Efficacy, Safety and Cardiovascular Protection of Mazdutide in Type 1 Diabetes

Inclusion Criteria:

1. Age ≥18 years at screening.

2. Patients with a clinical diagnosis of T1D for at least 12 months.

   Patients with T1D must satisfy all three of the following features:

   1. Clinical diagnosis of type 1 diabetes by a specialist physician;
   2. Any one of the following: age at onset <15 years; no overweight or obesity at onset; diabetic ketoacidosis at onset; peak stimulated C-peptide <200 pmol/L;
   3. Any one of the following: continuous insulin therapy since diagnosis (excluding pancreas or islet transplantation); one or more positive pancreatic islet autoantibodies (GADA / IAA / IA-2A / ZnT8).

3. Willingness to use once-weekly mazdutide.

4. HbA1c ≥7.0% and <10.0%.

5. Body mass index (BMI) ≥20 kg/m².

6. Continuous use of any of the following insulin regimens for at least 3 months prior to screening (no concomitant use of other oral glucose-lowering drugs or GLP-1RAs allowed), with a stable insulin dose for at least 2 weeks before enrollment:

   1. Multiple daily injections of basal insulin plus prandial insulin;
   2. Premixed insulin analog injected 2-3 times daily;
   3. Dual insulin analog (insulin degludec/aspart) injected twice daily;
   4. Continuous subcutaneous insulin infusion (CSII). Note: A stable insulin dose is defined as a daily insulin dose adjustment of no more than ±[value not specified in the source document].

7. Ability to provide informed consent prior to any study-related activity.

   • For participants enrolled in TIMES-CV, in addition to the above criteria, the following criteria must also be met: ***

1. Duration of type 1 diabetes ≥5 years. 2. Moderate or high 10-year atherosclerotic cardiovascular disease (ASCVD) risk (≥5.0%) as assessed by the China-PAR model.

3. Carotid atherosclerotic plaque confirmed by ultrasound.

Exclusion Criteria:

1. Other types of diabetes.
2. BMI <20 kg/m².
3. History of cardiovascular disease: previous myocardial infarction, unstable angina, coronary revascularization (PCI or CABG), stroke, transient ischemic attack (TIA), or symptomatic peripheral arterial disease.
4. Renal impairment: estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² (based on the CKD-EPI equation).
5. Hepatic disease: known severe hepatic disease, or ALT/AST levels >3 times the upper limit of normal.
6. Personal or family history of medullary thyroid carcinoma, or multiple endocrine neoplasia syndrome type 2.
7. Pancreatic disease: history of acute or chronic pancreatitis.
8. Pregnancy and lactation: women who are pregnant, breastfeeding, or planning pregnancy and unwilling to use effective contraception.
9. Medications: use of GLP-1 receptor agonists, GIP or GCG receptor agonists, other non-insulin glucose-lowering drugs, or finerenone within 3 months prior to screening.
10. Requirement for long-term use of systemic glucocorticoids (topical/inhaled use permitted).
11. History of hypersensitivity to GLP-1 receptor agonists, mazdutide, or any of its excipients.
12. Moderate or more severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy.
13. Any other serious medical or psychiatric condition that, in the judgment of the investigator, may interfere with study assessments or endanger the safety of the subject.