Type 2 Diabetes
Conditions
Keywords
T2DM, GLP-1 RA, Glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), GIP/GLP-1 dual receptor agonist
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.
Interventions
DRUGTirzepatide
Administered SC
DRUGSemaglutide
Administered SC
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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). |
| 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. |
| 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). |
| 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). |
| Percentage of Participants Who Achieved Weight Loss ≥5% | Week 40 | Percentage of Participants who Achieved Weight Loss ≥5%. |
| 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). |
| 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. |
| Percentage of Participants Achieving an HbA1c Target Value of <5.7% | Week 40 | Percentage of Participants Achieving an HbA1c Target Value of \<5.7%. |
Countries
Argentina, Australia, Brazil, Canada, Israel, Mexico, Puerto Rico, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 5 mg Tirzepatide 5 mg tirzepatide administered SC once a week. | 470 |
| 10 mg Tirzepatide 10 mg tirzepatide administered SC once a week. | 469 |
| 15 mg Tirzepatide 15 mg tirzepatide administered SC once a week. | 470 |
| 1 mg Semaglutide 1 mg semaglutide administered SC once a week. | 469 |
| Total | 1,878 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 4 | 1 | 3 |
| Overall Study | Death | 4 | 4 | 4 | 1 |
| Overall Study | Lost to Follow-up | 5 | 6 | 8 | 12 |
| Overall Study | Other - as reported by the investigator | 1 | 3 | 2 | 0 |
| Overall Study | Physician Decision | 0 | 2 | 0 | 4 |
| Overall Study | Pregnancy | 1 | 0 | 1 | 1 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 0 |
| Overall Study | Site terminated by Sponsor | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 7 | 8 | 4 |
Baseline characteristics
| Characteristic | 15 mg Tirzepatide | 1 mg Semaglutide | 5 mg Tirzepatide | Total | 10 mg Tirzepatide |
|---|---|---|---|---|---|
| Age, Continuous | 55.9 years STANDARD_DEVIATION 10.4 | 56.9 years STANDARD_DEVIATION 10.8 | 56.3 years STANDARD_DEVIATION 10 | 56.6 years STANDARD_DEVIATION 10.4 | 57.2 years STANDARD_DEVIATION 10.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 334 Participants | 336 Participants | 325 Participants | 1317 Participants | 322 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 136 Participants | 133 Participants | 145 Participants | 561 Participants | 147 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Hemoglobin A1c | 8.26 Percentage of HbA1c STANDARD_DEVIATION 1 | 8.25 Percentage of HbA1c STANDARD_DEVIATION 1.01 | 8.32 Percentage of HbA1c STANDARD_DEVIATION 1.08 | 8.28 Percentage of HbA1c STANDARD_DEVIATION 1.03 | 8.30 Percentage of HbA1c STANDARD_DEVIATION 1.02 |
| Race (NIH/OMB) American Indian or Alaska Native | 57 Participants | 45 Participants | 53 Participants | 208 Participants | 53 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 3 Participants | 6 Participants | 25 Participants | 11 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 15 Participants | 28 Participants | 79 Participants | 21 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 3 Participants | 1 Participants | 12 Participants | 8 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 0 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 392 Participants | 401 Participants | 382 Participants | 1551 Participants | 376 Participants |
| Region of Enrollment Argentina | 161 Participants | 161 Participants | 158 Participants | 640 Participants | 160 Participants |
| Region of Enrollment Australia | 12 Participants | 11 Participants | 12 Participants | 46 Participants | 11 Participants |
| Region of Enrollment Brazil | 36 Participants | 37 Participants | 37 Participants | 147 Participants | 37 Participants |
| Region of Enrollment Canada | 14 Participants | 15 Participants | 15 Participants | 59 Participants | 15 Participants |
| Region of Enrollment Israel | 22 Participants | 21 Participants | 22 Participants | 87 Participants | 22 Participants |
| Region of Enrollment Mexico | 88 Participants | 88 Participants | 89 Participants | 352 Participants | 87 Participants |
| Region of Enrollment Puerto Rico | 6 Participants | 3 Participants | 6 Participants | 19 Participants | 4 Participants |
| Region of Enrollment United Kingdom | 18 Participants | 18 Participants | 18 Participants | 72 Participants | 18 Participants |
| Region of Enrollment United States | 113 Participants | 115 Participants | 113 Participants | 456 Participants | 115 Participants |
| Sex: Female, Male Female | 256 Participants | 244 Participants | 265 Participants | 996 Participants | 231 Participants |
| Sex: Female, Male Male | 214 Participants | 225 Participants | 205 Participants | 882 Participants | 238 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 470 | 4 / 469 | 4 / 470 | 1 / 469 |
| other Total, other adverse events | 170 / 470 | 187 / 469 | 202 / 470 | 172 / 469 |
| serious Total, serious adverse events | 33 / 470 | 25 / 469 | 27 / 470 | 13 / 469 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg)
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Change From Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg) | -2.37 Percentage of HbA1c | Standard Error 0.048 |
