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.     

SGLT-2抑制剂和GLP-1受体激动剂的心血管安全性研究进展

2型糖尿病是动脉粥样硬化性心血管疾病发病的高危因素。研究发现,钠-葡萄糖共转运蛋白2(SGLT-2)抑制剂、胰高血糖素样多肽-1(GLP-1)受体激动剂对2型糖尿病合并心血管疾病的患者具有心血管保护作用。故从心血管安全性试验及其Meta分析、网状Meta分析方面,对SGLT-2抑制剂、GLP-1受体激动剂的心血管安全性研究进展进行归纳和总结。     

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。     

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.     

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.     

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.     

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。     

GLP-1生物学及基于GLP-1的抗糖尿病药物研究(英文)

在过去的几十年中,环境和生活方式的改变使得2型糖尿病患者的数量急剧增加, 其中一个重要的病理基础是胰岛素分泌缺陷。胰高血糖素样肽1(GLP-1)是一种由肠道细胞产生及分泌的多肽激素, 该激素以葡萄糖浓度依赖性方式促进胰岛β细胞分泌胰岛素, 调节血糖水平。研究表明GLP-1是糖尿病治疗中的一个有效靶点, 药物研发目前主要集中于GLP-1受体激动剂和降解酶抑制剂两个方面。以其强大的生物学活性为基础, GLP-1药物在临床上表现出高效、低副作用的显著优势。在此, 我们对GLP-1生物学和基于GLP-1的抗糖尿病药物研发进行综述。     

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.     

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.     

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...     

REVIEWMolecular mechanisms underlying physiological and receptor pleiotropic effects mediated by GLP-1R activation

The incidence of type 2 diabetes in developed countries is increasing yearly with a significant negative impact on patient quality of life and an enormous burden on the healthcare system. Current biguanide and thiazolidinedione treatments for type 2 diabetes have a number of clinical limitations, the most serious long-term limitation being the eventual need for insulin replacement therapy (Table 1). Since 2007, drugs targeting the glucagon-like peptide-1 (GLP-1) receptor have been marketed for the treatment of type 2 diabetes. These drugs have enjoyed a great deal of success even though our underlying understanding of the mechanisms for their pleiotropic effects remain poorly characterized even while major pharmaceutical companies actively pursue small molecule alternatives. Coupling of the GLP-1 receptor to more than one signalling pathway (pleiotropic signalling) can result in ligand-dependent signalling bias and for a peptide receptor such as the GLP-1 receptor this can be exaggerated with the use of small molecule agonists. Better consideration of receptor signalling pleiotropy will be necessary for future drug development. This is particularly important given the recent failure of taspoglutide, the report of increased risk of pancreatitis associated with GLP-1 mimetics and the observed clinical differences between liraglutide, exenatide and the newly developed long-acting exenatide long acting release, albiglutide and dulaglutide.Linked ArticlesThis article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-5     

GLP-1 receptor agonists in the treatment of polycystic ovary syndrome

Introduction: Polycystic ovarian syndrome (PCOS) affects many women of child-bearing age and is characterized by hyperandrogenism, ovulatory and metabolic dysfunction. A primary treatment goal is weight reduction. The weight loss effects of glucagon-like peptide-1 receptor agonists (GLP-1RA), previously demonstrated in diabetic and obese non-diabetic patients, offer a unique opportunity to expand the medical options available to PCOS patients.

Areas covered: Available clinical trials of glucagon-like peptide-1 receptor agonist therapy in PCOS were reviewed. Literature was searched from PubMed using appropriate search terms up to November 2016.

Expert commentary: The available studies of GLP-1 RA therapy in the treatment of excess body weight in women with PCOS demonstrate that exenatide and liraglutide are effective in weight reduction either as monotherapy or in combination with metformin. A few studies showed that androgens may be modestly decreased and menstrual frequency may be increased. Eating behavior may be improved with liraglutide therapy. Glucose parameters are generally improved. GLP-1RAs were well-tolerated, with nausea being the most significant adverse side effect. Barriers to utilization may be the short duration studies, lack of familiarity of the medication, the route of administration (injection) and the variable outcomes on ovulation and hyperandrogenism.     

胰高血糖素样肽-1受体激动剂调节2型糖尿病糖脂代谢研究进展

胰高血糖素样肽-1（glucagon-like peptide-1,GLP-1）受体激动剂类药物是一类新型抗糖尿病药物,可呈血糖依赖性地促进胰岛素的分泌、减慢胃排空、增加外周组织对葡萄糖的摄取,从而起到控制血糖的作用。本文对GLP-1受体激动剂近年来的国内外文献进行综述,从其对血糖、血脂及体质量等方面的影响展开分析,并比较了不同GLP-1受体激动剂之间,及与其他降糖药物之间的疗效差异,旨在阐明此类药物在改善2型糖尿病代谢方面的作用特点。     

Adding prandial GLP-1 receptor agonists to basal insulin: a promising option for type 2 diabetes therapy

Background: Diabetes mellitus is a serious and increasingly prevalent condition in Canada and around the world. Treatment strategies have become increasingly complex, with a widening array of pharmacological agents available for glycemic management in type 2 diabetes mellitus (T2DM). New therapies that act in concert with available basal insulins may represent alternatives to basal insulin intensification with prandial or pre-mixed insulin. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have recently shown promise as useful additions to basal insulin, with significant reductions in glycated hemoglobin and potentially beneficial effects on body weight. This review will focus on pivotal clinical trials to assess the potential benefits of adding prandial GLP-1 RAs to basal insulin in patients with T2DM.

