{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T23:36:38Z","timestamp":1793144198498,"version":"4.5.0"},"reference-count":10,"publisher":"The Endocrine Society","issue":"9","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":35,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>We report a paradoxical case of a 40-year-old man with class 2 obesity (body mass index 39.8\u2005kg\/m2) and insulin resistance (homeostatic model assessment of insulin resistance [HOMA-IR] 5.0; reference &amp;lt;2.0) who achieved minimal weight loss (&amp;lt;5%) despite tirzepatide dose escalation to 15\u2005mg weekly over 6 months. Following switch to semaglutide 2.4\u2005mg weekly, the patient achieved 20% weight loss over 6 months, with normalization of fasting glucose, resolution of insulin resistance, and marked improvement in appetite control. This case challenges the assumption that dual glucose-dependent insulinotropic polypeptide (GIP)\/glucagon-like peptide-1 (GLP-1) receptor agonism is universally superior to selective GLP-1 receptor agonism for weight management. Mechanistic analysis suggests that adipose tissue GIP receptor downregulation in the context of class 2 obesity and insulin resistance, combined with intact central GLP-1 receptor signaling, may explain the differential response in some individuals. Key learning points include: markedly elevated baseline insulin resistance (HOMA-IR \u22654-5) may be associated with poor tirzepatide response, though prospective validation is required; persistent hyperphagia during tirzepatide treatment is an early warning sign; and nonresponse to tirzepatide does not preclude semaglutide response. This case supports precision medicine approaches in obesity pharmacotherapy, including pretreatment phenotyping and early response assessment.<\/jats:p>","DOI":"10.1210\/jcemcr\/luag245","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T11:48:15Z","timestamp":1786535295000},"source":"Crossref","is-referenced-by-count":3,"title":["Tirzepatide non-response with subsequent semaglutide response in class 2 obesity"],"prefix":"10.1210","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7113-2372","authenticated-orcid":false,"given":"Sandro","family":"La Vignera","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania , Catania 95123 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosita A","family":"Condorelli","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania , Catania 95123 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