Improvement In Metabolic Parameters Research Articles

Effect of Mesembryanthemum crystallinum and its derived D‐pinitol on HMG‐CoA reductase and tyloxapol‐induced hyperlipedemia

AbstractSeveral previous research indicate that treating Mesembryanthemum crystallinum may aid in reducing adipogenesis and triacylglycerol level and improving hyperglycemia and diabetes. Therefore, the present study was designed to evaluate the effectiveness of M. crystallinum extract (MCE) in combating obesity and lowering fat/lipid/cholesterol levels. The study aimed to investigate the molecular docking model targeting 3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGCR) using MCE‐derived d‐pinitol or atorvastatin, an inhibitor of HMGCR. In this study, histological alterations in the liver of tyloxapol‐induced hyperlipidemia (TIH) model, hyperlipidemia‐related markers in serum, HMGCR activity, and cell viability in HepG2 cells were analyzed. Our findings revealed that tyloxapol treatment significantly led to increased hyperlipidemia‐related indicators and cardiovascular‐associated risk indices. However, MCE effectively mitigated tyloxapol‐induced hepatic fat accumulation and an increase in cholesterol levels. This was achieved through improvements in metabolic parameters, ultimately ameliorating TIH. These beneficial results suggest that MCE may be a strong potential for the treatment of hyperlipidemia‐related diseases.

Antarctic Krill Euphausia superba Oil Supplementation Attenuates Hypercholesterolemia, Fatty Liver, and Oxidative Stress in Diet-Induced Obese Mice.

Several Previous studies indicate that consuming krill oil may aid in reducing hypercholesterolemia and improving cholesterol metabolism. Therefore, our study was designed to investigate the effectiveness of Antarctic krill oil (Euphausia superba) (ESKO) in combating obesity and lowering fat/lipid/cholesterol levels. The study aimed to investigate the molecular docking model targeting 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) using ESKO-derived eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and astaxanthin. In this study, histological alterations in the liver of the obesity model (ICR male mouse), obesity-related or antioxidant markers in both liver and serum, the molecular mechanisms in HepG2 cells and liver tissue, and HMGCR activity were analyzed. Our findings revealed that a high-fat diet (HFD) significantly led to increased oxidative stress, obesity-related indicators, and cardiovascular-associated risk indices. However, ESKO effectively mitigated HFD-induced oxidative stress, fat accumulation, and the suppression of low-density lipoprotein receptor (LDLR) or activation of related molecular pathways. This was achieved through improvements in metabolic parameters, including CD36/liver X receptor α (LXRα)/sterol regulatory element-binding protein 1c (SREBP1c), proprotein convertase subtilsin/kexin type 9 (PCSK-9), and HMGCR, ultimately ameliorating HFD-induced hypercholesterolemia and obesity. These beneficial findings indicate that ESKO might have significant potential for preventing and treating obesity-related disorders.

BENEFÍCIOS E MALEFÍCIOS DAS NOVAS DROGAS PARA EMAGRECIMENTO: REVISÃO INTEGRATIVA

This integrative review examined the benefits and harms of the new weight-loss drugs, with an emphasis on GLP-1 receptor agonists such as semaglutide and liraglutide. These medications have demonstrated significant efficacy in inducing weight loss and controlling comorbidities associated with obesity. Studies, including Brazilian research, indicate that these drugs can promote a reduction in body weight of up to 12% in obese patients, in addition to substantial improvements in metabolic parameters, such as blood glucose and blood pressure. However, the most frequent adverse effects, such as nausea, vomiting, and diarrhea, have been the main factors for stopping treatment. More serious complications, such as cholelithiasis and pancreatitis, have also been reported, although less frequently. In addition, the psychological impact of rapid weight loss requires careful monitoring, as patients may experience mood swings and increased anxiety. The lack of data on the long-term use of these medications in Brazilian populations underscores the urgent need for future investigations. Thus, despite the significant benefits, the use of these drugs must be carried out under close monitoring, considering the individual characteristics and risks of each patient, in order to ensure the efficacy and safety of the treatment in the long term.

Will melatonin supplementation become a new form of obesity treatment? A review of recent literature.

