抗肥胖药物疗效及安全性临床研究进展

抗肥胖药物治疗是肥胖管理中的辅助治疗手段.很多曾被广泛应用的抗肥胖药物因其不良反应而受到限制.近年来一些抗肥胖新药陆续上市,如奥利司他、利拉鲁肽、绿卡色林、芬特明/托吡酯、纳曲酮/安非他酮等.研究显示,有些降糖药物如二甲双胍、普兰林肽也具有减重作用.其他抗肥胖药物还包括植物提取物等.对抗肥胖药物的疗效及安全性的了解,将为临床治疗肥胖提供有力的证据.     

减重药物的研究进展

肥胖是一种慢性疾病,其发病率持续上升,目前影响着超过全球5亿人。生活方式干预是肥胖管理的基石,但多数情况下无法达到减重目标并长期维持。人体通过中枢和外周调节能量平衡和食欲,减重药物以中枢及外周为靶点发挥作用。药物治疗是减重管理的重要措施之一。本研究总结已上市和正处于研发阶段的减重药物,梳理了减重药物的作用机制和研发思路。     

2型糖尿病患者体重管理的研究进展与思考

全球2型糖尿病患者人数仍在增加, 其中肥胖问题不容忽视。肥胖不仅可能导致2型糖尿病的发生, 也会进一步增加2型糖尿病患者的心血管疾病风险。因此, 近年来2型糖尿病疾病管理的目标已经从控制血糖转变为"控糖、减重"双重管理。现有的减重策略包括生活方式干预、药物治疗和代谢手术, 其中药物治疗的发展与日俱进。新型的双重或三重肠道激素受体激动剂的研发, 将为2型糖尿病合并超重/肥胖患者提供更多治疗选择。     

减肥药是否值得尝试?

正减肥新药可能较之前的药物更安全,作为治疗肥胖的新增选择。肥胖被认为不仅是其他情况的一个风险因素,它本身其实就是一个疾病。肥胖已经是重要的科学和医学研究的主题以研制出有效的治疗方法。但是研究的过程是有难度的。美国食品与药物监督管理局自2012年批准了四种药物:托吡酯复方制剂Qsymia(芬名特和托泰,即phentermine and topiramate)、氯卡色     

胰高血糖素样肽-1类似物对减重影响

随着发病率逐年增加,肥胖已成为全球公共健康问题。它不仅是一种多因素的慢性代谢性疾病,也是2型糖尿病、冠心病、高脂血症、肿瘤等多种疾病的危险因素。肥胖的发病机制复杂,与遗传、环境、氧化应激、肠道菌群及胰岛素抵抗密切相关。诊治肥胖,刻不容缓。胰高血糖素样肽-1(GLP-1)类似物是一种新型减重药物,既可保护B细胞功能、改善胰岛素抵抗,也可增加饱腹感、延缓胃排空、减少脂肪堆积,达到减肥目的。本文就肥胖发病现状、发病机制及GLP-1类似物对减重的影响进行综述。     

优化手术治疗2型糖尿病的疗效——多学科团队强化围手术期及术后的管理

对于内分泌科医师而言,糖尿病是慢性病,需要终身服药治疗,所需药物的剂量及种类也会随着病程的延长、病情进展而增加.即便这样,糖尿病的达标率仍不容乐观,我国的达标率不足40％[1],在欧美国家也不足50％[糖化血红蛋白（HbA1c）＜7％][2],至于血糖、血压和血脂同时达标的患者比例就更低了.而手术治疗2型糖尿病是国外学者对病态（极重度）肥胖患者进行减重手术治疗后的意外收获.Pories等[3]对病态性肥胖患者采用胃旁路术后14年的随访观察中发现手术除能有效减重外,还能使血糖得到有效的控制,部分甚至＆quot;痊愈＆quot;（不再需要降糖药物治疗）.Meta分析发现减重手术可使60％ ～ 85％的糖尿病、高血压、血脂异常和睡眠呼吸暂停综合征得到缓解[4-5],同时还能显著降低与糖尿病相关的死亡风险[6-7],减少药物及整体健康管理的花费[8-9].     

