RESUMO
The rising prevalence of obesity is of major concern. There are currently 5 Food and Drug Administration-approved medications for the treatment of obesity: orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide 3.0 mg, and semaglutide 2.4 mg. Surgical options such as bariatric surgery and endoscopic surgery induce more durable weight loss than pharmacotherapy or lifestyle interventions alone. However, patients often experience weight regain and weight loss plateau after surgery. The addition of multimodal or multihormonal pharmacotherapy is a promising tool to address these challenges. The optimal timing of obesity pharmacotherapy with surgical and endoscopic interventions requires further investigation.
Assuntos
Fármacos Antiobesidade , Naltrexona , Obesidade , Redução de Peso , Humanos , Fármacos Antiobesidade/uso terapêutico , Naltrexona/uso terapêutico , Cirurgia Bariátrica/métodos , Orlistate/uso terapêutico , Fentermina/uso terapêutico , Liraglutida/uso terapêutico , Bupropiona/uso terapêutico , Topiramato/uso terapêutico , Peptídeos Semelhantes ao Glucagon/uso terapêuticoRESUMO
Dose-scale pharmacodynamic bioequivalence is recommended for evaluating the consistency of generic and innovator formulations of certain locally acting drugs, such as orlistat. This study aimed to investigate the standard methodology for sample size determination and the impact of study design on dose-scale pharmacodynamic bioequivalence using orlistat as the model drug. A population pharmacodynamic model of orlistat was developed using NONMEM 7.5.1 and utilized for subsequent simulations. Three different study designs were evaluated across various predefined relative bioavailability ratios of test/reference (T/R) formulations. These designs included Study Design 1 (2×1 crossover with T1 60 mg, R1 60 mg, and R2 120 mg), Study Design 2 (2×1 crossover with T2 120 mg, R1 60 mg, and R2 120 mg), and Study Design 3 (2×2 crossover with T1 60 mg, T2 120 mg, R1 60 mg, and R2 120 mg). Sample sizes were determined using a stochastic simulation and estimation approach. Under the same T/R ratio and power, Study Design 3 required the minimum sample size for bioequivalence, followed by Study Design 1, while Study Design 2 performed the worst. For Study Designs 1 and 3, a larger sample size was needed on the T/R ratio < 1.0 side for the same power compared to that on the T/R ratio > 1.0 side. The opposite asymmetry was observed for Study Design 2. We demonstrated that Study Design 3 is most effective for reducing the sample size for orlistat bioequivalence studies, and the impact of T/R ratio on sample size shows asymmetry.
Assuntos
Estudos Cross-Over , Orlistate , Equivalência Terapêutica , Orlistate/farmacocinética , Orlistate/administração & dosagem , Humanos , Tamanho da Amostra , Projetos de Pesquisa , Disponibilidade Biológica , Modelos Biológicos , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/administração & dosagem , Lactonas/farmacocinética , Lactonas/administração & dosagem , Simulação por Computador , Relação Dose-Resposta a DrogaRESUMO
Importance: Obesity affects approximately 19% of women and 14% of men worldwide and is associated with increased morbidity. Antiobesity medications (AOMs) modify biological processes that affect appetite and significantly improve outcomes, such as type 2 diabetes, hypertension, and dyslipidemia. Observations: AOMs should be administered in combination with lifestyle interventions and can be classified according to their mechanisms of action. Orlistat modifies digestive tract absorption and causes gastrointestinal adverse effects, such as oily fecal spotting and urgency, in more than 25% of patients. Centrally acting drugs, such as phentermine-topiramate and naltrexone-bupropion, regulate appetite in the brain and are associated with constipation in approximately 20% of patients, although the incidence of other adverse effects (eg, paresthesia, nausea) varies by medication. Nutrient-stimulated hormone-based medications, such as liraglutide, semaglutide, and tirzepatide, mimic the actions of enteropancreatic hormones that modify central appetite regulation and provide multiple cardiometabolic weight-loss benefits. Adverse effects of these drugs include nausea (28%-44%), diarrhea (21%-30%), and constipation (11%-24%). The relative potency of adult obesity medications has been studied in meta-analyses. Compared with placebo, orlistat was associated with 3.1% greater weight loss (52 randomized clinical trials [RCTs]; 16â¯964 participants), phentermine-topiramate was associated with 8.0% greater weight loss (5 RCTs; 3407 participants), naltrexone-bupropion was associated with 4.1% greater weight loss (6 RCTs; 9949 participants), liraglutide was associated with 4.7% greater weight loss (18 RCTs; 6321 participants), semaglutide was associated with 11.4% greater weight loss (5 RCTs; 4421 participants), and tirzepatide 15 mg was associated with 12.4% greater weight loss (6 RCTs; 1972 participants). Conclusion and Relevance: Obesity is associated with increased morbidity. Antiobesity medications are effective adjunctive therapy to lifestyle changes for improved weight loss and health outcomes.
