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Effect of zenagamtide on major adverse cardiovascular events in overweight or obese adults with established atherosclerotic cardiovascular disease

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What is this trial about?

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

The study focuses on people who have already been diagnosed with atherousclerotic cardiovascular disease and who are also classified as overweight or obesity. The medication being tested is called zenagamtide, which is given as a small injection under the skin once a week.

The purpose of the study is to determine whether weekly dosing of the medication can lower the risk of a first major adverse cardiovascular event compared with a placebo, when both are added to standard care. Participants are randomly assigned to receive either the study drug or a placebo, continue their usual medicines, and attend regular clinic visits where the injection is administered and health checks are performed over several years.

The main outcomes being watched include death from heart problems, a non‑fatal myocardial infarction, a non‑fatal stroke, and hospital visits for heart failure. Additional outcomes include overall death, the need for a procedure to open blocked arteries known as coronary revascularization, and changes in kidney function measured by eGFR.

The research process

The trial runs in 7 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Randomisation

    After joining the study, you will be randomly assigned to receive either zenagamtide or a placebo. the assignment is done by the study team and you will not know which one you receive.

  2. Step 2

    Baseline assessments

    Before the first injection, you will have a series of assessments that may include a review of your medical history, physical measurements, and blood tests such as kidney function (eGFR). these assessments establish your starting point for the study.

  3. Step 3

    Start weekly subcutaneous injections

    You will begin receiving a subcutaneous injection (injection under the skin) once a week using a pre‑filled pen. the medication is either zenagamtide or a matching placebo. the exact dose will be set by the study team; the protocol lists the dose as 0 units because the amount is defined in the study instructions, not in the public description.

    The weekly injection continues for the entire duration of your participation, which may be several years depending on the study schedule.

  4. Step 4

    Regular clinic visits

    You will attend scheduled clinic visits, typically every three months, where study staff will check your health, record any events, and perform blood tests. these visits help monitor safety and the effect of the treatment.

  5. Step 5

    Report cardiovascular events

    If you experience any of the following events, you should inform the study team as soon as possible: death related to heart disease, non‑fatal heart attack, non‑fatal stroke, or hospitalization for heart failure. these events are part of the study’s primary outcome called major adverse cardiovascular events (mace).

  6. Step 6

    Continue standard of care medications

    Throughout the trial you will keep taking any usual medicines for your heart condition, blood pressure, cholesterol, diabetes, or other health issues, as prescribed by your regular doctor. the study medication is added on top of this standard care.

  7. Step 7

    Final study visit or early withdrawal

    At the end of the study period, or if you choose to stop early, you will have a final visit. this includes the same assessments as earlier visits and a review of any health changes that occurred while you were in the trial.

Who can join the trial?

8 criteria

  • Diagnosis of atherosclerotic cardiovascular disease (ASCVD) and being overweight or obese.
  • Meet the study’s CCI requirement (the specific clinical criteria set for the trial).
  • Have had a previous heart attack (myocardial infarction).
  • Have symptomatic peripheral artery disease (PAD), which means either leg pain while walking with a low ankle‑brachial index (ABI) < 0.85 or an amputation of the lower leg above the ankle caused by artery disease (not due to injury or infection).
  • Have had a prior stroke (cerebrovascular disease).
  • If you have type 2 diabetes, your diabetes medicines must have been stable for at least 90 days before screening.
  • Some diabetes medicines are not allowed: GLP‑1 receptor agonists, GIP analogues, and amylin analogues. If you use insulin, only long‑acting basal insulin is permitted.
  • Both men and women are eligible to join the study.

Who cannot join the trial?

9 criteria

  • Recent heart attack, stroke, unstable chest pain, or worsening heart failure that caused a hospital stay or required strong IV diuretic medication within the last 30 days.
  • Recent artery‑opening or repair procedures (such as coronary, carotid, or peripheral artery procedures) or valve repair/replacement done within the last 30 days, or any such procedures planned during the study.
  • Chronic heart failure that is present at the time of screening.
  • Severe low‑blood‑sugar episodes that happened repeatedly during the past year.
  • Loss of awareness of low blood sugar (the person cannot feel when blood sugar is low) as determined by a questionnaire.
  • Type 1 diabetes in the participant’s medical history.
  • Diabetic eye disease (retinopathy or maculopathy) that required laser treatment, eye surgery, or anti‑VEGF medication within the past 180 days, or is expected to need such treatment within 180 days after screening, and that has been confirmed by an eye exam within the past 90 days.
  • High glycated haemoglobin (HbA1c) level greater than 10 % (86 mmol/mol) measured at screening.
  • Use of certain diabetes medicines that mimic GLP‑1, GIP, or amylin (such as GLP‑1 receptor agonists, GIP receptor agonists, or amylin analogues) before screening.
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Investigated drugs

