Metreleptin Research Articles

Impaired functional exercise capacity and greater cardiovascular response to the 6-min walk test in congenital generalized lipodystrophy

BackgroundCongenital Generalized Lipodystrophy (CGL) is an ultra-rare disease characterized by metabolic disorders. However, the evaluation of functional exercise capacity, cardiovascular (CV) response to exercise, and peripheral arterial disease (PAD) in CGL is scarce. Here we evaluated the performance and CV response to exercise and their association with PAD in CGL compared to healthy individuals.MethodsTwelve CGL and 12 healthy subjects matched for age and gender were included. Functional exercise capacity, CV response, and PAD were measured using the six-minute walk test (6MWT) and ankle-brachial index (ABI), respectively.ResultsAt baseline, CGL subjects showed reduced predicted walked distance (6MWD) (p = 0.009) and increased heart rate (HR), systolic (SBP), and diastolic (DBP) pressures compared to healthy subjects (p < 0.05). Most CGL subjects presented normal ABI values (1.0 ≤ ABI ≤ 1.4). Only 25% (n = 3) had ABI ≤ 0.9. CGL subjects did not present changes in ABI and blood pressure 12 months after metreleptin (MLP) replacement, but they walked a greater 6MWD than baseline (p = 0.04). Further, 6MWD and right ABI measurements were positively correlated in CGL subjects (p = 0.03). Right ABI negatively correlated with glucose, triglycerides, and VLDL-c (p < 0.05).ConclusionsWe observed that CGL subjects had lower functional exercise capacity and higher cardiovascular effort for similar performance of 6MWT, suggesting that strategies for decreasing exercise effort in this population should be essential. Furthermore, better physical performance was associated with high ABI in CGL. Additional studies are needed to clarify leptin's role in preserving functional exercise capacity in CGL.

Máculas hiperpigmentadas: una reacción adversa del tratamiento con metreleptina

Máculas hiperpigmentadas: una reacción adversa del tratamiento con metreleptina

Correction to: Metreleptin in lipodystrophy: a profile of its use

Correction to: Metreleptin in lipodystrophy: a profile of its use

Immunogenicity of Metreleptin in Patients With Generalized Lipodystrophy

Immunogenicity of Metreleptin in Patients With Generalized Lipodystrophy

SUN-087 Effects of Leptin Replacement on Circulating Plasma Inhibitors of Lipoprotein Lipase in Patients with Lipodystrophy

Lipodystrophy syndromes (LD) result from selective deficiency of adipose tissue, leading to low leptin. Low leptin leads to hyperphagia and ectopic lipid storage, causing severe insulin resistance and metabolic complications including high triglycerides (TG) and subsequent pancreatitis. Replacement of leptin using metreleptin (ML) in LD decreases TG. TG are broken down to non-esterified fatty acids (NEFA) by lipoprotein lipase (LPL). We previously demonstrated that patients with LD had high apoCIII and ANGPLT8 (inhibitors of LPL) that decreased with ML, suggesting that ML may lower TG by reducing inhibition of LPL activity. We hypothesized that plasma from patients with LD would cause greater inhibition of LPL compared to controls, and that ML would ameliorate this. We further hypothesized that net inhibition of LPL in LD would be reflected by a decreased ratio of apoCII (an LPL stimulator) to apoCIII (an LPL inhibitor) vs. controls. METHODS: Plasma from ML-naive patients with LD (n=14) and a pooled high-TG control group (651 mg/dL, n=10) were diluted to the same concentration of TG. Samples were incubated with bovine LPL, and NEFA produced was measured enzymatically over 1hr at 37⁰C. Because the concentrations of added LPL and TG were equal in each patient sample, NEFA generation (nmole) reflected the net effect of LPL stimulators and inhibitors in plasma. To test the effects of ML, the same method was applied to samples from patients with LD after ML 5 mg Q12h for 2 weeks and 6 months. ApoCII and apoCIII were compared in patients with LD (n=14) versus healthy controls (TG = 74 [54, 97] mg/dL, n=28). RESULTS: Patients with LD had baseline TG 492 [208, 1016] mg/dL which decreased to 279 [171, 648] after 2 weeks of ML (n=14, p=.0023) and to 223 [118, 335] after 6 months of ML (n=11, p=0.15). Prior to ML, patients with LD had higher NEFA generation vs. controls (patients 0.79 ± 0.08; controls 0.59 ± 0.1; p<0.0001), consistent with less net inhibition of LPL. NEFA generation did not change with ML therapy after 2 weeks (0.77 ± 0.09) or 6 months (0.78 ± 0.12) compared to baseline (p>0.05). ApoCII:apoCIII ratio did not differ in LD vs controls (0.63±0.31 vs 0.54±0.17, p=0.6), and did not change after ML. CONCLUSIONS: Counter to our hypothesis, patients with LD had higher NEFA generation compared to high TG controls, consistent with less net inhibition of LPL, while the ratio of LPL activator (apoCII) to inhibitor (apoCIII) did not differ in LD vs normal TG controls. Furthermore, NEFA generation and apoCII:apoCIII ratio did not change after ML therapy, suggesting no net change in inhibition of LPL with ML. These findings suggest that changes in circulating activators and inhibitors of LPL are not a major mechanism by which ML lowers TG in LD. Studies including direct measurement of LPL activity after heparin stimulation are needed to further explore the role of LPL in regulating TG in LD.

