GLP-1受体激动剂的临床药效与安全性研究进展

胰高血糖素样肽-1(GLP-1)是一种由肠道分泌的内源性激素。该分子通过促进胰岛素分泌、降低胰高血糖素的含量、抑制胃排空和减少食物摄取等方式起到降低血糖和控制体重的效果。然而天然GLP-1分子由于肾小球滤过和二肽基肽酶-4(DPP-4)酶解作用而导致半衰期极短,限制了其在临床的应用。为此,研究者们通过氨基酸替换、化学修饰以及蛋白融合等技术来寻找抗DPP-4酶解以及长效化的新型GLP-1受体激动剂。通过对近年来有关GLP-1受体激动剂的相关临床试验结果进行汇总,该文对已上市的与正处于临床阶段的新型GLP-1受体激动剂的临床药效(糖化血红蛋白、空腹血糖和体重)以及安全性(心血管系统、消化系统、胰腺和低血糖症)进行了综述,并对其研究前景进行了展望;虽然GLP-1受体激动剂在某些安全性方面仍需要进一步确证,但其优秀的降糖效果以及相对较低的安全风险使其依然是研究开发的热点所在。     

GLP-1受体激动剂治疗2型糖尿病合并肾损伤患者的疗效和安全性:一项Meta分析

目的:评价胰高血糖素样肽-1受体激动剂(GLP-1RAs)在2型糖尿病(T2DM)合并肾损伤患者中的疗效和安全性,为该类药物的临床应用提供循证参考。方法:检索Medline、Embase、Cochrane Library、中国知网(CNKI)和万方数据库,查找有关GLP-1RAs治疗T2DM合并肾损伤患者的随机对照试验(RCT)。按照纳入与排除标准筛选文献,进行方法学质量评价之后提取相关资料,应用RevMan 5.3统计软件进行Meta分析。结果:最终纳入7项RCT,共计1 755例T2DM合并肾损伤患者。疗效方面,GLP-1RAs与胰岛素类似物或二肽基肽酶4抑制剂降低糖化血红蛋白的效应相当,但优于安慰剂,且该疗效在中重度肾损伤患者中比终末期肾病患者更佳;与对照组相比降低体质量[MD=－1.75,95% CI=(－2.18,－1.32),P<0.01]和降压作用[收缩压:MD=－7.79,95% CI=(－10.83,－4.74),P<0.01;舒张压:MD=－2.92,95% CI=(－4.79,－1.05),P=0.002]均有显著性差异;但降低空腹血糖和调节脂质代谢方面未见统计学差异。安全性方面,GLP-1RAs组与对照组致低血糖和肾损伤事件的发生率[RR=1.28,95% CI=(0.56,2.96),P=0.560;RR=0.85,95% CI=(0.44,1.62),P=0.620]无统计学差异,然而GLP-1RAs组胃肠道不良反应的发生率显著高于对照组(P<0.01)。结论:对于T2DM合并肾损伤患者,GLP-1RAs具有确切的降糖、减重和降压作用,而在终末期肾病患者中疗效降低;用药期间不增加低血糖和肾损伤风险,但应注意预防胃肠道不良反应的发生。     

SGLT-2抑制剂及GLP-1受体激动剂治疗2型糖尿病的心血管获益：一项系统回顾和网状Meta分析

目的 通过贝叶斯网状Meta分析系统评价上市的11种钠-葡萄糖共转运蛋白-2(SGLT-2)抑制剂和胰高血糖素样多肽-1(GLP-1)受体激动剂治疗2型糖尿病患者的心血管获益。方法 检索Medline、Embase和Cochrane数据库,检索日期为建库至2020年7月18日。研究终点为心血管不良事件,效应指标为风险比（hazard ratios, HR）及其95%可信区间（95%CI）。结果 与安慰剂相比,恩格列净、卡格列净、达格列净、阿必鲁肽、度拉糖肽、艾塞那肽、利拉鲁肽和索马鲁肽可降低2型糖尿病患者主要心血管不良事件的发生风险,HR及95%CI为0.75(0.60-0.95)～0.90(0.82-0.99);恩格列净、卡格列净、达格列净和艾托格列净可降低心力衰竭的发生风险,HR及95%CI为0.64(0.49-0.82)～0.74(0.65-0.85);恩格列净、卡格列净、达格列净、艾塞那肽、利拉鲁肽和口服索马鲁肽可降低全因死亡的发生风险,HR及95%CI为0.52(0.33-0.84)～0.89(0.80-0.99);恩格列净、卡格列净、利拉鲁肽和口服索马鲁肽可降低心血管死亡事...     

