Long-term effectiveness and safety of metreleptin in the treatment of patients with partial lipodystrophy.
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ABSTRACT:
SUBMITTER: Oral EA
PROVIDER: S-EPMC7340120 | biostudies-literature | 2019 Jun
REPOSITORIES: biostudies-literature
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Long-term effectiveness and safety of metreleptin in the treatment of patients with partial lipodystrophy.
Oral Elif A EA Gorden Phillip P Cochran Elaine E Araújo-Vilar David D Savage David B DB Long Alison A Fine Gregory G Salinardi Taylor T Brown Rebecca J RJ
Endocrine 20190225 3
<h4>Purpose</h4>To evaluate the effects of metreleptin in patients with partial lipodystrophy (PL).<h4>Methods</h4>Patients aged ≥ 6 months with PL, circulating leptin < 12.0 ng/mL, and diabetes mellitus, insulin resistance, or hypertriglyceridemia received metreleptin doses (once or twice daily) titrated to a mean of 0.124 mg/kg/day. Changes from baseline to month 12 in glycated hemoglobin (HbA1c) and fasting serum triglycerides (TGs; co-primary endpoints), fasting plasma glucose (FPG), and liv ...[more]
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Project description:PURPOSE:The purpose of this study is to summarize the effectiveness and safety of metreleptin in patients with congenital or acquired generalized lipodystrophy. METHODS:Patients (n?=?66) aged ?6 months had lipodystrophy, low circulating leptin, and ?1 metabolic abnormality (diabetes mellitus, insulin resistance, or hypertriglyceridemia). Metreleptin dose (once or twice daily) was titrated to a mean dose of 0.10?mg/kg/day with a maximum of 0.24?mg/kg/day. Means and changes from baseline to month 12 were assessed for glycated hemoglobin (HbA1c), fasting triglycerides (TGs), and fasting plasma glucose (FPG). Additional assessments included the proportions of patients achieving target decreases in HbA1c or fasting TGs at months 4, 12, and 36, medication changes, and estimates of liver size. Treatment-emergent adverse events (TEAEs) were recorded. RESULTS:Significant mean reductions from baseline were seen at month 12 for HbA1c (-2.2%, n?=?59) and FPG (-3.0?mmol/L, n?=?59) and mean percent change in fasting TGs (-32.1%, n?=?57) (all p???0.001). Reductions from baseline over time in these parameters were also significant at month 36 (all p?<?0.001, n?=?14). At month 4, 34.8% of patients had a ?1% reduction in HbA1c and 62.5% had a ?30% reduction in fasting TGs; at month 12, 80% of patients had a ?1% decrease in HbA1c or ?30% decrease in TGs, and 66% had a decrease of ?2% in HbA1c or ?40% decrease in TGs. Of those on medications, 41%, 22%, and 24% discontinued insulin, oral antidiabetic medications, or lipid-lowering medications, respectively. Mean decrease in liver volume at month 12 was 33.8% (p?<?0.001, n?=?12). Most TEAEs were of mild/moderate severity. CONCLUSIONS:In patients with generalized lipodystrophy, long-term treatment with metreleptin was well tolerated and resulted in sustained improvements in hypertriglyceridemia, glycemic control, and liver volume.