Background: In 2020, the World Health Organization (WHO) estimated that 650 million adults worldwide are obese, and 2.8 billion individuals struggle with overweight. Obesity is associated with an increased risk of cardiovascular diseases, type 2 diabetes, heart disease, adverse effects on mental health, the development of certain cancers, and other conditions. In recent years, there has been growing interest in the role of melatonin, which has therapeutic potential in the treatment of obesity. Studies suggest that melatonin supplementation may lead to weight reduction and improvement in metabolic parameters, significantly reduce cardiovascular disease risk factors, and enhance insulin sensitivity in obese individuals. Aim of study: This review aims to present the latest scientific findings on the impact of melatonin supplementation on the development of obesity and its complications. We focus primarily on the mechanisms of melatonin's action in the context of obesity, particularly on potential pathways that have not yet been thoroughly explored. Our aim is to provide deeper insights into research on obesity and its prevention. Materials and Methods: Search was conducted using PubMed and Google Scholar databases, utilizing the keywords "obesity," "melatonin," and "weight loss" in various configurations. The review primarily considers studies published after 2016 that are available online. Summary Melatonin supplementation leads to a statistically significant reduction in blood glucose levels and an increase in cellular insulin sensitivity. Its promising properties in the treatment of obesity have been demonstrated through the reduction of oxidative stress, indicating a potential adjunct for weight loss. Based on the cited studies, the beneficial effects of melatonin supplementation on cardiovascular risk factors have been confirmed. Melatonin could be considered as an adjunctive therapy for obese individuals who do not respond to other treatment modalities.

Ezetimibe, Niemann-Pick C1 like 1 inhibitor, modulates hepatic phospholipid metabolism to alleviate fat accumulation.

Ezetimibe, which lowers cholesterol by blocking the intestinal cholesterol transporter Niemann-Pick C1 like 1, is reported to reduce hepatic steatosis in humans and animals. Here, we demonstrate the changes in hepatic metabolites and lipids and explain the underlying mechanism of ezetimibe in hepatic steatosis. We fed Otsuka Long-Evans Tokushima Fatty (OLETF) rats a high-fat diet (60kcal % fat) with or vehicle (control) or ezetimibe (10mgkg-1) via stomach gavage for 12 weeks and performed comprehensive metabolomic and lipidomic profiling of liver tissue. We used rat liver tissues, HepG2 hepatoma cell lines, and siRNA to explore the underlying mechanism. In OLETF rats on a high-fat diet, ezetimibe showed improvements in metabolic parameters and reduction in hepatic fat accumulation. The comprehensive metabolomic and lipidomic profiling revealed significant changes in phospholipids, particularly phosphatidylcholines (PC), and alterations in the fatty acyl-chain composition in hepatic PCs. Further analyses involving gene expression and triglyceride assessments in rat liver tissues, HepG2 hepatoma cell lines, and siRNA experiments unveiled that ezetimibe's mechanism involves the upregulation of key phospholipid biosynthesis genes, CTP:phosphocholine cytidylyltransferase alpha and phosphatidylethanolamine N-methyl-transferase, and the phospholipid remodeling gene lysophosphatidylcholine acyltransferase 3. This study demonstrate that ezetimibe improves metabolic parameters and reduces hepatic fat accumulation by influencing the composition and levels of phospholipids, specifically phosphatidylcholines, and by upregulating genes related to phospholipid biosynthesis and remodeling. These findings provide valuable insights into the molecular pathways through which ezetimibe mitigates hepatic fat accumulation, emphasizing the role of phospholipid metabolism.

Sex-Differences in Response to Treatment with Liraglutide 3.0 mg.

Background: Sex differences characterize the prevalence and attitudes toward weight management. Despite limited evidence suggesting greater weight loss in women with anti-obesity pharmacotherapy, sex-specific analysis remains underexplored. This retrospective study aimed to evaluate the sex-specific response to liraglutide 3.0 mg treatment in people with obesity without type 2 diabetes (T2D). Methods: Data were collected from 47 patients (31 women, 16 men) with age > 18 years; BMI ≥ 30 kg/m2; absence of T2D; and exclusion of prior anti-obesity treatment, comorbidities, or bariatric surgery. Only patients who maintained the liraglutide 3.0 mg dose for at least 6 months were included. Results: Both sexes showed significant reductions in weight and BMI at 3 and 6 months. Men achieved greater weight loss (WL), BMI reduction, %WL, WL > 5%, and >10% than women, and they also showed more significant improvements in metabolic parameters (total and LDL cholesterol, Fibrosis-4 Index FIB-4). No significant sex differences were observed in glucose metabolism or renal function. Conclusions: This study showed a greater therapeutic effect of liraglutide 3.0 mg in men. Given men's higher risk of cardiovascular disease (CVD), and underrepresentation in clinical weight loss programs, these findings may increase male engagement and improve their CVD risk.

