Selection of Leptin Surrogates by a General Phenotypic Screening Method for Receptor Agonists.

There is a high demand for agonist biomolecules such as cytokine surrogates in both biological and medicinal research fields. These are typically sourced through natural ligand engineering or affinity-based screening, followed by individual functional validation. However, efficient screening methods for identifying rare hits within immense libraries are very limited. In this research article, we introduce a phenotypic screening method utilizing biological receptor activation-dependent cell survival (BRADS). This method offers a high-throughput, low-background, and cost-effective approach that can be implemented in virtually any biochemical laboratory setting. As a proof-of-concept, we successfully identified a surrogate for human leptin following a two-week cell culture process, without the need for specialized high-throughput equipment or reagents. This surrogate effectively emulates the activity of native human leptin in cell validation assays. Our findings not only underscore the effectiveness of BRADS but also suggest its potential applicability to a broad range of biological receptors, including Notch and GPCRs.

Therapeutic indications and metabolic effects of metreleptin in patients with lipodystrophy syndromes: Real-life experience from a national reference network.

AIM: To describe baseline characteristics and follow-up data in patients with lipodystrophy syndromes treated with metreleptin in a national reference network, in a real-life setting. PATIENTS AND METHODS: Clinical and metabolic data from patients receiving metreleptin in France were retrospectively collected, at baseline, at 1 year and at the latest follow-up during treatment. RESULTS: Forty-seven patients with lipodystrophy including generalized lipodystrophy (GLD; n = 28) and partial lipodystrophy (PLD; n = 19) received metreleptin over the last decade. At baseline, the median (interquartile range [IQR]) patient age was 29.3 (16.6-47.6) years, body mass index was 23.8 (21.2-25.7) kg/m2 and serum leptin was 3.2 (1.0-4.9) ng/mL, 94% of patients had diabetes (66% insulin-treated), 53% had hypertension and 87% had dyslipidaemia. Metreleptin therapy, administered for a median (IQR) of 31.7 (14.2-76.0) months, was ongoing in 77% of patients at the latest follow-up. In patients with GLD, glycated haemoglobin (HbA1c) and fasting triglyceride levels significantly decreased from baseline to 1 year of metreleptin treatment, from 8.4 (6.5-9.9)% [68 (48-85) mmol/mol] to 6.8 (5.6-7.4)% [51(38-57) mmol/mol], and 3.6 (1.7-8.5) mmol/L to 2.2 (1.1-3.7) mmol/L, respectively (P < 0.001), with sustained efficacy thereafter. In patients with PLD, HbA1c was not significantly modified (7.7 [7.1-9.1]% [61 (54-76) mmol/mol] at baseline vs. 7.7 [7.4-9.5]% [61(57-80) mmol/mol] at 1 year), and the decrease in fasting triglycerides (from 3.3 [1.9-9.9] mmol/L to 2.5 [1.6-5.3] mmol/L; P < 0.01) was not confirmed at the latest assessment (5.2 [2.2-11.3] mmol/L). However, among PLD patients, at 1 year, 61% were responders regarding glucose homeostasis, with lower baseline leptin levels compared to nonresponders, and 61% were responders regarding triglyceridaemia. Liver enzymes significantly decreased only in the GLD group. CONCLUSIONS: In this real-life setting study, metabolic outcomes are improved by metreleptin therapy in patients with GLD. The therapeutic indication for metreleptin needs to be clarified in patients with PLD.

Congenital generalized lipodystrophy type 4 due to a novel PTRF/CAVIN1 pathogenic variant in a child: effects of metreleptin substitution.

