Diabetes Mellitus, Type 2, Hypoglycemia
Conditions
Brief summary
The main purpose of this study is to learn more about how tirzepatide affects the body's response to low blood sugar (hypoglycemia). The study is open to participants with type 2 diabetes. It will last about 42 weeks for each participant.
Interventions
DRUGTirzepatide
Administered SC
DRUGPlacebo
Administered SC
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Have type 2 diabetes mellitus (T2DM) for at least 1 year * Treated with diet and exercise and stable dose(s) of metformin 3 months prior to study entry with or without 1 additional oral antidiabetic medication (OAM) other than metformin. * Have a hemoglobin A1c (HbA1c) value at screening of ≥6.5% and ≤9.0 % if on metformin only. * Have a HbA1c value at screening of ≥6.0% and ≤8.5 %, if on metformin and 1 more allowed OAM. * Have a body mass index (BMI) between 23 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 (\<6 months) ophthalmologic examination * Impaired renal estimated glomerular filtration rate (eGFR) \<60 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 of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal (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 * Have had acute myocardial infarction, congestive heart failure New York Heart Association Class III or IV, history of or suspected ischemic heart disease, and/or cerebrovascular accident (stroke \[including transient ischemic attack\])
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Glucagon Concentration During Induced Hypoglycemia From Target Plasma Glucose (PG) Concentration of 100 Milligrams Per Deciliter (mg/dL) to a Nadir Target of 45 mg/dL | Week 12 in each study period: Baseline and up to 30 minutes after reaching the nadir glucose level. | A linear mixed effects model, with treatment, treatment period, and treatment sequence as fixed effects, and patient as a random effect using restricted maximum likelihood (REML) method was used. PG of plateau 100 mg/dL was considered as baseline timepoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean C-peptide Concentrations From Induced Hypoglycemia Target PG Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL | Week 12 in each study period: Baseline and up to 30 minutes after reaching the nadir glucose level. | A linear mixed effects model, with treatment, treatment period, and treatment sequence as fixed effects, and patient as a random effect using REML method was used. |
| Time From Termination of Insulin Infusion at PG Concentration of 45 mg/dL to Reach Recovery PG Concentration (72 mg/dL) | Week 12 in each treatment period (treatment period = 12 weeks): 1 minute after reaching the nadir glucose level and when reaching normoglycemia (estimated as 30 mins). | A linear mixed effects model, with treatment, treatment period, and treatment sequence as fixed effects, and patient as a random effect using REML method was used. |
| Change in Mean Insulin Concentrations From Induced Hypoglycemia Target PG Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL | Week 12 in each study period: Baseline and up to 30 minutes after reaching the nadir glucose level. | A linear mixed effects model, with treatment, treatment period, and treatment sequence as fixed effects, and patient as a random effect using REML method was used. |
| Mean Change in Blood Pressure From Induced Hypoglycemia Target PG Nadir Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL | Week 12 in each study period: Baseline and up to 30 minutes after reaching the nadir glucose level. | A linear mixed effects model, with treatment, treatment period, and treatment sequence as fixed effects, and patient as a random effect using REML method was used. |
| Mean Change in Heart Rate From Induced Hypoglycemia Target PG Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL | Week 12 in each study period: Baseline and up to 30 minutes after reaching the nadir glucose level. | A linear mixed effects model, with treatment, treatment period, and treatment sequence as fixed effects, and patient as a random effect using REML method was used. |
| Hypoglycemia Symptoms Score From Induced Hypoglycemia at Target PG Concentrations of 100 mg/dL, 63 mg/dL, 45 mg/dL and Recovery (PG Concentration 72 mg/dL) | Week 12. | Hypoglycemia symptoms score was measured with the Edinburgh Hypoglycemia Symptom Scale (EHSS) which is a 13-item questionnaire for hypoglycemic symptoms: 10 neuroglycopenic symptoms (6 cognitive dysfunctions: inability to concentrate, blurred vision, anxiety, confusion, difficulty speaking, and double vision; 4 neuroglycopenia: drowsiness, tiredness, hunger, and weakness), and 3 autonomic symptoms (sweating, trembling, and warmness) and participants were asked to rate the intensity of their hypoglycemic symptoms on a 7-point Likert scale (1 = No symptom to 7 = Severe). The total score is the sum of scores from the 13 questions and ranged from 13 to 91. This score was scaled back to the range of 1 to 7 by taking average of the sum of scores (i.e., sum of the scores divided by number of questions), where lower score indicates fewer symptoms. |
