Lipid Regulation in Lipodystrophy Versus the Obesity-Associated Metabolic Syndrome: The Dissociation of HDL-C and Triglycerides

Context: There is an inverse relationship between triglycerides and high-density lipoprotein cholesterol (HDL-C) in insulin resistance, such that improvement in insulin resistance decreases triglycerides and increases HDL-C. Patients with lipodystrophy have extreme insulin resistance with high triglycerides and low HDL-C. Leptin replacement in lipodystrophy leads to a marked decrease in triglycerides (similar to 60%). Objective: Our objective was to study the effects of metreleptin on triglycerides and HDL-C in lipodystrophy in contrast to changes in triglycerides and HDL-C in interventions for the obesity-associated metabolic syndrome. Design, Setting, and Patients: This open-label nonrandomized study at the National Institutes of Health included 82 patients with various forms of lipodystrophy. Intervention: Metreleptin (0.06-0.24 mg/kg/d) was administered for 24 months in lipodystrophy. Main Outcome Measures: Serum triglycerides and HDL-C were measured. Results: At baseline, lipodystrophy patients had low HDL-C (30 +/- 1 mg/dL) and high triglycerides (961 +/- 220 mg/dL) with an inverse relationship between the two (R = -0.37, P = .0006). There was no change in HDL-C with metreleptin despite major improvement in triglycerides, and individual changes in triglycerides only weakly predicted HDL-C change. On linear regression, in obesity, a decrease of 0.1 mg/dL in log(triglycerides) was associated with a 4.2 mg/dL rise in HDL-C, whereas in lipodystrophy, a decrease of 0.1 mg/dL in log(triglycerides) was associated with only a 0.6 mg/dL rise in HDL-C. Conclusions: The normal reciprocal relationship between triglyceride and HDL-C change seen in response to interventions for the obesity-associated metabolic syndrome is quantitatively different from that seen in lipodystrophy in response to metreleptin. Further work is needed to understand HDL-C regulation in this condition.