| S-EPMC5936645 | biostudies-literature
Project description:ObjectiveTo evaluate the long-term clinical effect of treatment with metreleptin (an analogue of human leptin) on glycemic and lipid abnormalities and markers of hepatic steatosis in patients with inherited or acquired lipodystrophy.MethodsFifty-five patients (36 with generalized lipodystrophy and 19 with partial lipodystrophy) with at least 1 of 3 metabolic abnormalities (diabetes mellitus, fasting triglyceride level ≥200 mg/dL, and insulin resistance) and low leptin levels received subcutaneous injections of metreleptin once or twice daily in an ongoing clinical trial at the National Institutes of Health.ResultsAt baseline, hemoglobin A1c-8.5% ± 2.1% (mean ± standard deviation [SD])-and triglycerides-479 ± 80 mg/dL (geometric mean ± standard error [SE])-were substantially elevated. Robust and sustained reductions in both variables were evident for the observed patient population during a 3-year metreleptin treatment period (-2.1% ± 0.5% [mean ± SE] and -35.4% ± 13.7% [mean ± SE], respectively). Mean alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were elevated at baseline (100 ± 120 U/L and 71 ± 77 U/L [mean ± SD], respectively) and decreased by -45 ± 19 U/L and -33 ± 14 U/L (mean ± SE), respectively, during the 3-year metreleptin treatment period. Improvements in hemoglobin A1c, triglycerides, ALT, and AST were more pronounced in the subsets of patients having elevated levels at baseline. The most notable adverse events observed in this patient population were likely attributable to underlying metabolic abnormalities or comorbidities.ConclusionMetreleptin treatment substantially reduced glycemic variables, triglycerides, and liver enzymes (ALT and AST) and demonstrated durability of response throughout a 3-year treatment period. These results support metreleptin as a potential treatment for certain metabolic disorders (for example, diabetes mellitus and hypertriglyceridemia) associated with lipodystrophy.
| S-EPMC3498767 | biostudies-literature
Project description:OBJECTIVE:Patients with lipodystrophy have severe metabolic abnormalities (insulin resistance, diabetes, and hypertriglyceridemia) that may increase morbidity and mortality. Metreleptin is approved by the United States Food and Drug Administration for treatment of generalized forms of lipodystrophy. We aimed to determine the efficacy and safety of metreleptin among patients with partial lipodystrophy using an expanded-access model. METHODS:Study FHA101 (ClinicalTrials.gov identifier: NCT00677313) was an open-label, expanded-access, long-term clinical effectiveness and safety study in 23 patients with partial lipodystrophy and diabetes and/or hypertriglyceridemia with no prespecified leptin level. Metreleptin was administered subcutaneously at 0.02 mg/kg twice daily (BID) at Week 1, followed by 0.04 mg/kg BID at Week 2. Dose adjustments thereafter were based on patient response (maximum dose of 0.08 mg/kg BID). One-year changes in glycated hemoglobin (HbA1c), fasting plasma glucose, triglycerides, alanine and aspartate aminotransferases, and treatment-emergent adverse events (TEAEs) were evaluated. RESULTS:HbA1c, fasting plasma glucose, and triglycerides were numerically decreased throughout 1 year, with mean (standard error) changes from baseline of -0.88 (0.62)%, -42.0 (22.4) mg/dL, and -119.8 (84.1) mg/dL, respectively, which were greater among patients with higher baseline abnormalities. Liver enzymes did not worsen, and the most frequently observed TEAEs (? 10% incidence) were mild to moderate and included nausea (39.1%), hypoglycemia (26.1%), and urinary tract infections (26.1%)-all reported previously. There were no reports of clinically significant immune-related adverse events or new safety signals. CONCLUSIONS:Our clinical observations document the large heterogeneity and disease burden of partial lipodystrophy syndromes and suggest that metreleptin treatment benefits may extend to patients with partial lipodystrophy. Additional studies are needed to confirm these preliminary findings.
