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.

Impact of a Structured Weight Management Program on Worker Productivity.

OBJECTIVE: To determine the impact of an intensive behavioral weight management program on presenteeism and absenteeism in obese participants employed full-time. METHODS: Participants were recruited from the University of Michigan Weight Management program (WMP), a multidisciplinary lifestyle program targeting 15% body weight loss. Absenteeism and presenteeism were assessed using the World Health Organization Health and Work Performance Questionnaire (HPQ) at baseline and 6 months. RESULTS: One hundred forty-two participants, predominantly college-educated white-collar employees, were included in the study. After 6 months in the program, there was no significant change in absenteeism or presenteeism compared with baseline. There was a trend towards reduced absenteeism. CONCLUSIONS: Participation in an intensive weight management program did not adversely impact worker productive time. Conversely, our findings should be reassuring to employer groups and to employees with obesity concerned about time spent away from work.

Inhibition of IKKɛ and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes.

Numerous studies indicate an inflammatory link between obesity and type 2 diabetes. The inflammatory kinases IKKɛ and TBK1 are elevated in obesity; their inhibition in obese mice reduces weight, insulin resistance, fatty liver and inflammation. Here we studied amlexanox, an inhibitor of IKKɛ and TBK1, in a proof-of-concept randomized, double-blind, placebo-controlled study of 42 obese patients with type 2 diabetes and nonalcoholic fatty liver disease. Treatment of patients with amlexanox produced a statistically significant reduction in Hemoglobin A1c and fructosamine. Interestingly, a subset of drug responders also exhibited improvements in insulin sensitivity and hepatic steatosis. This subgroup was characterized by a distinct inflammatory gene expression signature from biopsied subcutaneous fat at baseline. They also exhibited a unique pattern of gene expression changes in response to amlexanox, consistent with increased energy expenditure. Together, these data suggest that dual-specificity inhibitors of IKKɛ and TBK1 may be effective therapies for metabolic disease in an identifiable subset of patients.

Impact of weight loss on waist circumference and the components of the metabolic syndrome.

OBJECTIVE: Central adiposity is a component of the metabolic syndrome (MetS). Little is known about the impact of medical weight loss and decreased waist circumference (WC) on the MetS. Our objective was to assess the impact of changes in WC on blood pressure, lipids and glycemia. RESEARCH DESIGN AND METHODS: We studied 430 obese patients enrolled in a 2-year, intensive, behavioral, weight management program. We report results for participants who completed 6-month and 2-year follow-up. RESULTS: Participants were 49±9 years of age (mean±SD), 56% were women and 85% were white. Baseline body mass index (BMI) was 41±6 kg/m2 and baseline WC was 120±14 cm. At 6 months, BMI decreased by 6±3 kg/m2 and WC by 14±9 cm. Relative change in WC was defined as the 6-month or 2-year WC minus the baseline WC divided by the baseline WC. Systolic blood pressure decreased by 8 mm Hg for the tertile of participants with the largest relative decrease in WC and by 2 mm Hg for those with the smallest relative decrease in WC (p=0.025). Similar patterns of improvement were observed in total cholesterol (-29 vs -12 mg/dL, p=0.017), low-density lipoprotein-cholesterol (-19 vs -4 mg/dL, p=0.033), and glycated hemoglobin (-1.2 vs -0.3%, p=0.006). At 2 years, BMI decreased by 5±4 kg/m2 and WC by 11±11 cm and similar patterns of improvements were seen in components of the MetS. At both 6 months and 2 years, larger relative decreases in WC were associated with greater improvements in lipids and glycemia independent of sex. CONCLUSIONS: In obese people, greater relative decreases in WC with medical weight loss are associated with greater improvements in components of the MetS independent of sex.

Spectrum of disease associated with partial lipodystrophy: lessons from a trial cohort.

CONTEXT: Partial lipodystrophy (PL) is associated with metabolic co-morbidities but may go undiagnosed as the disease spectrum is not fully described. OBJECTIVE: The objective of the study was to define disease spectrum in PL using genetic, clinical (historical, morphometric) and laboratory characteristics. DESIGN: Cross-sectional evaluation. PARTICIPANTS: Twenty-three patients (22 with familial, one acquired, 78·3% female, aged 12-64 years) with PL and non-alcoholic fatty liver disease (NAFLD). MEASUREMENTS: Genetic, clinical and laboratory characteristics, body composition indices, liver fat content by magnetic resonance imaging (MRI), histopathological and immunofluorescence examinations of liver biopsies. RESULTS: Seven patients displayed heterozygous pathogenic variants in LMNA. Two related patients had a heterozygous, likely pathogenic novel variant of POLD1 (NM002691·3: c.3199 G>A; p.E1067K). Most patients had high ratios (>1·5) of percentage fat trunk to percentage fat legs (FMR) when compared to reference normals. Liver fat quantified using MR Dixon method was high (11·3 ± 6·3%) and correlated positively with haemoglobin A1c and triglycerides while leg fat by dual-energy X-ray absorptiometry (DEXA) correlated negatively with triglycerides. In addition to known metabolic comorbidities; chronic pain (78·3%), hypertension (56·5%) and mood disorders (52·2%) were highly prevalent. Mean NAFLD Activity Score (NAS) was 5 ± 1 and 78·3% had fibrosis. LMNA-immunofluorescence staining from select patients (including one with the novel POLD1 variant) showed a high degree of nuclear atypia and disorganization. CONCLUSIONS: Partial lipodystrophy is a complex multi-system disorder. Metabolic parameters correlate negatively with extremity fat and positively with liver fat. DEXA-based FMR may prove useful as a diagnostic tool. Nuclear disorganization and atypia may be a common biomarker even in the absence of pathogenic variants in LMNA.

