Glucagon-like peptide-1 (GLP-1) receptor agonists, including tirzepatide (Mounjaro), are widely used to manage type 2 diabetes mellitus (T2DM) and obesity. While gastrointestinal side effects are common, acute pancreatitis remains a rare but significant complication. Limited evidence exists on the risks associated with switching between GLP-1 agonists, emphasizing the need for clinical awareness. We present a 59-year-old male with T2DM, hyperlipidemia, and hypertension, who was recently transitioned from semaglutide (Ozempic) to tirzepatide (Mounjaro). He presented with acute epigastric pain, nausea, and vomiting two days after initiating tirzepatide. Laboratory findings revealed elevated lipase levels (847 U/L), leukocytosis, and diagnostic imaging confirming acute pancreatitis with other causes ruled out. Supportive care improved symptoms initially, but the clinical course was complicated by fevers prompting repeat imaging, revealing worsening pancreatitis with colonic involvement and pleural effusion. The patient was treated with empiric antibiotics and supportive measures, resulting in resolution of symptoms. Tirzepatide was discontinued, with a follow-up arranged for glycemic management. Acute pancreatitis is a rare but documented adverse effect of GLP-1 agonists, with limited cases reported in the literature. Switching between GLP-1 agonists may increase the risk of adverse effects, especially if appropriate dose titration protocols are not followed. This case highlights the recognition of acute pancreatitis as a potential adverse effect of GLP-1 agonists when initiating or transitioning GLP-1 therapies and following titration protocols to help avoid this complication. GLP-1 agonists, including tirzepatide, offer significant therapeutic benefits for T2DM and obesity but carry risks of rare adverse effects like acute pancreatitis. Greater awareness, careful dose adjustments, and vigilant monitoring are essential to optimizing patient safety. Further research is needed to elucidate the safety profile of switching between GLP-1 agonists to guide clinical practice and improve patient outcomes.
