Potential use of exenatide for the treatment of obesity

Introduction: Obesity is a major health threat in the Western world because of its high incidence and prevalence, and its association with metabolic and cardiovascular disease as well as cancer. The reduction of food intake in obese patients can be achieved only transiently (generally for no longer than 6 months), in the absence of concomitant pharmacological therapy. Only bariatric surgery provides a means to increase satiety and/or decrease nutrient absorption in obese patients, in the long term.

Areas covered: This article reviews the available pharmacological treatments for obesity as well as the pharmacology and mechanism of action of exenatide in obese type 2 diabetic patients.

Expert opinion: Exenatide is a potential new candidate treatment for obesity, possibly in combination with other hormones that increase satiety (leptin) and slow gastric emptying (amylin).     

艾塞那肽联合吡格列酮治疗肥胖2型糖尿病患者的疗效观察

目的观察艾塞那肽联合吡格列酮治疗肥胖2型糖尿病（T2DM）患者的疗效及安全性。方法 68例肥胖T2DM患者,在口服吡格列酮一段时间后血糖控制不理想的情况下,加用艾塞那肽,疗程3个月,观察治疗前后空腹血糖（FPG）,餐后2 h血糖（2hPG）、糖化血糖蛋白（HbA1C）、胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、C肽（C-P）、体重指数（BMI）等变化情况,计算胰岛素抵抗（H0MA-R）,胰岛β细胞功能（H0MA-β）。结果治疗后BMI、FPG、2hPG、HbA1C、HoMA-IR、TC、TG均下降;C-P,HOMA-β高于治疗前（P〈0.05）。结论艾塞那肽联合吡格列酮可显著改善肥胖T2DM患者血糖控制水平,同时能降低患者的体重,改善患者的生活质量。     

聚乙二醇化艾塞那肽对肥胖恒河猴的减肥作用

目的研究聚乙二醇化艾塞那肽(PB199)长期给药对肥胖恒河猴的减肥作用。方法一个月内每周一次sc PB199,观察其对肥胖恒河猴体重、腹部脂肪体积、摄食量、血糖和血脂等肥胖相关指标的影响。结果给药一个月后,模型对照组动物的体重与给药前比增加1.34%,3、6μg·kg-1PB199组猴的体重与给药前比分别降低5.14%、5.68%,较模型对照组的差异显著(P<0.05)。与给药前比,3、6μg·kg-1PB199、艾塞那肽、奥利司他组猴的腹部皮下脂肪体积下降率分别为42.1%、42.2%、39.0%、41.8%,腹腔内脂肪的体积下降率分别为20.8%、20.8%、16.9%、20.5%,各组较模型对照组的差异显著(P<0.05)。结论一个月连续给药PB199对肥胖恒河猴具有显著的减肥作用。     

艾塞那肽治疗肥胖2型糖尿病23例临床分析

在2型糖尿病患者中存在较为严重的胰岛素抵抗,患者血糖波动大,不易控制。艾塞那肽(exenatide)是胰高血糖素样肽-1(GLP-1)受体激动剂,是一种新型的2型糖尿病治疗药物。本研究就艾塞那肽在肥胖2型糖尿病患者中的作用与疗效进行探讨。     

Exenatide enhances cognitive performance and upregulates neurotrophic factor gene expression levels in diabetic mice

Exenatide is a potent and selective agonist for the GLP‐1 (glucagon‐like peptide‐1) receptor. Recent studies are focused on the effects of GLP‐1 analogues on hippocampal neurogenesis, cognition, learning and memory functions. The aim of this study was to assess the effects of chronic exenatide treatment (0.1 μg/kg, s.c, twice daily for 2 weeks) on spatial memory functions by using the modified elevated plus maze (mEPM) test and emotional memory functions by using the passive avoidance (PA) test in streptozotocin/nicotinamide (STZ‐NA)‐induced diabetic mice. As the genes involved in neurite remodelling are among the primary targets of regulation, the effects of diabetes and chronic administration of exenatide on brain‐derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) messenger ribonucleic acid (mRNA) levels in the hippocampus of mice were also determined using quantitative real‐time polymerase chain reaction (RT‐PCR). This study revealed that in the mEPM and PA tests, type‐2 diabetes‐induced mice exhibited significant impairment of learning and memory which were ameliorated by GLP‐1 receptor agonist exenatide. Quantitative RT‐PCR revealed that CREB and BDNF gene expression levels were downregulated in diabetic mice, and these alterations were increased by exenatide treatment. Since, exenatide improves cognitive ability in STZ/NA‐induced diabetic mice and activates molecular mechanisms of memory storage in response to a learning experience, it may be a candidate for alleviation of mood and cognitive disorder.     