Metabolic Syndrome and Sleep Apnea: The Impact of Lifestyle Interventions

Abstract Contemporary healthcare focuses on assessing the efficacy of dietary and exercise interventions in mitigating metabolic syndrome and its association with sleep apnea. Results demonstrate notable reductions in the HOMA Index and triglyceride levels among treated cohorts, indicating improved glycemic control and lipid profile. Additionally, intervention groups exhibit significant decreases in cholesterol levels, indicative of enhanced lipid profile. Marginal alterations in C-Reactive Protein imply limited impact on systemic inflammation, while consistent uric acid levels suggest potential autonomy from the interventions. Remarkable correlations between clinical parameters and sleep apnea risk underscore the pivotal role of lifestyle modifications in metabolic syndrome management, offering insights into underlying mechanisms. The aim of this study is to further investigate the underlying mechanisms behind the observed improvements in metabolic parameters following dietary and exercise interventions, with a specific focus on elucidating the relationship between these interventions and the risk of sleep apnea in individuals with metabolic syndrome. These findings elucidate the intricate interplay between metabolic risk factors and sleep apnea susceptibility, thereby informing therapeutic and preventive approaches for individuals with metabolic syndrome.

Semaglutide for management of obesity in adolescents: efficacy, safety, and considerations for clinical practice.

The purpose of this review is to describe the existing limited data related to the use of semaglutide in adolescents with obesity, supplementing with findings from adult studies of semaglutide use. Semaglutide, as a once weekly subcutaneous injection for weight management, effectively reduces body mass index (BMI) while improving hyperglycemia, elevated alanine aminotransferase levels, hyperlipidemia, and quality of life in youth with obesity. As of this review, only one large randomized clinical trial of semaglutide in youth has been completed, with a follow-up duration of 68 weeks. Thus, long-term data on the safety in adolescents is limited, particularly regarding the risks of cholelithiasis, pancreatitis, suicidal ideation, and disordered eating. Due to the cost of semaglutide, particularly in the United States, limited cost effectiveness analyses have demonstrated unfavorable incremental cost-effectiveness ratios for semaglutide relative to phentermine-topiramate as an alternative antiobesity medication in adolescents. Semaglutide represents an important advance in the pediatric obesity management, with clear short-term reductions in BMI and improvement in metabolic parameters. However, its long-term safety and efficacy for youth with obesity remain to be demonstrated. Additional research is needed to assess trends in utilization and adherence to minimize the risk of worsening socioeconomic disparities in pediatric obesity.

TRACK_9: Testosterone replacement assessment: Classical vs. functional hypogonadism-knowledge from a 9-year study.

The longitudinal efficacy and clinical utility of Testosterone Therapy (TTh) in ameliorating functional hypogonadism (FH) remain contentious, with long-term data being scarce. To address this lacuna, a comprehensive long-term registry study, stratifying patients across a spectrum of hypogonadal etiologies, offers a robust investigative paradigm. This 9-year registry, encompassing 650 patients (equivalent to 4,362 cumulative years of treatment), included 188 patients diagnosed with FH (mean age 42.3±11.3 years) and 462 individuals with classical hypogonadism (CH). The cohort segregated into 266 men with primary hypogonadism (PH, mean age 34.0±11.7 years) and 196 with secondary hypogonadism (SH, mean age 31.9±12.0 years). Uniform treatment across the cohort involved intramuscular administration of testosterone undecanoate (1,000mg). A comparative analysis was conducted focusing on anthropometric, metabolic, and safety parameters. Serum testosterone levels increased from 6.6±2.4 to 19.3±2.9nmol/L (p<0.001). TTh was linked with weight reduction and decreased waist circumference (WC) in both CH and FH cohorts (both p<0.001). Cox regression and Kaplan-Meier analyses delineated disparities: men with FH demonstrated a higher propensity for losing>10% body weight and>5% WC compared to CH (hazard ratio [HR] 1.3 [1.1-1.4], p=0.008 and HR 1.4 [1.3-1.5], p=0.001). Increases in hematocrit>50% were uniform across groups, albeit amelioration of anemia was more pronounced in FH versus CH (p=0.002). Increments of prostate-specific antigen (PSA) levels were more likely to occur in FH (HR 1.3 [1.1-1.6], p=0.003). FH patients exhibited pronounced improvements in metabolic parameters and in aging male symptom score (AMS) and IIEF-EF questionnaire scores. These effects were markedly modulated by age and initial weight. Subgroup analysis of age-matched obese patients revealed an accentuated impact of TTh in CH compared to FH. The therapeutic outcomes of TTh across distinct hypogonadal populations demonstrate heterogeneous responses, significantly influenced by diagnostic categorization, age, and baseline risk factor profiles.