SGLT2抑制剂在肥胖2型糖尿病治疗中的价值

肥胖是2型糖尿病（T2DM）的主要危险因素之一,大部分T2DM患者合并超重或肥胖。钠-葡萄糖共转运蛋白2 （sodium-glucose cotransporter2,SGLT2）抑制剂通过抑制肾脏近曲小管的葡萄糖重吸收,增加葡萄糖从尿液排出而发 挥降糖作用,同时还具有降压、调脂、减重、改善肝功能、降尿酸等效应,从而缓解肥胖T2DM患者的代谢紊乱。 SGLT-2抑制剂是治疗肥胖T2DM的新途径,对改善远期预后具有重要的意义。     

减重手术在老年肥胖病人的应用

正随着生活水平的提高,肥胖病人的人数近年来日益增多,肥胖带来了一系列并发疾病,降低了病人的生活质量。目前,体质量管理手段主要包括饮食、运动、认知行为疗法、药物和手术等[1]。减重手术是治疗肥胖最有效的手段,其减重效果和对肥胖相关并发症的     

胰高血糖素样肽-1受体激动剂对阻塞性睡眠呼吸暂停作用的研究现状

阻塞性睡眠呼吸暂停(OSA)是最常见的睡眠呼吸障碍性疾病, 持续气道正压通气是治疗的金标准, 但患者依从性并不高, 因此, 有必要探讨新的治疗策略。该病常合并多种疾病, 尤其是2型糖尿病和肥胖症。已知有效的减重对于逆转OSA及其相关的合并症至关重要, 但单纯依靠生活方式改变难以实现持续减重, 而同时具有降糖和减重作用的药物是实现这种目标的途径。本文介绍了胰高血糖素样肽-1受体激动剂对此疾病的治疗作用。     

脑肠肽、摄食调控与肥胖关系的研究进展

单纯性肥胖的发生是能量代谢失衡的表现。脑肠肽包括促食欲肽和抑食欲肽,与摄食中枢的调节及能量摄入密切相关。Ghrelin是目前唯一可知的外周促食欲素,可以增加食欲,促进摄食。而另一些脑肠肽如胰多肽(PP)、肽YY(PYY)、胰高血糖素样肽-1(GLP-1)、胃泌酸调节素(OXM)的作用主要为抑制摄食。两类激素通过食欲调节中枢相互作用,对肥胖的发生发展产生重要的影响。研究并阐明脑肠肽激素在胃肠道中的分布、代谢与食欲调控机制,有可能成为未来肥胖预防和治疗的靶标。     

Efficacy and safety of lorcaserin in obese adults: a meta‐analysis of 1‐year randomized controlled trials (RCTs) and narrative review on short‐term RCTs

Lorcaserin is a new anti‐obesity drug recently approved by US Food and Drug Administration. We conducted a systematic review and meta‐analysis of randomized controlled trials (RCTs) to evaluate the association of lorcaserin therapy with weight loss and adverse events in obese adults (18–65 years old). Weight loss of 3.23 kg (95% confidence interval [CI]: 2.70, 3.75) and body mass index reduction of 1.16 kg m^?2 (95% CI: 0.98, 1.34) was observed compared with placebo in RCTs of 1 year duration. The use of lorcaserin for 8 and 12 weeks reduced weight of 1.60 kg (95% CI: 0.34, 2.86) and 2.9 kg (95% CI: 2.2, 3.5), respectively. In comparison to placebo, lorcaserin decreased waist circumference, blood pressure, total cholesterol, low‐density lipoprotein‐cholesterol and triglycerides, however did not statistically affect heart rate or high‐density lipoprotein‐cholesterol. Headache, nausea and dizziness were found to be significantly higher in the patients receiving lorcaserin than patients receiving placebo, whereas diarrhoea is no more likely than in patients receiving placebo. In conclusion, lorcaserin achieves modest weight loss and appears to be well tolerated. Clinical and pharmacovigilance studies with longer study duration are needed to inform of the long‐term efficacy and safety of lorcaserin.     

Lorcaserin treatment decreases body weight and reduces cardiometabolic risk factors in obese adults: A six-month,randomized, placebo-controlled,double-blind clinical trial

Lorcaserin is a serotonin 2c receptor agonist that promotes weight loss while contributing to the prevention and improvement of type 2 diabetes and improvement of atherogenic lipid profiles, without higher rates of major cardiovascular events. The full spectrum of possible lorcaserin-induced improvements in cardiometabolic health remains to be clarified. Thus, we investigated the way in which lorcaserin treatment may alter cardiovascular disease risk, either independently or through changes in body weight. We measured, for the first time, lipid particle quantification, lipid peroxidation, appetite-regulating hormones and mRNA expression of the 5-hydroxytryptamine 2c receptor (5-HT2c receptor). A total of 48 obese participants were enrolled in this six-month, randomized (1:1), placebo-controlled, double-blinded clinical trial. Lorcaserin treatment reduced fat mass (P < 0.001), the fatty liver index (P < 0.0001) and energy intake (P < 0.03) without affecting energy expenditure or lean mass. Total low-density lipoprotein (LDL) (P < 0.04) and small LDL particles (P < 0.03) decreased, while total high-density lipoprotein (HDL) P < 0.02) increased and heart rate significantly decreased with lorcaserin treatment. No mRNA expression of the 5-HT2c receptor was observed in peripheral organs. These data suggest that lorcaserin treatment for six months improves cardiometabolic health in obese individuals, acting mainly through the brain.     

