SAT-081 Advanced Lipoprotein Analysis Demonstrates Atherogenic Lipid Profile in Patients with Lipodystrophy That Improves after Metreleptin Treatment

Abstract

Lipodystrophies (LD) are defined by deficient adipose tissue, causing low leptin and metabolic disease including severe insulin resistance and hypertriglyceridemia. Recombinant leptin (metreleptin, ML) treatment in LD improves insulin resistance and lowers triglycerides without changing HDL. Detailed measurement of lipoprotein particles using NMR spectroscopy can offer insights into cardiovascular disease (CVD) risk and lipid metabolism beyond a standard lipid panel and has never been performed in LD. We hypothesized that patients with LD would have a more atherogenic lipid profile than controls at baseline, which would be ameliorated with ML treatment secondary to improvements in insulin sensitivity. Patients with LD (N=17) were enrolled in a study evaluating short- and long-term effects of ML on metabolic disease and compared to 51 insulin sensitive (SI<3 on IV glucose tolerance test) sex-matched controls. Lipoprotein profiles were assessed on samples obtained after a 10-12 hour fast using a new deconvolution algorithm, LP4, which reports 27 triglyceride rich lipoprotein particles (TRLP) and 7 HDL particles (HDLP). The major categories are small, medium, and large HDLP and LDL particles (LDLP) and very small, small, medium, large, and very large TRLP. LP4 was compared in controls vs. patients with LD prior to ML. LP4 was compared in patients with LD before vs. after 14 days and 6 months of ML. Particle size, concentration, and concentration of subclasses by size were measured for LDLP, HDLP, and TRLP. Insulin sensitivity before and after ML was measured as glucose disposal (mg/kgFFM/min) during hyperinsulinemic euglycemic clamp. Patients and controls did not differ by age, weight, or BMI. Patients with LD had elevated large TRLP and smaller sized HDLP and LDLP, all associated with increased atherogenicity, vs. controls. Five of 17 patients with LD had chylomicrons present, vs. 0 of 51 controls. ML treatment in LD decreased size and concentration of TRLP, eliminated chylomicrons in all but 1 patient, decreased LDLP concentration, and increased LDLP size. ML treatment did not have major effects on HDLP. Prior to ML in patients with LD, insulin sensitivity negatively correlated with very large TRLP (r= -0.76, p= 0.0007), TRLP size (r= -0.52, p= 0.04), and TRLP TG (r= -0.58, p= 0.02). Short term (Day 0 to Day 14) and long-term changes (Day 0 to 6 months) in insulin sensitivity were not significantly correlated with changes in any lipoprotein parameter. In conclusion, patients with LD had an atherogenic lipoprotein profile at baseline consistent with increased CVD risk, which improved after ML treatment. The presence of fasting chylomicrons in a subset of patients with LD suggests saturation of chylomicron clearance by lipoprotein lipase. Improvements in lipoprotein parameters with ML were independent of improved insulin sensitivity, possibly due to direct effects of ML on lipoprotein metabolism.