OBJECTIVES: Congenital generalized lipodystrophies (CGLs) are a heterogeneous group of rare autosomal recessive disorders characterized by near/total absence of body fat. Pathogenic variants in polymerase-I and transcript release factor gene (PTRF), or CAVIN1, is responsible for CGL4. In addition to generalized fat loss, patients with CGL4 were reported to suffer from myopathy, malignant cardiac arrhythmias, gastrointestinal disorders, and skeletal abnormalities. Here we describe the phenotype of a child with CGL4 due to a rare, novel pathogenic variant in the PTRF/CAVIN1 gene and the long-term effects of metreleptin substitution on comorbidities. CASE PRESENTATION: We describe a now 20-year-old female patient. At the age of 14-years, she was referred to the University Clinic because of uncontrolled diabetes with an HbA1c of 9.3%, requiring 2.4 IU insulin/kg total-body-weight to normalize blood glucose, hepatomegaly, and hypertriglyceridemia of 515 mg/dL. Additionally, she was suffering from malignant cardiac arrhythmia, myopathy, and hyperCKemia. In light of these clinical findings, she was diagnosed with CGL due to a rare, novel variant in the PTRF gene, and was started on metreleptin, a synthetic analog of human leptin. After the initiation of metreleptin treatment, insulin therapy could be stopped and improvement of sonographically assessed liver size was observed, even though serum liver function test stayed mildly elevated. Furthermore, a noticeable improvement of the serum triglyceride levels was also seen. Medical care and regular follow-up visits are being carried out by a multi-disciplinary team. CONCLUSIONS: Although CGL4 is rare, due to its life-threatening comorbidities and the opportunity for an early intervention, it is important that the clinicians should recognise these patients.

Endogenous Leptin Concentrations Poorly Predict Metreleptin Response in Patients With Partial Lipodystrophy.

CONTEXT: Leptin replacement with metreleptin improves glycemia and hypertriglyceridemia in severely hypoleptinemic patients with generalized lipodystrophy (GLD), but its effects are variable in partially leptin-deficient patients with partial lipodystrophy (PLD). OBJECTIVE: Compare 3 leptin assays (Study I); identify diagnostic performance of leptin assays to detect responders to metreleptin for each assay (Study II). DESIGN: Study I: cross-sectional analysis of average bias between leptin assays. Study II: retrospective analysis of diagnostic accuracy of potential leptin cut points to detect clinical responders to metreleptin. SETTING: National Institutes of Health; University of Michigan. PARTICIPANTS AND INTERVENTIONS: Study I: Metreleptin-naïve patients with lipodystrophy (GLD, n = 33, PLD, n = 67) and healthy volunteers (n = 239). Study II: GLD (n = 66) and PLD (n = 84) patients treated with metreleptin for 12 months. OUTCOME MEASURES: Leptin concentrations by Millipore radioimmunoassay (RIA), Millipore enzyme-linked immunosorbent assay (MELISA), and R&D Systems enzyme-linked immunosorbent assay (RDELISA). Response to metreleptin therapy was defined as either reduction ≥1.0% in A1c or ≥30% in serum triglycerides. RESULTS: RDELISA measured 3.0 ± 9.5 ng/mL higher than RIA; MELISA measured 11.0 ± 17.8 and 14.0 ±19.2 less than RIA and RDELISA, respectively. Leptin by RIA, MELISA, and RDELISA modestly predicted metreleptin response in GLD + PLD [receiver operating characteristic (ROC) area under the curve (AUC) 0.74, 0.69, and 0.71, respectively; P < 0.01 for all] with lower predictive power in PLD (ROC AUC 0.63, 0.61 and 0.65, respectively; P > 0.05 for all). The only reproducible cut point identified on sensitivity analyses was RIA leptin 7.2 ng/mL (sensitivity 56%; specificity 78%). CONCLUSIONS: Three common leptin assays are not interchangeable, and a reliable cut point to select responders to metreleptin was not identified.

Rapid amelioration of anorexia nervosa in a male adolescent during metreleptin treatment including recovery from hypogonadotropic hypogonadism.

With this case report we support our medical hypothesis that metreleptin treatment ameliorates starvation related emotional, cognitive and behavioral symptomatology of anorexia nervosa (AN) and show for the first time strong effects in a male patient with AN. A 15.9 year old adolescent with severe AN of eight-month duration was treated off-label with metreleptin. Hyperactivity was assessed with accelerometry. Visual analogue scales (VAS), validated self- and clinician rating scales and lab results tracked changes from baseline to end of the 24-day dosing period and a five-month follow-up. Substantial improvements of mood and eating disorder related cognitions and hyperactivity set in after two days of treatment. During dosing, sub-physiological testosterone and TT3 levels normalized; clinically libido reemerged. Weight did not increase substantially during the dosing period. During follow-up target weight was attained; mood did not deteriorate; hyperactivity ceased. The results substantiate the strong effects seen in female cases and underscore the need for a double-blind placebo-controlled trial to confirm the observed strong, multiple and rapid onset beneficial effects of metreleptin in AN.

