Type 2 Diabetes
Conditions
Brief summary
The purpose of this study is to determine the efficacy of tirzepatide in participants with type 2 diabetes.
Interventions
DRUGTirzepatide
Administered SC
DRUGPlacebo
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
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Have type 2 diabetes (T2DM) for ≥6 months according to the Criteria for Diagnosing Type 2 Diabetes Mellitus (American Diabetes Association 2017). * Have HbA1c of 7.0% to 10.5%, inclusive, as assessed by the central laboratory. * If on metformin, have been treated with stable doses of metformin for at least 3 months. * Have a body mass index (BMI) between 23 and 45 (Inclusive) kilograms per square meter.
Exclusion criteria
* Have type 1 diabetes (T1D). * Have used any glucose-lowering medication other than metformin within 3 months prior to study entry or during screening/lead-in period or have used any glucagon-like peptide-1 receptor agonists (GLP-1 RAs) at any time in the past 12 months. * Have had any of the following cardiovascular conditions: acute myocardial infarction (MI), New York Heart Association Class III or Class IV heart failure, or cerebrovascular accident (stroke). * Have acute or chronic hepatitis, signs and symptoms of any other liver disease other than nonalcoholic fatty liver disease (NAFLD), or alanine aminotransferase (ALT) level \>2.5 times the upper limit of the reference range, as determined by the central laboratory at study entry; participants with NAFLD are eligible for participation in this trial. * Have had chronic or acute pancreatitis any time prior to study entry. * Have an estimated glomerular filtration rate (eGFR) \<45 milliliters/minute/1.73 square meter, calculated by the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation. * Have serum calcitonin ≥20 picograms per milliliter, as determined by the central laboratory at study entry. * Have any condition that is a contraindication for use of the GLP-1 RA class (per country-specific labels) at study entry or develop such condition between study entry and randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Haemoglobin A1c (HbA1c) | Baseline, 3 Months | Least squares (LS) mean was calculated using mixed model repeated measures model (MMRM) with baseline + baseline BMI group + baseline metformin flag + treatment + time + treatment\*time as fixed factors. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Blood Glucose (FBG) | Baseline, 3 Months | LSMean was calculated using MMRM model with baseline + baseline HbA1C group + baseline BMI group + baseline Metformin flag + treatment + time + treatment\*time as fixed factors. |
| Change From Baseline in Body Weight | Baseline, 3 Months | LSMean was calculated using MMRM model with baseline + baseline HbA1C group + baseline BMI group + baseline Metformin flag + treatment + time + treatment\*time as fixed factors. |
| Change From Baseline in Waist Circumference | Baseline, 3 Months | LSMean was calculated using MMRM model with baseline + baseline HbA1C group + baseline BMI group + baseline Metformin flag + treatment + time + treatment\*time as fixed factors. |
| Percentage of Participants Achieving HbA1c Target of <7.0% | 3 Months | Percentage of participants achieving HbA1c target of \< (less than) 7.0%. |
| Number of Episodes of Total Hypoglycemia Episodes | Baseline through 3 Months | Number of episodes of total hypoglycemia episodes with plasma glucose \<= ( less than or equal to) 54 mg/dL. |
| Pharmacokinetics (PK): Average Trough Concentration (Conctrough) of Tirzepatide | Week 4, 8 12: Pre-dose | Pharmacokinetics (PK): Average Trough Concentration (Conctrough) of Tirzepatide. |
| Number of Participants With Anti Drug Antibodies | Baseline through 3 Months | Number of participants with anti drug antibodies. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo administered by SC injection. | 26 |