Countries
Austria
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo/Tirzepatide 15 mg Period 1: Participants received placebo administered SC QW for 12 weeks; Wash-out: 8-10 weeks; Period 2: Participants received a starting dose of 2.5 mg tirzepatide given SC QW for 2 weeks, followed by an increase to 5 mg QW for 2 weeks, and 10 mg QW for 4 weeks until the 15-mg dose was reached and maintained for the remainder of the treatment period (4 weeks). | 21 |
| Tirzepatide 15 mg/Placebo Period 1: Participants received a starting dose of 2.5 mg tirzepatide given SC QW for 2 weeks, followed by an increase to 5 mg QW for 2 weeks, and 10 mg QW for 4 weeks until the 15-mg dose was reached and maintained for the remainder of the treatment period (4 weeks); Wash-out: 8-10 weeks; Period 2: Participants received placebo administered SC QW for 12 weeks. | 21 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Adverse Event | 1 | 1 |
| Period 1 | Physician Decision | 2 | 2 |
| Period 1 | Withdrawal by Subject | 0 | 1 |
| Wash-out | Adverse Event | 0 | 1 |
| Wash-out | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo/Tirzepatide 15 mg | Total | Tirzepatide 15 mg/Placebo |
|---|---|---|---|
| Age, Continuous | 58.9 years STANDARD_DEVIATION 4.8 | 57.1 years STANDARD_DEVIATION 6.4 | 55.4 years STANDARD_DEVIATION 7.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 42 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 21 Participants | 42 Participants | 21 Participants |
| Region of Enrollment Austria | 21 Participants | 42 Participants | 21 Participants |
| Sex: Female, Male Female | 2 Participants | 9 Participants | 7 Participants |
| Sex: Female, Male Male | 19 Participants | 33 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 0 / 39 |
| other Total, other adverse events | 13 / 36 | 27 / 39 |
| serious Total, serious adverse events | 0 / 36 | 4 / 39 |
Outcome results
Primary
Change in Mean Glucagon Concentration During Induced Hypoglycemia From Target Plasma Glucose (PG) Concentration of 100 Milligrams Per Deciliter (mg/dL) to a Nadir Target of 45 mg/dL
A linear mixed effects model, with treatment, treatment period, and treatment sequence as fixed effects, and patient as a random effect using restricted maximum likelihood (REML) method was used. PG of plateau 100 mg/dL was considered as baseline timepoint.
Time frame: Week 12 in each study period: Baseline and up to 30 minutes after reaching the nadir glucose level.
Population: All participants who received at least one dose of study drug and had evaluable Pharmacodynamic (PD) data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Mean Glucagon Concentration During Induced Hypoglycemia From Target Plasma Glucose (PG) Concentration of 100 Milligrams Per Deciliter (mg/dL) to a Nadir Target of 45 mg/dL | 18.55 picomole per liter (pmol/L) | Standard Error 1.64 |
| Tirzepatide 15 mg | Change in Mean Glucagon Concentration During Induced Hypoglycemia From Target Plasma Glucose (PG) Concentration of 100 Milligrams Per Deciliter (mg/dL) to a Nadir Target of 45 mg/dL | 18.07 picomole per liter (pmol/L) | Standard Error 1.62 |
p-value: 0.755695% CI: [-3.64, 2.67]Mixed Models Analysis
Secondary
Change in Mean C-peptide Concentrations From Induced Hypoglycemia Target PG Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL
A linear mixed effects model, with treatment, treatment period, and treatment sequence as fixed effects, and patient as a random effect using REML method was used.
Time frame: Week 12 in each study period: Baseline and up to 30 minutes after reaching the nadir glucose level.
Population: All participants who received at least one dose of study drug and had evaluable PD data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Mean C-peptide Concentrations From Induced Hypoglycemia Target PG Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL | -177.69 picomole per liter (pmol/L) | Standard Error 51.78 |
| Tirzepatide 15 mg | Change in Mean C-peptide Concentrations From Induced Hypoglycemia Target PG Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL | -665.99 picomole per liter (pmol/L) | Standard Error 51.09 |
p-value: <0.000195% CI: [-621.25, -355.36]Mixed Models Analysis
Secondary
Change in Mean Insulin Concentrations From Induced Hypoglycemia Target PG Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL
A linear mixed effects model, with treatment, treatment period, and treatment sequence as fixed effects, and patient as a random effect using REML method was used.
