Type 2 Diabetes
Conditions
Brief summary
The reason for this study is to see if the study drug tirzepatide (LY3298176) is effective and safe compared to dulaglutide in participants with type 2 diabetes in Japan.
Interventions
DRUGTirzepatide
Administered SC
DRUGDulaglutide
Administered SC
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participant must: * Have been diagnosed with type 2 diabetes mellitus based on the World Health Organization classification before the screening visit. * Have HbA1c meeting the following criteria, as determined by the central laboratory at screening and baseline: * for participants who are oral antihyperglycemic medication (OAM)-naïve at screening, ≥7.0% to ≤10.0% at both screening and baseline. * for participants who have been taking OAM monotherapy at screening, ≥6.5% to ≤9.0% at screening, and ≥7.0% to ≤10.0% at baseline. * Have body mass index (BMI) of ≥23 kilograms per meter squared at screening. * Be of stable weight (±5%) during 3 months preceding screening; and agree to not initiate an intensive diet and/or exercise program during the study with the intent of reducing body weight other than the lifestyle and dietary measures for diabetes treatment.
Exclusion criteria
Participant must not: * 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 immediate or urgent 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 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1c (HbA1c) | Baseline, Week 52 | 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 for post-baseline measures: Variable = Baseline + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Serum Glucose | Baseline, Week 52 | 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 for post-baseline measures: Variable = Baseline + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares). |
| Change From Baseline in Average 7-Point Self-Monitored Blood Glucose (SMBG) Values | Baseline, Week 52 | 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. LS mean was determined by analysis of covariance (ANCOVA) model for with Baseline + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment (Type III sum of squares) as variables. |
| Change From Baseline in Body Weight | Baseline, Week 52 | Change from baseline in body weight. LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares). |
| Percentage of Participants Who Achieve Weight Loss ≥5% From Baseline | Week 52 | Percentage of participants who achieve weight loss ≥5% from baseline. |
| Change From Baseline in Fasting Insulin | Baseline, Week 52 | Fasting Insulin is a test used to measure the amount of insulin in the body. LS mean was determined by MMRM model for post-baseline measures with log (Actual Measurement) = log (Baseline) + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables. |
| Percentage of Participants With HbA1c of <7.0% | Week 52 | 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 Homeostasis Model Assessment B (HOMA-2B, Insulin) | Baseline, Week 52 | HOMA-2B is an estimated steady state beta cell function based on updated HOMA2 model. The HOMA2 model estimates steady state pancreatic beta cell function (%B) as a percentage of a normal reference population using simultaneously measured fasting plasma glucose and fasting insulin. LS mean was determined by MMRM model for post-baseline measures: log(Actual Measurement/Baseline) = log(Baseline) + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares). |
| Change From Baseline in HOMA-2S (Insluin) | Baseline, Week 52 | HOMA2-S is an estimated insulin sensitivity based on updated HOMA2 model. The HOMA2 model is a computer model that estimates insulin sensitivity (%S) as percentages of a normal reference population using simultaneously measured fasting plasma glucose and fasting insulin. LS mean was determined by MMRM model for post-baseline measures: log(Actual Measurement) = log(Baseline) + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares). |
| Rate of Hypoglycemia With Glucose < 54 mg/dL or Severe Hypoglycemia | Baseline through Week 52 | 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 for post-baseline comparisons between treatment and control group: number of episodes = baseline hypoglycemia incidence + baseline BMI Group (\<25 or \>=25 kg/m\^2) + washout of antidiabetic medication + baseline hemoglobin A1C (%) + treatment, with log (exposure in days/365.25) as an offset variable. |