Methods: Clinical studies combining prandial GLP-1 RAs and basal insulin (published between 2011 and July 2017) were identified and reviewed in PubMed, the Cochrane Central Register of Clinical Trials (Issue 6, June 2017), and clinicaltrials.gov.

Results: Most of the studies presented in this review show that the addition of a prandial GLP-1 RA to basal insulin results in equal or slightly superior efficacy compared to the addition of prandial insulin, together with weight loss and less hypoglycemia.

Conclusions: The results of the studies suggest that a prandial GLP-1 RA as an add-on to basal insulin may be a safe and effective treatment intensification option (vs basal-plus or basal-bolus insulin).     

Safety and tolerability of glucagon-like peptide-1 receptor agonists: unresolved and emerging issues

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a mainstay of treatment options for type 2 diabetes. They contribute to lowering blood glucose levels, generally have a favorable tolerability profile, and can be used alone or in combination with other antidiabetic agents. Based on the duration of their effects, GLP-1 RAs can be divided into two classes: short-acting and long-acting. Differences exist between these sub-classes, and between each drug, in terms of pharmacokinetic and pharmacodynamic profiles. Therefore, prescribers cannot necessarily assume GLP-1 RA ‘class effects’, especially in terms of tolerability.

Areas covered: This article reviews the published data on the safety and tolerability of currently available GLP-1 RAs and, recognizing the importance of safety profiles when selecting the appropriate treatment for each patient, examines the clinical implications of the differences between the drugs in this class. Cardiovascular safety, gastrointestinal tolerability, and tolerability in elderly patients are discussed as specific areas of interest to prescribers selecting between GLP-1 RAs for their patients.

Expert opinion: Although further research is needed, the current evidence offers the potential to tailor treatment more accurately to each patient. Ultimately, this may improve adherence and persistence, thereby improving glycemic control and, in turn, reducing the risk of macro- and micro-vascular complications.     

Glucose lowering and anti-atherogenic effects of incretin-based therapies: GLP-1 analogues and DPP-4-inhibitors

Background: Type 2 diabetes is a chronic, progressive disease with a multi-faceted pathophysiology. Beyond the known defects of insulin resistance and β-cell insufficiency, derangement of incretin hormones normally produced from the gut wall in response to food intake play an important role. In recent years, the ‘incretin-based’ therapies (IBTs) have been developed to address hyperglycemia through either mimicking the action of the endogenous incretin glucagon-like polypeptide (GLP-1) (GLP-1 receptor agonists) or by inhibiting the activity of the enzyme that degrades GLP-1 (the dipeptyl peptidase-4 inhibitors). Objective: We reviewed available evidence on the glucose lowering and anti-atherogenic effects of IBT. Results: In addition to their glucose-lowering and weight-neutral or weight-reducing actions, IBT decrease systolic blood pressure and improve fasting and postprandial lipid parameters by reducing total-cholesterol, low-density lipoprotein-cholesterol and triglycerides concentrations, and increasing high-density lipoprotein-cholesterol values. Reduced high-sensitivity C-reactive protein levels and improved endothelial dysfunction have been reported too. Conclusions: IBT have several beneficial effects on cardiovascular risk factors and, for this reason, it has been recently suggested to extend the use of these drugs in diabetic patients with cardiovascular complications. Yet, the long-term effects of IBT on subclinical or clinical atherosclerosis remain to be established by future studies.     

Pharmacological management of diabetes in severe mental illness: a comprehensive clinical review of efficacy,safety and tolerability

Introduction: The increased prevalence of Type 2 diabetes mellitus (T2DM) in severe mental illness (SMI) contributes to increased cardiovascular morbidity and reduced life expectancy for people with SMI.

Areas covered: In the present clinical review, we summarize the efficacy, safety and tolerability of selected diabetic pharmacotherapy options in SMI and discuss the quality and strength of evidence.

Expert commentary: General principles for treating T2DM in SMI involve identifying treatments which promote weight loss and which have low or no risk of hypoglycemia. Patient engagement in decision making about treatment choices is an important factor to ensure adherence and successful use of the chosen therapy. The first line therapeutic option for T2DM in SMI for which there is most evidence is metformin. Based on general population data, second line treatment options in combination with metformin to achieve glycated haemoglobin treatment goals include GLP-1R agonists, DPP-4 inhibitors, sulphonylureas, SGLT2 inhibitors, pioglitazone and insulin, with most evidence for the use of GLP-1R agonists in SMI. Alongside efficacy and tolerability, treatment for T2DM in SMI should be considered on a patient-tailored basis.     

胰高血糖素样肽1及其受体激动剂研究进展

胰高血糖素样肽1 (Glucagon-like Peptide-1,GLP-1) 是一种由肠道Ｌ细胞分泌的多肽激素,其与GLP-1受体结合后具有促进胰岛素分泌和生物合成,抑制胰高血糖素的分泌,促进胰岛?细胞增殖,抑制胰岛?细胞凋亡,保存?细胞对血糖的敏感性等多种生理功能,但是其在体内的半衰期很短 (<2 min),在临床应用上很受限制。根据GLP-1及其受体设计GLP-1类似物是目前开发糖尿病新药的前沿靶点之一,旨在寻找能够耐受二肽基肽酶4(DPP4)降解并具有GLP-1生理活性的长效肽类及非肽类化合物。本文对GLP-1及其受体激动剂的研究成果综述如下。