Multifunctional dietary interventions, low-grade inflammation and cardiometabolic profile: a scoping review.

Growing evidence highlights the significant impact of diet to modify low-grade inflammation closely linked to cardiometabolic profile. Multifunctionnal diets, combining several compounds have been shown to beneficially impact metabolic parameters. This study synthesizes the knowledge on the impact of RCTs combining dietary multifunctional compounds on low-grade inflammation in humans. We investigate whether the effects of dietary multifunctional interventions on inflammatory markers were parallel to alterations of cardiometabolic parameters. We considered both the integrated dietary interventions (ID, i.e. global diets such as Mediterranean, Nordic…) and the dietary interventions based on selected bioactive mix (BM) compounds, in healthy individuals and those at cardiometabolic risk. Out of 221 screened publications, we selected 27 studies: 11 for BM (polyphenols and/or omega-3 fatty acids and/or antioxidants and/or dietary fiber) and 16 for ID (Mediterranean, paleo, Nordic, Dietary Approaches to Stop Hypertension (DASH) diet…). ID studies reflected significant improvements in inflammatory markers (CRP, IL-6, IL-10, IL-1b), concomitantly with beneficial changes in metabolic parameters. In BM studies, pronounced effects on low-grade inflammatory markers were observed, while improvements in metabolic parameters were not consistent. Both types of studies suggested a favorable impact on oxidative stress, a factor closely linked to the inflammatory profile. Our findings showed that multifunctional RCT diets have differential role in managing low-grade inflammation and cardiometabolic health, with a large heterogeneity in explored inflammatory markers. Further research is imperative to elucidate the link between low-grade inflammation and other cardiometabolic risk factors, such as intestinal inflammation or postprandial inflammatory dynamics, aiming to attain a comprehensive understanding of the mechanisms involved in these processes. These future investigations not only have the potential to deepen our insights into the connections among these elements but also pave the way for significant advancements in the prevention and management of conditions related to the cardiovascular and metabolic systems.

Limosilactobacillus fermentum Strains as Novel Probiotic Candidates to Promote Host Health Benefits and Development of Biotherapeutics: A Comprehensive Review.

Fruits and their processing by-products are sources of potentially probiotic strains. Limosilactobacillus (L.) fermentum strains isolated from fruit processing by-products have shown probiotic-related properties. This review presents and discusses the results of the available studies that evaluated the probiotic properties of L. fermentum in promoting host health benefits, their application by the food industry, and the development of biotherapeutics. The results showed that administration of L. fermentum for 4 to 8weeks promoted host health benefits in rats, including the modulation of gut microbiota, improvement of metabolic parameters, and antihypertensive, antioxidant, and anti-inflammatory effects. The results also showed the relevance of L. fermentum strains for application in the food industry and for the formulation of novel biotherapeutics, especially nutraceuticals. This review provides evidence that L. fermentum strains isolated from fruit processing by-products have great potential for promoting host health and indicate the need for a translational approach to confirm their effects in humans using randomized, double-blind, placebo-controlled trials.

Effects of laparoscopic sleeve gastrectomy on thyroid hormones and relationship between metabolic parameters and long-term total weight loss.