Assuntos
Fármacos Antiobesidade , Dieta Saudável , Obesidade , Feminino , Humanos , Masculino , Fármacos Antiobesidade/uso terapêutico , Fármacos Antiobesidade/efeitos adversos , Bupropiona/uso terapêutico , Bupropiona/efeitos adversos , Combinação de Medicamentos , Frutose/análogos & derivados , Frutose/uso terapêutico , Frutose/efeitos adversos , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Lactonas/uso terapêutico , Lactonas/efeitos adversos , Liraglutida/uso terapêutico , Liraglutida/efeitos adversos , Naltrexona/uso terapêutico , Naltrexona/efeitos adversos , Obesidade/dietoterapia , Obesidade/tratamento farmacológico , Orlistate/uso terapêutico , Fentermina/uso terapêutico , Fentermina/efeitos adversos , Topiramato/uso terapêutico , Topiramato/efeitos adversos , Redução de Peso/efeitos dos fármacos , Terapia Combinada/métodosRESUMO
BACKGROUND: Polygonatum sibiricum polysaccharides protect against obesity and NAFLD. However, the potential effects of PS rhizome aqueous extracts (PSRwe) on adiposity and hepatic lipid accumulation remains unexplored. PURPOSE: Elucidating the impact and underlying mechanism of PSRwe on HFD-induced obesity and liver fat depostition. STUDY DESIGN: 56 male mice, aged eight weeks, were divided into seven groups: Positive, four doses of PSRwe, Model, and Control. HFD was fed for eight weeks, followed by alternate-day gavage of orlistat and PSRwe for an additional eight-week period. Integrative analysis encompassing multiomics, physiological and histopathological, and biochemical indexes was employed. METHODS: Body weight (BW); liver, fat and Lee's indexes; TC, TG, LDL-C, HDL-C, AST, ALT, FFA, leptin, and adiponectin in the liver and blood; TNFα, IL-6, and LPS in the colon, plasma, and liver; H&E, PAS and oil red O staining on adipose and liver samples were examined. OGTT and ITT were conducted The gut microbiome, microbial metabolome, colonic and liver transcriptome, plasma and liver metabolites were investigated. RESULTS: PSRwe at the dosage of 7.5 mg/kg demonstrated significant and consistent reduction in BW and hepatic fat deposition than orlistat. PSRwe significantly decreased TC, TG, LDL-C, LEP, FFA levels in blood and liver. PSRwe significantly enhanced the relative abundance of probiotics including Akkermansia muciniphila, Bifidobacterium pseudolongum, Lactobacillus reuteri, and metabolic pathways including glycolysis and fatty acids ß-oxidation. The 70 up-regulated microbial metabolites in PSRwe-treated mice mainly involved in nucleotides and amino acids metabolism, while 40 decreased metabolites primarily associated with lipid metabolism. The up-regulated colonic differentially expressed genes (DEGs) participate in JAK-STAT/PI3K-Akt/FoxO signaling pathway, serotonergic/cholinergic/glutamatergic synapses, while the down-regulated DEGs predominantly focused on fat absorption and transport. The up-regulated liver DEGs mainly concentrated on fatty acid oxidation and metabolism. Liver metabolisms revealed 131 differential metabolites, among which carnitine and oxidized lipids significantly increased in PSRwe-treated mice. In plasma, the 58 up-regulated metabolites mainly participate in co-factors/vitamins metabolism while 154 down-regulated ones in fatty acids biosynthesis. Comprehensive multiomics association analysis revealed significant associations between gut microbiota and colonic/liver gene expression, and suggested exogenous and endogenous betaine may be active compound in alleviating HFD-induced symptoms. CONCLUSION: PSRwe effectively mitigate HFD-induced obesity and hepatic steatosis by increasing beneficial bacteria, reducing colonic fat digestion/absorption, increasing hepatic lipid metabolism, and elevating betaine levels.
Assuntos
Fígado , Hepatopatia Gordurosa não Alcoólica , Obesidade , Extratos Vegetais , Polygonatum , Animais , Masculino , Camundongos , Akkermansia , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Multiômica , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Obesidade/etiologia , Orlistate/farmacologia , Extratos Vegetais/farmacologia , Polygonatum/química , Rizoma/química , Modelos Animais de DoençasRESUMO
BACKGROUND: Weight gain and metabolic disorders are commonly induced by antipsychotics. Orlistat is a lipase inhibitor used for weight control. The effect of orlistat on weight gain and metabolic disturbances in people (especially women) treated with antipsychotics has not been sufficiently studied. This study aimed to investigate the efficacy of orlistat in mitigating antipsychotic-induced weight gain and abnormal glycolipid metabolism. METHODS: Patients with schizophrenia or bipolar disorder with a weight gain ≥ 7% after taking antipsychotics were recruited. Participants were randomly allocated to two groups: one received eight weeks of orlistat (360 mg/day) and the other received a placebo. Anthropometric and fasting serum biochemical parameters were measured at baseline, week 4 and week 8. RESULTS: Sixty individuals (orlistat:placebo = 32:28) participated in the study. After controlling for the study center, the eight-week changes in body mass index (BMI), cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-CH) and low-density lipoprotein cholesterol (LDL-CH) were significantly different between the groups. According to the mixed linear models, CHOL and LDL-CH were significantly lower in the orlistat group than in the control group at week 8. The week 0-to-8 slopes of BMI, CHOL and LDL-CH were also significantly lower in the orlistat group. CONCLUSIONS: These findings suggested that orlistat is an effective intervention for attenuating weight gain and serum lipid disturbances in antipsychotic-treated patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03451734.