| 4, 8 and 12mg Tirzepatide Participants received Tirzepatide by SC injection in three dose escalations starting with 4mg for four weeks followed by 8mg for four weeks followed by 12mg for four weeks. | 29 |
| 2.5, 5, 10, and 15mg Tirzepatide Participants received Tirzepatide by SC injection in four dose escalations starting with 2.5mg for two weeks followed by 5mg for two weeks followed by 10mg for four weeks followed by 15mg for four weeks. | 28 |
| 2.5, 7.5 and 15mg Tirzepatide Participants received Tirzepatide by SC injection in three dose escalations starting with 2.5mg for four weeks followed by 7.5mg for four weeks followed by 15mg for four weeks. | 28 |
| Total | 111 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 | 1 | 0 |
| Overall Study | Sponsor Decision | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | 4, 8 and 12mg Tirzepatide | 2.5, 5, 10, and 15mg Tirzepatide | 2.5, 7.5 and 15mg Tirzepatide | Total |
|---|---|---|---|---|---|
| Age, Continuous | 56.0 years STANDARD_DEVIATION 10.13 | 61.2 years STANDARD_DEVIATION 7.56 | 55.5 years STANDARD_DEVIATION 8.54 | 56.6 years STANDARD_DEVIATION 9.21 | 57.4 years STANDARD_DEVIATION 9.06 |
| Body Weight | 89.58 kilogram (kg) STANDARD_DEVIATION 23.69 | 87.98 kilogram (kg) STANDARD_DEVIATION 17.35 | 88.74 kilogram (kg) STANDARD_DEVIATION 18.21 | 89.59 kilogram (kg) STANDARD_DEVIATION 16.91 | 88.95 kilogram (kg) STANDARD_DEVIATION 18.87 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 15 Participants | 14 Participants | 14 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 14 Participants | 14 Participants | 14 Participants | 52 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Fasting Blood Glucose (FBG) | 9.68 millimoles per liter (mmol/L) STANDARD_DEVIATION 3.44 | 9.76 millimoles per liter (mmol/L) STANDARD_DEVIATION 3.03 | 10.40 millimoles per liter (mmol/L) STANDARD_DEVIATION 4.04 | 10.67 millimoles per liter (mmol/L) STANDARD_DEVIATION 4.22 | 10.13 millimoles per liter (mmol/L) STANDARD_DEVIATION 3.69 |
| Hemoglobin A1c (HbA1c) | 8.23 Percentage of HbA1C STANDARD_DEVIATION 1.22 | 8.35 Percentage of HbA1C STANDARD_DEVIATION 0.897 | 8.48 Percentage of HbA1C STANDARD_DEVIATION 1.171 | 8.35 Percentage of HbA1C STANDARD_DEVIATION 1.12 | 8.35 Percentage of HbA1C STANDARD_DEVIATION 1.094 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 7 Participants | 5 Participants | 2 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 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 | 25 Participants | 19 Participants | 20 Participants | 23 Participants | 87 Participants |
| Region of Enrollment United States | 26 Participants | 29 Participants | 28 Participants | 28 Participants | 111 Participants |
| Sex: Female, Male Female | 14 Participants | 14 Participants | 12 Participants | 5 Participants | 45 Participants |
| Sex: Female, Male Male | 12 Participants | 15 Participants | 16 Participants | 23 Participants | 66 Participants |
| Waist Circumference | 109.09 centimeter (cm) STANDARD_DEVIATION 15.38 | 107.65 centimeter (cm) STANDARD_DEVIATION 12.22 | 107.02 centimeter (cm) STANDARD_DEVIATION 12.64 | 105.10 centimeter (cm) STANDARD_DEVIATION 12.19 | 107.19 centimeter (cm) STANDARD_DEVIATION 13.02 |
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 / 26 | 0 / 29 | 0 / 28 | 0 / 28 |
| other Total, other adverse events | 7 / 26 | 19 / 29 | 18 / 28 | 22 / 28 |
| serious Total, serious adverse events | 0 / 26 | 1 / 29 | 0 / 28 | 0 / 28 |
Outcome results
Primary
Change From Baseline in Haemoglobin A1c (HbA1c)
Least squares (LS) mean was calculated using mixed model repeated measures model (MMRM) with baseline + baseline BMI group + baseline metformin flag + treatment + time + treatment\*time as fixed factors.