SGLT2抑制剂与GLP-1受体激动剂对2型糖尿病合并感染患者肾功能的保护作用

目的探究钠-葡萄糖协同转运蛋白2(sodium-glucose cotransporter 2 Inhibitors, SGLT2)抑制剂和胰高血糖素样肽-1(glucagon-like peptide-1, GLP-1)受体激动剂对2型糖尿病合并感染患者肾功能的影响。方法选取2020年1月至2023年1月在济南市第二人民医院接受治疗的120例2型糖尿病合并感染患者作为研究对象, 利用抽签的方式将其随机平均分为两组。对照组男23例, 女37例, 年龄(55.23±5.46)岁;观察组男26例, 女34例, 年龄(54.87±4.98)岁。两组均维持原降糖治疗及抗感染治疗, 在此基础上对照组给予利拉鲁肽治疗, 观察组给予达格列净治疗, 均连续应用14 d。比较两组患者治疗前后空腹血糖(fasting plasma glucose, FPG)、糖化血红蛋白(hemoglobin a1c, HbA1c)、餐后2 h血糖(2-hour postprandial blood glucose, 2hPBG)、胰岛素抵抗指数(homeostatic model assessment of insul...     

GLP-1受体激动剂/类似物治疗2型糖尿病的研究进展

胰高血糖素样肽-1(GLP-1)是一种由肠道L细胞分泌,在碳水化合物的刺激下促进胰岛素的分泌进而降低血糖的一种物质。胰高血糖素样肽-1受体激动剂(GLP-1RA)是通过刺激人体内源性GLP-1的生成而产生降糖作用,因其良好的降糖效果及其对于大、小血管的保护作用而广受临床医生及科研专家的关注。本文通过检索文献对其心血管获益、减重方面进行综述,并对目前已在我国上市并在临床上取得良好应用的几种GLP-1RA进行简要介绍。     

基础胰岛素联合GLP-1受体激动剂治疗2型糖尿病疗效和安全性分析

为了探讨基础胰岛素联合胰高糖素样肽-1(GLP-1)受体激动剂治疗2型糖尿病(T2DM)疗效和安全性,选取2017年1月至2019年1月该院T2DM患者200例,依据随机数字表分为A组和B组,每组100例,A组给予基础胰岛素治疗,B组在此基础上给予GLP-1受体激动剂(利司那肽)治疗,比较两组胰岛素功能[空腹胰岛素(FINS)、胰岛素抵抗指数(HOMA-IR)、胰岛β细胞功能(HOMA-β)]、血糖控制[空腹血糖(FBG)、餐后2 h血糖(2hPBG)、糖基化血红蛋白(HbA1c)]、治疗疗效、不良反应。A组和B组治疗后FINS、HOMA-IR、FBG、2hPBG、HbA1c明显低于治疗前,B组治疗后FINS、HOMA-IR、FBG、2hPBG、HbA1c明显低于A组,A组和B组治疗后HOMA-β明显高于治疗前,B组治疗后HOMA-β明显高于A组,差异有统计学意义(P<0.05);B组治疗有效率明显高于A组,差异有统计学意义(P<0.05);A组和B组不良反应率比较,差异无统计学意义(P>0.05)。基础胰岛素联合GLP-1受体激动剂可有效改善T2DM患者胰岛素功能、血糖控制效果,有利于提高疗效,且安全性好,可供临床应用参考。     

GLP-1受体激动剂超说明书用药情况调查及合理性分析

目的 了解GLP-1受体激动剂超说明书用药情况,促进临床合理用药。方法 采用回顾性调查法,抽取内分泌科2015年12月3日-2016年12月14日使用过GLP-1受体激动剂进行治疗的住院病例,按照药品说明书,判断其超说明书用药情况,对超说明书用药进行分类和统计,并评价其合理性。结果 共调查内分泌科住院患者51例,有97例次存在超说明书用药情况,其中超适应证47例次（48.45%）,主要表现在联合用药方面,另有50例次（51.55%）属于用法用量超说明书。结论 GLP-1受体激动剂在临床超说明书使用的现象较普遍,某些有其合理性和必要性,但也有不合理用药情况,临床需引起高度重视。     

GLP-1受体激动剂和DPP-4抑制剂对心血管系统的保护作用

胰高糖素样肽1(GLP-1)受体激动剂和二肽基肽酶-4(DPP-4)抑制剂是近年上市的治疗2型糖尿病的新型药物。GLP-1主要通过抑制心肌细胞凋亡、改善内皮细胞功能、减轻体重、降低血糖、降低血压、改善心肌收缩力、舒张血管等直接或间接发挥其心脏保护作用,GLP-1受体激动剂和DPP-4抑制剂对体重、血压和血脂等心血管危险因素有改善作用。GLP-1受体激动剂和DPP-4抑制剂作用于新靶点,具有其独特的优点,将会是一类抗糖尿病新药。     

