Diabetes Mellitus, Type 2
Conditions
Brief summary
This is a study for participants with type 2 diabetes mellitus. The main purpose of this study is to learn more about how tirzepatide, semaglutide and placebo affect the body's ability to respond to blood sugar levels after a meal. The study will last up to 40 weeks, including a 28-week treatment period.
Interventions
DRUGTirzepatide
Administered SC
DRUGSemaglutide
Administered SC
DRUGPlacebo
Administered SC
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
* Have T2DM for at least 6 months * Treated with diet and exercise and stable dose(s) of metformin, with or without 1 additional stable dose of oral antihyperglycemia medication other than metformin, 3 months prior to study entry * Have a hemoglobin A1c (HbA1c) value at screening of ≥7% and ≤ 9.5 % if on metformin only; or ≥6.5% and ≤9.0% if on metformin in combination with oral antihyperglycemia medications other than metformin * Have a body mass index (BMI) between 25 and 45 kilograms per square meter (kg/m² ) inclusive, at screening; are of stable weight (±5%) \>3 months prior to screening
Exclusion criteria
* Have a history of proliferative retinopathy or maculopathy as determined by the investigator based on a recent (\<1.5 years) ophthalmologic examination * Impaired renal estimated glomerular filtration rate (eGFR) \<45 milliliters per minute per 1.73 square meters (mL/min/1.73 m²) calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) * Have a history or current cardiovascular, respiratory, hepatic, renal, GI,endocrine, hematological or neurological disorders capable of significantly altering the absorption, metabolism or elimination of drugs; of constituting a risk when taking the study drug; or of interfering with the interpretation of data
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Clamp Disposition Index (cDI) | Baseline, Week 28 | cDI is defined as the product of the M-value derived from the hyperinsulinemic euglycemic clamp over the last 30 minutes and total insulin secretion (ISR AUC0-120min) derived from the insulin secretion rate based on C-peptide using the using the deconvolution technique divided by the total glucose AUC0-120min from the hyperglycemic clamp portion of the study. Least squares (LS) mean was determined by analysis of covariance (ANCOVA) model for endpoint measures: log(Actual Measurement/Baseline) = log(Baseline) + Treatment (Type III sum of squares). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Postmeal Glucose | Baseline, Week 28 | Total AUC from time zero to 240 minutes after start of the meal \[AUC0-240min\]) during sMMTT was evaluated. LS mean was determined by ANCOVA model for endpoint measures: Variable = Baseline + Treatment (Type III sum of squares) and ANOVA model for baseline measures: Variable = Treatment (Type III sum of squares). |
| Change From Baseline in Hemoglobin A1c (HbA1c) | Baseline, Week 28 | HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. LS mean was determined by mixed model repeated measures; (MMRM) model for post-baseline measures: Variable = Baseline + Treatment + Time + Treatment\*Time (Type III sum of squares). |
| Change From Baseline in Total Insulin Secretion Rate During the 120-Minute Hyperglycemic Clamp (ISR0-120min) | Baseline and Week 28 | Total Insulin Secretion Rate During the 120-Minute Hyperglycemic Clamp (ISR0-120min) will be determined from C-peptide concentrations using the deconvolution technique. LS mean was determined by ANCOVA model for endpoint measures: log(Actual Measurement/Baseline) = log(Baseline) + Treatment (Type III sum of squares). |
| Change From Baseline in Fasting Glucose | Baseline, Week 28 | Fasting glucose is a test to determine sugar levels in blood sample after an overnight fast. Fasting glucose was measured prior to standardized mixed-meal tolerance tests (sMMTT). LS mean was determined by ANCOVA model for endpoint measures: Variable = Baseline + Treatment (Type III sum of squares). |
| Change From Baseline in Glucagon Concentration at Fasting | Baseline and Week 28 | Glucagon concentration was measured prior to sMMTT. LS mean was determined by ANCOVA model for endpoint measures: Variable = Baseline + Treatment (Type III sum of squares). |
| Change From Baseline in Glucagon Concentration at Postmeal | Baseline and Week 28 | Total AUC from time zero to 240 minutes after start of the meal \[AUC0-240min\]) during sMMTT. LS mean was determined by ANCOVA model for endpoint measures: Variable = Baseline + Treatment (Type III sum of squares). |