Time frame: Week 12 in each study period: Baseline and up to 30 minutes after reaching the nadir glucose level.
Population: All participants who received at least one dose of study drug and had evaluable PD data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Mean Insulin Concentrations From Induced Hypoglycemia Target PG Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL | -1053.31 picomole per liter (pmol/L) | Standard Error 54.2 |
| Tirzepatide 15 mg | Change in Mean Insulin Concentrations From Induced Hypoglycemia Target PG Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL | -1228.08 picomole per liter (pmol/L) | Standard Error 53.61 |
p-value: 0.004395% CI: [-290.34, -59.21]Mixed Models Analysis
Secondary
Hypoglycemia Symptoms Score From Induced Hypoglycemia at Target PG Concentrations of 100 mg/dL, 63 mg/dL, 45 mg/dL and Recovery (PG Concentration 72 mg/dL)
Hypoglycemia symptoms score was measured with the Edinburgh Hypoglycemia Symptom Scale (EHSS) which is a 13-item questionnaire for hypoglycemic symptoms: 10 neuroglycopenic symptoms (6 cognitive dysfunctions: inability to concentrate, blurred vision, anxiety, confusion, difficulty speaking, and double vision; 4 neuroglycopenia: drowsiness, tiredness, hunger, and weakness), and 3 autonomic symptoms (sweating, trembling, and warmness) and participants were asked to rate the intensity of their hypoglycemic symptoms on a 7-point Likert scale (1 = No symptom to 7 = Severe). The total score is the sum of scores from the 13 questions and ranged from 13 to 91. This score was scaled back to the range of 1 to 7 by taking average of the sum of scores (i.e., sum of the scores divided by number of questions), where lower score indicates fewer symptoms.
Time frame: Week 12.
Population: All participants who received at least one dose of study drug and had evaluable PD data for this outcome.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Hypoglycemia Symptoms Score From Induced Hypoglycemia at Target PG Concentrations of 100 mg/dL, 63 mg/dL, 45 mg/dL and Recovery (PG Concentration 72 mg/dL) | 100 mg/dL | 1.19 Score on a scale | Standard Error 0.03 |
| Placebo | Hypoglycemia Symptoms Score From Induced Hypoglycemia at Target PG Concentrations of 100 mg/dL, 63 mg/dL, 45 mg/dL and Recovery (PG Concentration 72 mg/dL) | 63 mg/dL | 1.35 Score on a scale | Standard Error 0.06 |
| Placebo | Hypoglycemia Symptoms Score From Induced Hypoglycemia at Target PG Concentrations of 100 mg/dL, 63 mg/dL, 45 mg/dL and Recovery (PG Concentration 72 mg/dL) | 45 mg/dL | 1.68 Score on a scale | Standard Error 0.08 |
| Placebo | Hypoglycemia Symptoms Score From Induced Hypoglycemia at Target PG Concentrations of 100 mg/dL, 63 mg/dL, 45 mg/dL and Recovery (PG Concentration 72 mg/dL) | 72 mg/dL | 1.50 Score on a scale | Standard Error 0.09 |
| Tirzepatide 15 mg | Hypoglycemia Symptoms Score From Induced Hypoglycemia at Target PG Concentrations of 100 mg/dL, 63 mg/dL, 45 mg/dL and Recovery (PG Concentration 72 mg/dL) | 72 mg/dL | 1.38 Score on a scale | Standard Error 0.09 |
| Tirzepatide 15 mg | Hypoglycemia Symptoms Score From Induced Hypoglycemia at Target PG Concentrations of 100 mg/dL, 63 mg/dL, 45 mg/dL and Recovery (PG Concentration 72 mg/dL) | 100 mg/dL | 1.13 Score on a scale | Standard Error 0.03 |
| Tirzepatide 15 mg | Hypoglycemia Symptoms Score From Induced Hypoglycemia at Target PG Concentrations of 100 mg/dL, 63 mg/dL, 45 mg/dL and Recovery (PG Concentration 72 mg/dL) | 45 mg/dL | 1.49 Score on a scale | Standard Error 0.08 |
| Tirzepatide 15 mg | Hypoglycemia Symptoms Score From Induced Hypoglycemia at Target PG Concentrations of 100 mg/dL, 63 mg/dL, 45 mg/dL and Recovery (PG Concentration 72 mg/dL) | 63 mg/dL | 1.17 Score on a scale | Standard Error 0.06 |
Comparison: For Overall Hypoglycemia Symptom Score at concentration of 100 mg/dL.p-value: 0.050595% CI: [-0.13, 0]Mixed Models Analysis
Comparison: For Overall Hypoglycemia Symptom Score at concentration of 63 mg/dL.p-value: 0.010495% CI: [-0.31, -0.05]Mixed Models Analysis
Comparison: For Overall Hypoglycemia Symptom Score at concentration of 45 mg/dL.p-value: 0.006895% CI: [-0.32, -0.06]Mixed Models Analysis
Comparison: For Overall Hypoglycemia Symptom Score at concentration of 72 mg/dL.p-value: 0.230295% CI: [-0.3, 0.08]Mixed Models Analysis
Secondary
Mean Change in Blood Pressure From Induced Hypoglycemia Target PG Nadir Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL
A linear mixed effects model, with treatment, treatment period, and treatment sequence as fixed effects, and patient as a random effect using REML method was used.
