Tirzepatide, a dual glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, is increasingly prescribed for obesity and glycemic control. Its effects on gastric emptying, appetite regulation, and rapid weight loss may influence thyroid hormone homeostasis and the pharmacokinetics of narrow-therapeutic-index medications such as levothyroxine. Emerging clinical experience suggests that GLP-1-based therapies can suppress thyroid-stimulating hormone (TSH), alter thyroid hormone dynamics, and precipitate symptoms of thyrotoxicosis in patients receiving thyroid hormone replacement. As use of incretin therapies expands, understanding their potential interaction with thyroid physiology is increasingly important. We describe a 52-year-old woman with a history of thyroidectomy complicated by postoperative hypothyroidism, maintained on stable doses of levothyroxine for several years. After six months of tirzepatide therapy, she experienced 48 pounds of intentional weight loss and developed dizziness, tachycardia, weakness, and confusion. Laboratory evaluation showed a markedly suppressed TSH and elevated free T4, consistent with significant over-replacement with levothyroxine. She required emergent dose reduction and supportive care, with gradual resolution of symptoms after adjustment of her thyroid regimen. Key contributing factors included substantial weight loss without proportional levothyroxine dose reduction, delayed gastric emptying altering levothyroxine absorption, and absence of endogenous thyroid reserve following thyroidectomy. These changes created a clinical environment highly susceptible to pharmacologic fluctuations and rapid shifts into iatrogenic thyrotoxicosis. Additionally, GLP-1 therapy-associated decreases in blood pressure and appetite likely amplified her acute presentation. This case highlights the importance of vigilant monitoring in post-thyroidectomy patients who begin tirzepatide or other incretin-based medications. Clinicians should anticipate the need for levothyroxine dose adjustments as weight decreases and gastrointestinal motility changes. Early follow-up, routine thyroid function testing, and prompt evaluation of new cardiovascular or neurocognitive symptoms are essential to prevent avoidable morbidity related to drug-hormone interactions.