| Change From Baseline in Food Intake During Ad Libitum Meal | Baseline, Week 28 | Ad libitum meal served buffet-style. Food intake was recorded during a 45 minute period. The sum of the caloric breakdown (carbohydrates, protein, and fats) was calculated from the respective nutritional information of the food items. LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Treatment + Time + Treatment\*Time (Type III sum of squares). |
| Change From Baseline in Hyperinsulinemic Euglycemic Clamp M-value | Baseline, Week 28 | Hyperinsulinemic euglycemic clamp M-value is calculated from glucose infusion rate (GIR) over the last 30 minutes, corresponding to steady-state (+150 to +180 minutes), corrected for urine loss and space. LS mean was determined by ANCOVA model for endpoint measures: Variable = Baseline + Treatment (Type III sum of squares). |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tirzepatide 15 mg Participants received 15 mg Tirzepatide administered SC once weekly for 28 weeks. | 45 |
| Semaglutide 1 mg Participants received 1 mg Semaglutide administered SC once weekly for 28 weeks. | 44 |
| Placebo Participants received Placebo administered SC once weekly for 28 weeks. | 28 |
| Total | 117 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 3 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 1 | 0 |
Baseline characteristics
| Characteristic | Tirzepatide 15 mg | Total | Placebo | Semaglutide 1 mg |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 14 Participants | 48 Participants | 10 Participants | 24 Participants |
| Age, Categorical Between 18 and 65 years | 31 Participants | 69 Participants | 18 Participants | 20 Participants |
| Age, Continuous | 61.1 years STANDARD_DEVIATION 7.1 | 61.9 years STANDARD_DEVIATION 6.9 | 60.4 years STANDARD_DEVIATION 7.6 | 63.7 years STANDARD_DEVIATION 5.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 45 Participants | 117 Participants | 28 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| HbA1c (%) | 7.83 percentage STANDARD_DEVIATION 0.72 | 7.80 percentage STANDARD_DEVIATION 0.63 | 7.90 percentage STANDARD_DEVIATION 0.51 | 7.70 percentage STANDARD_DEVIATION 0.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 44 Participants | 116 Participants | 28 Participants | 44 Participants |
| Region of Enrollment Germany | 45 Participants | 117 Participants | 28 Participants | 44 Participants |
| Sex: Female, Male Female | 14 Participants | 31 Participants | 7 Participants | 10 Participants |
| Sex: Female, Male Male | 31 Participants | 86 Participants | 21 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 44 | 0 / 45 |
| other Total, other adverse events | 18 / 28 | 43 / 44 | 41 / 45 |
| serious Total, serious adverse events | 2 / 28 | 0 / 44 | 1 / 45 |
Outcome results
Primary
Change From Baseline in Total Clamp Disposition Index (cDI)
cDI is defined as the product of the M-value derived from the hyperinsulinemic euglycemic clamp over the last 30 minutes and total insulin secretion (ISR AUC0-120min) derived from the insulin secretion rate based on C-peptide using the using the deconvolution technique divided by the total glucose AUC0-120min from the hyperglycemic clamp portion of the study. Least squares (LS) mean was determined by analysis of covariance (ANCOVA) model for endpoint measures: log(Actual Measurement/Baseline) = log(Baseline) + Treatment (Type III sum of squares).
Time frame: Baseline, Week 28
Population: All randomly assigned participants who received at least 1 dose of study drug and have evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tirzepatide 15 mg | Change From Baseline in Total Clamp Disposition Index (cDI) | 1.9 pmol*m-2*L*min-2*kg-1 | Standard Error 0.16 |
| Semaglutide 1 mg | Change From Baseline in Total Clamp Disposition Index (cDI) | 1.1 pmol*m-2*L*min-2*kg-1 | Standard Error 0.1 |
| Placebo | Change From Baseline in Total Clamp Disposition Index (cDI) | 0.0 pmol*m-2*L*min-2*kg-1 | Standard Error 0.03 |
p-value: <0.00195% CI: [0.87, 1.29]ANCOVA
p-value: <0.00195% CI: [1.59, 2.24]ANCOVA
p-value: <0.00195% CI: [0.46, 1.21]ANCOVA
Secondary
Change From Baseline in Fasting Glucose
Fasting glucose is a test to determine sugar levels in blood sample after an overnight fast. Fasting glucose was measured prior to standardized mixed-meal tolerance tests (sMMTT). LS mean was determined by ANCOVA model for endpoint measures: Variable = Baseline + Treatment (Type III sum of squares).