| Number of Participants With Anti-Tirzepatide Antibodies | Baseline through Week 52 | Number of participants with anti-tirzepatide antibodies. A participant is treatment emergent (TE) anti-drug antibody (ADA) evaluable if there is at least one non-missing test result for tirzepatide ADA for each of the baseline period and the postbaseline period. All percentages are relative to the total number of TE ADA evaluable participants in each treatment group. A TE ADA evaluable participant is considered to be TE ADA+ if the participant has at least one postbaseline titer that is a 4-fold or greater increase in titer from baseline measurement. |
| Change From Baseline in Fasting C-Peptide | Baseline, Week 52 | Fasting C-peptide is a test used to measure the amount of C-peptide in the body. A high level of C-peptide can mean that body is making too much insulin. LS mean was determined by MMRM model for post-baseline measures: log (Actual Measurement) = log (Baseline) + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares). |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 5 mg Tirzepatide Participants received 5 mg tirzepatide administered SC once weekly for 52 weeks. | 159 |
| 10 mg Tirzepatide Participants received 10 mg tirzepatide administered SC once weekly for 52 weeks | 158 |
| 15 mg Tirzepatide Participants received 15 mg tirzepatide administered SC once weekly for 52 weeks. | 160 |
| 0.75 mg Dulaglutide Participants received 0.75 mg dulaglutide administered SC once weekly for 52 weeks | 159 |
| Total | 636 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 2 | 4 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 0 |
| Overall Study | Relocation to other city | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 5 | 3 | 0 |
Baseline characteristics
| Characteristic | Total | 5 mg Tirzepatide | 10 mg Tirzepatide | 15 mg Tirzepatide | 0.75 mg Dulaglutide |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 158 Participants | 39 Participants | 35 Participants | 36 Participants | 48 Participants |
| Age, Categorical Between 18 and 65 years | 478 Participants | 120 Participants | 123 Participants | 124 Participants | 111 Participants |
| Hemoglobin A1c [HbA1c] | 8.18 percentage of HbA1c STANDARD_DEVIATION 0.87 | 8.18 percentage of HbA1c STANDARD_DEVIATION 0.88 | 8.19 percentage of HbA1c STANDARD_DEVIATION 0.86 | 8.19 percentage of HbA1c STANDARD_DEVIATION 0.89 | 8.15 percentage of HbA1c STANDARD_DEVIATION 0.86 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 636 Participants | 159 Participants | 158 Participants | 160 Participants | 159 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Japan | 636 Participants | 159 Participants | 158 Participants | 160 Participants | 159 Participants |
| Sex: Female, Male Female | 155 Participants | 46 Participants | 39 Participants | 28 Participants | 42 Participants |
| Sex: Female, Male Male | 481 Participants | 113 Participants | 119 Participants | 132 Participants | 117 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 | 0 / 159 | 0 / 158 | 0 / 160 | 0 / 159 |
| other Total, other adverse events | 131 / 159 | 121 / 158 | 134 / 160 | 120 / 159 |
| serious Total, serious adverse events | 8 / 159 | 10 / 158 | 7 / 160 | 14 / 159 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1c (HbA1c)
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 for post-baseline measures: Variable = Baseline + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Baseline, Week 52
Population: All randomized participants who received at least 1 dose of study drug and had a baseline and at least 1 post-baseline value, excluding data after initiating rescue antihyperglycemic medication or prematurely stopping study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 5 mg Tirzepatide | Change From Baseline in Hemoglobin A1c (HbA1c) | -2.37 percentage of HbA1c | Standard Error 0.066 |
| 10 mg Tirzepatide | Change From Baseline in Hemoglobin A1c (HbA1c) | -2.55 percentage of HbA1c | Standard Error 0.067 |
| 15 mg Tirzepatide | Change From Baseline in Hemoglobin A1c (HbA1c) | -2.82 percentage of HbA1c | Standard Error 0.066 |
| 0.75 mg Dulaglutide | Change From Baseline in Hemoglobin A1c (HbA1c) | -1.29 percentage of HbA1c | Standard Error 0.065 |
p-value: <0.00195% CI: [-1.27, -0.9]Mixed Models Analysis
p-value: <0.00195% CI: [-1.45, -1.08]Mixed Models Analysis
p-value: <0.00195% CI: [-1.71, -1.35]Mixed Models Analysis
Secondary
Change From Baseline in 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. LS mean was determined by analysis of covariance (ANCOVA) model for with Baseline + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment (Type III sum of squares) as variables.