Assuntos
Antipsicóticos , Índice de Massa Corporal , Lactonas , Orlistate , Esquizofrenia , Aumento de Peso , Humanos , Orlistate/uso terapêutico , Feminino , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Masculino , Aumento de Peso/efeitos dos fármacos , Adulto , Pessoa de Meia-Idade , Método Duplo-Cego , Esquizofrenia/tratamento farmacológico , Esquizofrenia/sangue , Lactonas/uso terapêutico , Lactonas/efeitos adversos , LDL-Colesterol/sangue , HDL-Colesterol/sangue , Fármacos Antiobesidade/uso terapêutico , Fármacos Antiobesidade/efeitos adversos , Transtorno Bipolar/tratamento farmacológicoRESUMO
During the past years, several drugs have been developed for the treatment of obesity. Some are already used in clinical practice: orlistat, GLP-1 receptor agonists (RA), GLP-1/GIP biagonists and the melanocortin 4 receptor (MC4R) agonist, setmelanotide. Some should be available in the future: GLP-1/glucagon biagonists, GLP-1/GIP/glucagon triagonists. These drugs act mainly by reducing food intake or fat absorption. However, many of them show specific effects on the adipose tissue. All these drugs show significant reduction of fat mass and, more particularly of visceral fat. If most of the drugs, except orlistat, have been shown to increase energy expenditure in rodents with enhanced thermogenesis, this has not yet been clearly demonstrated in humans. However, biagonists or triagonist stimulating glucagon seem to a have a more potent effect to increase thermogenesis in the adipose tissue and, thus, energy expenditure. Most of these drugs have been shown to increase the production of adiponectin and to reduce the production of pro-inflammatory cytokines by the adipose tissue. GLP-1RAs reduce the size of adipocytes and promote their differentiation. GLP-1RAS and GLP-1/GIP biagonists reduce, in the adipose tissue, the expression of several genes involved in lipogenesis. Further studies are still needed to clarify the precise roles, on the adipose tissue, of these drugs dedicated for the treatment of obesity.
Assuntos
Tecido Adiposo , Fármacos Antiobesidade , Metabolismo Energético , Obesidade , Humanos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Fármacos Antiobesidade/uso terapêutico , Fármacos Antiobesidade/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Metabolismo Energético/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Termogênese/efeitos dos fármacos , Termogênese/fisiologia , Peptídeo 1 Semelhante ao Glucagon/agonistas , Orlistate/uso terapêutico , Orlistate/farmacologiaRESUMO
Obesity is a major health issue that contributes significantly to increased mortality and morbidity worldwide. Obesity is caused by uncontrolled adipogenesis and lipogenesis, leading to several metabolism-associated problems. Pancreatic lipase, an enzyme that breaks down dietary lipids, is a prominent target for obesity. Orlistat, a known inhibitor of pancreatic lipase, is commonly employed for the management of obesity. However, its side effects, such as diarrhoea, nausea and bladder pain, urge to look out for safer alternatives. Morin is a pentahydroxyflavone, exerts a broad spectrum of pharmacological effects including antioxidant, anti-inflammatory, lipid lowering, anti-diabetic, anti-fibrotic, anti-cancer, etc. This study investigated the effect of morin on pancreatic lipase activity, in vitro and in vivo adipogenesis. Molecular docking and simulation studies showed morin to have a higher binding affinity towards pancreatic lipase compared with orlistat, which also inhibited its activity in vitro. Morin also reduced lipid droplet accretion and downregulated the expression of adipogenic and lipogenic genes. The acute oral toxicity of morin was determined in C57BL/6 mice, where morin did not show toxicity up to 2000 mg/kg body weight dose. Oral administration of morin to high fat diet fed mice reduced body weight, glucose and insulin levels. Also, the histopathological examination revealed reduction in adipocyte size and decreased mRNA expression of adipogenesis markers in white adipose tissue of morin administered group compared to high fat diet group. Overall, the results suggested morin inhibited pancreatic lipase activity, adipogenesis and further studies are warranted to explore its therapeutic potential for obesity.
Assuntos
Adipogenia , Flavonoides , Lipase , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Animais , Adipogenia/efeitos dos fármacos , Flavonoides/farmacologia , Camundongos , Lipase/antagonistas & inibidores , Lipase/metabolismo , Masculino , Células 3T3-L1 , Dieta Hiperlipídica/efeitos adversos , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Fármacos Antiobesidade/farmacologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Humanos , Orlistate/farmacologia , FlavonasRESUMO
BACKGROUND: The aim of this study is to examine the impact of the Orlistat on glucose levels and glucose tolerance in individuals with prediabetes, as well as assess its efficacy and safety in preventing the progression to diabetes. METHODS: For achieving the appropriate randomized controlled trials, we enrolled the public datas from the following electronic databases: The Cochrane library, Embase, China National Knowledge Infrastructure, VIP, Wan-Fang, and China Biology Medicine disc. The article focused on the orlistat intervention of glucose tolerance and glycemic status in prediabetic patients. We restricted the publication time from the creation to May 2023. RESULTS: Six subjects were included in the study, with a total of 1076 participants (532 in the control group vs 544 in the experimental group). The results indicated that the orlistat can reduce the fasting blood glucose [relative risk (RR)â =â -2.18, 95% confidence intervals (CI) (-2.471, -1.886)], as well as the 2 hour postprandial blood glucose [RRâ =â -1.497, 95% CI (-1.811, -1.183)]. Furthermore, it can prevent the impaired glucose tolerance patients to type 2 diabetes mellitus [RRâ =â 0.605, 95% CI (0.462, 0.791)], and reversal the impaired glucose tolerance [RRâ =â 2.092, 95% CI (1.249, 3.503)]. CONCLUSIONS: In prediabetic people, the orlistat can control weight, reduce the fasting blood glucose and the 2 hour postprandial blood glucose, and then delay the progression of diabetes. However, due to the quantitative restrictions, additional high-quality study needs to be conducted to improve the reliability of the results.