Time frame: Baseline, Week 28
Population: All randomly assigned participants who received at least 1 dose of study drug and have evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tirzepatide 15 mg | Change From Baseline in Fasting Glucose | -51.4 milligrams per decilitre (mg/dL) | Standard Error 2.3 |
| Semaglutide 1 mg | Change From Baseline in Fasting Glucose | -42.4 milligrams per decilitre (mg/dL) | Standard Error 2.22 |
| Placebo | Change From Baseline in Fasting Glucose | -4.3 milligrams per decilitre (mg/dL) | Standard Error 2.98 |
p-value: <0.00195% CI: [-45.4, -30.7]ANCOVA
p-value: <0.00195% CI: [-54.6, -39.5]ANCOVA
p-value: 0.00695% CI: [-15.4, -2.6]ANCOVA
Secondary
Change From Baseline in Food Intake During Ad Libitum Meal
Ad libitum meal served buffet-style. Food intake was recorded during a 45 minute period. The sum of the caloric breakdown (carbohydrates, protein, and fats) was calculated from the respective nutritional information of the food items. LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Baseline, Week 28
Population: All randomly assigned participants who received at least 1 dose of study drug and have evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tirzepatide 15 mg | Change From Baseline in Food Intake During Ad Libitum Meal | -348.4 kilocalorie (kcal) | Standard Error 34.59 |
| Semaglutide 1 mg | Change From Baseline in Food Intake During Ad Libitum Meal | -284.1 kilocalorie (kcal) | Standard Error 33.94 |
| Placebo | Change From Baseline in Food Intake During Ad Libitum Meal | -38.6 kilocalorie (kcal) | Standard Error 45.17 |
p-value: <0.00195% CI: [-357.7, -133.3]Mixed Models Analysis
p-value: <0.00195% CI: [-423, -196.6]Mixed Models Analysis
p-value: 0.18795% CI: [-160.3, 31.7]Mixed Models Analysis
Secondary
Change From Baseline in Glucagon Concentration at Fasting
Glucagon concentration was measured prior to sMMTT. LS mean was determined by ANCOVA model for endpoint measures: Variable = Baseline + Treatment (Type III sum of squares).
Time frame: Baseline and Week 28
Population: All randomly assigned participants who received at least 1 dose of study drug and have evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tirzepatide 15 mg | Change From Baseline in Glucagon Concentration at Fasting | -3.6 picomoles per litre (pmol/L) | Standard Error 0.55 |
| Semaglutide 1 mg | Change From Baseline in Glucagon Concentration at Fasting | -2.8 picomoles per litre (pmol/L) | Standard Error 0.55 |
| Placebo | Change From Baseline in Glucagon Concentration at Fasting | 0.8 picomoles per litre (pmol/L) | Standard Error 0.75 |
p-value: <0.00195% CI: [-5.5, -1.8]ANCOVA
p-value: <0.00195% CI: [-6.3, -2.6]ANCOVA
p-value: 0.27795% CI: [-2.4, 0.7]ANCOVA
Secondary
Change From Baseline in Glucagon Concentration at Postmeal
Total AUC from time zero to 240 minutes after start of the meal \[AUC0-240min\]) during sMMTT. LS mean was determined by ANCOVA model for endpoint measures: Variable = Baseline + Treatment (Type III sum of squares).
Time frame: Baseline and Week 28
Population: All randomly assigned participants who received at least 1 dose of study drug and have evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tirzepatide 15 mg | Change From Baseline in Glucagon Concentration at Postmeal | -843.6 (pmol/L)*min | Standard Error 86.26 |
| Semaglutide 1 mg | Change From Baseline in Glucagon Concentration at Postmeal | -502.0 (pmol/L)*min | Standard Error 87.33 |
| Placebo | Change From Baseline in Glucagon Concentration at Postmeal | -205.9 (pmol/L)*min | Standard Error 116.31 |
p-value: 0.04495% CI: [-584.8, -7.5]ANCOVA
p-value: <0.00195% CI: [-925.2, -350.2]ANCOVA
p-value: 0.00695% CI: [-585.2, -97.9]ANCOVA
Secondary
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. LS mean was determined by mixed model repeated measures; (MMRM) model for post-baseline measures: Variable = Baseline + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Baseline, Week 28
Population: All randomly assigned participants who received at least 1 dose of study drug and have evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tirzepatide 15 mg | Change From Baseline in Hemoglobin A1c (HbA1c) | 2.05 % of HbA1c | Standard Error 0.079 |
| Semaglutide 1 mg | Change From Baseline in Hemoglobin A1c (HbA1c) | -1.64 % of HbA1c | Standard Error 0.078 |
| Placebo | Change From Baseline in Hemoglobin A1c (HbA1c) | 0.29 % of HbA1c | Standard Error 0.101 |
p-value: <0.00195% CI: [-2.18, -1.67]Mixed Models Analysis
p-value: <0.00195% CI: [-2.58, -2.08]Mixed Models Analysis
p-value: <0.00195% CI: [-0.63, -0.19]Mixed Models Analysis
Secondary
Change From Baseline in Hyperinsulinemic Euglycemic Clamp M-value
Hyperinsulinemic euglycemic clamp M-value is calculated from glucose infusion rate (GIR) over the last 30 minutes, corresponding to steady-state (+150 to +180 minutes), corrected for urine loss and space. LS mean was determined by ANCOVA model for endpoint measures: Variable = Baseline + Treatment (Type III sum of squares).