Investigational treatments for Type 2 diabetes mellitus: exenatide and liraglutide

Although a number of compounds are currently used to treat Type 2 diabetes mellitus, achieving a sustained glycaemic control over time is often not possible using oral antidiabetics. Endogenous incretins exhibit beneficial effects that could be useful for Type 2 diabetes mellitus treatment, such as stimulating insulin secretion during hyperglycaemia, improving β-cell mass and function, reducing glucagon secretion, delaying gastric emptying, reducing postprandial hyperglycaemia and diminishing body weight; however, their short half-life makes them unsuitable for treatment. Incretin mimetics such as liraglutide and exenatide were developed to overcome this limitation. This review discusses the effects of these compounds and their potential as a new class of antidiabetic agents.     

Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide 1.2 mg as add-on to 1–3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10)

AimsSUSTAIN 10 compared the efficacy and safety of the anticipated most frequent semaglutide dose (1.0 mg) with the current most frequently prescribed liraglutide dose in Europe (1.2 mg), reflecting clinical practice.MethodsIn this phase 3b, open-label trial, 577 adults with type 2 diabetes (HbA_1c 7.0–11.0%) on 1–3 oral antidiabetic drugs were randomized 1:1 to subcutaneous once-weekly semaglutide 1.0 mg or subcutaneous once-daily liraglutide 1.2 mg. Primary and confirmatory secondary endpoints were changes in HbA_1c and body weight from baseline to week 30, respectively.ResultsMean HbA_1c (baseline 8.2%) decreased by 1.7% with semaglutide and 1.0% with liraglutide (estimated treatment difference [ETD] –0.69%; 95% confidence interval [CI] -0.82 to -0.56, P < 0.0001). Mean body weight (baseline 96.9 kg) decreased by 5.8 kg with semaglutide and 1.9 kg with liraglutide (ETD -3.83 kg; 95% CI -4.57 to -3.09, P < 0.0001). The proportions of subjects achieving glycaemic targets of < 7.0% and = 6.5%, weight loss of = 5% and = 10%, and a composite endpoint of HbA_1c < 7.0% without severe or blood glucose-confirmed symptomatic hypoglycaemia and no weight gain were greater with semaglutide vs liraglutide (all P < 0.0001). Both treatments had similar safety profiles, except for more frequent gastrointestinal disorders (the most common adverse events [AEs]) and AEs leading to premature treatment discontinuation with semaglutide vs liraglutide (43.9% vs 38.3% and 11.4% vs 6.6%, respectively).ConclusionSemaglutide was superior to liraglutide in reducing HbA_1c and body weight. Safety profiles were generally similar, except for higher rates of gastrointestinal AEs with semaglutide vs liraglutide.     

