Leptin Attenuates Cardiac Hypertrophy in Patients with Generalized Lipodystrophy.

CONTEXT Lipodystrophy syndromes are rare disorders of deficient adipose tissue, low leptin, and severe metabolic disease, affecting all adipose depots (generalized, GLD) or only some (partial, PLD). Left ventricular (LV) hypertrophy is common (especially in GLD); mechanisms may include hyperglycemia, dyslipidemia, or hyperinsulinemia. OBJECTIVE Determine effects of recombinant leptin (metreleptin) on cardiac structure and function in lipodystrophy. DESIGN/PARTICIPANTS/INTERVENTION/SETTING Open-label treatment study of 38 subjects (18 GLD, 20 PLD) at the National Institutes of Health before and after 1 (N=27), and 3-5y (N=23) of metreleptin. OUTCOME Echocardiograms, blood pressure (BP), triglycerides, A1c, HOMA-IR. RESULTS In GLD, metreleptin lowered triglycerides (median(IQR) 740(403-1239), 138(88-196), 211(136-558) mg/dL at baseline, 1y, 3-5y, P<0.0001), A1c (9.5±3.0, 6.5±1.6, 6.5±1.9%, P<0.001), and HOMA-IR (34.1(15.2-43.5), 8.7(2.4-16.0), 8.9(2.1-16.4), P<0.001). Only HOMA-IR improved in PLD (P<0.01). Systolic BP decreased in GLD but not PLD. Metreleptin improved cardiac parameters in patients with GLD, including reduced posterior wall thickness (9.8±1.7, 9.1±1.3, 8.3±1.7 mm, P<0.01), and LV mass (140.7±45.9, 128.7±37.9, 110.9±29.1 g, P<0.01), and increased septal e' velocity (8.6±1.7, 10.0±2.1, 10.7±2.4 cm/s, P<0.01). Changes remained significant after adjustment for BP. In GLD, multivariate models suggested that reduced posterior wall thickness and LV mass index correlated with reduced triglycerides and increased septal e' velocity correlated with reduced A1c. No changes in echocardiographic parameters were seen in PLD. CONCLUSION Metreleptin attenuated cardiac hypertrophy and improved septal e' velocity in GLD, which may be mediated by reduced lipotoxicity and glucose toxicity. The applicability of these findings to leptin-sufficient populations remains to be determined.