Efficacy of Metreleptin for Weight Loss in Overweight and Obese Adults with Low Leptin Levels

Leptin, an adipokine, regulates appetite, glucose and fat metabolism, and neuroendocrine function. A post-hoc pooled analysis of 4 studies (N=1064) in adults with BMI 27.0-40.0 kg/m2 showed that metreleptin (MTL), a leptin analogue, reduced weight in subgroups of adults with low baseline (BL) leptin levels (Fig. 1). A subsequent study (N=267) in adults with low BL leptin (females, ≤16 ng/mL; males, ≤5 ng/mL) and BMI 27.5-38.0 kg/m2 was conducted. Subjects (64% female; mean [SD] BL leptin, 14.2 [13.3] ng/mL) received QD subcutaneous MTL 10 mg, MTL 20 mg, or placebo. Both MTL doses decreased weight over time among subjects with low BL leptin (Fig. 2). MTL 20 mg showed statistically significant decreases by week 8. MTL was well tolerated. Thus, MTL 20 mg QD holds promise for weight loss among overweight and obese adults with low leptin levels. Disclosure A. DePaoli: Research Support; Self; Eli Lilly and Company, Merck Sharp &amp; Dohme Corp. A. Long: Employee; Self; Aegerion Pharmaceuticals. G.M. Fine: Employee; Self; Aegerion Pharmaceuticals. M. Stewart: Employee; Self; Novelion. Stock/Shareholder; Self; Novelion. S. O'rahilly: Advisory Panel; Self; Aegerion Pharmaceuticals, Pfizer Inc., AstraZeneca, MedImmune, Novo Nordisk Inc., ERX Pharmaceuticals, Inc..

Abstract #727: Impact of Metreleptin on Hepatomegaly in Patients with Generalized Lipodsytrophy

Abstract #727: Impact of Metreleptin on Hepatomegaly in Patients with Generalized Lipodsytrophy

Early intracellular signaling events induced by in vitro metreleptin administration in cardiac myocytes and uterine smooth muscle cells.

Intracellular signaling pathways regulated by leptin have largely been studied in metabolically important organs such as adipose tissue and peripheral blood mononuclear cells, suggesting that leptin plays a key role in pathophysiology of insulin resistance. However, whether synthetic analog of leptin, metreleptin, has similar effects on cardiac myocytes (CM) and uterine smooth muscle cells (USMC) has not yet been studied. Hence, in order to address these questions, we extended previous observations and investigated in vitro signaling study whether metreleptin may activate key signaling pathways. We observed that metreleptin activates Jak2 and STAT3 signaling pathways in dose- and time-dependent manner in CM and USMC. Also, we found that metreleptin increases ERK1/2, JNK and/or p38 phosphorylation in CM. In vitro metreleptin administration also increased ERK1/2 and/or p38 phosphorylation in USMC. By contrast, JNK was not regulated by in vitro metreleptin administration in USMC. Moreover, metreleptin-activated all signaling pathways were blocked by pre-treatment of PD98095 (ERK inhibitor), SB203580 (p38 inhibitor) and/or SP600125 (JNK inhibitor), respectively. Finally, metreleptin increased cell size (hypertrophy) in both CM and USMC. Our data provide novel insights into the role of Jak2, STAT3, ERK1/2, JNK and/or p38 as probable mediators of the action of leptin in regulating hypertrophy in CM and USMC.

