Efficacy of Mazdutide on Fatty Pancreas

Fatty pancreas is a clinicopathological syndrome characterized by fat infiltration in pancreatic tissue. It can be classified into three categories based on etiology and risk factors: ectopic pancreatic fat deposition due to overnutrition and metabolic dysfunction, secondary fatty replacement following pancreatic injury from various causes, and fatty pancreas associated with genetic or congenital diseases. Among these, excessive fat deposition within pancreatic tissue occurring against the backdrop of metabolic abnormalities is termed metabolic dysfunction-associated fatty pancreas (MAFP), which is commonly seen in individuals with overweight, obesity, or metabolic syndrome. MAFP can impair both endocrine and exocrine pancreatic functions, increase the risks of pancreatitis and glucose metabolism disorders, and significantly elevate the incidence of pancreatic cancer. Currently, there are no approved specific pharmacotherapies for fatty pancreas. Although lifestyle intervention serves as the foundational treatment, long-term patient adherence remains limited. Existing studies suggest that glucagon-like peptide-1 receptor agonists (GLP-1RAs) can effectively reduce visceral and ectopic fat deposition, lowering absolute pancreatic fat content by approximately 2%-6%, thereby demonstrating potential as therapeutic agents for MAFP. Mazdutide, a dual GLP-1 receptor/glucagon receptor (GLP-1R/GCGR) agonist, synergistically activates dual metabolic pathways, reducing visceral fat accumulation while achieving potent weight loss. Based on its unique mechanism of action and established evidence for weight reduction, mazdutide holds promising application prospects for alleviating MAFP and managing metabolic comorbidities. However, no dedicated studies have yet evaluated the impact of mazdutide on pancreatic fat content in obese patients.

Inclusion criteria

Patients participating in this study must meet all of the following criteria:

• Age 18-60 years (inclusive) at screening, regardless of gender;
• BMI at screening meets one of the following conditions: ① BMI ≥28 kg/m²; or ② 24 kg/m² ≤ BMI <28 kg/m², with at least one obesity-related metabolic abnormality (elevated fasting blood glucose, dyslipidemia, hypertension, etc.);
• Pancreatic MRI-PDFF quantitative assessment completed during the screening period, with intrapancreatic fat deposition (IPFD) ≥6%;
• Fully informed about the study and voluntarily signed written informed consent;
• Agreed to maintain a stable lifestyle (including diet and exercise habits) during the study.

Note: Diagnostic criteria for Metabolic Syndrome (meeting ≥3 of the following items) [ChineseDiabetesSociety(CDS)2020]:

• Abdominal obesity (central obesity): Waist circumference ≥90 cm in men, ≥85 cm in women;
• Fasting blood glucose ≥6.1 mmol/L and/or 2-hour postprandial blood glucose ≥7.8 mmol/L, and/or diagnosed diabetes under treatment;
• Blood pressure ≥130/85 mmHg, and/or diagnosed hypertension under treatment;
• Fasting triglycerides (TG) ≥1.7 mmol/L;
• Fasting HDL-C <1.04 mmol/L.

Exclusion criteria

Patients with any of the following conditions will be excluded from participation in this study:

• HbA1c ≥6.5% at screening; history of diabetic ketoacidosis (DKA) or other diabetic emergencies;
• Use of GLP-1 receptor agonists (GLP-1RA), DPP-4 inhibitors, or insulin within 3 months prior to screening;
• Use of any weight-loss drugs or dietary supplements for fat reduction within 1 month prior to screening enrollment; or use of systemic medications known to cause weight gain within 1 month prior to screening, including systemic glucocorticoids, tricyclic antidepressants, atypical antipsychotics, and mood stabilizers;
• Self-reported or documented significant weight fluctuation (>5%) within 3 months prior to screening;
• Current or history of acute pancreatitis, chronic pancreatitis, or gallbladder disease (gallstones, cholecystitis); or serum triglycerides (TG) >5 mmol/L during the screening period;
• Chronic kidney disease stage 3 or higher, eGFR <60 mL/(min·1.73m²) (calculated using the CKD-EPI formula);
• Obesity secondary to other endocrine disorders, such as Cushing's syndrome;
• Personal or family history of Multiple Endocrine Neoplasia type 2 (MEN2) or Medullary Thyroid Carcinoma (MTC);
• History of severe depression, or current severe psychiatric illness (schizophrenia, bipolar disorder, etc.), where the investigator judges that the patient cannot comply with the study procedures;
• History of allergy to Tirzepatide injection or its excipients;
• Pregnant or lactating women; women of childbearing potential unwilling to adopt effective contraceptive measures throughout the study and for 3 months after the last dose;
• Contraindications to MRI examination (e.g., magnetic metal implants in the body, severe claustrophobia), preventing completion of pancreatic MRI-PDFF assessment;
• Participation in other drug or medical device clinical trials within 3 months prior to screening;
• Other serious organic diseases judged by the investigator to interfere with efficacy/safety evaluation or pose a risk to subject safety.