新型GLP-1受体激动剂Lixisenatide的研究进展

据2012年国际糖尿病联盟的最新统计数据显示,2011年全球糖尿病人数高达3.66亿人,预计到2030年将上升到5.52亿人,Ⅱ型糖尿病患者占其中的90%以上。中国是全球糖尿病人数最多、增长速率最快的国家,且血糖控制情况较差,整体达标率（HbA1c6.5%）仅为26.8%,这可能与各类降糖药的副作用较大,如低血糖反应、体重增加等,致使患者不能坚持用药有关。糖尿病早已成为严重威胁人类健康的公共卫生问题,并对社会及经济发展造成沉重的负担。     

23例GLP-1受体激动剂致急性肾损伤不良反应文献分析

目的 分析GLP-1受体激动剂致急性肾损伤的临床表现、特点、规律及转归,为临床安全用药提供参考。方法 计算机检索自建库至2022年6月中国知网、维普中文科技期刊数据库、万方数据库、PubMed、Embase、Cochrane图书馆关于GLP-1受体激动剂致急性肾损伤个案报道,采用回顾性分析方法,对纳入病例中患者信息、ADR发生时间累及系统临床表现和转归等进行统计分析。结果 GLP-1受体激动剂致急性肾损伤的个案报道共23例(女性11例,45.83%;男性12例,54.17%);患者年龄以45～64岁年龄段较多(13例,56.52%);不良反应多发生在用药1月左右(11例,54.17%);GLP-1受体激动剂致急性肾损伤主要以泌尿系统损害(30例,44.12%)及胃肠系统损害(25例,36.76%)为主;20例经停药和/或对症支持治疗后症状治愈或好转;1例患者停药治疗后好转,再次用药后不良反应再现。结论 临床使用GLP-1受体激动剂时应慎重评估相关危险因素,尤其是对胃肠道反应较严重、合并用药较多、有相关肾脏疾病病史的老年患者需要调整药物使用剂量时,应加强对其肾功能的监测。     

Spotlight on Canagliflozin 300: review of its efficacy and an indirect comparison to other SGLT-2 inhibitors and long-acting GLP-1 receptor agonists

Introduction: Both sodium-glucose co-transporter-2 inhibitors (SGLT-2Is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been consistently found to lower blood glucose, body weight and systolic blood pressure (SBP) in patients with type 2 diabetes mellitus (T2DM). While all the SGLT-2Is inhibit glucose reabsorption by blocking SGLT-2 receptor in kidney, dose-dependently, the highest licensed dose of canagliflozin 300-mg has an additional ability to inhibit SGLT-1 receptor in intestine transiently, that may lead to additional inhibition of prandial glucose absorption, unlike other approved highly selective SGLT-2Is.

Areas covered: An electronic search on studies with highest licensed dose of all approved SGLT-2Is and long-acting GLP-1RAs was made up to December 2016. We systemically reviewed the studies of canagliflozin 300-mg and compared its glucose, body weight and SBP lowering with other approved SGLT-2Is and GLP-1RAs in their highest approved doses.

Expert commentary: From the available evidences, it appears that canagliflozin 300-mg may have the highest potential to improve gluco-metabolic profile in T2DM, amongst the SGLT-2Is class. While the highest approved dosage of GLP-1RAs lowered HbA1c better than canagliflozin 300-mg, weight and SBP lowering could be non-inferior or slightly better with the latter drug. Nonetheless, only head-to-head trial can conclusively answer these questions.     

A comparative safety review between GLP-1 receptor agonists and SGLT2 inhibitors for diabetes treatment

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium glucose cotransporter 2 inhibitors (SGLT2i) are of particular interest in type 2 diabetes treatment strategies, due to their efficacy in reducing HbA1c with a low risk of hypoglycaemia, to their positive effects on body weight and blood pressure and in light of their effects on cardiovascular risk and on nephroprotection emerged from the most recent cardiovascular outcome trials.

Since it is therefore very likely that GLP-1RA and SGLT2i use will become more and more common, it is more and more important to gather and discuss information about their safety profile.

