SAT089 Natural History Of Generalized Lipodystrophy Following Early Vs. Late Metreleptin Treatment
Authors: Brush Maiah , Lightbourne Marissa , Auh Sungyoung , Brown Rebecca J 
Published: October 2023

Disclosure: M. Brush: None. M. Lightbourne: None. S. Auh: None. R.J. Brown: None.

Generalized lipodystrophy (GLD) is characterized by near total loss of subcutaneous fat resulting in low leptin concentrations. Patients with GLD exhibit metabolic abnormalities such as severe insulin resistance, diabetes mellitus, hypertriglyceridemia, proteinuria, and non-alcoholic fatty liver disease (NAFLD), that are progressive over time. Leptin replacement therapy using metreleptin is effective in improving these metabolic abnormalities. It is unknown if starting metreleptin therapy early versus late in the clinical course will change the natural history of this disease. We hypothesize that starting metreleptin early versus late will lead to better long-term control of diabetes, hypertriglyceridemia, and proteinuric nephropathy. This is a single-center retrospective analysis of subjects with congenital and acquired generalized lipodystrophy (n=67). Fasting serum insulin, glucose, lipids, HbA1c (A1c), and 24 hr urine protein excretion, and insulin and c-peptide areas under the cover (AUC) from oral glucose tolerance tests were assessed at baseline, after 6 months of metreleptin, and at 12 month intervals thereafter. For each outcome parameter, subjects were divided into early and late treatment groups. For A1c, early treatment was defined as &lt;7%. For all other parameters, early treatment was defined as being &lt; the upper limit of normal for that parameter. The effect of early vs late treatment for each parameter was analyzed using linear mixed models adjusted for age and genetics, and excluding baseline metabolic parameters. Follow-up diabetes control was better with early metreleptin treatment as assessed by both glucose and A1c. Fasting glucose was 47 mg/dl lower during follow-up with early (&lt;100 mg/dL) vs. late (≥ 100 mg/dL) treatment (p=0.0038) and A1c was 1.37% lower with early (&lt;7%) vs late (≥7%) treatment (p=0.0015). At baseline, the early group defined by A1c had higher insulin secretion based on 48.3% higher c-peptide AUC (p=0.0185) and 161% higher insulin AUC (p=0.0029). At follow-up, the early group maintained a 37.8% higher c-peptide (p&lt;0.0001) and 80.4% higher insulin AUC (p&lt;0.0001).

Urine protein excretion was 366 mg/24hr lower during follow-up in the early group (&lt;300 mg/24hr) compared to the late group (≥300 mg/24hr) (P=0.0031). Triglycerides were 96 mg/dL lower during follow-up between the early (&lt;150 mg/dL) vs late (≥150) groups (p=0.0116). In conclusion, patients with generalized lipodystrophy treated with metreleptin prior to the onset of clinically significant metabolic disease showed better age-adjusted metabolic control over time for diabetes, hypertriglyceridemia, and proteinuria. Lower insulin and C-peptide secretion in the late treatment group suggest that worse diabetes control after metreleptin in this group may be attributable to irreversible loss of beta cell function prior to metreleptin.

Presentation: Saturday, June 17, 2023