A Study of Tirzepatide (LY3298176) Once a Week Versus Insulin Glargine Once a Day in Participants With Type 2 Diabetes and Increased Cardiovascular Risk

Study Overview
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Brief Summary
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The purpose of the trial is to assess the efficacy and safety of tirzepatide taken once a week to insulin glargine taken once daily in participants with type 2 diabetes and increased cardiovascular risk. The study will last about 108 weeks and may include up to 30 visits.

Official Title
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Efficacy and Safety of LY3298176 Once Weekly Versus Insulin Glargine in Patients With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4)

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Tirzepatide
* Drug: Insulin Glargine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must: Have been diagnosed with type 2 diabetes mellitus (T2DM) Have HbA1c between ≥7.5% and ≤10.5% Be on stable treatment with unchanged dose of at least 1 and no more than 3 types of oral antihyperglycemic drugs, which may only include metformin, SGLT-2 inhibitors, and/or sulfonylureas for at least 3 months before screening Have increased risk for cardiovascular (CV) events Be of stable weight (± 5%) Have a BMI ≥25 kilograms per meter squared (kg/m2) at screening Exclusion Criteria Participants 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 any other diabetes medicines other than metformin, SGLT-2 inhibitors, and/or sulfonylureas during the last 3 months Have been taking weight loss drugs, including over-the-counter medications during the last 3 months

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 5 mg Tirzepatide<br>5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week. | Drug: Tirzepatide<br>* Administered SC.<br>* Other names: LY3298176;|
| Experimental: 10 mg Tirzepatide<br>10 mg tirzepatide administered SC once a week. | Drug: Tirzepatide<br>* Administered SC.<br>* Other names: LY3298176;|
| Experimental: 15 mg Tirzepatide<br>15 mg tirzepatide administered SC once a week. | Drug: Tirzepatide<br>* Administered SC.<br>* Other names: LY3298176;|
| Active Comparator: Insulin Glargine<br>Insulin glargine administered SC once a day. Doses were individualized and titrated according to protocol-defined targets. The starting dose of insulin glargine was 10 IU/day at bedtime, titrated to a FBG <100 mg/dL, following a treat-to-target (TTT) algorithm. | Drug: Insulin Glargine<br>* Administered SC<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg) | 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 + Pooled Country + Baseline sodium-glucose co-transporter-2 inhibitor (SGLT-2i) use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares). | Baseline, Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HbA1c (5 mg) | 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 MMRM model for post-baseline measures: Variable = Baseline + Pooled Country + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares). | Baseline, Week 52 | 
| Change From Baseline in Body Weight | LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares). | Baseline, Week 52 | 
| Percentage of Participants With HbA1c of <7.0% | HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Imputed data includes observed value and imputed value if endpoint measure is missing. | Week 52 | 
| Change From Baseline in Fasting Serum Glucose | LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares). | Baseline, Week 52 | 
| Mean Change From Baseline in Daily 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 mixed-model repeated measures (MMRM) model with variables Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares). | Baseline, Week 52 | 
| Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve From Zero to Tau (AUC 0-Tau) of Tirzepatide | Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve From Zero to Tau (AUC 0-Tau) of Tirzepatide | 1 to 24 hours, 24 to 96 hours, or 120 to 168 hours post dose of Week 7, 15, 23, 35 | 
| Rate of Hypoglycemia With Blood Glucose <54 Milligram/Deciliter (mg/dL) [<3.0 (Millimole/Liter (mmol/L))] 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. Post-baseline comparisons between treatment and control group was evaluated using negative binomial model with variables : Number of episodes = Baseline HbA1c Group (<=8.5%, >8.5%) + Pooled Country + Baseline SGLT-2i use Flag (Yes, No) + Treatment, with log (exposure in days/365.25) as an offset variable | Baseline through Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GIP, GLP-1, glucose metabolism disorders, metabolic diseases, endocrine system diseases, cardiovascular risk