Hypertriglyceridemia-induced acute pancreatitis (HTG-AP) is associated with a high risk of recurrence despite standard lipid-lowering therapy and lifestyle modification. The goal of this clinical trial is to evaluate whether GLP-1 receptor agonist therapy can reduce the recurrence of HTG-AP in adults with a history of HTG-AP and hypertriglyceridemia.

The main questions this study aims to answer are:

• Whether GLP-1 receptor agonist therapy reduces the recurrence rate of HTG-AP.
• Whether GLP-1 receptor agonist therapy improves triglyceride control, body weight, and metabolic parameters.
• Whether GLP-1 receptor agonist therapy is safe and well tolerated in this patient population.

Researchers will compare GLP-1 receptor agonist therapy plus standard care with standard care alone to determine whether GLP-1 receptor agonist therapy provides additional benefit in preventing recurrent HTG-AP.

Participants will:

• Receive either GLP-1 receptor agonist therapy plus standard care or standard care alone.
• Undergo regular clinical follow-up visits and laboratory assessments.
• Receive monitoring of triglyceride levels, recurrence events, metabolic outcomes, and adverse events during the study period.

Inclusion Criteria

• Age ≥ 18 years old
• Previous diagnosis of index HTG-AP (defined as AP with serum TG >1000 mg/dL or a serum TG level of 500-1000 mg/dL accompanied by chylous serum)36-38
• Having HTG as the exclusive cause of AP
• Time from discharge of index HTG-AP to recruitment between 4 weeks to 3 months, without AP-related symptoms between discharge and recruitment
• Expression of the willingness to comply with lifestyle modification during the study period.
• Clinically stable at the time of inclusion
• The ability to understand the trial and completing it, as evaluated by the investigators.
• Patients who may get pregnant should ensure using contraceptives for 20 months after inclusion Exclusion Criteria
• History of malignancy in past 5 years
• History of hypothyroidism, nephrotic syndrome, Cushing's syndrome or AIDS
• History of chronic pancreatitis or pancreatic neoplasm
• History of severe cardiovascular and pulmonary diseases, such as heart failure, coronary heart disease and chronic obstructive pulmonary disease.
• Severe renal deficiency (glomerular filtration rate < 30 ml/min)
• Severe hepatic deficiency (Child-Pugh Class B or C)
• Previous pancreatic surgery
• Recurrent AP due to pancreatic diverticulum
• Recurrent AP due to known genetic mutations (eg. CFTR)
• Personal or family history of medullary thyroid carcinoma (MTC)
• Current or prior diagnosis or suspected diagnosis of multiple endocrine neoplasia type 2 (MEN2)
• Serious hypersensitivity reaction to semaglutide or any of the excipients in the investigational drug or placebo
• Pregnancy
• Breast-feeding