Long-Term Effects of Metreleptin in Rabson-Mendenhall Syndrome on Glycemia, Growth, and Kidney Function.

CONTEXT: Rabson-Mendenhall syndrome (RMS) is caused by biallelic pathogenic variants in the insulin receptor gene (INSR) leading to insulin-resistant diabetes, microvascular complications, and growth hormone resistance with short stature. Small, uncontrolled studies suggest that 1-year treatment with recombinant leptin (metreleptin) improves glycemia in RMS. OBJECTIVE: This study aimed to determine effects of long-term metreleptin in RMS on glycemia, anthropometrics, the growth hormone axis, and kidney function. METHODS: We compared RMS patients during nonrandomized open-label treatment with metreleptin (≥ 0.15 mg/kg/day) vs no metreleptin over 90 months (5 subjects in both groups at different times, 4 only in metreleptin group, 2 only in control group). Main outcome measures were A1c; glucose; insulin; 24-hour urine glucose; standard deviation scores (SDS) for height, weight, body mass index (BMI), and insulin-like growth factor 1 (IGF-1); growth hormone; and estimated glomerular filtration rate. RESULTS: Over time, metreleptin-treated subjects maintained 1.8 percentage point lower A1c vs controls (P = 0.007), which remained significant after accounting for changes in insulin doses. Metreleptin-treated subjects had a reduction in BMI SDS, which predicted decreased A1c. Growth hormone increased after metreleptin treatment vs control, with no difference in SDS between groups for IGF-1 or height. Reduced BMI predicted higher growth hormone, while reduced A1c predicted higher IGF-1. CONCLUSION: Metreleptin alters the natural history of rising A1c in RMS, leading to lower A1c throughout long-term follow-up. Improved glycemia with metreleptin is likely attributable to appetite suppression and lower BMI SDS. Lower BMI after metreleptin may also worsen growth hormone resistance in RMS, resulting in a null effect on IGF-1 and growth despite improved glycemia.

Familial partial lipodystrophy syndromes.

Lipodystrophies are a heterogeneous group of rare conditions characterised by the loss of adipose tissue. The most common forms are the familial partial lipodystrophy (FPLD) syndromes, which include a set of disorders, usually autosomal dominant, due to different pathogenetic mechanisms leading to improper fat distribution (loss of fat in the limbs and gluteal region and variable regional fat accumulation). Affected patients are prone to suffering serious morbidity via the development of metabolic complications associated to insulin resistance and an inability to properly store lipids. Although no well-defined diagnostic criteria have been established for lipodystrophy, there are certain clues related to medical history, physical examination and body composition evaluation that may suggest FPLD prior to confirmatory genetic analysis. Its treatment must be fundamentally oriented towards the control of the metabolic abnormalities. In this sense, metreleptin therapy, the newer classes of hypoglycaemic agents and other investigational drugs are showing promising results. This review aims to summarise the current knowledge of FPLD syndromes and to describe their clinical and molecular picture, diagnostic approaches and recent treatment modalities.

Effects of metreleptin in patients with lipodystrophy with and without baseline concomitant medication use.

