Can we win the war on obesity with pharmacotherapy?

Introduction: Obesity is a major health concern for several countries. The United States (U.S.) has arguably led the world in the percentage of overweight and/or obese per capita for several decades. As a result, numerous FDA-approved pharmacotherapeutic options are available for the long-term treatment of obesity. Although most of these medications have been on the U.S. market for a few years and have demonstrated efficacy for long-term weight loss in clinical trials, the impact of these medications on obesity in the U.S. has yet to be realized.

Areas covered: We will review and evaluate why pharmacotherapy for obesity has not produced a meaningful reduction in the number of overweight and obese adults in the U.S.

Expert commentary: Several obstacles, such as adverse drug effects, poor insurance coverage, not treating obesity as a chronic disease, and availability of other weight loss alternatives, has resulted in poor performance of pharmacotherapy for obesity in the U.S. market.     

Glucagon‐Like Peptide‐1 Receptor Agonist Administration Suppresses Both Water and Saline Intake in Rats

Glucagon‐like peptide‐1 (GLP‐1) plays an important role in energy homeostasis. Injections of GLP‐1 receptor (GLP‐1R) agonists suppress food intake, and endogenous GLP‐1 is released when nutrients enter the gut. There is also growing evidence that the GLP‐1 system is involved in the regulation of body fluid homeostasis. GLP‐1R agonists suppress water intake independent of their effects on food intake. It is unknown, however, whether this suppressive effect of GLP‐1R agonists extends to saline intake. Accordingly, we tested the effect of the GLP‐1R agonists liraglutide (0.05 μg) and exendin‐4 (0.05 μg) on water and saline intake, as stimulated either by angiotensin II (AngII) or by water deprivation with partial rehydration (WD‐PR). Each agonist suppressed AngII‐induced water intake; however, only exendin‐4 suppressed saline intake. WD‐PR‐induced water and saline intakes were both attenuated by each agonist. Analysis of drinking microstructure after WD‐PR found a reliable effect of the agonists on burst number. Furthermore, exendin‐4 conditioned a robust taste avoidance to saccharine; however, there was no similar effect of liraglutide. To evaluate the relevance of the conditioned taste avoidance, we tested whether inducing visceral malaise by injection of lithium chloride (LiCl) suppressed fluid intake. Injection of LiCl did not suppress water or saline intakes. Overall, these results indicate that the fluid intake suppression by GLP‐1R activation is not selective to water intake, is a function of post‐ingestive feedback, and is not secondary to visceral malaise.     

基于FAERS数据库利拉鲁肽不良反应信号挖掘与分析

目的： 通过对利拉鲁肽不良反应信号的挖掘分析,为临床合理安全用药提供依据。方法： 采用比例失衡法中的报告比值比法（ROR）和比例报告比值比法（PRR）对美国FDA不良事件报告系统（FAERS）利拉鲁肽2010年一季度至2019年一季度共37个季度的不良反应报告进行数据挖掘及分析。结果： 共收集到56 396条药品不良反应（Adverse Drug Reaction,ADR）报告,合并同义词后使用ROR与PRR法,经过二次筛选,得到ADR信号87个,主要集中于胃肠道系统损害、代谢和营养障碍、用药部位损害、内分泌紊乱等方面。结论： 对利拉鲁肽ADR信号进行挖掘和分析,为临床安全用药提供参考,采取相应的预防措施,或避免应用于高风险人群。     

Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus: a review

Over the last decade, the discovery of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) has increased the treatment options for patients with type 2 diabetes mellitus (T2DM). GLP-1 RAs mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases satiety and slows gastric emptying. This review evaluates the phase III trials for all approved GLP-1 RAs and reports that all GLP-1 RAs decrease HbA1c, fasting plasma glucose, and lead to a reduction in body weight in the majority of trials. The most common adverse events are nausea and other gastrointestinal discomfort, while hypoglycaemia is rarely reported when GLP-1 RAs not are combined with sulfonylurea or insulin. Treatment options in the near future will include co-formulations of basal insulin and a GLP-1 RA.     

利拉鲁肽治疗超重、肥胖2型糖尿病并肾脏疾病的临床观察

目的 观察利拉鲁肽治疗超重、肥胖2型糖尿病（type 2 dabetes mellitus,T2DM）并肾脏疾病的临床效果。 方法 筛选超重、肥胖T2DM患者70例,糖化血红蛋白（glycated hemoglobin,HbA1c）符合(7%≤HbA1c≤11％),随机分成2组,胰岛素联合二甲双胍和（或）阿卡波糖组（胰岛素组）、利拉鲁肽联合二甲双胍和（或）阿卡波糖（利拉鲁肽组）：治疗24周,观察治疗前后体重（body weight,WT）、腰围（waist circumference,WC）、HbA1c、胰岛素抵抗指数（insulin resistance index,HOMA-IR）、尿白蛋白肌酐比值（urinary albumin creatinine ratio,UACR）、估计肾小球滤过率(estimate glomerular filtration rate,eGFR)、血、尿α1-微球蛋白(α1 microglobulin,α1-MG )、血、尿β2-微球蛋白（β2 microglobulin,β2-MG）等指标的变化。 结果 研究结束时胰岛素组完成30例,利拉鲁肽组完成31例,胰岛素组治疗后与治疗前比较HbA1c、HOMA-IR、UACR、eGFR、血α1-MG、尿α1-MG 、血β2-MG、尿β2-MG明显降低,差异有统计学意义（P＜0.01）。利拉鲁肽组治疗后与治疗前比较WT、WC、体重指数、HbA1c、HOMA-IR、UACR、eGFR、血α1-MG、尿α1-MG 、血β2-MG、尿β2-MG明显降低,差异有统计学意义（P＜0.01）。利拉鲁肽组治疗后与胰岛素组治疗后比较,UACR、eGFR、血α1-MG、尿α1-MG 、尿β2-MG降低更加明显,差异有统计学意义（P＜0.05）。 结论 利拉鲁肽治疗超重、肥胖T2DM合并肾脏疾病患者不仅可以降低血糖、减轻体重,还可以改善肾功能,延缓肾脏疾病的进展,并且这种作用是独立于降糖之外的作用。     

达格列净联合利拉鲁肽对2型糖尿病患者相关代谢指标的影响

目的 分析达格列净联合利拉鲁肽对2型糖尿病患者相关代谢指标的影响,为临床治疗提供依据.方法 选取2018年3月至2020年9月我院收治的136例2型糖尿病患者作为研究对象,根据治疗方案的不同将其分为对照组和观察组,各68例.对照组在常规干预的基础上给予利拉鲁肽治疗,观察组在对照组基础上联合达格列净进行治疗.比较两组治疗前、后的血糖指标、胰岛功能指标、脂代谢指标、APN和氧化应激指标.结果 治疗后,两组的FPG、2 h PG水平及HbA1c均较治疗前明显降低,且观察组低于对照组,差异具有统计学意义(P<0.05).治疗后,两组的FINS、2 h INS、FCP、2 h CP水平及HOMA-β较治疗前升高,HOMA-IR较治疗前降低,且观察组优于对照组,差异具有统计学意义(P<0.05).治疗后,两组的TG、TC、LDL-C水平较治疗前降低,HDL-C水平较治疗前升高,且观察组优于对照组,差异具有统计学意义(P<0.05).治疗后,两组的APN、GSH-Px及SOD水平均较治疗前明显升高,且观察组高于对照组,差异具有统计学意义(P<0.05).结论 达格列净联合利拉鲁肽治疗2型糖尿病能有效控制血糖,提高胰岛功能,改善糖脂代谢水平及氧化应激指标.