Bariatric surgery has significant effects on metabolic parameters and hormone levels. However, the specific impact of laparoscopic sleeve gastrectomy (LSG) on thyroid hormones and other metabolic parameters remains unclear. This study aimed to investigate the short and long-term effects of LSG on thyroid hormone levels, HbA1c, and other metabolic parameters. A total of 619 euthyroid patients without a history of thyroid disease or thyroid hormone replacement therapy were included in the study. Patients with diabetes were excluded from the study. Preoperative, 1-year postoperative, and 5-year postoperative levels of thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), HbA1c, and other metabolic parameters were recorded and analyzed. LSG resulted in significant weight loss and improvements in metabolic parameters. At 1year postoperatively, there were significant reductions in BMI, HbA1c, TSH, fT3, and triglyceride levels, while fT4 levels increased. A statistically significant negative correlation was found between preoperative HbA1c level and percentage of total weight loss (%TWL) value at the fifth postoperative year. Additionally, a statistically significant negative correlation was found between the 5-year change in TSH and %TWL. Being the first study to predict long-term total weight loss based on preoperative HbA1c, it is significant. This finding has important implications for personalized patient management and could aid clinicians in identifying individuals who may benefit most from sleeve gastrectomy as a treatment modality. This is valuable in that it emphasizes multidisciplinary work, including the endocrinologist and dietician.

Metabolic changes with intermittent fasting.

The prevalence of obesity is rising globally and effective strategies to treat obesity are needed. Intermittent fasting, a dietary intervention for weight management, has received growing interest from the general public, as well as healthcare professionals, as a form of lifestyle intervention. We executed a rapid review using PUBMED database to identify systematic reviews that examined the impact of intermittent fasting on metabolic indices, published between 2011 and 2022. Intermittent fasting leads to weight loss of a similar magnitude to continuous energy restriction. Most of the evidence shows that intermittent fasting leads to greater fat loss as measured by fat mass (kg) or body fat percentage compared to an ad libitum diet, but fat loss attained during intermittent fasting is not significantly different to continuous energy restriction, although recent evidence shows intermittent fasting to be superior. There is mixed evidence for the impact of intermittent fasting on insulin resistance, fasting glucose and lipid profile. Some studies focused on populations of Muslim people, which showed that Ramadan fasting may lead to weight loss and improvement of metabolic parameters during fasting, although the effects are reversed when fasting is finished. Intermittent fasting is more effective than an ad libitum dietary intake, and equally or more effective as continuous energy restriction, for weight management. However, there is inconclusive evidence on whether intermittent fasting has a clinically beneficial effect on glucose and lipid metabolism.

Differences in carotid to femoral pulse wave velocity and carotid intima media thickness between vegetarian and omnivorous diets in healthy subjects: a systematic review and meta-analysis.

Background: Arterial stiffness and atherosclerosis are known risk factors for cardiovascular morbidity and mortality. Vegetarian diets have been associated with cardiovascular benefits, including improvements in metabolic parameters. However, the impact of a vegetarian diet on cardiovascular parameters, specifically arterial stiffness and atherosclerosis, in healthy individuals remains unclear. Thus, this study aims to analyze differences in arterial stiffness and atherosclerosis between vegetarian and omnivorous diets in healthy subjects. Methods: A systematic review and meta-analysis were conducted following established guidelines. PubMed, Scopus, Web of Science, and Cochrane Library databases were searched for studies examining the association between vegetarian and omnivorous diets with arterial stiffness and atherosclerosis. Cross-sectional studies reporting carotid to femoral pulse wave velocity (cf-PWv) as a measure of arterial stiffness and carotid intima media thickness (c-IMT) as a measure of atherosclerosis were included. Data were synthesized using random effects models, and sensitivity analyses, meta-regressions, and assessment of publication bias were performed. Results: Ten studies were included in the systematic review, and seven studies were included in the meta-analysis. The pooled analysis demonstrated that individuals following a vegetarian diet had differences in the levels of arterial stiffness (cf-PWv) compared to those following an omnivorous diet (MD: -0.43 m s-1; 95% CI: -0.63, -0.23). Similarly, atherosclerosis (c-IMT) was found to be different in individuals adhering to a vegetarian dietary pattern (MD = -29.86 mm; 95% CI: -58.41, -1.32). Conclusions: Our findings suggest that a vegetarian diet is associated with improved arterial stiffness and reduced atherosclerosis in healthy individuals. These results support the inclusion of a well-balanced vegetarian dietary pattern in the prevention and management of cardiovascular diseases. However, further research is needed to explore the effects of a vegetarian diet on arterial health in diverse populations and to assess long-term cardiovascular outcomes.

Metabolic Syndrome Components in Patients with Pituitary Adenoma.