| S-EPMC5026130 | biostudies-literature
Project description:ContextFamilial partial lipodystrophy (FPLD) is most commonly caused by pathogenic variants in LMNA and PPARG. Leptin replacement with metreleptin has largely been studied in the LMNA group.ObjectiveTo understand the efficacy of metreleptin in PPARG vs LMNA pathogenic variants and investigate predictors of metreleptin responsiveness.DesignSubgroup analysis of a prospective open-label study of metreleptin in lipodystrophy.SettingNational Institutes of Health, Bethesda, Maryland.ParticipantsPatients with LMNA (n = 22) or PPARG pathogenic variants (n = 7), leptin <12 ng/mL, and diabetes, insulin resistance, or high triglycerides.InterventionMetreleptin (0.08 to 0.16 mg/kg) for 12 months.OutcomeHemoglobin A1c (HbA1c), lipids, and medication use at baseline and after 12 months.ResultsBaseline characteristics were comparable in patients with PPARG and LMNA: HbA1c, 9.2 ± 2.3 vs 7.8 ± 2.1%; median [25th, 75th percentile] triglycerides, 1377 [278, 5577] vs 332 [198, 562] mg/dL; leptin, 6.3 ± 3.8 vs 5.5 ± 2.5 ng/mL (P > 0.05). After 12 months of metreleptin, HbA1c declined to 7.7 ± 2.4 in PPARG and 7.3 ± 1.7% in LMNA; insulin requirement decreased from 3.8 [2.7, 4.3] to 2.1 [1.6, 3.0] U/kg/d in PPARG and from 1.7 [1.3, 4.4] to 1.2 [1.0, 2.3] U/kg/d in LMNA (P < 0.05). Triglycerides decreased to 293 [148, 406] mg/dL in LMNA (P < 0.05), but changes were not significant in PPARG: 680 [296, 783] mg/dL at 12 months (P = 0.2). Both groups were more likely to experience clinically relevant triglyceride (≥30%) or HbA1c (≥1%) reduction with metreleptin if they had baseline triglycerides ≥500 mg/dL or HbA1c >8%.ConclusionMetreleptin resulted in similar metabolic improvements in patients with LMNA and PPARG pathogenic variants. Our findings support the efficacy of metreleptin in patients with the two most common genetic causes of FPLD.
| S-EPMC6563798 | biostudies-literature
Project description:OBJECTIVE:Recombinant human leptin (metreleptin) improves glycaemia and hypertriglyceridaemia in patients with generalized lipodystrophy; antibody development with in vitro neutralizing activity has been reported. We aimed to characterize antimetreleptin antibody development, including in vitro neutralizing activity. DESIGN:Two randomized controlled studies in patients with obesity (twice-daily metreleptin ± pramlintide for 20-52 weeks; 2006-2009); two long-term, open-label studies in patients with lipodystrophy (once-daily or twice-daily metreleptin for 2 months to 12·3 years; 2000-2014). PATIENTS:A total of 579 metreleptin-treated patients with obesity and 134 metreleptin-treated patients with lipodystrophy (antibody/neutralizing activity data: n = 105). MEASUREMENTS:Antimetreleptin antibodies, in vitro neutralizing activity. RESULTS:Antimetreleptin antibodies developed in most patients (obese: 96-100%; lipodystrophy: 86-92%). Peak antibody titers (approximately 1:125 to 1:3125) generally occurred within 4-6 months and decreased with continued therapy (lipodystrophy). Antibody development did not adversely impact efficacy or safety (patients with obesity), except for inflammatory injection site reactions, but was associated with elevated leptin concentrations. Three patients with obesity developed in vitro neutralizing activity coincident with weight gain. Weight later returned to baseline in one patient despite persistent neutralizing activity. Four patients with generalized lipodystrophy developed in vitro neutralizing activity concurrent with worsened metabolic control; two with confounding comorbidities had sepsis. One patient with lipodystrophy had resolution of neutralizing activity on metreleptin. CONCLUSIONS:Development of in vitro neutralizing activity could be associated with loss of efficacy but has not been consistently associated with adverse clinical consequences. Whether neutralization of endogenous leptin with clinical consequences occurs remains unclear.
| S-EPMC4875885 | biostudies-literature
Project description:Lipodystrophies are extreme forms of metabolic syndrome. Metreleptin was approved in the United States for generalized lipodystrophy (GLD) but not partial lipodystrophy (PLD).The objective of the study was to test metreleptin's efficacy in PLD vs GLD and find predictors for treatment response.This 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.The study was conducted at the National Institutes of Health (Bethesda, Maryland).Patients 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.The interventions included sc metreleptin injections (0.06-0.24 mg/kg · d).Changes in glycated hemoglobin A1c (HbA1c) and triglycerides after 6 and 12 months of metreleptin were measured.Baseline 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.In addition to its proven efficacy in GLD, metreleptin is effective in selected PLD patients with severe metabolic derangements or low leptin.
