coronavirus test positive 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Lipase increased 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    Metabolism and nutrition disorders
    Dehydration 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Hypoglycaemia 1/470 (0.2%) 1 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Hyponatraemia 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Musculoskeletal and connective tissue disorders
    Back pain 0/470 (0%) 0 0/469 (0%) 0 0/470 (0%) 0 1/469 (0.2%) 1
    Osteoarthritis 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Endometrial adenocarcinoma 1/265 (0.4%) 1 0/231 (0%) 0 0/256 (0%) 0 0/244 (0%) 0
    Glioblastoma multiforme 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Lung carcinoma cell type unspecified stage iii 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Metastatic squamous cell carcinoma 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    Non-hodgkin's lymphoma 0/470 (0%) 0 0/469 (0%) 0 0/470 (0%) 0 1/469 (0.2%) 1
    Renal cell carcinoma 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    Squamous cell carcinoma of skin 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Uterine leiomyoma 0/265 (0%) 0 0/231 (0%) 0 1/256 (0.4%) 1 0/244 (0%) 0
    Uterine neoplasm 1/265 (0.4%) 1 0/231 (0%) 0 0/256 (0%) 0 0/244 (0%) 0
    Nervous system disorders
    Cerebellar infarction 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Cerebrovascular accident 0/470 (0%) 0 0/469 (0%) 0 2/470 (0.4%) 2 0/469 (0%) 0
    Headache 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Ischaemic stroke 0/470 (0%) 0 0/469 (0%) 0 0/470 (0%) 0 1/469 (0.2%) 1
    Syncope 0/470 (0%) 0 1/469 (0.2%) 1 1/470 (0.2%) 1 0/469 (0%) 0
    Psychiatric disorders
    Post-traumatic stress disorder 0/470 (0%) 0 0/469 (0%) 0 0/470 (0%) 0 1/469 (0.2%) 1
    Suicide attempt 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    End stage renal disease 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    Nephrolithiasis 1/470 (0.2%) 1 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    Urinary tract obstruction 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Reproductive system and breast disorders
    Metrorrhagia 1/265 (0.4%) 1 0/231 (0%) 0 0/256 (0%) 0 0/244 (0%) 0
    Uterine prolapse 0/265 (0%) 0 0/231 (0%) 0 0/256 (0%) 0 1/244 (0.4%) 1
    Respiratory, thoracic and mediastinal disorders
    Asthma 0/470 (0%) 0 0/469 (0%) 0 0/470 (0%) 0 1/469 (0.2%) 1
    Chronic obstructive pulmonary disease 0/470 (0%) 0 1/469 (0.2%) 1 0/470 (0%) 0 0/469 (0%) 0
    Dyspnoea 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Pleural effusion 1/470 (0.2%) 1 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Pulmonary embolism 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Respiratory failure 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Skin and subcutaneous tissue disorders
    Diabetic ulcer 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Surgical and medical procedures
    Abdominal hernia repair 1/470 (0.2%) 1 0/469 (0%) 0 0/470 (0%) 0 0/469 (0%) 0
    Vascular disorders
    Deep vein thrombosis 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Hypertension 0/470 (0%) 0 0/469 (0%) 0 0/470 (0%) 0 1/469 (0.2%) 1
    Orthostatic hypotension 0/470 (0%) 0 0/469 (0%) 0 1/470 (0.2%) 1 0/469 (0%) 0
    Peripheral vascular disorder 0/470 (0%) 0 0/469 (0%) 0 0/470 (0%) 0 1/469 (0.2%) 1
    Venous thrombosis limb 0/470 (0%) 0 0/469 (0%) 0 0/470 (0%) 0 1/469 (0.2%) 1
    Other (Not Including Serious) Adverse Events
    5 mg Tirzepatide 10 mg Tirzepatide 15 mg Tirzepatide 1 mg Semaglutide
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 170/470 (36.2%) 187/469 (39.9%) 202/470 (43%) 172/469 (36.7%)
    Gastrointestinal disorders
    Abdominal pain 14/470 (3%) 16 20/469 (4.3%) 25 24/470 (5.1%) 30 24/469 (5.1%) 29
    Constipation 31/470 (6.6%) 35 21/469 (4.5%) 23 21/470 (4.5%) 23 27/469 (5.8%) 32
    Diarrhoea 62/470 (13.2%) 120 77/469 (16.4%) 98 65/470 (13.8%) 102 54/469 (11.5%) 68
    Dyspepsia 34/470 (7.2%) 46 29/469 (6.2%) 43 43/470 (9.1%) 51 31/469 (6.6%) 42
    Nausea 82/470 (17.4%) 110 90/469 (19.2%) 121 104/470 (22.1%) 136 84/469 (17.9%) 126
    Vomiting 27/470 (5.7%) 35 39/469 (8.3%) 54 46/470 (9.8%) 61 39/469 (8.3%) 53
    Metabolism and nutrition disorders
    Decreased appetite 35/470 (7.4%) 38 34/469 (7.2%) 43 42/470 (8.9%) 51 25/469 (5.3%) 26

    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.

    Results Point of Contact

    Name/Title Chief Medical Officer
    Organization Eli Lilly and Company
    Phone 800-545-5979
    Email ClinicalTrials.gov@lilly.com
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT03987919
    Other Study ID Numbers:
    • 17001
    • I8F-MC-GPGL
    • 2018-004422-29
    First Posted:
    Jun 17, 2019
    Last Update Posted:
    Feb 14, 2022
    Last Verified:
    Jul 1, 2021