Pituitary adenomas are benign tumors of the anterior portion of the pituitary gland (adenohypophysis), representing the 25% of all the tumor alterations. Pituitary adenomas are classified by the type of hormone secreted, cellularity, size, and structural alterations by the hormonal segregation. The diagnosis consists on the histopathological identification of cell types and the image-guided by magnetic resonance or tomography; the treatment can be both pharmacological and surgical. Metabolic Syndrome is the set of clinical conditions that increase the risk of cardiovascular diseases with an estimated prevalence of 25% worldwide. The alterations of metabolic syndrome are obesity, hypertension, dyslipidemia, insulin resistance, and diabetes mellitus type II. Pituitary adenomas and metabolic syndrome have an important relationship, hormone-secreting by pituitary adenomas affects a myriad of signaling pathways, which allows a favorable environment for the appearance of the metabolic syndrome. Moreover, patients with pituitary adenomas are shown to have an improvement in metabolic parameters after the medical/surgical treatment. The objective of this review is to explore the possible mechanisms through which PAs contributes to MetSx.

Impact of Weight Change on Glycemic Control and Metabolic Parameters in T2D: A Retrospective US Study Based on Real-World Data.

Weight loss has been identified as a key strategy for improving glycemic and metabolic outcomes in people with type2 diabetes (T2D). However, the long-term, real-world impact of weight loss on these outcomes remains unclear. This study aimed to investigate (1) the association between weight loss and glycemic control, (2) association between weight loss and metabolic parameters, and (3) predictors of weight loss and how weight change trajectory varies based on index body mass index (BMI). A retrospective, longitudinal cohort study using the linked IQVIA Ambulatory electronic medical records and PharMetrics® Plus databases was performed from January1, 2010 through December31, 2019 in adults with T2D. Participants were categorized into 1-year and 5-year follow-up cohorts based on their observed weight change over time. Longitudinal values for vital signs and laboratory parameters, including BMI, weight, glycated hemoglobin (HbA1c), and metabolic parameters (liver enzymes and cholesterol), were reported at index date and every 6months post index date. Multivariable logistic regression analysis was used to evaluate the factors associated with weight loss. Of 1,493,964 people evaluated, 1,061,354 (71%) and 308,320 (20.6%) were classified into the 1-year and 5-year follow-up cohorts. Average HbA1c reductions of 1.2% and 0.5% were observed among people who lost ≥ 15% of index weight in the 1-year and 5-year follow-up cohorts, respectively. Higher weight loss percentages were associated with numerically greater improvements in metabolic parameters. The presence of bariatric surgery and higher index BMIs were identified as the strongest predictors of ≥ 15% and ≥ 10% weight loss in both follow-up cohorts. Results from this study suggest that modest and sustained weight loss can lead to clinically meaningful improvements in glycemic and metabolic parameters among people with T2D. These findings highlight the importance of weight management in managing T2D and preventing its associated complications.

Protein PRDM16 and its importance for adipose tissue (literature review)

Currently, in Russia and in the world, there is an increase in the proportion of overweight and obese people among the population, which contributes to an increase in the number of socially significant diseases. Obesity is associated with the predominance of the proportion of fat mass in the component composition of the body. Based on this, increased attention is paid to a comprehensive study of the functioning of all types of human adipose tissue, which is necessary for the further use of this knowledge in the fight against obesity. This article provides an overview of the literature data on the structure and properties of the PRDM16 gene, the features of its functioning in brown, white and beige adipose tissue. The influence of the PRDM16 gene on the activation of brown adipogenesis and the formation of beige adipocytes in white adipose tissue, which contribute to increased heat production of cells by means of non-contractile thermogenesis and improvement of metabolic parameters of the body, is considered. Data on the role of PRDM16 protein in the treatment of obesity, type 2 diabetes mellitus and other human diseases associated with it are analyzed. The results on the methods of effective activation of brown and beige adipocytes and the use of these methods in the treatment of obesity are presented.

