Leptin Attenuates Cardiac Hypertrophy in Patients With Generalized Lipodystrophy

Abstract

Context: Lipodystrophy syndromes are rare disorders of deficient adipose tissue, low leptin, and severe metabolic disease, affecting all adipose depots (generalized lipodystrophy, GLD) or only some (partial lipodystrophy, 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.

Methods: 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 to 5 years (N = 23) of metreleptin. Outcomes were echocardiograms, blood pressure (BP), triglycerides, A1c, and homeostasis model assessment of insulin resistance.

Results: In GLD, metreleptin lowered triglycerides (median [interquartile range] 740 [403-1239], 138 [88-196], 211 [136-558] mg/dL at baseline, 1 year, 3-5 years, P < .0001), A1c (9.5 ± 3.0, 6.5 ± 1.6, 6.5 ± 1.9%, P < .001), and HOMA-IR (34.1 [15.2-43.5], 8.7 [2.4-16.0], 8.9 [2.1-16.4], P < .001). Only HOMA-IR improved in PLD (P < .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 < .01), and LV mass (140.7 ± 45.9, 128.7 ± 37.9, 110.9 ± 29.1 g, P < .01), and increased septal e' velocity (8.6 ± 1.7, 10.0 ± 2.1, 10.7 ± 2.4 cm/s, P < .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.

Trial registration: ClinicalTrials.gov NCT00025883 NCT00001987 NCT01778556.

Keywords: Leptin; cardiomyopathy; left ventricular hypertrophy; lipodystrophy.

Published by Oxford University Press on behalf of the Endocrine Society 2021.

Figures

Figure 1.

Flow diagram of subjects participating in the study.

Figure 2.

Changes in measures of left ventricular (LV) hypertrophy, including (A) interventricular septum thickness, (B) posterior wall thickness, (C) LV mass, (D) LV mass index, and diastolic parameters including (E) septal e′ velocity and (F) E/A ratio from baseline (prior to metreleptin), to after 1 and 3 to 5 years of metreleptin. The subgroup with generalized lipodystrophy is shown as black circles with solid lines, and the subgroup with partial lipodystrophy as white squares with dashed lines. P values derive from mixed models including all time points. Asterisks indicate Dunnett-corrected P < .05 from baseline to 1 year or 3-5 years on post hoc testing. Graphs show mean and 95% confidence interval.

Figure 3.

Probability of having (A) interventricular septum thickness, (B) posterior wall thickness, and (C) left ventricular mass index above the normal range at time 0 (prior to metreleptin), and after 1 and 3 to 5 years of metreleptin. The combined cohort of generalized plus partial lipodystrophy is shown in gray bars, the subgroup with generalized lipodystrophy in black bars, and the subgroup with partial lipodystrophy in white bars. P values and probabilities derive from mixed models including all time points. Asterisks indicate Dunnett-corrected P < .05 from time 0 to time 1 or 3 to 5 on post hoc testing. Error bars indicate standard error of the mean.