Recent progress and novel perspectives on obesity pharmacotherapy

O aumento da prevalência da obesidade, nas últimas décadas, é alarmante, o que implica um grande número de pacientes sob risco de complicações metabólicas e cardiovasculares associadas. A eficácia modesta a longo prazo das modificações de estilo de vida isoladamente exige a necessidade de intervenções mais agressivas, seja por meio do uso adjuvante de medicamentos ou da abordagem mais radical cirúrgica. A cirurgia bariátrica, embora até hoje tenha se mostrado o método mais efetivo de tratamento dessa enfermidade, pode estar associada a complicações nutricionais e metabólicas ainda não totalmente esclarecidas. Contrasta com esse fato a disponibilidade limitada de agentes antiobesidade atualmente no mercado, além de fatos históricos que envolveram a suspensão de alguns fármacos previamente existentes, por questões de segurança. Este artigo tem como objetivo apresentar dados recentes de estudos clínicos de novas drogas propostas para o tratamento da obesidade com perspectivas breves de serem lançadas no mercado, caso passem pela aprovação das agências regulatórias. Nesta revisão serão discutidas a eficácia e a segurança desses fármacos, que incluem a lorcaserina (agonista serotoninérgico seletivo 5-HT2c), tesofensina (inibidor triplo de recaptação de monoaminas), liraglutide (análogo do GLP-1) e cetilistate (inibidor de lipases gastrointestinais), além das combinações de bupropiona/naltrexona, bupropiona/zonisamida, fentermina/topiramato e pramlintide/metreleptina.Obesity prevalence has risen dramatically over the past decades, which poses a great number of patients at risk of metabolic and cardiovascular complications. Long-term efficacy of lifestyle modification isolated has shown to be modest which, therefore, urges the need of more aggressive interventions such as adjuvant pharmacotherapy or the more radical surgical approach. Bariatric surgery has proven to date to be the most effective treatment, although it may be associated with nutritional and metabolic complications not yet completely recognized. By contrast, there is limited availability of antiobesity agents currently in the market, as well as historical facts involving the suspension of previously existing medications due to safety concerns. This article aims to present recent data on clinical trials of novel weight-loss drugs with short perspective to enter the market, if approved by the regulatory agencies. This review will discuss the efficacy and safety of these compounds, which include lorcaserin (selective serotonin 5-HT2c agonist), tesofensine (triple monoamine reuptake inhibitor), liraglutide (GLP-1 analogue) and cetilistat (gastrointestinal lipase inhibitor), as well as the combination therapies of bupropion/naltrexone, bupropion/zonisamide, phentermine/topiramate and pramlintide/metreleptin

Polimorfismo N363S do gene do receptor de glucocorticoide: efeito sobre a adiposidade visceral medida pela tomografia computadorizada

OBJECTIVE: To verify whether N363S polymorphism of the glucocorticoid receptor-gene can be associated to visceral fat by CT scan in obese individuals, and the impact of this variant on metabolic profile. METHODS: The N363S variant was screened in 295 Brazilians, 195 were obese and 100 presented normal weight. Based on genotype, obese N363S SNP carriers were paired with obese wild-type subjects. This group was submitted to a CT scan and metabolic profile assessment. RESULTS: Ten subjects were found to be heterozygous for the variant (A/G genotype frequency 3.4%), 8 (4.1%) obese and 2 (2.0%) non-obese. No differences were reported for visceral adiposity area (145.8 ± 49.9 vs.147.7 ± 48.8 cm²; p = 0.92) based on CT scan results but N363S SNP carriers showed a proneness to unfavorable metabolic changes. CONCLUSION: The N363S polymorphism prevalence is low in the Brazilian population, although its presence may contribute to the worsening of individuals' metabolic profiles.OBJETIVO: Verificar se a presença do polimorfismo N363S do gene do receptor de glucocorticoide estaria associada, em indivíduos obesos, à presença de adiposidade visceral pela tomografia computadorizada, e sobre o impacto desta variante genética no perfil metabólico. MÉTODOS: A variante N363S do receptor do glicocorticoide foi verificada em um grupo de 295 indivíduos brasileiros, sendo 295 obesos e 100 com peso normal. Com base na genotipagem, os indivíduos obesos carreadores do polimorfismo N363S foram pareados com obesos normais. O grupo com polimorfismo foi submetido a exames de tomografia computadorizada abdominal e laboratoriais para a caracterização de seu perfil metabólico. RESULTADOS: Dez indivíduos eram heterozigotos para a variante AG (3,4%), sendo oito obesos (4,1%) e dois não-obesos (2%). Não foram encontradas diferenças na quantidade de adiposidade visceral (145,8 ± 49,9 versus 147,7 ± 48,8 cm²; p = 0,92) baseados no TC de abdômen. No entanto, os indivíduos carreadores do N363S SNP (single nucleotide polymorphism) apresentaram tendência a perfil metabólico desfavorável. CONCLUSÃO: O polimorfismo N363S do gene do receptor de glucocorticoide teve prevalência baixa na população estudada. A sua presença pode contribuir para a deterioração do perfil metabólico desses indivíduos