Area Covered: adverse events and the safety concerns most often emerged in trials with GLP-1RA namely, exenatide long acting release (LAR), dulaglutide, liraglutide, semaglutide, lixisenatide or SGLT2i, namely empagliflozin, dapagliflozin, canagliflozin and SGLT2i with an attempt at comparing the safety profiles of molecules of these two classes.

Expert opinion: GLP-1RA and SGLT2i, although each associated with different specific side effects, share a ‘similar’ safety profile and are both drugs relatively easy to handle. The potentially complementary mechanisms of action, the cardio and nephroprotective effects demonstrated by molecules of both classes, make these drugs potentially useful even in add on to each other.     

Cardiovascular safety and benefits of GLP-1 receptor agonists

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) constitute a class of drugs for the treatment of type 2 diabetes, and currently, six different GLP-1RAs are approved. Besides improving glycemic control, the GLP-1RAs have other beneficial effects such as weight loss and a low risk of hypoglycemia. Treatment with the GLP-1RA lixisenatide has been shown to be safe in patients with type 2 diabetes and recent acute coronary syndrome. Furthermore, liraglutide and semaglutide have been shown to reduce cardiovascular (CV) disease (CVD) risk in type 2 diabetes patients with established and/or high risk of CVD. The CV safety of the remaining GLP-1RAs in type 2 diabetes patients with established and/or high risk of CVD remains uncertain, but ongoing CV outcome trials (CVOTs) will elucidate this within a few years.

Areas covered: The aim of this review is to provide an overview of the existing GLP-1RAs with a particular focus on their clinical effects on CV risk factors and their CV safety and benefits.

Expert opinion: Data on the CV risks and benefits associated with GLP-1RA treatment in patients with type 2 diabetes and high risk of CVD are emerging – and look promising (especially for liraglutide and semaglutide). Data from ongoing CVOTs will be crucial for the positioning of the individual GLP-1RAs in the treatment of patients with type 2 diabetes and high risk of CVD. However, the long-term CV safety and the potential of GLP-1RAs to prevent CVD in type 2 diabetes patients with less risk of CVD (e.g. newly diagnosed patients) remain uncertain.     

A comparison of currently available GLP-1 receptor agonists for the treatment of type 2 diabetes

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists are a valuable addition to the type 2 diabetes armamentarium. They increase insulin secretion and reduce glucagon secretion in a glucose-dependent manner, posing a relatively low hypoglycemia risk. GLP-1 receptor agonists also offer weight-loss benefits. Because GLP-1 receptor agonists are relatively new agents, there is limited direction on their use.

Areas covered: This article aims to provide guidance to physicians when considering GLP-1 receptor agonist use in individual patients. It examines the clinical profiles of the currently available GLP-1 receptor agonists: exenatide twice-daily (BID), liraglutide once daily and exenatide extended release (ER) once weekly. Phase III clinical trial data on efficacy, safety and patient satisfaction are compared, with a primary focus on head-to-head trials.

Expert opinion: Liraglutide seems to be the most effective GLP-1 receptor agonist in terms of HbA_1c reduction and weight loss. Exenatide BID may offer an advantage where postprandial glucose control is a primary concern. Exenatide ER generally outperforms exenatide BID and is a good option for patients who struggle to adhere to more frequent regimens. The future may hold interesting developments in terms of reduced dosing frequency, oral formulations and alternative therapeutic uses.     

胰高血糖素样肽-1受体激动剂和二肽基肽酶-4抑制剂联用二甲双胍治疗2型糖尿病的疗效与安全性对比的系统评价

目的：比较胰高血糖素样肽-1（GLP-1）受体激动剂和二肽基肽酶-4（DPP-4）抑制剂联用二甲双胍治疗2型糖尿病的疗效和安全性。方法：计算机检索Pubmed,Embase,Cochrane Library,CNKI,WanFang,VIP,CBM数据库,纳入GLP-1受体激动剂和DPP-4抑制剂联用二甲双胍比较治疗2型糖尿病的随机对照试验（RCT）,检索时间截止至2016年6月1日。由两位研究者根据纳入排除标准筛选文献、提取资料以及对文献质量进行评价,采用Rev-Man 5.3.5软件对数据进行分析。结果：共纳入14篇RCT。Meta分析结果显示：GLP-1受体激动剂+二甲双胍在降低糖化血红蛋白,降低空腹血糖,减轻体重,降低收缩压方面均优于DPP-4抑制剂+二甲双胍,差异具有统计学意义;在降低舒张压方面,2组并无差别;DPP-4抑制剂+二甲双胍组不良反应发生率更低,差异具有统计学意义;在低血糖方面,2组发生率相当,没有统计学差异。结论：GLP-1受体激动剂+二甲双胍在降低2型糖尿病患者的血糖,体质量控制以及降低收缩压方面优于DPP-4抑制剂+二甲双胍,但是不良反应发生率更高。     

Cardiovascular safety of therapies for type 2 diabetes

Introduction: Dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP-1) analogs and sodium-glucose cotransporter 2 (SGLT2) inhibitors are relatively new therapies for the treatment of type 2 diabetes mellitus. Given the high prevalence of cardiovascular complications in patients with type 2 diabetes and recent concerns questioning CV safety of newer antidiabetic medications, cardiovascular safety of these medications requires evaluation.

