Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Cook K

PROVIDER: S-EPMC8277211 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Cook Keziah K Ali Omer O Akinci Baris B Foss de Freitas Maria Cristina MC Montenegro Renan Magalhães RM Fernandes Virginia Oliveira VO Gupta Deepshekhar D Lou Kai-Jye KJ Tuttle Edward E Oral Elif A EA Brown Rebecca J RJ

The Journal of clinical endocrinology and metabolism 20210701 8

<h4>Context</h4>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.<h4>Objective</h4>This study aimed to estimate the treatment effect of metreleptin on survival in patients with GL and PL.<h4>Design/setting/patients</h4>Demographic and clinical characteristics were used to match metreleptin-treated and metreleptin-naïve patients with GL and PL. Differences ...[more]

PMID: 33822100

Similar Datasets

Project description:Aims/hypothesisPartial lipodystrophy (PL) is most commonly characterized by loss of subcutaneous fat in the extremities with preservation of truncal fat and is associated with insulin resistance, diabetes and hyperlipidaemia. Recombinant human leptin (r-metHuLeptin) therapy has been shown to be effective in treating metabolic abnormalities associated with congenital or acquired generalized lipodystrophy and PL associated with lamin A/C (LMNA) gene mutations or highly active antiretroviral therapy (HAART). Our aim was to assess the effectiveness of leptin therapy in treating metabolic complications of PL associated with heterozygous peroxisome proliferator activated receptor gamma (PPARG) mutations. This is the first report to detail the clinical response of a patient with PL due to a PPARG mutation treated with r-metHuLeptin.MethodsA 36-year-old female with PL associated with a heterozygous PPARG mutation complicated by poorly controlled diabetes and severe, refractory hypertriglyceridaemia was enrolled in a National Institutes of Health (NIH) protocol to evaluate the role of r-metHuLeptin in lipodystrophy. The patient received escalating doses of r-metHuLeptin until a dose 0.12 mg/kg/day was reached. Metabolic parameters, including serum chemistries, fasting blood glucose, glycated haemoglobin (HbA1c), lipid profile, an oral glucose tolerance test (OGTT), an insulin tolerance test (ITT), liver volume, percentage body fat and energy expenditure were followed at regular time intervals over 18 months of therapy.ResultsEighteen months of r-MetHuLeptin therapy was associated with a marked improvement in glucose homeostasis as evidenced by normalization of the fasting blood glucose (baseline = 8.3 mmol/l; 18 months = 4.9 mmol/l), lowering of HbA1c (baseline = 9.9%; 18 months = 7.2%) and improved tolerance to an oral glucose load. In addition, a striking amelioration in the patient's refractory, severe hypertriglyceridaemia was observed (baseline = 21.15 mmol/l; 18 months = 5.96 mmol/l).Conclusionr-MetHuLeptin is effective in treating metabolic complications associated with PL due to PPARG mutations. In the context of previously published work, our findings suggest that the response to r-MetHuLeptin is independent of the aetiology in lipodystrophy.

Project description:ContextLipodystrophy 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.ObjectiveDetermine effects of recombinant leptin (metreleptin) on cardiac structure and function in lipodystrophy.MethodsOpen-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.ResultsIn 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.ConclusionMetreleptin 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.