Hipertensão arterial, diabetes melito e dislipidemia de acordo com o índice de massa corpórea: estudo em uma população brasileira

OBJECTIVE: To determine the prevalence of systemic hypertension, diabetes mellitus, hypercholesterolemia, and hypertriglyceridemia in a Brazilian population in relation to body mass index. METHOD: Retrospective evaluation of 1213 adults (mean age: 45.2 ± 12.8; 80.6% females) divided into groups according to body mass index [normal (18.5 - 24.4 kg/m²); overweight (25 - 29.9 kg/m²); grade 1 obesity (30 - 34.9 kg/m²); grade 2 obesity (35 - 39.9 kg/m²), and grade 3 obesity (>; 40 kg/m²)]. The prevalence of hypertension, diabetes mellitus, hypercholesterolemia, and hypertriglyceridemia were analyzed in each group. The severity of cardiovascular risk was determined. High-risk patients were considered those reporting 2 or more of the following factors: systemic hypertension, HDL ; 240 mg/dL, triglycerides >; 200 mg/dL when HDL ; 126 mg/dL. Moderate-risk patients were those reporting 2 or more of the following factors: systemic hypertension, HDL ; 200 mg/dL, and total cholesterol >; 200 mg/dL. RESULTS: The prevalence of systemic hypertension, diabetes mellitus, hypertriglyceridemia, and low HDL-cholesterol levels increased along with weight, but the prevalence of hypercholesterolemia did not. The odds ratio adjusted for gender and age, according to grade of obesity compared with patients with normal weight were respectively 5.9, 8.6, and 14.8 for systemic hypertension, 3.8, 5.8, and 9.2 for diabetes mellitus and 1.2, 1.3, and 2.6 for hypertriglyceridemia. We also verified that body mass index was positively related to cardiovascular high risk (P ;240mg/dl, triglicérides >;200mg/dl quando HDL ;126mg/dl; risco moderado aqueles com 2 ou mais dos seguintes fatores: hipertensão arterial, HDL ;200mg/dl e colesterol total >;200mg/dl. RESULTADOS: Houve aumento significativo da prevalência de hipertensão arterial, diabete melito, hipertrigliceridemia, HDL-colesterol baixo, porém não houve maior prevalência de hipercolesterolemia. O odds ratio, ajustado para idade e sexo, para obesidade em relação aos indivíduos de peso normal foi 5,9, 8,6 e 14,8 para hipertensão; 3,8, 5,8 e 9,2 para diabete melito e 1,2, 1,3 e 2,6 para hipertrigliceridemia. Após estabelecer severidade do risco cardiovascular, verificamos que o índice de massa corpórea se correlacionou de forma significativa com alto risco cardiovascular (p< 0.0001). CONCLUSÃO: Em nossa população, observamos aumento do risco cardiovascular com aumento do índice de massa corpórea

Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial.

In the SELECT cardiovascular outcomes trial, semaglutide showed a 20% reduction in major adverse cardiovascular events in 17,604 adults with preexisting cardiovascular disease, overweight or obesity, without diabetes. Here in this prespecified analysis, we examined effects of semaglutide on weight and anthropometric outcomes, safety and tolerability by baseline body mass index (BMI). In patients treated with semaglutide, weight loss continued over 65 weeks and was sustained for up to 4 years. At 208 weeks, semaglutide was associated with mean reduction in weight (-10.2%), waist circumference (-7.7 cm) and waist-to-height ratio (-6.9%) versus placebo (-1.5%, -1.3 cm and -1.0%, respectively; P -2) there were lower rates (events per 100 years of observation) of serious adverse events with semaglutide (43.23, 43.54, 51.07 and 47.06 for semaglutide and 50.48, 49.66, 52.73 and 60.85 for placebo). Semaglutide was associated with increased rates of trial product discontinuation. Discontinuations increased as BMI class decreased. In SELECT, at 208 weeks, semaglutide produced clinically significant weight loss and improvements in anthropometric measurements versus placebo. Weight loss was sustained over 4 years. ClinicalTrials.gov identifier: NCT03574597

Safety and efficacy of hydrothermal duodenal mucosal resurfacing in patients with type 2 diabetes: the randomised, double-blind, sham-controlled, multicentre REVITA-2 feasibility trial