| S-EPMC4422900 | biostudies-literature
Project description:Lipodystrophy syndromes are rare disorders of deficient adipose tissue. Metreleptin, a human analog of leptin, improved metabolic abnormalities in mixed cohorts of children and adults with lipodystrophy and low leptin.Determine effects of metreleptin on diabetes, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), growth, and puberty in pediatric patients with lipodystrophy and low leptin.Prospective, single-arm, open-label studies with continuous enrollment since 2000.National Institutes of Health, Bethesda, Maryland.Fifty-three patients aged 6 months to <18 years with lipodystrophy, leptin level <8 ng/mL (male patients) or <12 ng/mL (female patients), and ?1 metabolic abnormality (diabetes, insulin resistance, or hypertriglyceridemia).Subcutaneous metreleptin injections (0.04 to 0.19 mg/kg/d).Change in A1c, lipid, and transaminase levels after a mean ± standard deviation (SD) of 12 ± 0.2 months and 61 ± 39 months. Changes in liver histology, growth, and pubertal development throughout treatment.After 12 months, the A1c level (mean ± SD) decreased from 8.3% ± 2.4% to 6.5% ± 1.8%, and median triglyceride level decreased from 374 mg/dL [geometric mean (25th,75th percentile), 190, 1065] to 189 mg/dL (112, 334; P < 0.0001), despite decreased glucose- and lipid-lowering medications. The median [geometric mean (25th,75th percentile)] alanine aminotransferase level decreased from 73 U/L (45, 126) to 41 U/L (25, 59; P = 0.001), and that of aspartate aminotransferase decreased from 51 U/L (29, 90) to 26 U/L (18, 42; P = 0.0002). These improvements were maintained over long-term treatment. In 17 patients who underwent paired biopsies, the NAFLD activity score (mean ± SD) decreased from 4.5 ± 2.0 to 3.4 ± 2.0 after 3.3 ± 3.2 years of metreleptin therapy (P = 0.03). There were no clinically significant changes in growth or puberty.Metreleptin lowered A1c and triglyceride levels, and improved biomarkers of NAFLD in pediatric patients with lipodystrophy. These improvements are likely to reduce the lifetime burden of disease.
| S-EPMC5443330 | biostudies-literature
Project description:Patients with lipodystrophy have high prevalence of proteinuria. To assess kidney disease in patients with generalized (GLD) versus partial lipodystrophy (PLD), and effects metreleptin on proteinuria in patients with lipodystrophy. Prospective, open-label studies of metreleptin treatment in patients with GLD and PLD at the National Institutes of Health, Bethesda, MD. 24-hour urinary albumin and protein excretion rates, estimated glomerular filtration rate (eGFR), and creatinine clearance (CrCl) were measured at baseline and during up to 24 months of metreleptin treatment. Patients with increases in medications affecting outcome measures were excluded. At baseline, patients with GLD had significantly greater albuminuria, proteinuria, eGFR, and CrCl compared to patients with PLD. CrCl was above the normal range in 69% of patients with GLD, and 39% with PLD (P=0.02). With up to 24 months of metreleptin treatment, there were significant reductions in albuminuria and proteinuria in patients with GLD, but not in those with PLD. No changes in eGFR or CrCl were observed in patients with GLD or PLD during metreleptin treatment. Patients with GLD had significantly greater proteinuria than those with PLD, which improved with metreleptin treatment. The mechanisms leading to proteinuria in lipodystrophy and improvements in proteinuria with metreleptin are not clear. Hyperfiltration was also more common in GLD versus PLD but did not change with metreleptin.
| S-EPMC6688455 | biostudies-literature
Project description:Generalized and partial lipodystrophy are rare and complex diseases with progressive clinical and humanistic burdens stemming from selective absence of subcutaneous adipose tissue, which causes reduced energy storage capacity and a deficiency of adipokines such as leptin. Treatment options were limited before leptin replacement therapy (metreleptin) became available. This retrospective study evaluates both clinical and humanistic consequences of the disease and treatment. Chart data were abstracted from a cohort of metreleptin-treated patients with generalized and partial lipodystrophy (n = 112) treated at the US National Institutes of Health. To quantify the quality-of-life consequences of the lipodystrophy disease attributes recorded in chart data, a discrete choice experiment was completed in 6 countries (US, n = 250; EU, n = 750). Resulting utility decrements were used to estimate the quality-adjusted life-year consequences of changes in lipodystrophy attribute prevalence before and after metreleptin. In addition to metabolic impairment, patients with generalized and partial lipodystrophy experienced a range of lipodystrophy consequences, including liver abnormality (94%), hyperphagia (79%), impaired physical appearance (77%), kidney abnormality (63%), reproductive dysfunction (80% of females of reproductive age), and pancreatitis (39%). Improvement was observed in these attributes following initiation of metreleptin. Quality-adjusted life-year gains associated with 12 months of treatment with metreleptin were estimated at 0.313 for generalized and 0.117 for partial lipodystrophy, reducing the gap in quality of life between untreated lipodystrophy and perfect health by approximately 59% and 31%, respectively. This study demonstrates that metreleptin is associated with meaningful clinical and quality-of-life improvements.