Efficacy and Safety of Metreleptin in Patients with Partial Lipodystrophy: Lessons from an Expanded Access Program.

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.

A Report of Three Cases With Acquired Generalized Lipodystrophy With Distinct Autoimmune Conditions Treated With Metreleptin.

CONTEXT: Acquired generalized lipodystrophy (AGL) is associated with leptin deficiency as a result of adipose tissue loss and hypertriglyceridemia, insulin resistance, and hepatic steatosis. It may coexist with other autoimmune diseases such as Hashimoto's thyroiditis, rheumatoid arthritis, hemolytic anemia, and chronic active hepatitis. Metreleptin therapy has been shown to improve metabolic abnormalities in lipodystrophy, but the effect on AGL patients with active autoimmune disease is unknown. CASE DESCRIPTION: We report 3 cases of pediatric patients with AGL and distinct active autoimmune diseases who were treated with metreleptin over a period of 4-6 years. Case 1 is a 9-year-old girl with active juvenile dermatomyositis, who was successfully treated with leptin with no worsening of her dermatomoysitis. Case 2 is a 16-year-old female with Graves' disease, who could discontinue all her antidiabetic medication completely with improved triglyceride levels. Case 3 is an 11-year-old boy with active autoimmune hepatitis and chronic urticaria, whose hyperphagia has resolved and his liver enzymes and hepatosplenomegaly have improved. CONCLUSION: Metreleptin therapy is of considerable clinical benefit to reduce insulin resistance and hypertriglyceridemia and did not appear to alter the clinical course of autoimmune disease nor clinical efficacy of immunosuppressive treatments. Our observations suggest that risk or presence of autoimmune disease should not lead to withholding of metreleptin treatment from patients with AGL, but should prompt close clinical follow up in light of cautionary preclinical data.

Factors associated with participant retention in a clinical, intensive, behavioral weight management program.

BACKGROUND: We sought to identify factors associated with participant retention in a 2-year, physician-lead, multidisciplinary, clinical weight management program that employs meal replacements to produce weight loss and intensive behavioral interventions and financial incentives for weight loss maintenance. We studied 270 participants enrolled in 2010 and 2011. Sociodemographic factors, health insurance, distance traveled, body mass index, comorbidities, health-related quality-of-life, and depression were explored as potential predictors of retention. RESULTS: Mean age was 49 ± 8 years and BMI was 41 ± 5 kg/m(2). Retention was excellent at 3 months (90%) and 6 months (83%). Attrition was greatest after participants were transitioned to regular foodstuffs and fell to 67% at 12 months and 51% at 2 years. Weight decreased by 15 ± 12 kg and BMI decreased by 5.1 ± 4.0 kg/m(2) in 2-year completers. Older age, lower baseline BMI, and financial incentives for program participation were independently associated with retention. Fewer depressive symptoms at baseline were associated with retention. CONCLUSIONS: This multidisciplinary, clinical, weight management program demonstrated high retention and excellent outcomes. Older age at baseline, less extreme obesity, and financial incentives were associated with program retention.

Hemodynamic, autonomic, and vascular effects of exposure to coarse particulate matter air pollution from a rural location.

BACKGROUND: Fine particulate matter (PM) air pollution is associated with numerous adverse health effects, including increased blood pressure (BP) and vascular dysfunction. Coarse PM substantially contributes to global air pollution, yet differs in characteristics from fine particles and is currently not regulated. However, the cardiovascular (CV) impacts of coarse PM exposure remain largely unknown. OBJECTIVES: Our goal was to elucidate whether coarse PM, like fine PM, is itself capable of eliciting adverse CV responses. METHODS: We performed a randomized double-blind crossover study in which 32 healthy adults (25.9 ± 6.6 years of age) were exposed to concentrated ambient coarse particles (CAP; 76.2 ± 51.5 µg/m(3)) in a rural location and filtered air (FA) for 2 hr. We measured CV outcomes during, immediately after, and 2 hr postexposures. RESULTS: Both systolic (mean difference = 0.32 mmHg; 95% CI: 0.05, 0.58; p = 0.021) and diastolic BP (0.27 mmHg; 95% CI: 0.003, 0.53; p = 0.05) linearly increased per 10 min of exposure during the inhalation of coarse CAP when compared with changes during FA exposure. Heart rate was on average higher (4.1 bpm; 95% CI: 3.06, 5.12; p < 0.0001) and the ratio of low-to-high frequency heart rate variability increased (0.24; 95% CI: 0.07, 0.41; p = 0.007) during coarse particle versus FA exposure. Other outcomes (brachial flow-mediated dilatation, microvascular reactive hyperemia index, aortic hemodynamics, pulse wave velocity) were not differentially altered by the exposures. CONCLUSIONS: Inhalation of coarse PM from a rural location is associated with a rapid elevation in BP and heart rate during exposure, likely due to the triggering of autonomic imbalance. These findings add mechanistic evidence supporting the biological plausibility that coarse particles could contribute to the triggering of acute CV events.