Time frame: Baseline, Week 52
Population: All randomized participants who received at least 1 dose of study drug and had a baseline and at least 1 post-baseline value, excluding data after initiating rescue antihyperglycemic medication or prematurely stopping study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 5 mg Tirzepatide | Change From Baseline in Average 7-Point Self-Monitored Blood Glucose (SMBG) Values | -59.5 mg/dL | Standard Error 1.46 |
| 10 mg Tirzepatide | Change From Baseline in Average 7-Point Self-Monitored Blood Glucose (SMBG) Values | -64.2 mg/dL | Standard Error 1.5 |
| 15 mg Tirzepatide | Change From Baseline in Average 7-Point Self-Monitored Blood Glucose (SMBG) Values | -68.6 mg/dL | Standard Error 1.5 |
| 0.75 mg Dulaglutide | Change From Baseline in Average 7-Point Self-Monitored Blood Glucose (SMBG) Values | -42.2 mg/dL | Standard Error 1.48 |
p-value: <0.00195% CI: [-21.4, -13.2]ANCOVA
p-value: <0.00195% CI: [-26.1, -17.9]ANCOVA
p-value: <0.00195% CI: [-30.5, -22.2]ANCOVA
Secondary
Change From Baseline in Body Weight
Change from baseline in body weight. LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Baseline, Week 52
Population: All randomized participants who received at least 1 dose of study drug and had a baseline and at least 1 post-baseline value, excluding data after initiating rescue antihyperglycemic medication or prematurely stopping study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 5 mg Tirzepatide | Change From Baseline in Body Weight | -5.8 kilogram (kg) | Standard Error 0.41 |
| 10 mg Tirzepatide | Change From Baseline in Body Weight | -8.5 kilogram (kg) | Standard Error 0.42 |
| 15 mg Tirzepatide | Change From Baseline in Body Weight | -10.7 kilogram (kg) | Standard Error 0.41 |
| 0.75 mg Dulaglutide | Change From Baseline in Body Weight | -0.5 kilogram (kg) | Standard Error 0.41 |
p-value: <0.00195% CI: [-6.4, -4.1]Mixed Models Analysis
p-value: <0.00195% CI: [-9.1, -6.8]Mixed Models Analysis
p-value: <0.00195% CI: [-11.3, -9]Mixed Models Analysis
Secondary
Change From Baseline in Fasting C-Peptide
Fasting C-peptide is a test used to measure the amount of C-peptide in the body. A high level of C-peptide can mean that body is making too much insulin. LS mean was determined by MMRM model for post-baseline measures: log (Actual Measurement) = log (Baseline) + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Baseline, Week 52
Population: All randomized participants who received at least 1 dose of study drug and had a baseline and at least 1 post-baseline value, excluding data after initiating rescue antihyperglycemic medication or prematurely stopping study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 5 mg Tirzepatide | Change From Baseline in Fasting C-Peptide | -0.25 micrograms per liter (ug/L) | Standard Error 0.045 |
| 10 mg Tirzepatide | Change From Baseline in Fasting C-Peptide | -0.39 micrograms per liter (ug/L) | Standard Error 0.042 |
| 15 mg Tirzepatide | Change From Baseline in Fasting C-Peptide | -0.37 micrograms per liter (ug/L) | Standard Error 0.042 |
| 0.75 mg Dulaglutide | Change From Baseline in Fasting C-Peptide | 0.01 micrograms per liter (ug/L) | Standard Error 0.052 |
p-value: <0.00195% CI: [-0.4, -0.13]Mixed Models Analysis
p-value: <0.00195% CI: [-0.53, -0.27]Mixed Models Analysis
p-value: <0.00195% CI: [-0.51, -0.25]Mixed Models Analysis
Secondary
Change From Baseline in Fasting Insulin
Fasting Insulin is a test used to measure the amount of insulin in the body. LS mean was determined by MMRM model for post-baseline measures with log (Actual Measurement) = log (Baseline) + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables.