OBJECTIVE: To evaluate the effects of metreleptin in distinct subgroups of patients with generalized lipodystrophy (GL) and partial lipodystrophy (PL), using multivariate linear regression modeling to account for the role of patients' baseline usage of concomitant glucose and lipid-lowering medications and other covariates on their outcomes. MATERIALS AND METHODS: A post-hoc statistical analysis of two published single-arm, interventional, phase 2 clinical trials at NIH was conducted. Concomitant medication use was assessed for the clinical trial population using prescription fill data, measured at baseline and the post-one year following metreleptin initiation. Pre-specified co-primary efficacy endpoints measured were change from baseline in HbA1c at month 12, and the percent change from baseline in fasting serum triglycerides (TG) at month 12. Descriptive and statistical analyses were conducted for the overall population, the separate populations with GL and PL, and additional PL subgroups defined by baseline metabolic markers of elevated HbA1c and elevated fasting TG. RESULTS: As previously reported, improvement in HbA1c and fasting TG from baseline to 12 months on metreleptin were observed in the overall population (mean change -1.57 percentage points and median change -37.9%, respectively) and subgroups. For both HbA1c and TG, baseline levels were significant predictors of changes after metreleptin. After considering baseline characteristics such as disease type, age, sex, and baseline HbA1c, baseline insulin use was not found to be a significant predictor of HbA1c improvement following metreleptin initiation. Similar results were seen for TG levels, with the use of any lipid-lowering medications at baseline not found to be a significant predictor of reductions in fasting TG levels. CONCLUSIONS: Patients treated with metreleptin experienced statistically significant improvement in metabolic markers of glycemic and hypertriglyceridemic control-e.g. HbA1c and triglyceride levels-across various subgroups after controlling for baseline characteristics and concomitant medication usage.

Metreleptin treatment of non-HIV lipodystrophy syndromes.

Lipodystrophy syndromes (LS) constitute a group of rare diseases of the adipose tissue, characterized by a complete or selective deficiency of the fat mass. These disorders are associated with important insulin resistance, cardiovascular and metabolic comorbidities that impact patient's survival and quality of life. Management is challenging and includes diet, physical activity, and specific pharmacological treatment of LS-associated comorbidities. Because of a common pathophysiology involving decreased concentration of the adipokine leptin, efforts have been made to develop therapeutic strategies with leptin replacement therapy. Metreleptin, a recombinant human leptin analogue, has been proposed in hypoleptinemic patients since the beginning of 2000's. The treatment leads to an improvement in metabolic parameters, more important in generalized than in partial LS forms. In this review, the current knowledge about the development of the drug, its outcomes in the treatment of lipodystrophic patients as well as the peculiarities of its use will be presented.

Leptin Attenuates Cardiac Hypertrophy in Patients With Generalized Lipodystrophy.

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 ±â€…3.0, 6.5 ±â€…1.6, 6.5 ±â€…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 ±â€…1.7, 9.1 ±â€…1.3, 8.3 ±â€…1.7 mm, P < .01), and LV mass (140.7 ±â€…45.9, 128.7 ±â€…37.9, 110.9 ±â€…29.1 g, P < .01), and increased septal e' velocity (8.6 ±â€…1.7, 10.0 ±â€…2.1, 10.7 ±â€…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.

Case Report: Metreleptin and SGLT2 Inhibitor Combination Therapy Is Effective for Acquired Incomplete Lipodystrophy.

Childhood cancer survivors (CCSs) who have undergone bone marrow transplantation with systemic chemotherapy and whole-body irradiation often experience impaired glucose tolerance with marked insulin resistance. Incomplete acquired diabetic lipodystrophy should be considered as a late complication of bone marrow transplantation. A 24-year-old Japanese female patient with incomplete acquired lipodystrophy, a CCS of acute lymphocytic leukemia at the age of 3 years, was treated for diabetes mellitus and dyslipidemia at our hospital. Administration of multiple daily insulin injections (70 units/day), and oral administration of 500 mg/day metformin, 15 mg/day pioglitazone, and 200 mg/day bezafibrate had proven ineffective for her metabolic disorders. Subcutaneous administration of metreleptin improved her insulin resistance and hypertriglyceridemia within a month; however, it failed to maintain adequate plasma glucose levels in the long term. When oral administration of 10 mg/day empagliflozin was added to the metreleptin supplementation, her HbA1c value (National Glycohemoglobin Standardization Program) improved from 11% to 8%, which was maintained for an additional 18 months. This is the first case report of incomplete lipodystrophy that shows efficacy of a combination therapy with metreleptin and a sodium glucose cotransporter 2 (SGLT2) inhibitor for the treatment of diabetes and dyslipidemia. An SGLT2 inhibitor attenuates hyperglycemia through urinary glucose excretion and has been suggested to enhance lipid catabolism in the extra-adipose tissues, especially in the liver and skeletal muscles. Furthermore, metreleptin supplementation could enhance the action of the SGLT2 inhibitor by promoting satiety and lipolysis through the central nervous system. Combination therapy with metreleptin and an SGLT2 inhibitor was suggested to recover the volume of adipose tissue, possibly through improvement of insulin resistance in the adipose tissue. This report highlights the pathophysiological mechanism of an SGLT2 inhibitor in the improvement of glucose metabolism in non-healthy lean CCSs with insulin resistance. Administration of SGLT2 inhibitor, along with metreleptin supplementation, could be a good alternative therapy for diabetic lipodystrophy observed in CCSs.