Time frame: Baseline, 3 Months
Population: All participants who received at least 1 dose of study drug and had baseline and at least one post baseline data. Participants who discontinued study drug or initiated rescue drug were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Haemoglobin A1c (HbA1c) | 0.2 Percentage of HbA1C | Standard Error 0.21 |
| 4, 8 and 12mg Tirzepatide | Change From Baseline in Haemoglobin A1c (HbA1c) | -1.7 Percentage of HbA1C | Standard Error 0.19 |
| 2.5, 5, 10, and 15mg Tirzepatide | Change From Baseline in Haemoglobin A1c (HbA1c) | -2.0 Percentage of HbA1C | Standard Error 0.2 |
| 2.5, 7.5 and 15mg Tirzepatide | Change From Baseline in Haemoglobin A1c (HbA1c) | -1.8 Percentage of HbA1C | Standard Error 0.19 |
p-value: <0.00195% CI: [-2.5, -1.4]Mixed Models Analysis
p-value: <0.00195% CI: [-2.8, -1.7]Mixed Models Analysis
p-value: <0.00195% CI: [-2.5, -1.4]Mixed Models Analysis
Secondary
Change From Baseline in Body Weight
LSMean was calculated using MMRM model with baseline + baseline HbA1C group + baseline BMI group + baseline Metformin flag + treatment + time + treatment\*time as fixed factors.
Time frame: Baseline, 3 Months
Population: All participants who received at least 1 dose of study drug and had baseline and at least one post baseline data. Participants who discontinued study drug or initiated rescue drug were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Body Weight | -0.5 kilogram (kg) | Standard Error 0.86 |
| 4, 8 and 12mg Tirzepatide | Change From Baseline in Body Weight | -5.3 kilogram (kg) | Standard Error 0.78 |
| 2.5, 5, 10, and 15mg Tirzepatide | Change From Baseline in Body Weight | -5.5 kilogram (kg) | Standard Error 0.8 |
| 2.5, 7.5 and 15mg Tirzepatide | Change From Baseline in Body Weight | -5.7 kilogram (kg) | Standard Error 0.79 |
p-value: <0.00195% CI: [-7.1, -2.6]Mixed Models Analysis
p-value: <0.00195% CI: [-7.2, -2.7]Mixed Models Analysis
p-value: <0.00195% CI: [-7.5, -2.9]Mixed Models Analysis
Secondary
Change From Baseline in Fasting Blood Glucose (FBG)
LSMean was calculated using MMRM model with baseline + baseline HbA1C group + baseline BMI group + baseline Metformin flag + treatment + time + treatment\*time as fixed factors.
Time frame: Baseline, 3 Months
Population: All participants who received at least 1 dose of study drug and had baseline and at least one post baseline data. Participants who discontinued study drug or initiated rescue drug were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Blood Glucose (FBG) | -12.3 milligrams per deciliter (mg/dL) | Standard Error 9.27 |
| 4, 8 and 12mg Tirzepatide | Change From Baseline in Fasting Blood Glucose (FBG) | -60.7 milligrams per deciliter (mg/dL) | Standard Error 8.21 |
| 2.5, 5, 10, and 15mg Tirzepatide | Change From Baseline in Fasting Blood Glucose (FBG) | -70.2 milligrams per deciliter (mg/dL) | Standard Error 8.72 |
| 2.5, 7.5 and 15mg Tirzepatide | Change From Baseline in Fasting Blood Glucose (FBG) | -74.2 milligrams per deciliter (mg/dL) | Standard Error 8.67 |
p-value: <0.00195% CI: [-70.6, -26.3]Mixed Models Analysis
p-value: <0.00195% CI: [-80.7, -35.2]Mixed Models Analysis
p-value: <0.00195% CI: [-84.6, -39.2]Mixed Models Analysis
Secondary
Change From Baseline in Waist Circumference
LSMean was calculated using MMRM model with baseline + baseline HbA1C group + baseline BMI group + baseline Metformin flag + treatment + time + treatment\*time as fixed factors.