Time frame: Baseline, Week 52
Population: All randomized participants who received at least 1 dose of study drug and had a baseline and at least 1 post-baseline value, excluding data after initiating rescue antihyperglycemic medication or prematurely stopping study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 5 mg Tirzepatide | Change From Baseline in Fasting Insulin | -1.07 milliunits per litre (mU/L) | Standard Error 0.374 |
| 10 mg Tirzepatide | Change From Baseline in Fasting Insulin | -1.87 milliunits per litre (mU/L) | Standard Error 0.344 |
| 15 mg Tirzepatide | Change From Baseline in Fasting Insulin | -2.00 milliunits per litre (mU/L) | Standard Error 0.335 |
| 0.75 mg Dulaglutide | Change From Baseline in Fasting Insulin | 1.40 milliunits per litre (mU/L) | Standard Error 0.482 |
p-value: <0.00195% CI: [-3.67, -1.28]Mixed Models Analysis
p-value: <0.00195% CI: [-4.43, -2.11]Mixed Models Analysis
p-value: <0.00195% CI: [-4.55, -2.25]Mixed Models Analysis
Secondary
Change From Baseline in Fasting Serum Glucose
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 for post-baseline measures: Variable = Baseline + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Baseline, Week 52
Population: All randomized participants who received at least 1 dose of study drug and had a baseline and at least 1 post-baseline value, excluding data after initiating rescue antihyperglycemic medication or prematurely stopping study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 5 mg Tirzepatide | Change From Baseline in Fasting Serum Glucose | -57.9 milligrams per decilitre (mg/dL) | Standard Error 1.73 |
| 10 mg Tirzepatide | Change From Baseline in Fasting Serum Glucose | -64.6 milligrams per decilitre (mg/dL) | Standard Error 1.76 |
| 15 mg Tirzepatide | Change From Baseline in Fasting Serum Glucose | -67.6 milligrams per decilitre (mg/dL) | Standard Error 1.75 |
| 0.75 mg Dulaglutide | Change From Baseline in Fasting Serum Glucose | -31.9 milligrams per decilitre (mg/dL) | Standard Error 1.73 |
p-value: <0.00195% CI: [-30.7, -21.1]Mixed Models Analysis
p-value: <0.00195% CI: [-37.5, -27.8]Mixed Models Analysis
p-value: <0.00195% CI: [-40.6, 30.9]Mixed Models Analysis
Secondary
Change From Baseline in HOMA-2S (Insluin)
HOMA2-S is an estimated insulin sensitivity based on updated HOMA2 model. The HOMA2 model is a computer model that estimates insulin sensitivity (%S) as percentages of a normal reference population using simultaneously measured fasting plasma glucose and fasting insulin. LS mean was determined by MMRM model for post-baseline measures: log(Actual Measurement) = log(Baseline) + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Baseline, Week 52
Population: All randomized participants who received at least 1 dose of study drug and had a baseline and at least 1 post-baseline value, excluding data after initiating rescue antihyperglycemic medication or prematurely stopping study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 5 mg Tirzepatide | Change From Baseline in HOMA-2S (Insluin) | 14.5 percentage of insulin sensitivity | Standard Error 3.38 |
| 10 mg Tirzepatide | Change From Baseline in HOMA-2S (Insluin) | 21.6 percentage of insulin sensitivity | Standard Error 3.83 |
| 15 mg Tirzepatide | Change From Baseline in HOMA-2S (Insluin) | 25.7 percentage of insulin sensitivity | Standard Error 3.95 |
| 0.75 mg Dulaglutide | Change From Baseline in HOMA-2S (Insluin) | -5.4 percentage of insulin sensitivity | Standard Error 2.52 |
p-value: <0.00195% CI: [11.7, 28.2]Mixed Models Analysis
p-value: <0.00195% CI: [18, 36]Mixed Models Analysis
p-value: <0.00195% CI: [22, 40.4]Mixed Models Analysis
Secondary
Change From Baseline in Homeostasis Model Assessment B (HOMA-2B, Insulin)
HOMA-2B is an estimated steady state beta cell function based on updated HOMA2 model. The HOMA2 model estimates steady state pancreatic beta cell function (%B) as a percentage of a normal reference population using simultaneously measured fasting plasma glucose and fasting insulin. LS mean was determined by MMRM model for post-baseline measures: log(Actual Measurement/Baseline) = log(Baseline) + Baseline HbA1c Group (\<=8.5%, \>8.5%) + Baseline BMI Group (\<25 or \>=25 kg/m\^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Baseline, Week 52
Population: All randomized participants who received at least 1 dose of study drug and had a baseline and at least 1 post-baseline value, excluding data after initiating rescue antihyperglycemic medication or prematurely stopping study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 5 mg Tirzepatide | Change From Baseline in Homeostasis Model Assessment B (HOMA-2B, Insulin) | 38.5 percentage of insulin sensitivity | Standard Error 2.15 |
| 10 mg Tirzepatide | Change From Baseline in Homeostasis Model Assessment B (HOMA-2B, Insulin) | 43.0 percentage of insulin sensitivity | Standard Error 2.38 |
| 15 mg Tirzepatide | Change From Baseline in Homeostasis Model Assessment B (HOMA-2B, Insulin) | 46.3 percentage of insulin sensitivity | Standard Error 2.44 |
| 0.75 mg Dulaglutide | Change From Baseline in Homeostasis Model Assessment B (HOMA-2B, Insulin) | 22.4 percentage of insulin sensitivity | Standard Error 1.66 |
p-value: <0.00195% CI: [10.7, 21.4]Mixed Models Analysis
p-value: <0.00195% CI: [14.9, 26.3]Mixed Models Analysis
p-value: <0.00195% CI: [18.1, 29.7]Mixed Models Analysis
Secondary
Number of Participants With Anti-Tirzepatide Antibodies
Number of participants with anti-tirzepatide antibodies. A participant is treatment emergent (TE) anti-drug antibody (ADA) evaluable if there is at least one non-missing test result for tirzepatide ADA for each of the baseline period and the postbaseline period. All percentages are relative to the total number of TE ADA evaluable participants in each treatment group. A TE ADA evaluable participant is considered to be TE ADA+ if the participant has at least one postbaseline titer that is a 4-fold or greater increase in titer from baseline measurement.