Assuntos
Fármacos Antiobesidade , Glicemia , Diabetes Mellitus Tipo 2 , Progressão da Doença , Orlistate , Estado Pré-Diabético , Humanos , Orlistate/uso terapêutico , Orlistate/farmacologia , Estado Pré-Diabético/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicemia/efeitos dos fármacos , Fármacos Antiobesidade/uso terapêutico , Fármacos Antiobesidade/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Lactonas/uso terapêuticoRESUMO
Background: Obesity is one of the most prevalent and perilous health affairs. Male obesity-associated secondary hypogonadism (MOSH) is one of many of its complexities, which is mounting in parallel with the aggravation of obesity. Magnetic nanoparticles seem to be an advanced favorable trend in multiple biomedical fields. Aim: In this study, we explore the therapeutic effects of superparamagnetic iron oxide nanoparticles (SPIONs) coated with carboxymethyl cellulose (CMC) on an obese male rat model with MOSH syndrome, comparing their impacts with a well-known anti-obesity medication (Orlistat). Methods: 42 male albino rats split into 7 equal groups: 1-negative control: nonobese, untreated; 35 rats fed the high fat-high fructose (HFHF) diet for a period of 12 weeks. Obese rats splitted into 6 equal groups; 2-positive control: obese untreated; 3-obese given Orlistat (30 mg/kg); 4-obese given CMC-SPIONs (25 mgFe/kg); 5-obese given CMC-SPIONs (50 mgFe/kg); 6-obese given CMC-SPIONs(25 mgFe/kg) + Orlistat (30 mg/kg), 7-obese given CMC-SPIONs (50 mgFe/kg) + Orlistat (30 mg/kg); all treatments given orally for 4 weeks. During sacrifice, blood serum and sectioned hypothalamic, pituitary, testicular, and adipose tissues were collected for biochemical and biomolecular assessments. Results: The HFHF diet for 12 weeks resulted in a significant upsurge in body weight, body mass index, serum fasting glucose, insulin resistance, TAG, total cholesterol, and LDL-c; HDL-c was dropped. Serum FSH, LH, and testosterone values declined. A significant disorder in expression levels of genes regulating the hypothalamic-pituitary-testicular-axis pathway. Hypothalamic GnRH, Kisspeptin-1, Kisspeptin-r1, and Adipo-R1 values declined. GnIH and Leptin-R1 values raised up. Pituitary GnRH-R values declined. Testicular tissue STAR, HSD17B3, and CYP19A1 values declined. Adipose tissue adiponectin declined, while leptin raised up. CMC-SPIONs 25-50 mg could modulate the deranged biochemical parameters and correct the deranged expression levels of all previous genes. Co-treatments revealed highly synergistic effects on all parameters. Overall, CMC-SPIONs have significant efficiency whether alone or with Orlisat in limiting obesity and consequence subfertility. Conclusion: CMC-SPIONs act as an incoming promising contender for obesity and MOSH disorders management, and need more studies on their mechanisms.
Assuntos
Hipogonadismo , Obesidade , Doenças dos Roedores , Ratos , Masculino , Animais , Leptina/metabolismo , Leptina/uso terapêutico , Orlistate/metabolismo , Orlistate/farmacologia , Orlistate/uso terapêutico , Testículo/metabolismo , Obesidade/genética , Obesidade/metabolismo , Obesidade/veterinária , Hipogonadismo/metabolismo , Hipogonadismo/veterinária , Hipotálamo/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Liberador de Gonadotropina/uso terapêutico , Nanopartículas Magnéticas de Óxido de FerroRESUMO
Lipid-based formulations (LBFs) are an enabling-formulation approach for lipophilic poorly water-soluble compounds. In LBFs, drugs are commonly pre-dissolved in lipids, and/or surfactants/cosolvents, hereby avoiding the rate-limiting dissolution step. According to the Lipid formulation classification system, proposed by Pouton in 2006, in type II LBFs a surfactant with an HLB-value lower than 12 is added to the lipids. If high drug doses are required, e.g. for preclinical toxicity studies, supersaturated LBFs prepared at elevated temperatures may be a possibility to increase drug exposure. In the present study, the impact of digestion on drug absorption in rats was studied by pre-dosing of the lipase inhibitor orlistat. The lipid chain length of the type II LBFs was varied by administration of a medium-chain- (MC) and a long-chain (LC)-based formulation. Different drug doses, both non-supersaturated and supersaturated, were applied. Due to an inherent precipitation tendency of cinnarizine in supersaturated LBFs, the effect of the addition of the precipitation inhibitor Soluplus® was also investigated. The pharmacokinetic results were also evaluated by multiple linear regression. In most cases LC-based LBFs did not perform better in vivo, in terms of a higher area under the curve (AUC0-24 h) and maximal plasma concentration (Cmax), than MC-based LBFs. The administration of supersaturated LBFs resulted in increased AUC0-24 h (1.5 - 3.2-fold) and Cmax (1.1 - 2.6-fold)-values when compared to the non-supersaturated equivalents. Lipase inhibition led to a decreased drug exposure in most cases, especially for LC formulations (AUC0-24 h reduced to 47 - 67%, Cmax to 46 - 62%). The addition of Soluplus® showed a benefit to drug absorption from supersaturated type II LBFs (1.2 - 1.7-fold AUC0-24 h), due to an increased solubility of cinnarizine in the formulation. Upon dose-normalization of the pharmacokinetic parameters, no beneficial effect of Soluplus® could be demonstrated.