| 15 mg Tirzepatide | Change From Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg) | -2.46 Percentage of HbA1c | Standard Error 0.048 |
| 1 mg Semaglutide | Change From Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg) | -1.86 Percentage of HbA1c | Standard Error 0.048 |
p-value: <0.00195% CI: [-0.64, -0.38]Mixed Models Analysis
p-value: <0.00195% CI: [-0.73, -0.47]Mixed Models Analysis
Secondary
Change From Baseline in Body Weight
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Change From Baseline in Body Weight | -7.8 Kilograms (kg) | Standard Error 0.33 |
| 15 mg Tirzepatide | Change From Baseline in Body Weight | -10.3 Kilograms (kg) | Standard Error 0.34 |
| 1 mg Semaglutide | Change From Baseline in Body Weight | -12.4 Kilograms (kg) | Standard Error 0.34 |
| 1 mg Semaglutide | Change From Baseline in Body Weight | -6.2 Kilograms (kg) | Standard Error 0.33 |
p-value: <0.00195% CI: [-2.6, -0.7]Mixed Models Analysis
p-value: <0.00195% CI: [-5, -3.2]Mixed Models Analysis
p-value: <0.00195% CI: [-7.1, -5.3]Mixed Models Analysis
Secondary
Change From Baseline in Fasting Serum Glucose (FSG)
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Change From Baseline in Fasting Serum Glucose (FSG) | -56.0 milligram per Deciliter (mg/dL) | Standard Error 1.57 |
| 15 mg Tirzepatide | Change From Baseline in Fasting Serum Glucose (FSG) | -61.6 milligram per Deciliter (mg/dL) | Standard Error 1.6 |
| 1 mg Semaglutide | Change From Baseline in Fasting Serum Glucose (FSG) | -63.4 milligram per Deciliter (mg/dL) | Standard Error 1.59 |
| 1 mg Semaglutide | Change From Baseline in Fasting Serum Glucose (FSG) | -48.6 milligram per Deciliter (mg/dL) | Standard Error 1.58 |
p-value: 0.00195% CI: [-11.7, -3]Mixed Models Analysis
p-value: <0.00195% CI: [-17.4, -8.6]Mixed Models Analysis
p-value: <0.00195% CI: [-19.1, -10.3]Mixed Models Analysis
Secondary
Change From Baseline in HbA1c (5 mg)
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Change From Baseline in HbA1c (5 mg) | -2.09 Percentage of HbA1c | Standard Error 0.047 |
| 15 mg Tirzepatide | Change From Baseline in HbA1c (5 mg) | -1.86 Percentage of HbA1c | Standard Error 0.048 |
p-value: <0.00195% CI: [-0.36, -0.1]Mixed Models Analysis
Secondary
Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| 10 mg Tirzepatide | Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score | Hyperglycemia | -1.3 Units on a Scale | Standard Error 0.1 |
| 10 mg Tirzepatide | Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score | Total Score | 15.7 Units on a Scale | Standard Error 0.18 |
| 10 mg Tirzepatide | Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score | Hypoglycemia | -0.7 Units on a Scale | Standard Error 0.1 |
| 15 mg Tirzepatide | Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score | Hyperglycemia | -1.4 Units on a Scale | Standard Error 0.1 |
| 15 mg Tirzepatide | Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score | Total Score | 15.6 Units on a Scale | Standard Error 0.19 |
| 15 mg Tirzepatide | Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score | Hypoglycemia | -0.7 Units on a Scale | Standard Error 0.1 |
| 1 mg Semaglutide | Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score | Hypoglycemia | -0.8 Units on a Scale | Standard Error 0.1 |
| 1 mg Semaglutide | Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score | Hyperglycemia | -1.5 Units on a Scale | Standard Error 0.1 |
| 1 mg Semaglutide | Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score | Total Score | 16.1 Units on a Scale | Standard Error 0.19 |
| 1 mg Semaglutide | Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score | Hyperglycemia | -1.1 Units on a Scale | Standard Error 0.1 |
| 1 mg Semaglutide | Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score | Total Score | 15.8 Units on a Scale | Standard Error 0.19 |
| 1 mg Semaglutide | Diabetes Treatment Satisfaction as Measured by the Diabetes Treatment Satisfaction Questionnaire, Change Version (DTSQc) Hyperglycemia, Hypoglycemia and Total Score | Hypoglycemia | -0.7 Units on a Scale | Standard Error 0.1 |
Comparison: Hyperglycemiap-value: 0.08495% CI: [-0.5, 0.03]ANCOVA
Comparison: Hyperglycemiap-value: 0.0595% CI: [-0.54, 0]ANCOVA
Comparison: Hyperglycemiap-value: 0.00595% CI: [-0.66, -0.12]ANCOVA
Comparison: Hypoglycemiap-value: 0.68895% CI: [-0.33, 0.22]ANCOVA
Comparison: Hypoglycemiap-value: 0.90995% CI: [-0.29, 0.26]ANCOVA
Comparison: Hypoglycemiap-value: 0.35895% CI: [-0.4, 0.15]ANCOVA
Comparison: Total Scorep-value: 0.70195% CI: [-0.62, 0.41]ANCOVA
Comparison: Total Scorep-value: 0.34195% CI: [-0.78, 0.27]ANCOVA
Comparison: Total Scorep-value: 0.32195% CI: [-0.26, 0.79]ANCOVA
Secondary
Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values | -65.4 mg/dL | Standard Error 1.04 |
| 15 mg Tirzepatide | Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values | -70.6 mg/dL | Standard Error 1.05 |
| 1 mg Semaglutide | Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values | -74.3 mg/dL | Standard Error 1.05 |
| 1 mg Semaglutide | Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values | -61.4 mg/dL | Standard Error 1.04 |
Secondary
Percentage of Participants Achieving an HbA1c Target Value of <5.7%
Percentage of Participants Achieving an HbA1c Target Value of \<5.7%.
