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Evaluating Once Daily Orforglipron (LY3502970) Compared to Insulin Glargine in Adults with Type 2 Diabetes and Obesity or Overweight who Have Increased Cardiovascular Risk

Verified siteRegistered drugNo placebo
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What is this trial about?

A plain-language summary of the goals, design and what participants do

This clinical trial is investigating orforglipron (also called LY3502970) compared to insulin glargine in adults who have Type 2 Diabetes along with obesity or being overweight and who are at increased risk for cardiovascular (heart and blood vessel) problems. Type 2 Diabetes is a condition where the body doesn't use insulin properly, resulting in high blood sugar levels. People in this study will have evidence of heart disease and will already be taking diabetes medications.

The purpose of this study is to determine if daily oral orforglipron is as effective as insulin glargine (an injectable insulin) in preventing major heart-related events in these patients. The study will look at outcomes such as myocardial infarction (heart attack), stroke, hospitalization for unstable angina (chest pain), and death related to heart disease.

This is a Phase 3, open-label study, which means participants and researchers will know which treatment is being given. Participants will either take orforglipron once daily by mouth or use insulin glargine injections while continuing their existing diabetes medications. The study will monitor their health status over time to compare the safety and effectiveness of these two treatment approaches.

The research process

The trial runs in 5 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Starting the Study

    After joining the study, you will be randomly assigned to receive either orforglipron (LY3502970) taken by mouth once daily as a capsule or insulin glargine (Abasaglar) as an injectable solution using a pre-filled pen.

    You will continue taking your current diabetes medications (1 to 3 oral medications) that you have been taking for at least 3 months before joining the study.

  2. Step 2

    Treatment Period

    If assigned to the orforglipron group, you will take a daily oral capsule of orforglipron. The exact dosage is not specified in the provided information.

    If assigned to the insulin glargine group, you will use Abasaglar 100 units/mL KwikPen solution for injection. The dosage will be determined by your study doctor based on your blood sugar levels.

    Throughout the treatment period, you will continue to take your background diabetes medications such as metformin, empagliflozin, canagliflozin, dapagliflozin, or ertugliflozin as prescribed before the study.

  3. Step 3

    Regular Monitoring

    You will have regular check-ups where your blood sugar levels will be monitored, including hemoglobin A1C (HbA1c) tests. This is a blood test that shows your average blood sugar level over the past 2-3 months.

    Your heart health will be monitored throughout the study to track any cardiovascular events. These include heart attacks (myocardial infarction), strokes, hospitalization for unstable chest pain (unstable angina), or heart-related death.

  4. Step 4

    Study Duration

    The study begins on July 5, 2023, and is scheduled to end on August 27, 2025. You may participate for all or part of this period depending on when you join the study.

    The exact duration of your participation will depend on the study protocol and your individual situation.

  5. Step 5

    Study Completion

    At the end of your participation, you will have a final assessment to evaluate the effects of the treatment on your diabetes and heart health.

    After completing the study, your doctor will discuss appropriate options for continuing your diabetes management outside of the study.

Who can join the trial?

5 criteria

  • Have Type 2 Diabetes
  • Be taking a consistent dose of 1 to 3 diabetes medications by mouth for the last 3 months
  • Have heart disease (cardiovascular disease)
  • Have high blood sugar as measured by hemoglobin A1C (HbA1c) of at least 7.0% (this is a blood test that shows your average blood sugar levels over the past 2-3 months)
  • Be overweight or obese (having a body weight higher than what is considered healthy for a given height)

Who cannot join the trial?

13 criteria

  • If you have a heart attack, stroke, hospitalization for unstable chest pain (angina), or death due to heart disease in the past 60 days.
  • If you have experienced dangerously low blood sugar levels (severe hypoglycemia) in the past 6 months.
  • If you have had diabetic ketoacidosis (a serious complication where your body produces high levels of blood acids) in the past year.
  • If you have been diagnosed with Type 1 diabetes (a condition where your body doesn't produce any insulin).
  • If you have severe liver problems or severe kidney disease requiring dialysis.
  • If you have had pancreatitis (inflammation of the pancreas) or pancreatic injury.
  • If you have a personal or family history of a specific type of thyroid cancer called medullary thyroid carcinoma.
  • If you have Multiple Endocrine Neoplasia syndrome type 2 (a rare condition that causes tumors in the endocrine glands).
  • If you are currently using certain medications like other GLP-1 receptor agonists (medications that work similar to the study drug).
  • If you have a history of gastroparesis (delayed stomach emptying).
  • If you are pregnant, planning to become pregnant, or breastfeeding.
  • If you have participated in another clinical trial within the past 30 days.
  • If you have any condition that the study doctor believes would make it unsafe for you to participate.
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Investigated drugs