Case Report: Metreleptin Treatment in a Patient With a Novel Mutation for Familial Partial Lipodystrophy Type 3, Presenting With Uncontrolled Diabetes and Insulin Resistance.

Background: Familial partial lipodystrophy type 3 (FPLD3) is a very rare autosomal dominant genetic disorder which is caused by mutations in the peroxisome proliferator activated receptor gamma (PPARG) gene. It is characterized by a partial loss of adipose tissue leading to subnormal leptin secretion and metabolic complications. Metreleptin, a synthetic analogue of human leptin, is an effective treatment for generalized lipodystrophies, but the evidence for efficacy in patients with FPLD3 is scarce. Case Presentation: We present a 61-year-old woman, initially misdiagnosed as type 1 diabetes since the age of 29, with severe insulin resistance, who gradually displayed a more generalized form of lipoatrophy and extreme hypertriglyceridemia, hypertension and multiple manifestations of cardiovascular disease. She was found to carry a novel mutation leading to PPARGGlu157Gly variant. After six months of metreleptin treatment, HbA1c decreased from 10 to 7.9% and fasting plasma triglycerides were dramatically reduced from 2.919 mg/dl to 198 mg/dl. Conclusions: This case highlights the importance of early recognition of FPLD syndromes otherwise frequently observed as difficult-to-classify and manages diabetes cases, in order to prevent cardiovascular complications. Metreleptin may be an effective treatment for FPLD3.

Leptin Decreases Energy Expenditure Despite Increased Thyroid Hormone in Patients With Lipodystrophy.

CONTEXT: Leptin is an adipokine that signals energy sufficiency. In rodents, leptin deficiency decreases energy expenditure (EE), which is corrected following leptin replacement. In humans, data are mixed regarding leptin-mediated effects on EE. OBJECTIVE: To determine the effects of metreleptin on EE in patients with lipodystrophy. DESIGN, SETTING, AND PATIENTS: Nonrandomized crossover study of 25 patients with lipodystrophy (National Institutes of Health, 2013-2018). INTERVENTION: The initiation cohort consisted of 17 patients without prior exposure to metreleptin, studied before and after 14 days of metreleptin. The withdrawal cohort consisted of 8 previously metreleptin-treated patients, studied before and after 14 days of metreleptin withdrawal. MAIN OUTCOMES: 24-h total energy expenditure (TEE), resting energy expenditure (REE), autonomic nervous system activity [heart rate variability (HrV)], plasma-free triiodothyronine (T3), free thyroxine (T4), epinephrine, norepinephrine, and dopamine. RESULTS: In the initiation cohort, TEE and REE decreased by 5.0% (121 ±â€…152 kcal/day; P = 0.006) and 5.9% (120 ±â€…175 kcal/day; P = 0.02). Free T3 increased by 19.4% (40 ±â€…49 pg/dL; P = 0.01). No changes in catecholamines or HrV were observed. In the withdrawal cohort, free T3 decreased by 8.0% (P = 0.04), free T4 decreased by 11.9% (P = 0.002), and norepinephrine decreased by 34.2% (P = 0.03), but no changes in EE, epinephrine, dopamine, or HrV were observed. CONCLUSIONS: Metreleptin initiation decreased EE in patients with lipodystrophy, but no changes were observed after metreleptin withdrawal. Thyroid hormone was higher on metreleptin in both initiation and withdrawal cohorts. Decreased EE after metreleptin in lipodystrophy may result from reductions in energy-requiring metabolic processes that counteract increases in EE via adipose tissue-specific neuroendocrine and adrenergic signaling.

