A woman with genetically confirmed Prader-Willi syndrome (15q11.2-q13.1 heterozygous deletion, verified by DNA methylation analysis) presented with refractory type 2 diabetes resistant to an aggressive five-drug regimen — insulin, metformin, chiglitazar sodium, a GLP-1 receptor agonist, and an SGLT-2 inhibitor. Swapping the GLP-1 agonist for tirzepatide, a dual GIP/GLP-1 receptor co-agonist, produced meaningful improvements in appetite suppression, body weight, and glycemic control where the prior combination had failed.
This case carries mechanistic weight beyond its single-patient design. PWS diabetes is uniquely hostile: hyperphagia driven by hypothalamic dysregulation compounds severe insulin resistance and β-cell dysfunction simultaneously, creating a metabolic environment that standard agents — even GLP-1 monotherapy — struggle to penetrate. Tirzepatide's additional GIP receptor engagement may be key here; GIP signaling modulates central reward circuitry and adipose tissue metabolism through pathways distinct from GLP-1, potentially addressing the hypothalamic hyperphagia that defines PWS in a way no prior drug reached. This aligns with emerging evidence that tirzepatide achieves superior weight loss versus semaglutide in general obesity trials, likely through this dual mechanism.
Critically, this remains a single case report — causality cannot be established, dose-response data are absent, and PWS patients represent an extreme metabolic phenotype unlikely to generalize broadly. Still, for a population with virtually no evidence-based pharmacological framework, this signals tirzepatide as a rational first-line candidate deserving prospective study.