Project description:ContextLipodystrophies are extreme forms of metabolic syndrome. Metreleptin was approved in the United States for generalized lipodystrophy (GLD) but not partial lipodystrophy (PLD).ObjectiveThe objective of the study was to test metreleptin's efficacy in PLD vs GLD and find predictors for treatment response.DesignThis was a prospective, single-arm, open-label study since 2000 with continuous enrollment. Current analysis included metreleptin treatment for 6 months or longer as of January 2014.SettingThe study was conducted at the National Institutes of Health (Bethesda, Maryland).ParticipantsPatients clinically diagnosed with lipodystrophy, leptin less than 8 ng/mL (males) or less than 12 (females), age older than 6 months, and one or more metabolic abnormalities (diabetes, insulin resistance, or hypertriglyceridemia) participated in the study.InterventionThe interventions included sc metreleptin injections (0.06-0.24 mg/kg · d).Main outcomes and measuresChanges in glycated hemoglobin A1c (HbA1c) and triglycerides after 6 and 12 months of metreleptin were measured.ResultsBaseline metabolic parameters were similar in 55 GLD [HbA1c 8.4% ± 2.3%; triglycerides, geometric mean (25th, 75th percentile), 467 mg/dL (200, 847)] and 31 PLD patients [HbA1c 8.1% ± 2.2%, triglycerides 483 mg/dL (232, 856)] despite different body fat and endogenous leptin. At 12 months, metreleptin decreased HbA1c (to 6.4% ± 1.5%, GLD, P < .001; 7.3% ± 1.6%, PLD, P = .004) and triglycerides [to 180 mg/dL (106, 312), GLD, P < .001; 326 mg/dL (175, 478), PLD, P = .02]. HbA1c and triglyceride changes over time significantly differed between GLD and PLD. In subgroup analyses, metreleptin improved HbA1c and triglycerides in all GLD subgroups except those with baseline triglycerides less than 300 mg/dL and all PLD subgroups except baseline triglycerides less than 500 mg/dL, HbA1c less than 8%, or endogenous leptin greater than 4 ng/mL.ConclusionsIn addition to its proven efficacy in GLD, metreleptin is effective in selected PLD patients with severe metabolic derangements or low leptin.

Project description:Context and objectiveLeptin treatment has dramatic clinical effects on glucose and lipid metabolism in leptin-deficient patients with lipodystrophy. Further elucidation of metabolic effects of exogenous leptin therapy will shed light on understanding leptin physiology in humans. Our objective was to utilize metabolomic profiling to examine the changes associated with administration of short-term metreleptin therapy in patients with lipodystrophy.Study designWe conducted a pre-post-treatment study in 19 patients (75% female) with varying forms of lipodystrophy (congenital generalized lipodystrophy, n = 10; acquired generalized lipodystrophy, n = 1; familial partial lipodystrophy, n = 8) who received daily subcutaneous metreleptin injections for a period of 16 to 23 weeks. A 3-hour oral glucose tolerance test and body composition measurements were conducted before and after the treatment period, and fasting blood samples were used for metabolomic profiling. The study outcome aimed at measuring changes in physiologically relevant metabolites before and after leptin therapy.ResultsMetabolomic analysis revealed changes in pathways involving branched-chain amino acid metabolism, fatty acid oxidation, protein degradation, urea cycle, tryptophan metabolism, nucleotide catabolism, vitamin E, and steroid metabolism. Fold changes in pre- to post-treatment metabolite levels indicated increased breakdown of fatty acids, branched chain amino acids proteins, and nucleic acids.ConclusionsLeptin replacement therapy has significant effects on important metabolic pathways implicated in patients with lipodystrophy. Continued metabolomic studies may provide further insight into the mechanisms of action of leptin replacement therapy and provide novel biomarkers of lipodystrophy.Abbreviations: 1,5-AG, 1,5-anhydroglucitol; 11βHSD1, 11-β hydroxysteroid dehydrogenase 1; BCAA, branched-chain amino acid; FFA, free fatty acid; GC-MS, gas chromatography mass spectrometry; IDO, indoleamine 2,3-dioxygenase; IFN-γ, interferon-γ; m/z, mass to charge ratio; OGTT, oral glucose tolerance test; TDO, tryptophan 2,3-dioxygenase; TNF-α, tumor necrosis factor-α; UPLC-MS/MS, ultra-performance liquid chromatography-tandem mass spectrometry.

Dataset Information

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

Context

Objective

Design/setting/patients

Outcome measures

Results

Conclusions

Publications

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

Similar Datasets

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