Objective: Hydrothermal duodenal mucosal resurfacing (DMR) is a safe, outpatient endoscopic procedure. REVITA-2, a double-blind, superiority RCT, investigates safety and efficacy of DMR using the single catheter Revita system (Revita DMR [catheter and system], on glycaemic control and liver fat content in Type 2 Diabetes (T2D).Design: Eligible patients (HbA1c 59–86mmol/mol, BMI ≥24 and ≤40kg/m2, fasting insulin >48.6pmol/L, ≥1 oral antidiabetic medication) enrolled in Europe and Brazil. Primary endpoints were safety, change from baseline in HbA1c at 24 weeks, and liver magnetic resonance imaging proton-density fat fraction (MRI-PDFF) at 12 weeks. Results: Overall mITT (DMR N=56; sham N=52), 24-weeks post-DMR, median (IQR) HbA1c change was −10.4 (18.6) mmol/mol in DMR group versus −7.1 (16.4) mmol/mol in sham group (p=0.147). In patients with baseline liver MRI-PDFF >5% (DMR n=48; sham n=43), 12-week post-DMR liver-fat change was −5.4 (5.6)% in DMR group versus −2.9 (6.2)% in sham group (p=0.096). Results from prespecified interaction testing and clinical parameter assessment showed heterogeneity between European (DMR N=39; sham N=37) and Brazilian (DMR N=17; sham N=16) populations (p=0.063), therefore, results were stratified by region. In European mITT, 24-weeks post-DMR, median (IQR) HbA1c change was –6.6 mmol/mol (17.5 mmol/mol) versus –3.3 mmol/mol (10.9 mmol/mol) post-sham (p=0.033); 12-week post-DMR liver-fat change was –5.4% (6.1%) versus –2.2% (4.3%) post-sham (p=0.035). Brazilian mITT results trended towards DMR benefit in HbA1c, but not liver fat, in context of a large sham effect. In overall PP, patients with high baseline fasting plasma glucose ([FPG] ≥10 mmol/L) had significantly greater reductions in HbA1c post-DMR versus sham (p=0.002). Most adverse events were mild and transient. Conclusions: DMR is safe and exerts beneficial disease-modifying metabolic effects in T2D with or without non-alcoholic liver disease (NAFLD), particularly in patients with high FPG

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Long-Term Pharmacotherapy for Obesity in Elderly Patients A Retrospective Evaluation of Medical Records from a Specialized Obesity Outpatient Clinic

Background: Obesity is a serious chronic disease and the prevalence of this condition is increasing among the elderly. Although the benefits of weight loss to improve control of associated diseases are well known in young adults, they are not in older patients. The use of anti-obesity drugs to promote weight loss is widespread in Brazil and other countries, and obesity specialists frequently prescribe medicines in doses and for durations previously unreported in the literature. Sibutramine, orlistat and amfepramone (diethylpropion) have been evaluated in clinical trials of more than 2 years` duration in adults, demonstrating safety and efficacy, but long-term studies in obesity treatment are absent for other drugs. The efficacy and safety of obesity pharmacotherapy among the elderly is unknown. Objective: To describe the experience of obesity pharmacotherapy in the elderly in a specialized obesity care setting in Brazil, with a focus on efficacy and safety. Methods: A retrospective evaluation was conducted on medical charts from an outpatient clinic of a specialized tertiary centre for the treatment of obesity. We included patients who had had at least one consultation between January and December 2007, were aged >= 60 years at the beginning of the treatment, had had at least 6 months of follow-up and had received a prescription of at least one potential weight-loss drug. Diagnoses reported on medical records were documented. Age, weight, height and body mass index (BMI) were recorded at admission, after 6, 12, 18 and 24 months, and at the last available visit. The medicines prescribed, together with the dose, duration of use, adverse effects and reasons for discontinuation, were documented. Results: The group consisted of 44 women (86%) and 7 men (14%), with a mean +/- SD age of 65.2 +/- 4.5 years, weight of 95.3 +/- 12.5 kg and BMI of 38.5 +/- 4.3 kg/m(2). The mean +/- SD time of follow-up was 39.3 +/- 26.4 months, and the mean weight loss was 6.65 kg (p < 0.01). After the first 6 months, the mean +/- SD weight loss was 5.7 +/- 3.8 kg (p < 0.0001). A smaller weight loss was seen between the 6th and 12th months, with no statistically significant change in weight thereafter. A weight loss of >= 5% was achieved by 64.71%, 63.64%, 62.16% and 69.70% in the 6th, 12th, 18th and 24th months, respectively, and a weight loss of >= 10% was achieved by 17.65%, 34.09%, 32.43% and 39.39% in the 6th, 12th, 18th and 24th months, respectively. The medicines prescribed were sibutramine, orlistat, fluoxetine, sertraline, topiramate, fenproporex, mazindol and amfepramone, alone or in combinations, concomitantly or sequentially. The reasons for discontinuation were lack of response (n = 13), loss of response (development of tolerance) [n= 11], lack of adherence (n = 14) and adverse effects (n= 14). One episode of atrial flutter occurred in a patient taking fenproporex. The weight-loss medications were generally well tolerated, and only transient adverse events were reported. Conclusions: Long-term pharmacotherapy for obesity was effective and well tolerated by this group of elderly patients