NNC0487-0111 B 10141 is a medication that contains the active ingredient zenagamtide. It is given as a small amount injected under the skin using a pre‑filled pen. In the study, it is taken once a week and is added to the usual heart medicines that participants are already taking. The goal is to see if it can lower the chance of serious heart problems such as heart attacks or strokes.

NNC0487-0111 B 10142 is a formulation of zenagamtide provided in a solution for injection. Participants receive it subcutaneously (under the skin) with a pre‑filled pen, once each week, alongside their regular cardiovascular treatments. The study is testing whether this drug can reduce the risk of major cardiovascular events in people who have existing artery disease and are overweight or obese.

NNC0487-0111 B 10143 is a subcutaneous injection of zenagamtide packaged in a ready‑to‑use pen. It is administered weekly in addition to the participant’s standard heart‑health medicines. Researchers are looking to determine if it helps prevent heart attacks, strokes, or other serious cardiovascular complications.

NNC0487-0111 B 10144 delivers zenagamtide as a solution for injection that is given under the skin using a pre‑filled pen. The drug is taken once a week together with the usual care for cardiovascular disease, and the trial aims to see if it can lower the risk of major adverse cardiovascular events.

NNC0487-0111 B 10145 is a weekly subcutaneous injection of zenagamtide supplied in a pre‑filled pen. Participants continue their regular heart medications while receiving this study drug, which is being evaluated for its ability to reduce serious heart‑related outcomes in people with established artery disease and excess weight.

NNC0487-0111 B 10146 is a zenagamtide solution designed for injection under the skin, administered with a pre‑filled pen once a week. It is added to participants’ standard cardiovascular treatments, and the trial is testing whether it can decrease the likelihood of major cardiovascular events such as heart attacks or strokes.

The trial also involves participants continuing their usual cardiovascular care, often called “standard of care.” This includes the medicines and lifestyle measures they normally take to manage heart disease, such as blood pressure pills, cholesterol‑lowering drugs, and diet or exercise recommendations. The study adds zenagamtide to this existing treatment plan to see if the combination provides extra protection against heart problems.

What is already known about the treatment

Zenagamtide - Zenagamtide is given as a clear solution for injection that is used with a pre‑filled pen and injected under the skin once a week. It is an experimental drug currently being studied in clinical trials and is not yet approved for routine medical use. The medicine is being tested to help lower the risk of heart attacks, strokes and other major cardiovascular problems in people who already have atherosclerotic cardiovascular disease and are overweight or obese. Zenagamtide works by mimicking a natural hormone that reduces appetite and improves how the body handles fats, which can lead to lower blood pressure and better heart health; it belongs to the class of peptide‑based appetite‑regulating agents.

Investigated diseases

  • Atherosclerotic cardiovascular disease

    A build‑up of fatty deposits called plaque inside the walls of arteries that supply the heart and brain. Over time the plaque can harden and narrow the arteries, reducing blood flow. This may lead to episodes of chest pain, heart attacks, or strokes as the artery becomes blocked. The condition often develops slowly over many years and can affect multiple vessels.

  • Overweight

    A condition where a person’s body weight is higher than what is considered healthy for their height, usually defined by a body‑mass index of 25 to 29.9 kg/m². Excess weight can cause the heart to work harder and may increase the amount of fatty tissue in blood vessels. As the extra weight persists, the risk of developing heart and blood‑vessel problems grows gradually.

  • Obesity

    A chronic condition characterized by an excess amount of body fat, typically defined by a body‑mass index of 30 kg/m² or higher. The surplus fat can lead to inflammation and accumulation of plaque in arteries over time. This progressive buildup can worsen blood flow and increase the chance of heart‑related events as the condition continues.

Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2026-525182-53-00Protocol codeNN9490-8037Estimated enrolment8 500 patientsSponsorNovo Nordisk A/S

sourced from the EU Clinical Trials Register and site verification

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