Assuntos
Cinarizina , Lipídeos , Cinarizina/química , Cinarizina/farmacocinética , Cinarizina/administração & dosagem , Animais , Masculino , Lipídeos/química , Solubilidade , Lactonas/química , Lactonas/farmacocinética , Lactonas/administração & dosagem , Ratos Wistar , Orlistate/administração & dosagem , Orlistate/farmacocinética , Absorção Intestinal , Ratos , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Lipase/antagonistas & inibidores , Polivinil/química , Precipitação Química , Tensoativos/química , Química Farmacêutica/métodosRESUMO
PURPOSE: A significant proportion of patients experience insufficient weight loss or weight regain after bariatric surgery. There is a paucity of literature describing anti-obesity medication (AOM) use following bariatric surgery. We sought to identify prevalence and trends of AOM use following bariatric surgery. MATERIALS AND METHODS: We utilized the IBM Explorys® database to identify all adults with prior bariatric surgery (Roux-en-Y gastric bypass or sleeve gastrectomy). Those prescribed AOMs (semaglutide, liraglutide, topiramate, phentermine/topiramate, naltrexone/bupropion, orlistat) within 5 years of surgery were further identified. Data was analyzed to characterize AOM utilization among different age, demographic, and comorbid populations. RESULTS: A total of 59,160 adults with prior bariatric surgery were included. Among AOMs studies, prevalence of use was highest for topiramate (8%), followed by liraglutide (2.9%), phentermine/topiramate (1.03%), naltrexone/bupropion (0.95%) semaglutide (0.52%), and orlistat (0.17%). Age distribution varied, with the highest utilization among those age 35-39 years for topiramate, 40-44 years for phentermine/topiramate and naltrexone/bupropion, 45-49 years for semaglutide, and 65-69 years for liraglutide and orlistat. African American race was associated with higher utilization across all AOMs. Among comorbidities, hypertension, hyperlipidemia, and diabetes mellitus were most associated with AOM use. CONCLUSION: Despite a relatively high incidence of weight regain, AOMs are underutilized following bariatric surgery. It is imperative that barriers to their use be addressed and that AOMs be considered earlier and more frequently in patients with insufficient weight loss or weight regain after bariatric surgery.
Assuntos
Fármacos Antiobesidade , Artrite , Cirurgia Bariátrica , Doenças do Tecido Conjuntivo , Derivação Gástrica , Perda Auditiva Neurossensorial , Obesidade Mórbida , Descolamento Retiniano , Adulto , Humanos , Orlistate , Topiramato/uso terapêutico , Liraglutida/uso terapêutico , Naltrexona/uso terapêutico , Bupropiona , Obesidade Mórbida/cirurgia , Estudos Retrospectivos , Fármacos Antiobesidade/uso terapêutico , Fentermina/uso terapêutico , Redução de Peso , Aumento de PesoRESUMO
The prevalence of obesity with various complications is increasing rapidly in Korea. Although lifestyle modification is fundamental in obesity treatment, more effective treatment tools are required. Many advances in obesity treatment have been reported recently, including lifestyle modifications and pharmacological, endoscopic, and surgical treatments. Drugs with proven long-term efficacy and safety are preferred because management for obesity treatment is a long-term process. Currently, four medications are available for long-term use in Korea: Orlistat, Naltrexone/bupuropion NR, Phentermine/topiramate capsule, and Liraglutide. Recently, semaglutide and tirzepatide have been attracting attention because of their effectiveness and convenience, but they are not yet available in Korea. In addition, there are limitations such as the yo-yo effect when discontinuing the drug, long-term safety, and cost. Patients and medical staff must be aware of the advantages and side effects of each medication to ensure the successful treatment of obesity.