Time frame: Baseline, Week 28
Population: All randomly assigned participants who received at least 1 dose of study drug and have evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tirzepatide 15 mg | Change From Baseline in Hyperinsulinemic Euglycemic Clamp M-value | 19.2 umol/min/kg [body weight] | Standard Error 1.93 |
| Semaglutide 1 mg | Change From Baseline in Hyperinsulinemic Euglycemic Clamp M-value | 10.7 umol/min/kg [body weight] | Standard Error 1.99 |
| Placebo | Change From Baseline in Hyperinsulinemic Euglycemic Clamp M-value | -0.6 umol/min/kg [body weight] | Standard Error 2.53 |
p-value: <0.00195% CI: [4.9, 17.7]ANCOVA
p-value: <0.00195% CI: [13.4, 26.1]ANCOVA
p-value: 0.00395% CI: [3, 14]ANCOVA
Secondary
Change From Baseline in Postmeal Glucose
Total AUC from time zero to 240 minutes after start of the meal \[AUC0-240min\]) during sMMTT was evaluated. LS mean was determined by ANCOVA model for endpoint measures: Variable = Baseline + Treatment (Type III sum of squares) and ANOVA model for baseline measures: Variable = Treatment (Type III sum of squares).
Time frame: Baseline, Week 28
Population: All randomly assigned participants who received at least 1 dose of study drug and have evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tirzepatide 15 mg | Change From Baseline in Postmeal Glucose | -17414.0 Milligrams per decilitre*minute | Standard Error 726.02 |
| Semaglutide 1 mg | Change From Baseline in Postmeal Glucose | 14236.9 Milligrams per decilitre*minute | Standard Error 709.53 |
| Placebo | Change From Baseline in Postmeal Glucose | 459.2 Milligrams per decilitre*minute | Standard Error 947.5 |
p-value: <0.00195% CI: [-17045, -12347.3]ANCOVA
p-value: <0.00195% CI: [-20239, -15507.4]ANCOVA
p-value: 0.00295% CI: [-5194.3, -1159.8]ANCOVA
Secondary
Change From Baseline in Total Insulin Secretion Rate During the 120-Minute Hyperglycemic Clamp (ISR0-120min)
Total Insulin Secretion Rate During the 120-Minute Hyperglycemic Clamp (ISR0-120min) will be determined from C-peptide concentrations using the deconvolution technique. LS mean was determined by ANCOVA model for endpoint measures: log(Actual Measurement/Baseline) = log(Baseline) + Treatment (Type III sum of squares).
Time frame: Baseline and Week 28
Population: All randomly assigned participants who received at least 1 dose of study drug and have evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tirzepatide 15 mg | Change From Baseline in Total Insulin Secretion Rate During the 120-Minute Hyperglycemic Clamp (ISR0-120min) | 388.6 pmol/min/m^2 | Standard Error 20.17 |
| Semaglutide 1 mg | Change From Baseline in Total Insulin Secretion Rate During the 120-Minute Hyperglycemic Clamp (ISR0-120min) | 286.6 pmol/min/m^2 | Standard Error 15.82 |
| Placebo | Change From Baseline in Total Insulin Secretion Rate During the 120-Minute Hyperglycemic Clamp (ISR0-120min) | 7.4 pmol/min/m^2 | Standard Error 7.15 |
p-value: <0.00195% CI: [245.1, 313.18]ANCOVA
p-value: <0.00195% CI: [339.29, 423.17]ANCOVA
p-value: <0.00195% CI: [51.84, 152.33]ANCOVA