New options for the treatment of obesity and type 2 diabetes mellitus (narrative review)

Moderate weight loss (> 5%), which has been associated with improvements in glycemic parameters in patients with dysglycemia, also reduces the presence of other comorbidities, including dyslipidemia and hypertension, culminating in a reduced risk of cardiovascular disease. Lifestyle changes are the recommended preliminary approach to weight loss, with an initial weight-loss goal of 10% of body weight achieved over 6 months at a rate of 1–2 pounds per week selected as an appropriate target to decrease the severity of obesity-related risk factors. Implementing and maintaining the lifestyle changes associated with weight loss can, however, be challenging for many patients. Therefore, additional interventions sometimes may be necessary. Bariatric surgery can also be a highly effective option for weight loss and comorbidity reduction, but surgery carries considerable risks and is still applicable only to selected patients with type 2 diabetes. Thus, attention is turning to the use of weight-loss medications, including 2 recently approved compounds: twice-daily lorcaserin and a once-daily combination of phentermine and topiramate extended-release, both shown to be safe and effective therapies in the management of obesity in patients with type 2 diabetes.     

Effects of lorcaserin on fat and lean mass loss in obese and overweight patients without and with type 2 diabetes mellitus: the BLOSSOM and BLOOM‐DM studies

Body composition was determined using dual‐energy X‐ray absorptiometry (DXA) in a subset of patients without (BLOSSOM) and with (BLOOM‐DM) type 2 diabetes who received diet and exercise counselling along with either lorcaserin 10 mg twice daily or placebo. DXA scans were performed on study day 1 (baseline), week 24 and week 52. Baseline demographics of the subpopulations (without diabetes, n = 189; with diabetes, n = 63) were similar between studies and representative of their study populations. At week 52, patients without diabetes on lorcaserin lost significantly more fat mass relative to those on placebo (?12.06% vs ?5.93%; p = 0.008). In patients with diabetes, fat mass was also decreased with lorcaserin relative to placebo (?9.87% vs ?1.65%; p < 0.05). More fat mass was lost in the trunk region with lorcaserin compared with placebo (without diabetes: ?3.31% vs ?2.05%; with diabetes: ?3.65% vs ?0.36%). Weight loss with lorcaserin was associated with a greater degree of fat mass loss than lean mass loss, and most of the fat mass lost for patients without and with diabetes was from the central region of the body.     

A CONTROLLED INVESTIGATION OF THE " GLYCOLYPTIC " ACTION OF FENFLURAMINE

The " glycolyptic " action of fenfluramine was investigated travenous administration to one normal subject, and by a 6-week metabolic-balance study on four obese patients. Fenfluramine in combination with a reducing diet did not cause a greater weight-loss than the same reducing diet given with identical placebo tablets. A double-blind assessment of the mental state of the patients on fenfluramine indicated that it caused loss of appetite and often depression. It is postulated that the glycolyptic effect may in fact be a reflection of storage of glucose as glycogen. If this explanation is correct, the useful action of fenfluramine in the treatment of obesity is that it reduces appetite. No evidence has been found of any other mechanism by which fenfluramine can promote weight-loss.     

Pharmacologic Treatment Options for Obesity: What Is Old Is New Again

After a long period of failure in development, two new medications (phentermine/topiramate ER – Qsymia? and lorcaserin – Belviq®) have been approved by the US Food and Drug Administration for long-term weight management in persons with obesity (BMI?≥?30 kg/m²) or in overweight persons (BMI?≥?27 kg/m²) with comorbidities. Another medication, bupropion/naltrexone, is undertaking a cardiovascular outcomes trial and an analysis in 2014 will determine its approval and release. The most widely prescribed drug for obesity, phentermine, used since 1959 for short-term weight management, has been released in a new formulation. This paper reviews these new medications, and other important events in the landscape for management of obesity, with an eye to the interests of physicians who manage hypertension. All the new drugs under discussion are re-fittings of old agents or fresh approaches to old targets; thus, what is old is new again in the pharmacotherapy of obesity.     