Areas covered: Cardiovascular effects of these drug classes from preclinical and clinical data as well as non-cardiovascular safety issues are delineated from literature searches covering the last decade and up to June 2016. Major clinical trials assessing the cardiovascular safety of GLP-1 agonists (ELIXA and LEADER), DPP-4 inhibitors (SAVOR-TIMI 53, EXAMINE, and TECOS) and SGLT2 inhibitors (EMPA-REG OUTCOME) are reviewed and interpreted.

Expert opinion: Based on review of the present evidence, these 3 classes of antihyperglycemic therapies have acceptably safe CV safety profiles for patients with type 2 diabetes. The latest evidence from LEADER and EMPA-REG OUTCOME trials indicate that liraglutide and empagliflozin have cardiovascular benefits that may prove to be of clinical importance in the management of type 2 DM.     

Physician perceptions of GLP-1 receptor agonists in the UK

Objectives Glucagon-like peptide-1 (GLP-1) receptor agonists have been used to treat type 2 diabetes for almost a decade, and new treatments in this class have recently been introduced. The purpose of this study was to examine perceptions of GLP-1 receptor agonists among physicians who treat patients with type 2 diabetes in the UK.

Methods A total of 670 physicians (226 diabetes specialists; 444 general practice [GP] physicians) completed a survey in 2014.

Results Almost all physicians had prescribed GLP-1 receptor agonists (95.4% total sample; 99.1% specialists; 93.5% GP), most frequently to patients whose glucose levels are not adequately controlled with oral medications (85.9% of physicians) and obese/overweight patients (83.7%). Physicians’ most common reasons for prescribing a GLP-1 receptor agonist were: associated with weight loss (65.8%), good efficacy (55.7%), less hypoglycemia risk than insulin (55.2%), not associated with weight gain (34.5%), and better efficacy than oral medications (32.7%). Factors that most commonly cause hesitation when prescribing this class were: not considered first line therapy according to guidelines (56.9%), injectable administration (44.6%), cost (36.7%), gastrointestinal side effects (33.4%), and risk of pancreatitis (26.7%). Almost all specialists (99.1%) believed they had sufficient knowledge to prescribe a GLP-1 receptor agonist, compared with 76.1% of GPs.

Conclusions Results highlight the widespread use of GLP-1 receptor agonists for treatment of type 2 diabetes in the UK. However, almost a quarter of GPs reported that they do not have enough knowledge to prescribe GLP-1s, suggesting a need for increased dissemination of information to targeted groups of physicians. Study limitations were that the generalizability of the clinician sample is unknown; survey questions required clinicians to select answers from multiple response options rather than generating the responses themselves; and responses to this survey conducted in 2014 do not reflect perceptions of the most recently introduced GLP-1 receptor agonists.     

An overview of new GLP-1 receptor agonists for type 2 diabetes

Introduction: The increasing prevalence of type 2 diabetes mellitus (T2DM) and the eventual need for multiple medications in most patients stimulated the development of new drug classes to reduce plasma glucose levels. The GLP-1 receptor agonists (GLP-1RAs) are established as an option for treatment of T2DM after metformin. They are also effective in reducing body weight but current GLP-1RAs have to be given by subcutaneous injection daily or once weekly.

Areas covered: This review focuses on the new GLP-1RAs currently undergoing development, some of which require less frequent subcutaneous administration and others that are being developed in oral formulations that may favor patient adherence.

Expert opinion: The new GLP-1RAs may have the benefit of requiring less frequent subcutaneous dosing or being active by oral administration. However, cardiovascular outcome trials have shown that DPP4 inhibitors are neutral for cardiovascular events and the first cardiovascular outcome trial with lixisenatide reported similar results, whereas the trial with the SGLT2 inhibitor empagliflozin showed a reduction in cardiovascular events. These findings in patients with high cardiovascular risk may favor the use of SGLT2 inhibitors as a second line treatment after metformin but there should still be an important role for novel GLP-1RAs, especially when weight reduction is required.