People with type 2 diabetes who also have a higher chance of heart and blood‑vessel problems often need more than one or two pills to keep their blood sugar under control. In this study a new medicine called zenagamtide given by a small injection under the skin once a week is being compared with a well‑known insulin called insulin glargine that is injected once a day.
The aim is to find out whether the weekly injection works at least as well as the daily insulin for lowering blood sugar and reducing serious heart events. Blood sugar control will be measured by the level of HbA1c, a lab test that shows average sugar over the past few months, and heart safety will be judged by the occurrence of a major heart problem known as MACE, which includes heart‑related death, heart attacks, strokes or hospital stays for severe chest pain.
Participants will continue the oral diabetes medicines they are already taking. They will be randomly assigned to receive either the weekly test medication or the daily insulin, using a pre‑filled pen. Over about a year they will visit the clinic several times for simple checks such as blood draws, weight measurements, and brief safety questions. The study will watch for any side effects and track how well the blood sugar numbers and heart health stay stable.
1baseline visit
you attend a baseline visit after joining the study. during this visit, the study team records your height, weight, waist size, blood pressure, and takes blood samples to measure your current hbA1c level and other laboratory values.
the information collected at this visit will be used as the reference point for all future comparisons during the trial.
2injection training
you receive instruction on how to use the pre‑filled pen for a subcutaneous injection. the training covers where on the body to inject, how to prepare the pen, and how to store the medication safely.
3start of study medication
you begin taking the assigned study medication. if you are assigned to the test drug, you will inject zenagamtideonce weekly under the skin. if you are assigned to the comparator, you will inject insulin glargineonce daily under the skin.
the exact dose is set by the study doctor and may be adjusted according to your response.
4ongoing self‑administration
you continue to give yourself the injections according to the schedule (weekly for zenagamtide or daily for insulin glargine) for the entire duration of the trial.
you keep a simple record of each injection date and any noticeable side effects.
5periodic clinic assessments
you attend scheduled clinic visits at regular intervals. at each visit, the study staff checks your weight, waist circumference, blood pressure, and collects blood samples to monitor hbA1c, cholesterol, triglycerides, and other safety markers.
the first major assessment occurs at week 52, when a detailed measurement of hbA1c and body weight is performed.
6cardiovascular event monitoring
throughout the study, you are asked to report any symptoms that could indicate a cardiovascular problem, such as chest pain, shortness of breath, or sudden weakness.
the study team evaluates any reported events to determine whether they meet the definition of a major adverse cardiovascular event (MACE).
7final assessments
the trial continues up to week 104 or longer if required. at the end of the study period, you undergo a final set of measurements similar to the baseline visit, including weight, waist size, blood pressure, and laboratory tests.
the results from the final visit are compared with the baseline and the week‑52 data to evaluate the overall effectiveness and safety of the medication.
Who Can Join the Study?
Informed consent must be given before any study procedures are done.
Must be a male or female (including all gender identities).
Must be at least 45 years old when signing the consent.
Must have been diagnosed with type 2 diabetes (T2D) at least 180 days (about 6 months) before the screening visit.
Must be taking 1 to 3 approved oral glucose‑lowering medications (such as metformin, sulfonylureas, SGLT2 inhibitors, etc.) and the dose must have been stable for a set period before screening.
Must have a lab test of haemoglobin A1c (HbA1c) performed at the screening center, meeting the study’s required range (the exact range is set by the trial laboratory).
Must meet the central laboratory criteria for HbA1c (referred to as CCI in the protocol).
Must have an increased risk of cardiovascular problems, shown by at least one of the following: a previous myocardial infarction (heart attack); documented coronary artery disease such as a 50% or greater blockage, evidence of reduced blood flow on a stress test, unstable chest pain with changes on an electrocardiogram (ECG), or past heart bypass surgery or stent placement; a prior stroke (either ischemic or hemorrhagic); a history of chronic kidney disease as judged by the doctor and lab tests; or symptomatic peripheral arterial disease (PAD) in the legs, which can include pain when walking (called intermittent claudication) with a low ankle‑brachial index (ABI), a 50% or greater blockage in a leg artery, previous procedures to restore blood flow (revascularisation), or an amputation due to artery disease.
Who Cannot Join the Study?
Had a heart attack (myocardial infarction), stroke, mini‑stroke (transient ischaemic attack), or was hospitalized for unstable chest pain (unstable angina) within the last 60 days.
Plans to have a procedure to open or repair heart, neck, or leg arteries (such as coronary, carotid, or peripheral artery re‑vascularisation).
Requires kidney‑cleaning treatment (either hemodialysis or peritoneal dialysis) continuously or intermittently within the past 90 days.
Has lab results that show a medical condition considered unsafe for the study (identified as a CCI by the central laboratory).
Is using any diabetes or obesity medication that is not listed in the study’s allowed medicines, except short‑term insulin (up to 14 days) or insulin for gestational diabetes.
Has taken diabetes medicines such as GLP‑1 receptor agonists, dual GLP‑1/GIP receptor agonists, DPP‑4 inhibitors, or amylin analogues before screening.
Has diabetic eye disease (diabetic retinopathy or maculopathy) that needed retinal photocoagulation (laser treatment), vitrectomy (eye surgery), or anti‑VEGF eye injections within the past 180 days, or is expected to need such treatment within the next 180 days, and does not have a recent eye exam.
Shows hypoglycaemic unawareness (does not recognize low‑blood‑sugar symptoms) as identified by the doctor using the Clarke questionnaire.
Has ever experienced diabetic ketoacidosis (a serious condition where the body builds up acids called ketones) before screening.
Has thyroid disease that is not under control, according to the doctor’s judgment.
Azienda Sociosanitaria Ligure N 4 Sistema Sanitario Regione Liguria
Chiavari
Italy
Irmed Klimkiewicz Rudziewicz-Kowalska sp. j.
Piotrkow Trybunalski
Poland
Maciej Wiza Gaja Poradnie Lekarskie
Poznan
Poland
Centrum Medyczne MBB-MED Marta Błach-Burek
Libiąż
Poland
Ambulatoria Za Individualna Praktika Za Spetsializirana Izvanbolnicha Meditsinska Pomosht Po Endokrinologia I Bolesti Na Obmyanata D-R Velichka Zlatareva EOOD
zenagamtide
zenagamtide is an experimental injectable medicine that is given under the skin once a week. In this study it is being tested to see if it can lower blood sugar in people with type 2 diabetes who are not well‑controlled on oral medicines. Researchers want to know if it works as well as the standard daily insulin and whether it is safe for patients with a higher risk of heart problems.
insulin glargine
insulin glargine is a long‑acting form of insulin that is injected under the skin once a day. It helps lower blood sugar by replacing the insulin the body needs. In this trial it is used as the comparison treatment to see if the new weekly injection (zenagamtide) can provide similar control of blood sugar and have comparable safety for people with type 2 diabetes and increased cardiovascular risk.
Type 2 diabetes mellitus with increased cardiovascular risk – Type 2 diabetes mellitus is a long‑lasting condition in which the body does not use insulin effectively, causing elevated blood glucose levels. Persistent high glucose can gradually damage blood vessels, nerves, and organs. When cardiovascular risk is also elevated, the disease often leads to the buildup of plaque in arteries, which can result in heart disease and stroke. The combination of uncontrolled blood sugar and vascular changes tends to worsen over time, leading to more extensive cardiovascular complications. Progression is typically slow and may become apparent only after several years of persistent metabolic imbalance.
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