A Study of Tirzepatide in Participants With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Placebo-Controlled, Crossover Study to Investigate the Effect of Once-Weekly Tirzepatide on the Counter-Regulatory Response to Hypoglycemia in Patients With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2, Hypoglycemia

Intervention / Treatment
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* Drug: Tirzepatide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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])

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tirzepatide<br>Tirzepatide administered subcutaneously (SC) in one of two study periods. | Drug: Tirzepatide<br>* Administered SC<br>* Other names: LY3298176;|
| Placebo Comparator: Placebo<br>Placebo administered SC in one of two study periods. | Drug: Placebo<br>* Administered SC<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Change in Mean Glucagon Concentration During Induced Hypoglycemia from 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mean Insulin Concentrations from Induced Hypoglycemia Target PG Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL | 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 | 
| Change in Mean C-peptide Concentrations from Induced Hypoglycemia Target PG Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL | 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 | 
| Time from Termination of Insulin Infusion at PG Concentration of 45 mg/dL to Reach Recovery PG Concentration (72 mg/dL) | 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) | 
| 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 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 in each treatment period (treatment period = 12 weeks): 1 minute after reaching the nadir glucose level and when reaching normoglycemia (estimated as 30 mins) | 
| Mean Change in Blood Pressure from Induced Hypoglycemia Target PG Nadir Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL | 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 | 
| Mean Change in Heart Rate from Induced Hypoglycemia Target PG Concentration of 100 mg/dL to a Nadir Target of 45 mg/dL | 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 |