Serum leptin level as a diagnostic and prognostic marker in infectious diseases and sepsis: A comprehensive literature review.

BACKGROUND: Infections and sepsis are common causes of morbidity and mortality, with an increasing incidence worldwide. Leptin is involved in the inflammatory process and may modulate the cytokine production, immune cell proliferation and endothelial function. There are conflicting results regarding alterations of leptin levels in infectious diseases and the outcome from sepsis.The aim of the current article is to provide an overview of the medical literature on the correlations between variations of leptin levels and infectious diseases and sepsis. METHODS: We performed an extensive literature search in PubMed and Google Scholar databases, using keywords to identify articles related to leptin in infectious diseases and sepsis. Searches were referenced using medical subject headings that included "leptin," "adipokines," "sepsis," "infectious diseases," "leptin deficiency," "leptin resistance" or "hyperleptinemia." The language of publication, journal, or country were not included as limitation criteria.Articles or abstracts containing adequate information, such as age, sex, anthropometric indices, clinical presentation, comorbidities, and management were included in the study, whereas articles with insufficient clinical and demographic data were excluded. We assessed the quality of the studies selected.The final review of all databases was conducted on June 18, 2020. RESULTS: We find the results from the current review to be of great importance due to the possible therapeutic role of leptin analogs in states of leptin deficiency associated with infectious diseases or sepsis.In hyperleptinemia, a therapeutic plan for obtaining leptin neutralization also needs further investigations. This could lead to the reduction of proinflammatory responses.There is a need for further studies to demonstrate the specificity and sensitivity of leptin in the early diagnosis of sepsis and the need to measure serum leptin levels in routine evaluation of the critical patient. CONCLUSION: The multiple effects of leptin are of growing interest, but further studies are needed to elucidate the role of leptin signalling in infectious diseases and sepsis. Because very few human studies are reported, we recommend the need for further research.Better understanding of the pathophysiology of sepsis and the implication of circulating total leptin in this process could help physicians in managing this life-threatening condition.

Effect of Leptin Therapy on Survival in Generalized and Partial Lipodystrophy: A Matched Cohort Analysis.

CONTEXT: Data quantifying the impact of metreleptin therapy on survival in non-human immunodeficiency virus (HIV)-related generalized lipodystrophy (GL) and partial lipodystrophy (PL) are unavailable. OBJECTIVE: This study aimed to estimate the treatment effect of metreleptin on survival in patients with GL and PL. DESIGN/SETTING/PATIENTS: Demographic and clinical characteristics were used to match metreleptin-treated and metreleptin-naïve patients with GL and PL. Differences in mortality risk were estimated between matched cohorts of metreleptin-treated and metreleptin-naïve patient cohorts using Cox proportional hazard models. Sensitivity analyses assessed the impact of study assumptions and the robustness of results. OUTCOME MEASURES: This study assessed time-to-mortality and risk of mortality. RESULTS: The analysis evaluated 103 metreleptin-naïve patients with characteristics matched to 103 metreleptin-treated patients at treatment initiation. Even after matching, some metabolic and organ abnormalities were more prevalent in the metreleptin-treated cohort due to bias toward treating more severely affected patients. A Cox proportional hazards model associated metreleptin therapy with an estimated 65% decrease in mortality risk (hazard ratio [HR] 0.348, 95% confidence interval (CI): 0.134-0.900; P = 0.029) even though the actual number of events were relatively small. Results were robust across a broad range of alternate methodological assumptions. Kaplan-Meier estimates of time-to-mortality for the metreleptin-treated and the matched metreleptin-naïve cohorts were comparable. CONCLUSIONS: Metreleptin therapy was associated with a reduction in mortality risk in patients with lipodystrophy syndromes despite greater disease severity in treated patients, supporting the view that metreleptin can have a positive disease-modifying impact. Confirmatory studies in additional real-world and clinical datasets are warranted.

Molecular and Cellular Bases of Lipodystrophy Syndromes.

