Sustained weight loss exceeding 100 kg with sequential incretin-based therapy in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a neurogenetic disorder characterized by hyperphagia, severe obesity, and early-onset metabolic complications, in which durable weight loss is rarely achieved. We report a 29-year-old man with genetically confirmed maternal uniparental disomy PWS who presented with severe obesity (185 kg; body mass index [BMI] 59.7 kg/m2) and newly diagnosed type 2 diabetes (glycated hemoglobin [HbA1c], 8.3% [SI: 67 mmol/mol] [reference range, <5.7% (SI: <39 mmol/mol)]). He received sequential incretin-based therapy, initiated with retatrutide (1-12 mg weekly) within a clinical trial, followed by oral semaglutide and then dulaglutide after retatrutide became unavailable, together with a structured hypocaloric diet and supervised exercise. At 18 months, total weight loss reached 58.8% (-108.7 kg), with HbA1c of 4.9% (SI: 30 mmol/mol), consistent with diabetes remission after discontinuation of all glucose-lowering medications. Mild transient gastrointestinal symptoms occurred during dose escalation, with no serious adverse events. Follow-up bioimpedance showed a skeletal muscle mass of 38.5 kg after a 58.8% reduction in total body weight.