Time frame: Baseline through Week 52
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5 mg Tirzepatide | Number of Participants With Anti-Tirzepatide Antibodies | 97 participants |
| 10 mg Tirzepatide | Number of Participants With Anti-Tirzepatide Antibodies | 102 participants |
| 15 mg Tirzepatide | Number of Participants With Anti-Tirzepatide Antibodies | 123 participants |
| 0.75 mg Dulaglutide | Number of Participants With Anti-Tirzepatide Antibodies | 8 participants |
Secondary
Percentage of Participants Who Achieve Weight Loss ≥5% From Baseline
Percentage of participants who achieve weight loss ≥5% from baseline.
Time frame: Week 52
Population: All randomized participants who received at least 1 dose of study drug and had a baseline and at least 1 post-baseline value, excluding data after initiating rescue antihyperglycemic medication or prematurely stopping study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5 mg Tirzepatide | Percentage of Participants Who Achieve Weight Loss ≥5% From Baseline | 60.76 percentage of participants |
| 10 mg Tirzepatide | Percentage of Participants Who Achieve Weight Loss ≥5% From Baseline | 82.05 percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants Who Achieve Weight Loss ≥5% From Baseline | 89.31 percentage of participants |
| 0.75 mg Dulaglutide | Percentage of Participants Who Achieve Weight Loss ≥5% From Baseline | 10.69 percentage of participants |
p-value: <0.00195% CI: [7.88, 26.46]Regression, Logistic
p-value: <0.00195% CI: [23.12, 87.45]Regression, Logistic
p-value: <0.00195% CI: [39.84, 171.52]Regression, Logistic
Secondary
Percentage of Participants With HbA1c of <7.0%
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 52
Population: All randomized participants who received at least 1 dose of study drug and had a baseline and at least 1 post-baseline value, excluding data after initiating rescue antihyperglycemic medication or prematurely stopping study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5 mg Tirzepatide | Percentage of Participants With HbA1c of <7.0% | 93.67 percentage of participants |
| 10 mg Tirzepatide | Percentage of Participants With HbA1c of <7.0% | 96.79 percentage of participants |
| 15 mg Tirzepatide | Percentage of Participants With HbA1c of <7.0% | 99.37 percentage of participants |
| 0.75 mg Dulaglutide | Percentage of Participants With HbA1c of <7.0% | 67.30 percentage of participants |
p-value: <0.00195% CI: [4.53, 21.55]Regression, Logistic
p-value: <0.00195% CI: [7.73, 54.71]Regression, Logistic
p-value: <0.00195% CI: [15.8, 460.58]Regression, Logistic
Secondary
Rate of Hypoglycemia With Glucose < 54 mg/dL 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 for post-baseline comparisons between treatment and control group: number of episodes = baseline hypoglycemia incidence + baseline BMI Group (\<25 or \>=25 kg/m\^2) + washout of antidiabetic medication + baseline hemoglobin A1C (%) + treatment, with log (exposure in days/365.25) as an offset variable.
Time frame: Baseline through Week 52
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5 mg Tirzepatide | Rate of Hypoglycemia With Glucose < 54 mg/dL or Severe Hypoglycemia | 0 Episodes/participant/365.25 days |
| 10 mg Tirzepatide | Rate of Hypoglycemia With Glucose < 54 mg/dL or Severe Hypoglycemia | 0 Episodes/participant/365.25 days |
| 15 mg Tirzepatide | Rate of Hypoglycemia With Glucose < 54 mg/dL or Severe Hypoglycemia | 0.012 Episodes/participant/365.25 days |
| 0.75 mg Dulaglutide | Rate of Hypoglycemia With Glucose < 54 mg/dL or Severe Hypoglycemia | 0 Episodes/participant/365.25 days |