Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that produces substantial weight loss and improves multiple cardiometabolic risk factors. Current evidence supports its cardiovascular safety, with no established association between licensed tirzepatide therapy and acute coronary syndrome (ACS). As its clinical use continues to expand, reporting unusual cardiovascular presentations remains important for pharmacovigilance. We present a case of a 48-year-old South Asian man with obesity, diet-controlled prediabetes, a history of smoking, and a family history of premature coronary artery disease who had been receiving tirzepatide for approximately 18 months, achieving a weight loss of approximately 30 kg. Following increased physical activity, he developed progressive exertional chest pain and dyspnoea. Electrocardiography demonstrated inferolateral ischaemic changes, and serial high-sensitivity troponin T measurements were consistent with a non-ST elevation myocardial infarction (NSTEMI). Transthoracic echocardiography showed preserved left ventricular systolic function with inferior regional wall motion abnormalities. Coronary angiography revealed severe triple-vessel coronary artery disease involving the left anterior descending, left circumflex, and right coronary arteries. He subsequently underwent successful coronary artery bypass grafting with an uncomplicated postoperative recovery. Although a temporal association existed between prolonged tirzepatide therapy, substantial weight loss, and presentation with NSTEMI, the presence of advanced multivessel coronary artery disease suggests longstanding atherosclerosis rather than a direct adverse effect of tirzepatide. A more plausible explanation is that significant weight loss improved functional capacity, allowing increased physical activity that unmasked previously silent obstructive coronary artery disease. This interpretation is consistent with current evidence demonstrating favourable cardiovascular effects of tirzepatide while acknowledging that causality cannot be established from a single case. This case highlights the importance of thoroughly evaluating new exertional chest pain in patients receiving tirzepatide despite marked improvements in weight and metabolic health. Clinicians should remain vigilant for underlying coronary artery disease in individuals with traditional cardiovascular risk factors. This report describes a temporal association rather than a causal relationship and contributes to the growing body of real-world experience with tirzepatide.