Tratamento de curto prazo com liraglutide no reganho de peso após cirurgia bariátrica

OBJETIVO: avaliar os resultados da utilização do liraglutide em um grupo de pacientes submetidos ao tratamento cirúrgico da obesidade mórbida com perda insatisfatória de peso ou ganho de mais de 15% do seu peso mínimo atingido. MÉTODOS: realizou-se análise retrospectiva de 15 pacientes operados que tiveram perda de excesso de peso <50% após dois anos de seguimento ou reganho de peso de mais de 15% do peso mínimo atingido. Foram incluídos apenas pacientes que apresentavam a "anatomia cirúrgica" normal avaliada por radiografia contrastada e endoscopia digestiva alta. A média de idade foi 47,2±12,5 anos e os pacientes receberam liraglutide na dose de 1,2 a 3,0mg/dia por oito a 28 semanas de seguimento. RESULTADOS: o tratamento cirúrgico induziu uma perda de peso de 34,1± 16,5Kg. A média de reganho de peso após 5,3 ±3,3 anos foi 14,2±12,1Kg. A media de peso reduziu significativamente após o tratamento com liraglutide (100,9±18,3Kg vs. 93,5±17,4Kg; p<0,0001). Seis pacientes apresentaram náuseas e dois descontinuaram o tratamento em decorrência do custo da medicação. CONCLUSÃO: o tratamento clínico medicamentoso dirigido para o controle da saciedade com o uso do liraglutide pode ser uma alternativa para manejo dos pacientes com reganho de peso ou perda insuficiente após o tratamento cirúrgico, quando nenhum problema técnico tenha sido identificado

Genetic Variations in Sweet Taste Receptor Gene Are Related to Chocolate Powder and Dietary Fiber Intake in Obese Children and Adolescents

Childhood obesity is a major public health problem. It has a direct impact on the quality of life of children and adolescents, as well as on their future risk of developing chronic diseases. Dietary patterns rich in fats and sugars and lacking dietary fibers, vitamins, and minerals, as well as lack of physical exercise have been associated with the rise of obesity prevalence. However, factors that contribute to the preference for foods rich in these nutrients are not well established. Taste is recognized as an important predictor of food choices, and polymorphisms in taste-related genes may explain the variability of taste preference and food intake. The aim of this research is to evaluate the influence of polymorphisms of the sweet taste receptor gene TAS1R2 on diet and metabolic profile in obese children and adolescents. A cross-sectional study with 513 obese children and adolescents and 135 normal-weight children was carried out. A molecular study was performed for the single nucleotide polymorphisms (SNPs) rs9701796 and rs35874116 of TAS1R2, and dietary intake, anthropometric parameters (weight, height, waist circumference, waist-to-height ratio (WHtR)), and metabolic profile (including fasting glucose, insulin, triglyceride, high-density lipoprotein (HDL)–cholesterol, and leptin levels) were analyzed. The variant rs9701796 was associated with increased waist-height ratio, as well as with a higher chocolate powder intake in obese children. The variant rs35874116 was associated with a lower dietary fiber intake. In conclusion, there was no relationship between genotypes and risk of obesity. Obese adolescents carrying the serine allele of SNP rs9701796 in TAS1R2 showed higher waist-to-height ratio and chocolate powder intake, whereas those carrying the valine allele of SNP rs35874116 in TAS1R2 were characterized by lower dietary fiber intake

Combinations of drugs in the Treatment of Obesity

Obesity is a chronic disease associated with excess morbidity and mortality. Clinical treatment, however, currently offers disappointing results, with very high rates of weight loss failure or weight regain cycles, and only two drugs (orlistat and sibutramine) approved for long-term use. Drugs combinations can be an option for its treatment but, although widely used in clinical practice, very few data are available in literature for its validation. Our review focuses on the rationale for their use, with advantages and disadvantages; on combinations often used, with or without studies; and on new perspectives of combinations being studied mainly by the pharmaceutical industry