Metreleptin therapy lowers plasma angiopoietin-like protein 3 in patients with generalized lipodystrophy

Background Reduced triglyceride clearance due to impaired lipoprotein lipase–mediated lipolysis contributes to severe hypertriglyceridemia in lipodystrophy. Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) impair clearance of triglycerides by inhibiting lipoprotein lipase. Whether circulating ANGPTL3/4 levels are altered in lipodystrophy and the effects of leptin replacement on these ANGPTLs are unknown. Objective To examine if ANGPTL3/4 levels are elevated in patients with generalized lipodystrophy and assess the effects of leptin replacement on these ANGPTLs. Methods Preleptin treatment plasma levels of ANGPTLs in patients with generalized lipodystrophy (n = 22) were compared with healthy controls (n = 39) using a post hoc case-control study design. In a prospective open-label study, we studied the effects of metreleptin therapy (16–32 weeks) on plasma ANGPTL3/4 in patients with generalized lipodystrophy. Results Plasma ANGPTL3 (geometric mean [95% confidence interval]; 223 [182–275] vs 174 ng/mL [160–189], P = .02) but not ANGPTL4 levels (55 [37–81] vs 44 ng/mL [37–52], P = .26) were higher in patients with lipodystrophy compared with healthy controls. There was a significant decrease in total cholesterol, triglycerides, and glycosylated hemoglobin (A1C) levels following metreleptin therapy. After metreleptin, ANGPTL3 concentrations decreased significantly (223 [182–275] vs 175 ng/mL [144–214], P = .01) with no change in ANGPTL4 (55 [37–81] vs 48 ng/mL [32–73], P = .11). Conclusions These findings suggest that elevated plasma levels of ANGPTL3 in leptin-deficient states is attenuated with leptin therapy.