Presentation (CTI)

OBJECTIVES: Metreleptin is the only approved disease-modifying therapy for generalized lipodystrophy, creating a critical need to identify disease progression pathways where treatment is expected to provide the greatest patient benefit. This study aimed to identify clinically meaningful health-state transitions in generalized lipodystrophy and assess their alignment with the published clinical evidence for metreleptin.
METHODS: A systematic literature review was carried out in MEDLINE, Embase, Cochrane CENTRAL, LILACS and ClinicalTrials.gov, without language or publication date restrictions, to identify published clinical evidence on metreleptin in patients with generalized lipodystrophy. Six organ-specific Markov models representing the natural history of generalized lipodystrophy were derived from the published evidence using transition probabilities from a previously adapted model for the Brazilian context. WINGS, an MCDA method, was employed to the Markov models to identify and classify clinically meaningful health-state transitions as mild, moderate, marked, substantial and pronounced.
RESULTS: The hepatic model contained the most clinically meaningful health-state transitions, including pronounced transitions from bleeding to decompensated cirrhosis with varices and hepatocellular carcinoma to death, marked transitions from decompensated cirrhosis with varices to bleeding and bleeding to death, moderate transitions from decompensated cirrhosis to decompensated cirrhosis with varices and death, decompensated cirrhosis with varices to death, and transplant to death, and five additional mild transitions. The literature review demonstrated that metreleptin improves hepatic disease, glycaemic control, proteinuria, cardiac abnormalities and survival by correcting the underlying leptin deficiency and improving the severe metabolic abnormalities responsible for insulin resistance, hypertriglyceridaemia, ectopic fat accumulation and progressive multiorgan damage. Improvements in hepatic steatosis, liver enzymes and fibrosis were consistently reported, indicating that metreleptin acts on the mechanisms underlying progression toward decompensated cirrhosis, decompensated cirrhosis with varices, variceal bleeding, hepatocellular carcinoma and death.
CONCLUSIONS: Published clinical evidence for metreleptin closely aligns with the clinically meaningful transitions driving generalized lipodystrophy progression.