Green tea extract:A potential cause of acute liver failure

The use of herbal products has increased significantly in recent years.Because these products are not subject to regulation by the Food and Drug Administration and are often used without supervision by a healthcare provider,the indication for and consumption of these supplements is quite variable.Moreover,their use is generally regarded as safe and natural by the lay-public.Unfortunately,there has been an increase in the number of reported adverse events occurring with the use of herbal products.We present a case of acute impending liver failure in an adolescent male using a weightloss product containing green tea extract.Our case adds to the growing concern surrounding the ingestion of green tea extract and serves to heighten healthcare provider awareness of a potential green tea extract hepatotoxicity.Despite the generally touted benefits of green tea as a whole,clinical concern regarding its use is emerging and has been linked to its concentration in multiple herbal supplements.Interestingly,the suspected harmful compounds are those previously proposed to be advantageous for weight-loss,cancer remedy,and anti-inflammatory purposes.Yet,we emphasize the need to be aware of not just green tea extract,but the importance of monitoring patient use of all dietary supplements and herbal products.     

Weight loss interventions and nonalcoholic fatty liver disease: Optimizing liver outcomes

The growth in prevalence of obesity, type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) has become one of the most important global health challenges. The three chronic diseases are closely linked in their epidemiology and pathophysiology. Currently, weight loss is the most effective treatment for NAFLD (even in the minority of patients with NAFLD who do not have obesity) and is recommended in all national and international guidelines. Accumulating evidence has shown that weight loss, whether achieved by diet and lifestyle interventions, bariatric surgery or pharmacotherapy, can improve biomarkers of NAFLD, as well as prevent progression and, in some cases, reverse fibrosis. There is a dose dependency of weight loss with NAFLD improvement. Pharmacotherapy with antiobesity medications, alone or in combination with intensive lifestyle interventions or other weight-loss drugs, is closing the efficacy gap between diet and exercise and weight-loss surgery in efficacy at reversing obesity. Given the importance of providing effective weight-loss treatment to patients with NAFLD, weight management services need to be made increasingly available and embedded within hepatology services. This narrative review addresses the evidence that weight loss optimizes liver outcomes in people with NAFLD.     

Weight Loss Strategies for Treatment of Obesity

Obesity is one of the most serious and prevalent non-communicable diseases of the 21st century. It is also a patient-centered condition in which affected individuals seek treatment through a variety of commercial, medical and surgical approaches. Considering obesity as a chronic medical disease state helps to frame the concept of using a three-stepped intensification of care approach to weight management. As a foundation, all patients should be counseled on evidence-based lifestyle approaches that include diet, physical activity and behavior change therapies. At the second tier, two new pharmacological agents, phentermine–topiramate and lorcaserin, were approved in 2012 as adjuncts to lifestyle modification. The third step, bariatric surgery, has been demonstrated to be the most effective and long-term treatment for individuals with severe obesity or moderate obesity complicated by comorbid conditions that is not responsive to non-surgical approaches. By using a medical model, clinicians can provide more proactive and effective treatments in assisting their patients with weight loss.     

Higher sleep fragmentation predicts a lower magnitude of weight loss in overweight and obese women participating in a weight-loss intervention

Background:

Sleep has been identified as having an influence on the success of weight-loss interventions; however, knowledge of the mechanisms and the extent to which sleep disturbances affect the magnitude of weight reduction is inconclusive.

Objective:

To determine if sleep duration and quality can predict the magnitude of weight reduction in a weight-loss intervention program for overweight and obese women.

Methods:

Ninety overweight and obese women aged 25–65 years completed the 7-month weight-loss phase of our weight-loss intervention. Sleep duration and quality were evaluated before the intervention by the Pittsburg Sleep Quality Index (PSQI), a self-report questionnaire, and by actigraphy. Serum levels of ghrelin, leptin, cortisol and insulin also were measured at baseline. Insulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA-IR).

Results:

The mean reduction rate of body mass index (BMI) after the intervention was 13.6%. Multiple linear regression revealed that the number of wake episodes (WEs) per night had a significant relationship with the reduction of BMI even after adjusting for other clinical variables (β=−0.341, P=0.001). The participants with five or more WEs per night (high-WE group) had a significantly lower reduction in BMI compared with those with fewer than five (normal-WE group), after adjusting for confounding variables. In contrast, the PSQI-assessed parameters, reflecting the subjective assessments of sleep quality and duration, failed to detect an association with the reduction in BMI. Baseline HOMA-IR was significantly higher in the high-WE group than in the normal-WE group after adjusting for confounding variables.

Conclusions:

Higher sleep fragmentation, as manifested by the increased number of WEs, predicts a lower magnitude of weight reduction in persons participating in weight-loss programs.