Recombinant human leptin treatment in genetic lipodystrophic syndromes: the long-term Spanish experience

Lipodystrophies are a group of diseases mainly characterized by a loss of adipose tissue and frequently associated with insulin resistance, hypertriglyceridemia, and hepatic steatosis. In uncommon lipodystrophies, these complications frequently are difficult to control with conventional therapeutic approaches. This retrospective study addressed the effectiveness of recombinant methionyl leptin (metreleptin) for improving glucose metabolism, lipid profile, and hepatic steatosis in patients with genetic lipodystrophic syndromes. We studied nine patients (five females and four males) with genetic lipodystrophies [seven with Berardinelli-Seip syndrome, one with atypical progeroid syndrome, and one with type 2 familial partial lipodystrophy (FPLD)]. Six patients were children under age 9 years, and all patients had baseline triglycerides levels >2.26 mmol/L and hepatic steatosis; six had poorly controlled diabetes mellitus. Metreleptin was self-administered subcutaneously daily at a final dose that ranged between 0.05 and 0.24 mg/(kg day) [median: 0.08 mg/(kg day)] according to the body weight. The duration of treatment ranged from 9 months to 5 years, 9 months (median: 3 years). Plasma glucose, hemoglobin A1c (Hb A1c), lipid profile, plasma insulin and leptin, and hepatic enzymes were evaluated at baseline and at least every 6 months. Except for the patient with FPLD, metreleptin replacement significantly improved metabolic control (Hb A1c: from 10.4 to 7.1 %, p < 0.05). Plasma triglycerides were reduced 76 % on average, and hepatic enzymes decreased more than 65 %. This study extends knowledge about metreleptin replacement in genetic lipodystrophies, bearing out its effectiveness for long periods of time.

A leptina e o seu impacto metabólico nas lipodistrofias

Leptin is a hormone produced predominantly by adipocytes, essential in energy homeostasis regulation. It acts as a sensor of body fat mass stores, being involved in lipids control in non adipose tissues, food intake and thermogenesis with subsequent metabolic implications.Leptin administration in replacement doses constitutes an important step forward in the understanding and treatment of various lipodystrophic syndromes, conditions characterized by a hypoleptinemic state. Particularly, recombinant methionyl leptin administration in patients with lipodystrophy exhibiting severe hypoleptinemia ameliorated hyperinsulinemia, insulin resistance, hyperglycemia, hypertriglyceridemia, and neuroendocrine abnormalities without significant adverse effects, providing the rationale for metreleptin treatment in these patients.

Metreleptin Improves Blood Glucose in Patients With Insulin Receptor Mutations

Rabson-Mendenhall syndrome (RMS) is caused by mutations of the insulin receptor and results in extreme insulin resistance and dysglycemia. Hyperglycemia in RMS is very difficult to treat, and patients are at risk for early morbidity and mortality from complications of diabetes. Our objective was to study 1-year effects of recombinant human methionyl leptin (metreleptin) in 5 patients with RMS and 10-year effects in 2 of these patients. We conducted an open-label nonrandomized study at the National Institutes of Health. Patients were adolescents with RMS and poorly controlled diabetes. Two patients were treated with escalating doses (0.02 up to 0.22 mg/kg/d) of metreleptin for 10 years, including 3 cycles of metreleptin withdrawal and reinitiation. In all 5 patients, 1-year effects of metreleptin (0.22 mg/kg/d) were studied. Hemoglobin A1c (HbA1c) and body mass index (BMI) z-scores were evaluated every 6 months. HbA1c decreased from 11.4% ± 1.1% at baseline to 9.3% ± 1.9% after 6 months and 9.7% ± 1.6% after 12 months of metreleptin (P = .007). In patients treated for 10 years, HbA1c declined with each cycle of metreleptin and rose with each withdrawal. BMI z-scores declined from -1.4 ± 1.8 at baseline, to -2.6 ± 1.6 after 12 months of metreleptin (P = .0006). Changes in BMI z-score correlated with changes in HbA1c (P < .0001). Metreleptin treatment for 12 months was associated with a 1.7% reduction in HbA1c; part of this improvement was likely mediated via decreased BMI. Metreleptin is a promising treatment option for RMS, but additional therapies are needed to achieve HbA1c targets.

Congenital leptin deficiency and thyroid function

Thyroid function is closely related to leptin's secretion by the adipose tissue. In states of leptin-deficiency, the circadian rhythm of TSH is altered, leading to central hypothyroidism in animal models. In humans, central hypothyroidism has also been described in rare cases of congenital leptin deficiency. However, the thyroid phenotype in these cases is heterogeneous, with the occurrence of central hypothyroidism in a minority of cases. Here we describe thyroid function in four leptin-deficient humans (2 males aged 5 and 27, and 2 females aged 35 and 40), before and during leptin replacement with recombinant human methionyl leptin (r-metHuLeptin). The child was evaluated for four years, and the adults, for eight years. In addition, the adults were submitted to a brief withdrawal of leptin during six weeks in the sixth year. Our results show that, regardless of leptin replacement, our leptin-deficient patients have normal thyroid function. In spite of having an important role in regulating the hypothalamic-pituitary-thyroidal axis, leptin is not required for normal thyroid function.ClinicalTrials.gov Identifiers: NCT00659828 and NCT00657605

Metreleptin promising in lipodystrophy

Metreleptin promising in lipodystrophy