FRI058 Treatment With Mibavademab, A Novel Leptin Receptor Agonist, Is Associated With Improvement In Metabolic Parameters In Individuals With Generalized Lipodystrophy

Abstract Disclosure: B. Olenchock: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Podgrabinska: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. C. Hou: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B. Musser: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. J. Mendell: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. A. Harman: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. R.J. Sanchez: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. K. Miller: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. P. Parasoglou: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Hectors: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Karnik: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. O.E. Pagovich: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. R. SinhaRoy: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. C.A. Harris: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B. Akinci: Advisory Board Member; Self; Regeneron Pharmaceuticals, Amryt Pharmaceuticals. Consulting Fee; Self; Amryt Pharmaceuticals, Regeneron Pharmaceuticals, Third Rock Ventures, AstraZeneca, Lilly USA, LLC, Novartis Pharmaceuticals, Novo Nordisk, Boehringer Ingelheim, Servier, Sanofi-Aventis, MSD. I. Yildirim simsir: None. S. Ozen: None. E. Sorkina: Advisory Board Member; Self; Amryt Pharmaceuticals, Regeneron Pharmaceuticals. A. Garg: Consulting Fee; Self; Aegerion Pharmaceuticals, Regeneron Pharmaceuticals. Grant Recipient; Self; Aegerion Pharmaceuticals, Pfizer, Inc., Regeneron Pharmaceuticals, Amryt Pharmaceuticals, Ionis Pharmaceuticals Inc. R.J. Vargas Gonzalez: None. D.M. Weinreich: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. G. Herman: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. E.A. Oral: Consulting Fee; Self; Regeneron Pharmaceuticals, Third Rock Ventures, Amryt Pharmaceuticals, Rejuvenate Inc, Ionis Pharmaceuticals. Grant Recipient; Self; Gemphire Theraputics, Amryt Pharmaceuticals, Ionis Pharmaceuticals. R.J. Brown: Grant Recipient; Self; Regeneron Pharmaceuticals. Background: Generalized lipodystrophy (GLD) is characterized by the deficiency of adipose tissue and consequently, low levels of the adipose-derived hormone leptin. Leptin deficiency in GLD leads to metabolic abnormalities which are often refractory to treatment with conventional agents. Recombinant human leptin, the only approved therapeutic, improves metabolic abnormalities of GLD, however, daily dosing is required and there is a risk of immunogenicity. There is an unmet need for effective therapies in GLD that are safe, administered less frequently, and can treat patients who have developed neutralizing antibodies to recombinant leptin. Mibavademab is an investigational human leptin receptor agonist monoclonal antibody. We report here the safety, tolerability and pharmacodynamic (PD) responses to mibavademab in a Phase 2 trial (NCT04159415) in patients with GLD. Methods: Patients ≥12 years with acquired or congenital GLD were randomized to mibavademab or placebo. After a single-blind placebo run-in, patients were randomized 1:1 to one of two fixed sequence arms comprising sequential 8-week treatment periods (Arm A: placebo, low-dose mibavademab, high-dose mibavademab; Arm B: low-dose mibavademab, high-dose mibavademab, high-dose mibavademab). Patients in each arm received an IV loading dose of placebo or mibavademab followed by weekly SC administration of study drug tiered by body weight (≥50 kg or &amp;lt;50 kg). Both arms were followed by an open-label high-dose mibavademab treatment period. Safety, pharmacokinetics, and PD of mibavademab were assessed. Primary efficacy endpoints, glycated hemoglobin (HbA1c) and fasting triglycerides (TGs) were measured at Week 8 and at predetermined time points thereafter until study completion. Results: Sixteen patients with GLD and baseline diabetes (mean HbA1c 9.6%, range 6.0%-12.2%) or hypertriglyceridemia (median TGs 669 mg/dL, range 107-2899 mg/dL) were randomized and completed ≥28 weeks of mibavademab treatment. After 8 weeks of low-dose mibavademab, drug levels were significantly lower than predicted in the active arm, and clinically meaningful differences were not observed for any of the primary efficacy endpoints as compared to placebo. In an exploratory pooled analyses after 28 weeks of mibavademab administration, serum drug concentrations were significantly higher than observed at Week 8, and clinically significant reductions from baseline in HbA1c (mean: -1.9%, SD: 2.0) and in TGs (median: -102.1 mg/dL, IQR: 1355.5 mg/dL, -49.3% [57.2%]). Mibavademab was generally well tolerated with no serious adverse events related to administration. Conclusions: Treatment with high-dose mibavademab for up to 28 weeks was associated with clinically meaningful improvements in metabolic parameters, and was generally well-tolerated. Mibavademab represents a potential new therapeutic option for patients with GLD. Presentation: Friday, June 16, 2023

FRI057 Drug Concentrations And Dosing Considerations For Mibavademab, A Novel Leptin Receptor Agonist, In Individuals With Generalized Lipodystrophy

