Lipid regulation in lipodystrophy versus the obesity-associated metabolic syndrome: the dissociation of HDL-C and triglycerides

Abstract

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 (∼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.

Trial registration: ClinicalTrials.gov NCT00025883.

Figure 1.

Change in log(triglycerides) and HDL-C in response to metreleptin in lipodystrophy compared with interventions for the obesity-associated MetSyn. Subject level data in lipodystrophy patients after 24 months of metreleptin is shown in open circles (linear regression as dashed line). Mean changes in log(triglyceride) vs HDL-C at 6, 12, and 18 months of metreleptin treatment in lipodystrophy are shown as filled circles, falling on the same regression line as that for individual subjects at 24 months. Mean changes in log(triglyceride) and HDL-C from clinical trials in the obesity associated metabolic syndrome are shown as black squares (linear regression in black line). There was a 7-fold difference in the HDL-C increase associated with a given log(triglyceride) decrease in lipodystrophy vs the obesity-associated MetSyn.