Time frame: Week 12 in each study period: Baseline and up to 30 minutes after reaching the nadir glucose level.
Population: All participants who received at least one dose of study drug and had evaluable PD data for this outcome.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change in Blood Pressure From Induced Hypoglycemia Target PG Nadir Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL | Systolic Blood Pressure | -5.01 millimeters of Mercury (mmHg) | Standard Error 2.22 |
| Placebo | Mean Change in Blood Pressure From Induced Hypoglycemia Target PG Nadir Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL | Diastolic Blood Pressure | -9.84 millimeters of Mercury (mmHg) | Standard Error 1.16 |
| Tirzepatide 15 mg | Mean Change in Blood Pressure From Induced Hypoglycemia Target PG Nadir Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL | Systolic Blood Pressure | -5.51 millimeters of Mercury (mmHg) | Standard Error 2.17 |
| Tirzepatide 15 mg | Mean Change in Blood Pressure From Induced Hypoglycemia Target PG Nadir Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL | Diastolic Blood Pressure | -7.88 millimeters of Mercury (mmHg) | Standard Error 1.13 |
Comparison: For systolic blood pressure.p-value: 0.829895% CI: [-5.28, 4.27]Mixed Models Analysis
Comparison: For diastolic blood pressure.p-value: 0.151695% CI: [-0.76, 4.67]Mixed Models Analysis
Secondary
Mean Change in Heart Rate From Induced Hypoglycemia Target PG Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL
A linear mixed effects model, with treatment, treatment period, and treatment sequence as fixed effects, and patient as a random effect using REML method was used.
Time frame: Week 12 in each study period: Baseline and up to 30 minutes after reaching the nadir glucose level.
Population: All participants who received at least one dose of study drug and had evaluable PD data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change in Heart Rate From Induced Hypoglycemia Target PG Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL | 5.56 beats per minute (beats/min) | Standard Error 1.26 |
| Tirzepatide 15 mg | Mean Change in Heart Rate From Induced Hypoglycemia Target PG Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL | 4.67 beats per minute (beats/min) | Standard Error 1.23 |
p-value: 0.577695% CI: [-4.1, 2.33]Mixed Models Analysis
Secondary
Time From Termination of Insulin Infusion at PG Concentration of 45 mg/dL to Reach Recovery PG Concentration (72 mg/dL)
A linear mixed effects model, with treatment, treatment period, and treatment sequence as fixed effects, and patient as a random effect using REML method was used.
Time frame: Week 12 in each treatment period (treatment period = 12 weeks): 1 minute after reaching the nadir glucose level and when reaching normoglycemia (estimated as 30 mins).
Population: All participants who received at least one dose of study drug and had evaluable PD data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Time From Termination of Insulin Infusion at PG Concentration of 45 mg/dL to Reach Recovery PG Concentration (72 mg/dL) | 43.34 minutes (min) | Standard Error 1.29 |
| Tirzepatide 15 mg | Time From Termination of Insulin Infusion at PG Concentration of 45 mg/dL to Reach Recovery PG Concentration (72 mg/dL) | 47.73 minutes (min) | Standard Error 1.27 |
p-value: 0.002395% CI: [1.69, 7.08]Mixed Models Analysis