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Zenagamtide versus semaglutide: a study of blood sugar and weight reduction in adults with type 2 diabetes inadequately controlled on metformin and/or SGLT2 inhibitor

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What is this trial about?

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

The trial focuses on adults with type 2 diabetes whose blood sugar remains high despite stable doses of metformin and/or a SGLT2i. The investigational medication is zenagamtide, identified in the study by the code NNC0487-0111, and it is given as a subcutaneous injection once a week. It is being compared with the approved drug semaglutide, also administered once weekly.

The purpose is to confirm that zenagamtide is not inferior to semaglutide in reducing blood sugar levels measured by HbA1c. Participants are randomly assigned to receive either the investigational drug, the comparator, or a placebo, and they self‑inject the assigned medication each week while attending regular clinic visits for safety checks and blood sampling over several months.

The study evaluates the change in HbA1c as the primary result, and secondary results include the relative change in body weight, the level of triglycerides (a type of fat in the blood), the measurement of systolic blood pressure (the top number in a blood pressure reading), the amount of non-HDL cholesterol (bad cholesterol not measured by the usual LDL test), and the concentration of hsCRP (a marker that can indicate inflammation).

The research process

The trial runs in 6 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Start of Treatment

    You have been assigned to receive either zenagamtide or semaglutide as part of the study.

    The medication is supplied as a solution for injection in a pre‑filled pen and is given by subcutaneous (under the skin) injection.

    You will inject the medication once each week; the exact dose is determined by the study protocol and is not altered by you.

  2. Step 2

    Continue Background Medications

    You will continue to take your regular dose of metformin and/or an SGLT2 inhibitor (a class of diabetes medicines) throughout the trial.

  3. Step 3

    Weekly Injection Procedure

    Each week you will administer the injection under the skin, typically in the abdomen or thigh, using the pre‑filled pen provided.

    Follow the written instructions that accompany the pen to ensure correct use.

    Record the date of each injection and note any reactions you experience.

  4. Step 4

    Clinic Visits for Assessments

    You will attend scheduled clinic visits where blood samples are taken to measure HbA1c (a marker of average blood sugar), body weight, triglycerides, blood pressure, non‑HDL cholesterol, and high‑sensitivity C‑reactive protein (hsCRP).

    These visits occur at intervals defined by the study and are used to monitor how well the medication works and its safety.

  5. Step 5

    Safety Monitoring

    The study team will review any side effects you report and may adjust the timing of visits if necessary to ensure your safety.

  6. Step 6

    End of Study

    At the conclusion of the study period you will have a final assessment of your blood sugar control, weight, and other measurements.

    After the final assessment you will stop receiving the study medication.

Who can join the trial?

5 criteria

  • Be a man or a woman, regardless of gender identity.
  • Be at least 18 years old when you sign the consent form.
  • Have a diagnosis of type 2 diabetes (a condition where the body has difficulty controlling blood sugar) for at least 180 days (about 6 months) before the screening visit.
  • Take a steady daily amount of metformin (a common diabetes medicine), an SGLT2 inhibitor (a medicine that helps the kidneys remove excess sugar), or both, without recent changes in the dose.
  • Provide a blood test result for HbA1c (a test that shows your average blood sugar level over the past 2‑3 months) that is measured by the study laboratory at screening.

Who cannot join the trial?

8 criteria

  • Women who are pregnant, breastfeeding, planning to become pregnant, or who could become pregnant and are not using an effective birth‑control method cannot join the study.
  • Heart attack, stroke, transient ischemic attack (a brief “mini‑stroke”), or hospitalization for unstable angina (chest pain due to reduced blood flow to the heart) within the past 60 days are reasons to be excluded.
  • Severe chronic heart failure classified as New York Heart Association (NYHA) Class IV (the most serious level, where symptoms are present even at rest) at the time of screening disqualifies a participant.
  • Planned procedures to open or repair blocked arteries in the heart (coronary), neck (carotid) or legs (peripheral artery) during the study period are not allowed.
  • Any other condition specified by the study as making participation unsafe will exclude a person.
  • Use of diabetes or weight‑loss medicines not listed in the study’s allowed medications, except for short‑term insulin use (up to 14 consecutive days) or insulin used for diabetes during pregnancy, will lead to exclusion.
  • Use of medicines that act like the hormone GLP‑1 (called GLP‑1 receptor agonists), medicines that combine GLP‑1 with the hormone GIP, or medicines similar to amylin before screening disqualifies a participant.
  • Diabetic eye disease (diabetic retinopathy or maculopathy) with recent eye treatments—such as laser therapy (retinal photocoagulation), eye surgery (vitrectomy), or injections that block a protein called VEGF (anti‑VEGF) within the past 180 days—or an expectation of needing such treatment in the next 180 days, and without an eye exam confirming the condition within the past 90 days, excludes a participant.
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Investigated drugs

  • zenagamtide

    is a medication that is given as a subcutaneous injection (under the skin) once a week using a pre‑filled pen. In this trial it is being tested to see how well it lowers blood sugar (measured by HbA1c) and how safe it is for people with type 2 diabetes who are already taking metformin, an SGLT2 inhibitor, or both. The study compares different formulations of the same drug, but the description focuses on the overall purpose of zenagamtide as a new treatment option for improving blood‑sugar control.

  • semaglutide

    is an already approved medication that is also injected under the skin once a week with a pre‑filled pen. It works to lower blood sugar in type 2 diabetes and is used as a reference (comparator) in this study. The trial evaluates whether zenagamtide can achieve similar or better reductions in HbA1c compared with semaglutide while maintaining safety.

What is already known about the treatment

  • Zenagamtide

    This investigational drug is supplied as a solution for injection in a pre‑filled pen and is given subcutaneously once a week. It is currently in clinical development and not yet approved or widely described in medical literature. Zenagamtide is being studied for the treatment of type 2 diabetes, where it works by activating the GLP‑1 receptor to increase insulin release and lower glucagon levels. It belongs to the class of GLP‑1 receptor agonist peptides.

  • Semaglutide

    Semaglutide is provided as a solution for injection in a pre‑filled pen and is administered subcutaneously once weekly. It is an approved medication with extensive clinical data and is listed in treatment guidelines for type 2 diabetes (and obesity). The drug mimics the natural hormone GLP‑1, binding to its receptor to boost insulin secretion, reduce glucagon, and slow stomach emptying. It is classified as a GLP‑1 receptor agonist peptide.

Investigated diseases

Type 2 diabetes - A chronic condition where the body does not use insulin effectively, leading to higher blood‑sugar levels. It usually begins with insulin resistance, causing the pancreas to work harder to keep glucose under control. Over time the pancreas may produce less insulin, and blood‑sugar levels rise further. The disease often progresses slowly, with symptoms such as increased thirst, frequent urination, and fatigue becoming more noticeable as control worsens.
Trial detailsLast updated 25 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2026-525472-26-00Protocol codeNN9489-8035Estimated enrolment825 patientsSponsorNovo Nordisk A/S

sourced from the EU Clinical Trials Register and site verification

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