Time frame: Baseline, 3 Months
Population: All participants who received at least 1 dose of study drug and had baseline and at least one post baseline data. Participants who discontinued study drug or initiated rescue drug were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Waist Circumference | -2.5 centimeter (cm) | Standard Error 1.01 |
| 4, 8 and 12mg Tirzepatide | Change From Baseline in Waist Circumference | -4.8 centimeter (cm) | Standard Error 0.9 |
| 2.5, 5, 10, and 15mg Tirzepatide | Change From Baseline in Waist Circumference | -4.9 centimeter (cm) | Standard Error 0.94 |
| 2.5, 7.5 and 15mg Tirzepatide | Change From Baseline in Waist Circumference | -4.9 centimeter (cm) | Standard Error 0.93 |
p-value: 0.07595% CI: [-4.7, 0.2]Mixed Models Analysis
p-value: 0.06595% CI: [-4.9, 0.1]Mixed Models Analysis
p-value: 0.06595% CI: [-4.9, 0.2]Mixed Models Analysis
Secondary
Number of Episodes of Total Hypoglycemia Episodes
Number of episodes of total hypoglycemia episodes with plasma glucose \<= ( less than or equal to) 54 mg/dL.
Time frame: Baseline through 3 Months
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Episodes of Total Hypoglycemia Episodes | 0 Episodes |
| 4, 8 and 12mg Tirzepatide | Number of Episodes of Total Hypoglycemia Episodes | 0 Episodes |
| 2.5, 5, 10, and 15mg Tirzepatide | Number of Episodes of Total Hypoglycemia Episodes | 0 Episodes |
| 2.5, 7.5 and 15mg Tirzepatide | Number of Episodes of Total Hypoglycemia Episodes | 1 Episodes |
Secondary
Number of Participants With Anti Drug Antibodies
Number of participants with anti drug antibodies.
Time frame: Baseline through 3 Months
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Anti Drug Antibodies | 0 participants |
| 4, 8 and 12mg Tirzepatide | Number of Participants With Anti Drug Antibodies | 10 participants |
| 2.5, 5, 10, and 15mg Tirzepatide | Number of Participants With Anti Drug Antibodies | 8 participants |
| 2.5, 7.5 and 15mg Tirzepatide | Number of Participants With Anti Drug Antibodies | 4 participants |
Secondary
Percentage of Participants Achieving HbA1c Target of <7.0%
Percentage of participants achieving HbA1c target of \< (less than) 7.0%.
Time frame: 3 Months
Population: All participants who received at least 1 dose of study drug and had baseline and at least one post baseline data. Participants who discontinued study drug or initiated rescue drug were excluded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Achieving HbA1c Target of <7.0% | 10 percentage of participants |
| 4, 8 and 12mg Tirzepatide | Percentage of Participants Achieving HbA1c Target of <7.0% | 74.1 percentage of participants |
| 2.5, 5, 10, and 15mg Tirzepatide | Percentage of Participants Achieving HbA1c Target of <7.0% | 87 percentage of participants |
| 2.5, 7.5 and 15mg Tirzepatide | Percentage of Participants Achieving HbA1c Target of <7.0% | 84.6 percentage of participants |
p-value: <0.00195% CI: [9.43, 338.97]Regression, Logistic
p-value: <0.00195% CI: [22, 999]Regression, Logistic
p-value: <0.00195% CI: [21.63, 999]Regression, Logistic
Secondary
Pharmacokinetics (PK): Average Trough Concentration (Conctrough) of Tirzepatide
Pharmacokinetics (PK): Average Trough Concentration (Conctrough) of Tirzepatide.
Time frame: Week 4, 8 12: Pre-dose
Population: All randomized participants who received at least one dose of study drug and had evaluable PK samples.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Pharmacokinetics (PK): Average Trough Concentration (Conctrough) of Tirzepatide | 508 nanograms per milliliter (ng/mL) | Standard Deviation 366 |
| 4, 8 and 12mg Tirzepatide | Pharmacokinetics (PK): Average Trough Concentration (Conctrough) of Tirzepatide | 704 nanograms per milliliter (ng/mL) | Standard Deviation 518 |
| 2.5, 5, 10, and 15mg Tirzepatide | Pharmacokinetics (PK): Average Trough Concentration (Conctrough) of Tirzepatide | 630 nanograms per milliliter (ng/mL) | Standard Deviation 414 |