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Effect of Leptin Replacement Therapy (LRT) on Survival and Disease Progression in Generalized and Partial Lipodystrophy (GL, PL)

Lipodystrophy (LD) is an ultra-rare disease associated with significant morbidity and mortality. Effects of LRT on metabolic disease in GL and PL have been studied; but effects on mortality are unknown. We investigated these effects using data from GL and PL patients treated with LRT at NIH (N=114) and cared for but not treated with LRT at 3 centers in the U.S. and Turkey (N=178). Four abnormalities (liver, kidney, heart, and HbA1c ≥6.5%) were considered. LRT patients had a mean of 2.8 abnormalities prior to treatment, while the mean for untreated patients was 0.7 at a similar age. We used a matching approach to create comparable samples of treated and untreated patients. Each treated patient was matched (using Mahalanobis distance) to an untreated patient to balance across age, gender, type of LD, and number of abnormalities. LRT treatment effect was examined via Cox proportional hazards models of 1) mortality and 2) development of subsequent abnormalities. Additionally, the relationship between abnormalities and mortality was studied in the sample of untreated patients. Results: A Cox proportional hazards model relating treatment to mortality yielded a hazard ratio (HR) for LRT of 0.34 (p=0.047), meaning that LRT was associated with a 66% decrease in mortality risk. Adjusting for covariates including gender, type of LD, and type of abnormality resulted in a larger decrease in mortality risk (HR 0.21, p One possible mechanism for the effect of LRT on mortality is its role in mitigating or resolving abnormalities. A time-varying Cox proportional hazards model relating number of abnormalities present (0 to 4) to mortality among untreated patients found a positive relationship between additional abnormalities and mortality (HR 3.2, p In conclusion, these are the first data suggesting that LRT reduces mortality in LD. Disclosure O.A. Ali: Consultant; Self; Aegerion Pharmaceuticals. K. Cook: Consultant; Self; Aegerion Pharmaceuticals. D. Gupta: Consultant; Self; Aegerion Pharmaceuticals. D. Holmqvist: Consultant; Self; Aegerion Pharmaceuticals. D. Lee: Consultant; Self; Aegerion Pharmaceuticals. C.K. Ng: Consultant; Self; Aegerion Pharmaceuticals. P. Bradt: Employee; Self; Aegerion Pharmaceuticals. R. Brown: None.