Abstract Disclosure: J. Mendell: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. Y. Wang: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B.A. Olenchock: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Podgrabinska: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. O.E. Pagovich: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. E.A. Oral: Advisory Board Member; Self; Regeneron Pharmaceuticals. Consulting Fee; Self; Third Rock Ventures, Rejuvenate Inc. Grant Recipient; Self; Amryt Pharamceuticals, Ionis Pharmaceuticals Inc., Gemphire Theraputics. Research Investigator; Self; Regeneron Pharmaceuticals, Novo Nordisk, Rhythm pharmaceuticals, Fractyl Laboratories, GI Dynamics. Other; Self; Has IP rights to Metreleptin manufactured by Amryt Pharmaceuticals and receives royalty payments. R.J. Brown: Research Investigator; Self; Regeneron Pharmaceuticals. J. Davis: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. Background: Generalized lipodystrophy (GLD) is characterized by deficiency of adipose tissue and, consequently, low levels of the adipose-derived hormone leptin. Leptin deficiency in GLD causes metabolic abnormalities and complications that are often refractory to treatment with usual glucose/lipid-lowering agents. Mibavademab is a first-in-class human leptin receptor (LEPR) agonist monoclonal antibody that activates LEPR. We investigated baseline serum leptin in patients with GLD, pharmacokinetics (PK) of mibavademab, and soluble LEPR (sLEPR) levels from a phase 2 study. Methods: In this phase 2 trial (NCT04159415), patients with GLD (≥12 yrs old) underwent a single-blind placebo run-in, followed by 1:1 randomization to one of two fixed sequence arms: Treatment A (placebo for 8 weeks, then mibavademab low dose for 8 weeks, then mibavademab high dose for 20 weeks) or Treatment B (mibavademab low dose for 8 weeks, then mibavademab high dose for 28 weeks). A loading dose of intravenous mibavademab was administered before low-dose treatment. Mibavademab and sLEPR concentrations in serum were serially measured during mibavademab treatment using validated bioanalytical methods. Results: Sixteen patients were enrolled with median body weight (BW) of 51 kg, corresponding to the approximate BW cut point for mibavademab. Baseline serum leptin was below the lower limit of quantitation (0.078 mg/L) in 5 patients with a median concentration of 0.345 mg/L (n=15). Baseline sLEPR concentrations with Treatments A and B were 30.6 and 33.9 μg/L, respectively. At Week 8, mean (SD) mibavademab trough concentrations (Ctrough) with Treatments A and B were 0 (0) and 1.61 (1.71) mg/L, respectively. Low-dose PK were less than predicted from a first in human study in healthy volunteers with higher leptin levels, reflecting higher target mediated clearance in patients with GLD. At Week 16, Ctrough for Treatments A and B increased to 2.31 and 43.0 mg/L, respectively, but were still below predicted. At Week 36, Ctrough for Treatments A and B were 60 (35.3) and 67.7 (44.2) mg/L, respectively. Clinically meaningful metabolic benefit (i.e reflected by reductions in fasting triglycerides and glycated hemoglobin) was observed at Week 36 with both Treatments A and B. Conclusions: Mibavademab concentrations by Week 36 were associated with clinically meaningful improvement in metabolic parameters. Presentation: Friday, June 16, 2023

Impact of Ramadan fasting on eGFR in patients with late stage chronic kidney disease

Aims: Ramadan fasting is a significant religious practice observed annually by approximately 1.9 billion adult Muslims worldwide. However, its potential impact on kidney health in individuals with chronic kidney disease (CKD) remains a subject of concern. This study aimed to investigate the effects of Ramadan fasting on renal function in patients with stage 3-5 CKD and to identify any associated risk factors.&#x0D; Methods: A single-center, self-controlled longitudinal observational study was conducted on 192 stable patients with stage 3-5 CKD who observed Ramadan fasting. The fasting period was about 14-15 hours per day for one month Various clinical parameters, including eGFR, blood urea nitrogen (BUN), sodium (Na+), potassium (K+), calcium (Ca++), phosphorus, parathyroid hormone (PTH), albumin, uric acid, fasting glucose, total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and hemoglobin (Hgb), were measured before and after Ramadan fasting. P0.05). Furthermore, the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB) did not impact eGFR (0.084). Notably, Ramadan fasting led to improvements in metabolic parameters, such as fasting glucose and lipid profile, except for triglyceride levels (p