Assuntos
Fármacos Antiobesidade , Humanos , Fármacos Antiobesidade/uso terapêutico , Fentermina/uso terapêutico , Obesidade/tratamento farmacológico , Obesidade/complicações , Orlistate/uso terapêutico , Liraglutida/uso terapêuticoRESUMO
INTRODUCTION: The study addresses concerns about potential psychiatric side effects of Glucagon-like peptide-1 receptor agonists (GLP-1 RA). AIM: The aim of this work was to analyse adverse drug reports (ADRs) from the Food and Drug Administration Adverse Events Reporting System (FAERS) using metformin and orlistat as comparators. METHODS: Descriptive and pharmacovigilance disproportionality analyses was performed. RESULTS: A total of 209,354 ADRs were reported, including 59,300 serious cases. Of those, a total of 5378 psychiatric disorder cases, including 383 'serious' cases related to selected ADRs were registered during 2005-2023. After unmasking, 271 cases where individual GLP-1 RA were implicated showing liraglutide (n = 90; Reported Odds Ratio (ROR) = 1.64), exenatide (n = 67; ROR = 0.80), semaglutide (n = 61; ROR = 2.03), dulaglutide (n = 45; ROR = 0.84), tirzepatide (n = 5; ROR = 1.76) and albiglutide (n = 2; ROR = 0.04). A greater association between these ADRs with metformin was observed, but not orlistat. With regards to selected preferred terms (PTs), 42 deaths including 13 completed suicides were recorded. Suicidal ideation was recorded in n = 236 cases for 6/7 GLP-1 RA (excluding lixisenatide). DISCUSSION: Suicide/self-injury reports pertaining to semaglutide; tirzepatide; and liraglutide were characterised, although lower than metformin. It is postulated that rapid weight loss achieved with GLP-1 RA can trigger significant emotional, biological, and psychological responses, hence possibly impacting on suicidal and self-injurious ideations. CONCLUSIONS: With the current pharmacovigilance approach, no causality link between suicidal ideation and use of any GLP-1 RA can be inferred. There is a need for further research and vigilance in GLP-1 RA prescribing, particularly in patients with co-existing psychiatric disorders.
Assuntos
Fármacos Antiobesidade , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon , Farmacovigilância , Comportamento Autodestrutivo , Ideação Suicida , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Fármacos Antiobesidade/efeitos adversos , Fármacos Antiobesidade/uso terapêutico , Exenatida/uso terapêutico , Exenatida/efeitos adversos , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon/efeitos adversos , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Liraglutida/uso terapêutico , Liraglutida/efeitos adversos , Metformina/efeitos adversos , Metformina/uso terapêutico , Orlistate/efeitos adversos , Comportamento Autodestrutivo/epidemiologia , Redução de Peso/efeitos dos fármacosRESUMO
Purpose: Anti-obesity medications (AOMs), along with lifestyle interventions, are effective means of inducing and maintaining weight loss in patients with obesity. Although the efficacy of AOMs has been reported, there have been no direct comparisons of these drugs. Therefore, in the present study, we aimed to compare the efficacy of all the AOMs available in Korea in a real-world setting. Patients and Methods: The body weight and composition of 205 adults treated with phentermine, phentermine/topiramate, liraglutide, naltrexone/bupropion, lorcaserin, or orlistat for at least 6 months were analyzed at 2 month intervals. The prevalence of the achievement of a ≥5% weight loss and the changes in body composition were compared between participants using each AOM at each visit. Results: A total of 132 (64.4%) participants achieved ≥5% weight loss within 6 months (prevalence of ≥5% weight loss after 6 months: phentermine, 87.2%; phentermine/topiramate, 67.7%; liraglutide, 58.1%; naltrexone/bupropion, 35.3%; lorcaserin, 75%; orlistat, 50%). At each visit, after adjustment for age, sex, and baseline body weight, phentermine use was associated with a significantly higher prevalence of ≥5% weight loss than the use of the other AOMs, except for liraglutide. There were significant differences in the body weight, body mass index and body fat mass among the AOM groups by visit (P for interaction <0.05), but not in their waist circumference, skeletal muscle mass, percentage body fat, or visceral fat area. Conclusion: All the AOMs were effective at inducing and maintaining weight loss, in the absence of significant changes in muscle mass, over a 6 month period, and the short-term use of phentermine and the long-term use of phentermine/topiramate or liraglutide would be practical choices for the treatment of obesity. However, further, large-scale studies are necessary to confirm these findings.
Assuntos
Fármacos Antiobesidade , Liraglutida , Adulto , Humanos , Orlistate/uso terapêutico , Topiramato/uso terapêutico , Liraglutida/uso terapêutico , Naltrexona/uso terapêutico , Bupropiona/uso terapêutico , Frutose , Fármacos Antiobesidade/uso terapêutico , Obesidade/tratamento farmacológico , Peso Corporal , Fentermina/efeitos adversos , Redução de PesoRESUMO
BACKGROUND: Obesity is associated with elevated serum uric acid (SUA) levels and frequent gout flares. Losing weight can reduce the SUA level and gout flares. The effect of orlistat on SUA levels and gout flares in patients with overweight/obesity and hyperuricemia (HUA) has not been extensively studied. This study investigated the effects of orlistat on SUA levels and gout flares compared to placebo in overweight and obese patients with HUA. METHODS: A total of 72 Chinese patients with overweight/obesity and HUA were randomly divided into a placebo group (35, 48.6%) and an orlistat group (37, 51.4%); the trial lasted 12 weeks. The primary endpoints were the relative changes in body weight, the SUA level, and gout flares in the per-protocol population. RESULTS: Orlistat reduced the proportion of patients with gout flares (log-rank P = 0.023, hazard ratio = 0.31, 95% confidence interval 0.11-0.85). There was no significant difference in SUA level between the two groups. The average weight loss of the orlistat group was 2.85 kg, and the average weight loss of the placebo group was 0.76 kg. The weight loss in the orlistat group was significantly greater than that in the control group (P < 0.05). CONCLUSIONS: This study is the first to demonstrate that orlistat has no significant effect on SUA levels in patients with overweight/obesity and HUA. The utility of orlistat as an adjunct therapy to prevent gout flares during weight loss in patients with HUA was emphasized. TRIAL REGISTRATION: Clinicaltrials.gov NCT05496075.
