A Study of Orforglipron (LY3502970) Compared With Semaglutide in Participants With Type 2 Diabetes Inadequately Controlled With Metformin

Study Overview
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Brief Summary
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The main purpose of this study is to assess efficacy and safety of orforglipron compared with oral semaglutide in participants with Type 2 diabetes and inadequate glycemic control with metformin.The study will last around 61 weeks.

Official Title
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A Phase 3, Randomized, Open-Label Study to Investigate the Efficacy and Safety of Once Daily Oral LY3502970 Compared With Oral Semaglutide in Adult Participants With Type 2 Diabetes and Inadequate Glycemic Control With Metformin (ACHIEVE-3)

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Orforglipron
* Drug: Semaglutide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have Type 2 Diabetes Have HbA1c ≥7.0% (53 mmol/mol) to ≤10.5% (91 mmol/mol), as determined by the central laboratory at screening. Have been on stable diabetes treatment with metformin ≥1500 milligram (mg)/day during the 90 days prior to screening and maintained through randomization. Are of stable body weight (±5%) for at least 90 days prior to screening and agree to not initiate an intensive diet or exercise program during the study with the intent of reducing body weight, other than the lifestyle and/or dietary measures for diabetes treatment Exclusion Criteria: Have Type 1 Diabetes Are currently receiving or planning to receive treatment for diabetic retinopathy and/or macular edema, for example, laser photocoagulation or intravitreal injections of anti-vascular endothelial growth factor inhibitors. Have a history of ketoacidosis or hyperosmolar state or coma within the last 6 months prior to screening, or between screening and randomization. Have a New York Heart Association functional classification IV congestive heart failure. Have an estimated glomerular filtration rate (eGFR) <45 milliliter/minute (mL/min)/1.73 square meter (m²) or lower than the country-specific threshold for discontinuing metformin therapy per local label as determined by the central laboratory at screening. Have a serum calcitonin level of ≥35 nanogram/Liter (ng/L), as determined by the central laboratory at screening. Have a history of an active or untreated malignancy or are in remission from a clinically significant malignancy for less than 5 years.

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: Orforglipron Dose 1<br>Participants will receive orforglipron orally. | Drug: Orforglipron<br>* Administered orally<br>* Other names: LY3502970;|
| Experimental: Orforglipron Dose 2<br>Participants will receive orforglipron orally. | Drug: Orforglipron<br>* Administered orally<br>* Other names: LY3502970;|
| Active Comparator: Semaglutide Dose 1<br>Participants will receive semaglutide orally. | Drug: Semaglutide<br>* Administered orally<br>|
| Active Comparator: Semaglutide Dose 2<br>Participants will receive semaglutide orally. | Drug: Semaglutide<br>* Administered orally<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) |  | Baseline, Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in HbA1c |  | Baseline, Week 52 | 
| Percentage of Participants Who Achieved HbA1c <7.0% 53 millimole/mole (mmol/mol) |  | Week 52 | 
| Percentage of Participants Who Achieved HbA1c ≤6.5% (48 mmol/mol) |  | Week 52 | 
| Percentage Change from Baseline in Body Weight |  | Baseline, Week 52 | 
| Change from Baseline in Body Weight |  | Baseline, Week 52 | 
| Percentage of Participants Who Achieved HbA1c <5.7% (39 mmol/mol) |  | Week 52 | 
| Change from Baseline in Fasting Serum Glucose |  | Baseline, Week 52 | 
| Change from Baseline in Daily Average 7-point Self-monitored Blood Glucose (SMBG) |  | Baseline, Week 52 | 
| Percentage of Participants Who Achieved Weight Loss of ≥5% |  | Week 52 | 
| Percentage of Participants Who Achieved Weight Loss of ≥10% |  | Week 52 | 
| Percentage of Participants Who Achieved Weight Loss of ≥15% |  | Week 52 | 
| Change from Baseline in Systolic Blood Pressure (SBP) |  | Baseline, Week 52 | 
| Change from Baseline in Diastolic Blood Pressure (DBP) |  | Baseline, Week 52 | 
| Percentage Change from Baseline in Total Cholesterol |  | Baseline, Week 52 | 
| Percentage Change from Baseline in High Density Lipoprotein (HDL)-Cholesterol |  | Baseline, Week 52 | 
| Percentage Change from Baseline in Low Density Lipoprotein (LDL)-Cholesterol |  | Baseline, Week 52 | 
| Percentage Change from Baseline in Very Low Density Lipoprotein (VLDL)-Cholesterol |  | Baseline, Week 52 | 
| Percentage Change from Baseline in Non-HDL-Cholesterol |  | Baseline, Week 52 | 
| Percentage Change from Baseline in Triglycerides |  | Baseline, Week 52 | 
| Change from Baseline in Short Form 36 Version 2 (SF-36-v2) Acute Form Domain Summary Scores |  | Baseline, Week 52 |