小剂量多次注射可增强艾塞那肽对2型糖尿病患者的治疗效果

目的 探讨艾塞那肽小剂量多次注射对2型糖尿病患者的疗效及安全性.方法 选择2014年1-7月在西南医院内分泌科住院的2型糖尿病患者23例,其中男性12例、女性11例,平均年龄49.2岁,随机分为艾塞那肽2针治疗组12例,3针治疗组11例,比较治疗前后6个月体质量、BMI、腰围、腰臀比、空腹血糖(FPG)、餐后2h血糖(2hPG)、糖化血红蛋白(HbAlc)、空腹及餐后C肽、自我血糖监测(SMBG)、总胆固醇(Tch)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(LDL-C)、谷丙转氨酶(ALT)、谷草转氨酶(AST)、血肌酐(Cr)、尿素氮(UN).结果 两组体质量、腰围、腰臀比、FPG、PPG、HbAlc、Tch、TG、LDL-C、HDL-C均较治疗前有所下降,组间比较差异无统计学意义(P＞0.05),两组患者治疗后BMI较治疗前明显下降,其中3针治疗组患者BMI下降较2针治疗组明显,差异具有统计学意义(P＜0.05),两组患者治疗后SMBG均较治疗前明显下降,3针治疗组患者午餐后血糖[(12.56±1.32) mmol/L]及睡前血糖[(8.97±1.07) mmol/L]较2针治疗组的午餐后血糖[(13.25±1.23) mmol/L]、睡前血糖[(9.78±0.70) mmol/L]更低,且差异具有统计学意义(P＜0.05).结论 每天3次5μg艾塞那肽注射更有利于2型糖尿病患者餐后血糖的控制.     

艾塞那肽在糖调节受损的青少年肥胖患者中的近、远期效果的临床研究

目的：评价艾塞那肽在肥胖青少年糖代谢异常中的近、远期效果观察。方法入选92例糖代谢异常的青少年肥胖患者,随机分为对照组45例和试验组47例,对照组口服盐酸二甲双胍0．5 g,每日3次;试验组口服盐酸二甲双胍0．5 g,每日3次,加皮下注射艾塞那肽,疗程为6个月。近期观察2组治疗前后患者体重、腰围、体质指数、空腹血糖、餐后2 h血糖（2 hPG）、糖化血红蛋白、收缩压、舒张压、三酰甘油、总胆固醇、高密度脂蛋白胆固醇（ HDL－C ）、低密度脂蛋白胆固醇（ LDL－C）及空腹胰岛素、胰岛素抵抗水平（ Homa IR）、胰岛β细胞功能指数（ HOMA－β）。远期观察2组患者3年后糖尿病、高血压病发生情况。结果治疗后,试验组体重、腰围、体质指数有明显改善（P＜0．01）,餐后2 h血糖、糖化血红蛋白较治疗前明显改善（均 P ＜0．05）;三酰甘油、总胆固醇、LDL－C明显降低（均P＜0．05）;收缩压明显降低（ P＜0．05）;空腹胰岛素、胰岛素敏感指数、HOMA－IR明显降低,HOMA－β升高（均P＜0．01）。治疗后,试验组较对照组改善更明显（ P＜0．01）。结论艾塞那肽能明显减轻体重,改善内分泌代谢,减少因肥胖带来的代谢性异常的疾病发生。     

Diabesity: therapeutic options

A pathogenic relationship exists between type 2 diabetes and obesity. Over the last decade, the escalation in diabetes cases has paralleled the rapid increase in obesity rates, constituting a global health crisis. Environmental risk factors attributed to the global increase in obesity include the consumption of high‐calorie, high‐fat foods and inadequate physical activity. Obese individuals may also have a genetic predisposition for obesity. Both diabetes and obesity confer an elevated risk of developing a range of complications and comorbidities, including cardiovascular disease, hypertension and stroke, which can complicate disease management. This review examines the aetiology of the linkages between diabetes and obesity and the range of available therapies. Recent clinical evidence substantiating the efficacy and safety of incretin‐based antidiabetic therapies is analysed, in addition to data on antiobesity therapeutic strategies, such as antiobesity agents, behaviour modification and bariatric surgery. Glucose control is often accompanied by weight‐neutral or modest weight reduction effects with DPP‐4 inhibitor treatment (sitagliptin, vildagliptin, saxagliptin) and weight loss with GLP‐1 receptor agonist therapy (exenatide, liraglutide). Studies of antiobesity agents including orlistat, sibutramine and rimonabant have shown attrition rates of 30–40%, and the long‐term effects of these agents remain unknown. Bariatric surgical procedures commonly performed are laparoscopic adjustable banding of the stomach and the Roux‐en‐Y gastric bypass, and have produced type 2 diabetes remission rates of up to 73%. Therapeutic strategies that integrate glycaemic control and weight loss will assume greater importance as the prevalence of diabetes and obesity increase.