Assuntos
Hiperuricemia , Orlistate , Sobrepeso , Humanos , Masculino , Método Duplo-Cego , Gota/complicações , Gota/tratamento farmacológico , Hiperuricemia/complicações , Hiperuricemia/tratamento farmacológico , Obesidade/complicações , Obesidade/tratamento farmacológico , Orlistate/efeitos adversos , Sobrepeso/complicações , Sobrepeso/tratamento farmacológico , Ácido Úrico , Redução de PesoRESUMO
AIMS: To describe trends in the use of anti-obesity drugs in Norway during the period 2004-2022. MATERIALS AND METHODS: We assessed the annual utilization of any available drug indicated for obesity recorded in the nationwide Norwegian Prescribed Drug Register for adults (age 18-79 years) from 1 January 2004 to 31 December 2022. Prevalence was stratified by sex and age group (18-29 years and 10-year age groups thereafter). Additional analyses were performed in individuals initiating treatment with an anti-obesity drug and on the cost of the anti-obesity drugs since 2017. RESULTS: The prevalence of anti-obesity drug use decreased from 2009, when sibutramine and rimonabant were withdrawn from the market, and increased again after the approval of bupropion-naltrexone in 2017 and liraglutide in 2018. The use of the peripheral-acting anti-obesity drug orlistat decreased from 2004. In 2022, 1.04% of the adult Norwegian population (72.8% women) filled at least one prescription of bupropion-naltrexone, 0.91% used liraglutide (Saxenda; 74.2% women), and semaglutide without reimbursement was used by 0.68% (76.7% women). The prevalence increased with age, peaking in the age group 50 to 59 years, and decreased in older age groups. From 2017 to 2022, 2.8% of the adult residents initiated treatment with an anti-obesity drug. The total sale of those drugs increased from 1.1 million euros in 2017 to 91.8 million euros in 2022. CONCLUSIONS: The use of anti-obesity drugs in Norway has increased substantially in recent years, especially among women aged 40 to 59 years. Changes in availability and reimbursement have influenced the use of these drugs in recent years.
Assuntos
Fármacos Antiobesidade , Bupropiona , Liraglutida , Naltrexona , Obesidade , Humanos , Adulto , Noruega/epidemiologia , Pessoa de Meia-Idade , Feminino , Masculino , Fármacos Antiobesidade/uso terapêutico , Fármacos Antiobesidade/economia , Obesidade/tratamento farmacológico , Obesidade/epidemiologia , Adolescente , Idoso , Adulto Jovem , Liraglutida/uso terapêutico , Bupropiona/uso terapêutico , Naltrexona/uso terapêutico , Orlistate/uso terapêutico , Rimonabanto/uso terapêutico , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Custos de Medicamentos/estatística & dados numéricos , Sistema de Registros , Prevalência , Uso de Medicamentos/tendências , Uso de Medicamentos/estatística & dados numéricos , CiclobutanosRESUMO
This systematic review and meta-analysis evaluated the efficacy of anti-obesity agents for hormonal, reproductive, metabolic, and psychological outcomes in polycystic ovary syndrome (PCOS) to inform the 2023 update of the International Evidence-based Guideline on PCOS. We searched Medline, EMBASE, PsycInfo, and CINAHL until July 2022 with a 10-year limit to focus on newer agents. Eleven trials (545 and 451 participants in intervention and control arms respectively, 12 comparisons) were included. On descriptive analyses, most agents improved anthropometric outcomes; liraglutide, semaglutide and orlistat appeared superior to placebo for anthropometric outcomes. Meta-analyses were possible for two comparisons (exenatide vs. metformin and orlistat + combined oral contraceptive pill [COCP] vs. COCP alone). On meta-analysis, no differences were identified between exenatide versus metformin for anthropometric, biochemical hyperandrogenism, and metabolic outcomes, other than lower fasting blood glucose more with metformin than exenatide (MD: 0.10 mmol/L, CI 0.02-0.17, I2 = 18%, 2 trials). Orlistat + COCP did not improve metabolic outcomes compared with COCP alone (fasting insulin MD: -8.65 pmol/L, -33.55 to 16.26, I2 = 67%, 2 trials). Published data examining the effects of anti-obesity agents in women with PCOS are very limited. The role of these agents in PCOS should be a high priority for future research.
