Tirzepatide non-response with subsequent semaglutide response in class 2 obesity.

We report a paradoxical case of a 40-year-old man with class 2 obesity (body mass index 39.8 kg/m2) and insulin resistance (homeostatic model assessment of insulin resistance [HOMA-IR] 5.0; reference <2.0) who achieved minimal weight loss (<5%) despite tirzepatide dose escalation to 15 mg weekly over 6 months. Following switch to semaglutide 2.4 mg 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 ≥4-5) 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.