  • LY3502970

    is a once-daily medication being studied for people with type 2 diabetes who also have obesity or are overweight and at increased risk for cardiovascular problems. It is an experimental treatment that is being tested to see how it affects blood sugar control and cardiovascular outcomes.

  • Insulin Glargine

    is a long-acting insulin that is injected once daily to help control blood sugar levels throughout the day and night. It works by helping glucose (sugar) enter cells to be used for energy. It is a standard treatment for people with type 2 diabetes.

What is already known about the treatment

  • LY3502970

    This is an investigational medication being studied in phase 3 clinical trials for the treatment of type 2 diabetes in adults with obesity or overweight who are at increased cardiovascular risk. It is administered as a once-daily injection and is being compared to insulin glargine in the ACHIEVE-4 trial. The medication likely works by regulating blood glucose levels through novel mechanisms, though specific molecular actions aren't fully published yet. While still in development and not yet approved for general use, this compound is being evaluated for its effectiveness in managing diabetes while potentially offering cardiovascular benefits, with researchers specifically assessing whether it is non-inferior to insulin glargine regarding major adverse cardiovascular events.

  • Insulin Glargine

    This is a long-acting synthetic insulin analog administered by subcutaneous injection once daily to help control blood glucose levels. It is widely used and well-established in medical literature as a standard treatment for both type 1 and type 2 diabetes. Insulin glargine works by slowly releasing insulin into the bloodstream over 24 hours, mimicking the body's natural basal insulin secretion pattern, which helps maintain consistent glucose control between meals and overnight. At the molecular level, it binds to insulin receptors on cell membranes, facilitating glucose uptake into cells and reducing blood glucose levels. This medication belongs to the pharmacological class of long-acting insulin analogs and serves as a comparison treatment in the ACHIEVE-4 clinical trial.

Investigated diseases

  • Type 2 Diabetes

    A chronic metabolic disorder characterized by high blood sugar levels due to insulin resistance and insufficient insulin production. The body either resists the effects of insulin or doesn't produce enough insulin to maintain normal glucose levels. It develops gradually, often beginning with insulin resistance where cells don't respond properly to insulin. Risk factors include being overweight, physical inactivity, and genetic predisposition.

  • Cardiovascular Disease

    A class of diseases involving the heart and blood vessels. It includes conditions such as coronary artery disease, heart failure, arrhythmias, and valve disorders. These conditions develop when plaque builds up in the walls of arteries, narrowing them and making it harder for blood to flow through. The process often occurs over many years and can affect various parts of the circulatory system.

  • Chronic Kidney Disease

    A condition characterized by gradual loss of kidney function over time. The kidneys filter wastes and excess fluids from the blood, which are then excreted in urine. When chronic kidney disease reaches an advanced stage, dangerous levels of fluid, electrolytes, and wastes can build up in the body. The disease progresses through five stages of decreasing kidney function.

  • Obesity

    A complex disease involving an excessive amount of body fat. It's defined as having a body mass index (BMI) of 30 or higher. Obesity occurs when a person consumes more calories than they burn through normal daily activities and exercise. It increases the risk of other health problems and is associated with poorer metabolic health.

  • Myocardial Infarction

    Commonly known as a heart attack, it occurs when blood flow to a part of the heart is blocked, causing damage to the heart muscle. The blockage is most often a buildup of fat, cholesterol, and other substances that form a plaque in the coronary arteries. The plaque can rupture and form a clot that blocks blood flow.

  • Stroke

    A condition where poor blood flow to the brain results in cell death. There are two main types: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. It can cause parts of the brain to become damaged or die, affecting body functions controlled by those areas. Symptoms can include sudden numbness, confusion, trouble seeing or walking, and severe headache.

Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2022-502833-25-00Protocol codeJ2A-MC-GZGSEstimated enrolment2 620 patientsSponsorEli Lilly & Co.

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