Lipodystrophy syndromes are rare diseases originating from a generalized or partial loss of adipose tissue. Adipose tissue dysfunction results from heterogeneous genetic or acquired causes, but leads to similar metabolic complications with insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, dysfunctions of the gonadotropic axis and endocrine defects of adipose tissue with leptin and adiponectin deficiency. Diagnosis, based on clinical and metabolic investigations, and on genetic analyses, is of major importance to adapt medical care and genetic counseling. Molecular and cellular bases of these syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet, and/or premature cellular senescence. Lipodystrophy syndromes frequently present as systemic diseases with multi-tissue involvement. After an update on the main molecular bases and clinical forms of lipodystrophy, we will focus on topics that have recently emerged in the field. We will discuss the links between lipodystrophy and premature ageing and/or immuno-inflammatory aggressions of adipose tissue, as well as the relationships between lipomatosis and lipodystrophy. Finally, the indications of substitutive therapy with metreleptin, an analog of leptin, which is approved in Europe and USA, will be discussed.

Metreleptin therapy for nonalcoholic steatohepatitis: Open-label therapy interventions in two different clinical settings.

BACKGROUND: Recombinant leptin therapy reverses nonalcoholic steatohepatitis (NASH) in leptin-deficient lipodystrophy. We inquired if leptin therapy would improve nonalcoholic steatohepatitis in more common forms of this heterogeneous condition. METHODS: Nine male patients with relative leptin deficiency (level < 25th percentile of body mass index- and gender-matched United States population) and biopsy-proven NASH and 23 patients with partial lipodystrophy and NASH were recruited for two distinctive open-label trials. Participants received leptin therapy in the form of metreleptin for 12 months. The primary endpoints were the global nonalcoholic steatohepatitis scores from paired liver biopsies scored blindly. FINDINGS: Of 9 participants recruited in the relative leptin deficiency treatment study, 7 completed 12-months of therapy. Mean global NASH scores were reduced from 8 ± 3 to 5 ± 2 (range: from 1 to 6, P = 0.004). In the partial lipodystrophy study, 19 of 22 subjects completed 12 months of treatment, and 18 completed a second liver biopsy. Global NASH scores also reduced significantly from 6 ± 2 to 5 ± 2 (range: from -2 to 4, P = 0.008). In both studies, the predominant changes were in steatosis and hepatic injury scores. CONCLUSION: Our findings show that patients with NASH associated with both relative leptin deficiency and partial lipodystrophy have reductions in hepatic steatosis and injury in response to exogenous leptin therapy. Moreover, leptin deficiency may have regulatory effects in mediating fat deposition and ensuing injury in the liver.TRIAL REGISTRATION. ClinicalTrials.gov NCT00596934 and NCT01679197.

Metreleptin worked in a diabetic woman with a history of hematopoietic stem cell transplantation (HSCT) during infancy: further support for the concept of 'HSCT-associated lipodystrophy'.

A 17-year-old woman with a history of childhood leukemia and hematopoietic stem cell transplantation (HSCT), preceded by total body irradiation, developed diabetes, dyslipidemia, fatty liver, and marked insulin resistance. Based on Dunnigan phenotype, HSCT-associated lipodystrophy was suspected. Because of rapid deterioration of diabetes control, metreleptin was introduced at 23 years of age upon receipt of her caregiver's documented consent. This trial was initially planned as a prospective 18 month-long study, with regular assessments of the patient's physical activity, food intake, and body composition analysis. However, because an abrupt and transient attenuation of the metreleptin effect occurred 16 months after the treatment initiation, the entire course of 28 months is reported here. Over the period, her HbA1c decreased from 10.9% to 6.7% despite no significant increase of physical activity and with a stable food intake. Decreased levels of triglyceride and non-HDL cholesterol were found. Her liver function improved, indicating the amelioration of fatty liver. In addition, a 25% reduction in the subcutaneous fat area at umbilical level was found, accompanied by a decrease in fat percentage of both total-body and trunk. The formation of neutralizing antibodies to metreleptin may be responsible for the transient loss of efficacy, considering a sudden elevation in her serum leptin level. In conclusion, metreleptin is useful for the management of HSCT-associated lipodystrophy, supporting the concept that adipose tissue dysfunction is responsible for diverse post-HSCT metabolic aberrations.