Assuntos
Fármacos Antiobesidade , Metformina , Síndrome do Ovário Policístico , Feminino , Humanos , Síndrome do Ovário Policístico/tratamento farmacológico , Fármacos Antiobesidade/uso terapêutico , Anticoncepcionais Orais Combinados/uso terapêutico , Orlistate/uso terapêutico , Exenatida/uso terapêutico , Metformina/uso terapêutico , Hipoglicemiantes/uso terapêuticoRESUMO
This study investigates the impact of orlistat on oxidative stress, spatial memory, recognition memory, and hippocampal tissue in obese rats. The study groups were divided into control, high fat diet-induced obese (HFDIO), HFDIO+orlistat (HFDIO+ORL) groups, each consisting of 8 animals. While control fed with standart diet, HFDIO and HFDIO+ORL fed with high-fat diets for 8 weeks to induce obesity. Then, ORL treated 10 mg/kg for 7 weeks, while control and HFDIO get water. At 16th week, novel object recognition (NOR) and Morris water maze (MWM) tests were performed. TNF-alpha, IL-1beta levels in hippocampal tissue, and total/native thiol/disulphide levels in serum were measured. TNF-alpha level of HFDIO was higher than control, while lower in HFDIO+ORL compared to HFDIO as like IL-1beta level. On the contrary, serum total thiol level was lower in HFDIO than control and higher in HFDIO+ORL compared to the HFDIO, while disulphide level was opposite of the total thiol levels. While recognition index was higher in HFDIO+ORL, in MWM, latency of finding platform in HFDIO was higher than control and latency of HFDIO+ORL was very similar to control in 2-4 days. The HFDIO group demonstrated decrease in time spent in platform zone compared to control, whereas time spent of the HFDIO+ORL was higher than HFDIO. Our study demonstrates that orlistat administration exerts beneficial effects on oxidative stress, spatial memory, recognition memory, and hippocampal tissue in obese rats. It shows that orlistat may have potential therapeutic implications for obesity-related cognitive impairments and hippocampal dysfunction.
Assuntos
Memória Espacial , Fator de Necrose Tumoral alfa , Ratos , Animais , Orlistate/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Hipocampo , Estresse Oxidativo , Obesidade/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Dissulfetos/farmacologia , Compostos de Sulfidrila/farmacologiaRESUMO
Lipase inhibition is one of the directions to control obesity. In vitro assays have confirmed the inhibitory effect of selected xanthophylls, including astaxanthin, fucoxanthinol, fucoxanthin, and neoxanthin. Similarly, an in-silico study also demonstrated the successful inhibition of pancreatic lipase by astaxanthin. Unfortunately, the efficacy of these protocols in the emulsion state typical of lipid digestion remains untested. To address this issue, the current study employed the pH-stat test, which mimics lipid digestion in the gastrointestinal tract, to evaluate native and prepared sea buckthorn and rapeseed oils with varying xanthophyll contents from 0 to 1400 mg/kg oil. Furthermore, a molecular docking of zeaxanthin and violaxanthin (commonly found in plant-based foods), astaxanthin (widely distributed in foods of marine origin) and orlistat (approved as a drug) was performed. The in-silico studies revealed comparable inhibitory potential of all tested xanthophylls (variation from - 8.0 to - 9.3 kcal/mol), surpassing that of orlistat (- 6.5 kcal/mol). Nonetheless, when tested in an emulsified state, the results of pH-stat digestion failed to establish the inhibitory effect of xanthophylls in the digested oils. In fact, lipolysis of native xanthophyll-rich sea buckthorn oil was approximately 22% higher than that of the xanthophyll-low preparation. The key insight derived from this study is that the amphiphilic properties of xanthophylls during the digestion of xanthophyll-rich lipids/meals facilitate emulsion formation, which leads to enhanced fat lipolysis.
Assuntos
Lipase , Xantofilas , Hidrólise , Orlistate , Emulsões , Simulação de Acoplamento Molecular , Xantofilas/farmacologia , Luteína , Lipídeos , Óleos , DigestãoRESUMO
OBJECTIVES: This study aimed to assess the cost-effectiveness of weight-management pharmacotherapies approved by Canada Health, i.e., orlistat, naltrexone 32 mg/bupropion 360 mg (NB-32), liraglutide 3.0 mg and semaglutide 2.4 mg as compared to the current standard of care (SoC). METHODS: Analyses were conducted using a cohort with a mean starting age 50 years, body mass index (BMI) 37.5 kg/m2, and 27.6% having type 2 diabetes. Using treatment-specific changes in surrogate endpoints from the STEP trials (BMI, glycemic, blood pressure, lipids), besides a network meta-analysis, the occurrence of weight-related complications, costs, and quality-adjusted life-years (QALYs) were projected over lifetime. RESULTS: From a societal perspective, at a willingness-to-pay (WTP) threshold of CAD 50 000 per QALY, semaglutide 2.4 mg was the most cost-effective treatment, at an incremental cost-utility ratio (ICUR) of CAD 31 243 and CAD 29 014 per QALY gained versus the next best alternative, i.e., orlistat, and SoC, respectively. Semaglutide 2.4 mg extendedly dominated other pharmacotherapies such as NB-32 or liraglutide 3.0 mg and remained cost-effective both under a public and private payer perspective. Results were robust to sensitivity analyses varying post-treatment catch-up rates, longer treatment durations and using real-world cohort characteristics. Semaglutide 2.4 mg was the preferred intervention, with a likelihood of 70% at a WTP threshold of CAD 50 000 per QALY gained. However, when the modeled benefits of weight-loss on cancer, mortality, cardiovascular disease (CVD) or osteoarthritis surgeries were removed simultaneously, orlistat emerged as the best value for money compared with SoC, with an ICUR of CAD 35 723 per QALY gained. CONCLUSION: Semaglutide 2.4 mg was the most cost-effective treatment alternative compared with D&E or orlistat alone, and extendedly dominated other pharmacotherapies such as NB-32 or liraglutide 3.0 mg. Results were sensitive to the inclusion of the combined benefits of mortality, cancer, CVD, and knee osteoarthritis.