Time frame: Week 40
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg Tirzepatide | Percentage of Participants Achieving an HbA1c Target Value of <5.7% | 29.28 Percentage of Participants |
| 15 mg Tirzepatide | Percentage of Participants Achieving an HbA1c Target Value of <5.7% | 44.66 Percentage of Participants |
| 1 mg Semaglutide | Percentage of Participants Achieving an HbA1c Target Value of <5.7% | 50.86 Percentage of Participants |
| 1 mg Semaglutide | Percentage of Participants Achieving an HbA1c Target Value of <5.7% | 19.74 Percentage of Participants |
p-value: <0.00195% CI: [1.35, 2.57]Regression, Logistic
p-value: <0.00195% CI: [2.88, 5.39]Regression, Logistic
p-value: <0.00195% CI: [3.73, 6.97]Regression, Logistic
Secondary
Percentage of Participants Achieving an HbA1c Target Value of <7%
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg Tirzepatide | Percentage of Participants Achieving an HbA1c Target Value of <7% | 85.47 Percentage of Participants |
| 15 mg Tirzepatide | Percentage of Participants Achieving an HbA1c Target Value of <7% | 88.89 Percentage of Participants |
| 1 mg Semaglutide | Percentage of Participants Achieving an HbA1c Target Value of <7% | 92.24 Percentage of Participants |
| 1 mg Semaglutide | Percentage of Participants Achieving an HbA1c Target Value of <7% | 81.13 Percentage of Participants |
p-value: 0.02395% CI: [1.06, 2.23]Regression, Logistic
p-value: <0.00195% CI: [1.44, 3.17]Regression, Logistic
p-value: <0.00195% CI: [1.97, 4.66]Regression, Logistic
Secondary
Percentage of Participants Who Achieved Weight Loss ≥5%
Percentage of Participants who Achieved Weight Loss ≥5%.
Time frame: Week 40
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg Tirzepatide | Percentage of Participants Who Achieved Weight Loss ≥5% | 68.55 Percentage of Participants |
| 15 mg Tirzepatide | Percentage of Participants Who Achieved Weight Loss ≥5% | 82.35 Percentage of Participants |
| 1 mg Semaglutide | Percentage of Participants Who Achieved Weight Loss ≥5% | 86.21 Percentage of Participants |
| 1 mg Semaglutide | Percentage of Participants Who Achieved Weight Loss ≥5% | 58.44 Percentage of Participants |
p-value: 0.00195% CI: [1.2, 2.08]Regression, Logistic
p-value: <0.00195% CI: [2.57, 4.75]Regression, Logistic
p-value: <0.00195% CI: [3.32, 6.38]Regression, Logistic
Secondary
Rate of Hypoglycemia With Blood Glucose <54 Milligram/Deciliter (mg/dL) [<3.0 Millimole/Liter (mmol/L)] or Severe Hypoglycemia
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)
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Tirzepatide | Rate of Hypoglycemia With Blood Glucose <54 Milligram/Deciliter (mg/dL) [<3.0 Millimole/Liter (mmol/L)] or Severe Hypoglycemia | 0.0102 Episodes/participant/365.25 days | Standard Error 0.00423 |
| 15 mg Tirzepatide | Rate of Hypoglycemia With Blood Glucose <54 Milligram/Deciliter (mg/dL) [<3.0 Millimole/Liter (mmol/L)] or Severe Hypoglycemia | 0.0046 Episodes/participant/365.25 days | Standard Error 0.00488 |
| 1 mg Semaglutide | Rate of Hypoglycemia With Blood Glucose <54 Milligram/Deciliter (mg/dL) [<3.0 Millimole/Liter (mmol/L)] or Severe Hypoglycemia | 0.0202 Episodes/participant/365.25 days | Standard Error 0.0084 |
| 1 mg Semaglutide | Rate of Hypoglycemia With Blood Glucose <54 Milligram/Deciliter (mg/dL) [<3.0 Millimole/Liter (mmol/L)] or Severe Hypoglycemia | 0.0046 Episodes/participant/365.25 days | Standard Error 0.0034 |