| S-EPMC7993583 | biostudies-literature
Project description:Abstract Introduction Metreleptin treatment may improve the metabolic aspects of partial lipodystrophy; however, the treatment response is heterogeneous. This study aimed to explore changes in circulating apolipoprotein concentrations, as well as ANGPLT3, ANGPLT4, and IGF-1 levels in patients treated with Metreleptin as part of a clinical study investigating the efficacy of Metreleptin in nonalcoholic steatohepatitis (NASH) associated with partial lipodystrophy (ClinicalTrials.gov identifier: NCT01679197). Methods Serum samples of 18 patients with partial lipodystrophy who underwent a full metabolic evaluation and paired liver biopsies before and after Metreleptin were studied. Patients were tested at baseline, month (M) 3, M6, and M12. Glycemic response was defined as “more than 1% HbA1c reduction from baseline”. Lipid response was defined as “more than 30% decrease in triglycerides from baseline”. The hepatic response was defined as “a decrease of 2 points or more from baseline in NASH score, without an increase in fibrosis”. Patients with “any 2 of 3 above” at M12 were defined as metabolic responders. Results Metreleptin treatment resulted in significant reductions in triglycerides (346 mg/dL vs. 253 mg/dL; F: 8.474; p < 0.001), apo B (145.24 mg/dL vs. 111.09 mg/dL; F: 9.266: p < 0.001), apo CII (18.65 mg/dL vs. 15.95 mg/dL; F: 6.663: p = 0.001), apo CIII (62.95 mg/dL vs. 49.33 mg/dL; F: 5.640, p = 0.002), apo E (8.16 mg/dL vs. 6.52 mg/dL; F: 11.056, p < 0.001), and ANGPLT3 (14.36 ng/mL vs. 12.00 mg/dL; F: 4.348; p = 0.008) over time. IGF-1 levels significantly increased at M3 (134 ng/mL vs. 139 ng/mL; p = 0.001), however the difference was not significant over time. Metabolic responders had lower baseline leptin (12.4 ng/mL vs. 27.8 ng/mL; p = 0.024) and IGF-1 (95 ng/ml vs. 151 ng/mL; p = 0.008), and higher apo CII (39.06 mg/dL vs. 17.90 mg/dL; p = 0.011), apo CIII (173.57 mg/dL vs. 51.51 mg/dL; p = 0.015), apo E (18.41 mg/dL vs. 5.89 mg/dL; p = 0.002), and ANGPLT3 (17.33 ng/mL vs. 10.06 ng/mL; p = 0.04). Metabolic responders had a significant increase in IGF-1 (95 ng/mL vs. 134 ng/mL; p = 0.019), which was statistically distinguished from non-responders (p = 0.004). Responders also had a greater reduction in apo CII (20.51 mg/dL vs. -1.84 mg/dL; p = 0.001), apo CIII (32.59 mg/dL vs. -7.83 mg/dL; p = 0.007), apo E (8.17 mg/dL vs. 0.22 mg/dL; p = 0.001), and ANGPLT3 (6.08 ng/mL vs. -0.16 ng/mL; p = 0.005) early after treatment at M3. Conclusions Metreleptin treatment lowers levels of apolipoproteins associated with triglyceride metabolism as well as ANGPLT3 in patients with partial lipodystrophy. Metabolic response to Metreleptin appears to be correlated with early changes in these factors and an increase in IGF-1 levels.
| S-EPMC7207763 | biostudies-literature