Glucagon-like receptor 1 agonists and DPP-4 inhibitors: potential therapies for the treatment of stroke

During the past decades, candidate drugs that have shown neuroprotective efficacy in the preclinical setting have failed in clinical stroke trials. As a result, no treatment for stroke based on neuroprotection is available today. The activation of the glucagon-like peptide 1 receptor (GLP-1) for reducing stroke damage is a relatively novel concept that has shown neuroprotective effects in animal models. In addition, clinical studies are currently ongoing. Herein, we review this emerging research field and discuss the next milestones to be achieved to develop a novel antistroke therapy.     

胰高血糖素样肽1及其类似物治疗阿尔茨海默病作用机制研究进展

研究发现阿尔茨海默病(AD)的许多病理特征和认知功能下降可能与脑内胰岛素抵抗有关。对AD动物模型和轻度认知功能障碍患者的脑组织进行研究,结果表明应用胰高血糖素样肽1(GLP-1)类似物如利拉鲁肽、艾塞那肽治疗后,脑内胰岛素抵抗和许多病理特征减少或是逆转。这一研究结果为GLP-1类似物对AD的潜在治疗研究提供理论基础。对GLP-1及其类似物在AD中的潜在治疗作用做一综述。     

利拉鲁肽与艾塞那肽治疗2型糖尿病降低体质量指标的meta分析

目的：系统评价类胰高血糖素样肽1类似物利拉鲁肽与艾塞那肽治疗2型糖尿病降低体质量指标情况。方法计算机检索Cochrane图书馆、PubMed、EMBASE、CNKI、CBM、中国生物医学文献数据库、中国期刊全文数据库,对纳入的随机对照试验（RCT）进行质量评价,并用Stata11.0软件对提取的相关数据进行meta分析。结果共纳入31个RCT,共计7036例患者,对其体质量降低情况进行了meta分析。结果发现,利拉鲁肽与对照组相比,当注射剂量为1.8 mg时,能有效降低体质量（WMD=-0.45,95%CI：-0.59,-0.31）;与阳性对照相比,当注射剂量为1.2 mg和1.8 mg时,均能有效降低体质量（WMD=-0.91,95%CI：-1.07,-0.75;WMD=-0.78,95%CI：-1.02,-0.54）。艾塞那肽与对照组相比,当注射剂量为5μg和10μg时,均能有效降低体质量（WMD=-0.36,95%CI：-0.64,-0.09;WMD=-0.99,95%CI：-1.27,-0.72）;与阳性对照相比,当注射剂量为10μg时,能有效降低体质量（WMD=-1.14,95%CI：-1.46,-0.82）。结论利拉鲁肽和艾塞那肽作为新的肠促胰岛激素类似物,均能够减轻体质量,为2型糖尿病患者提供了新的降糖药选择。     

Pharmacological management of type 2 diabetes: the potential of incretin-based therapies

Management guidelines recommend metformin as the first-line therapy for most patients with type 2 diabetes uncontrolled by diet and exercise. Efficacy with metformin therapy is usually of limited duration, which necessitates the early introduction of one or two additional oral agents or the initiation of injections, glucagon-like peptide-1 (GLP-1) agonists or insulin. Although safe and effective, metformin monotherapy has been associated with gastrointestinal side effects (≈20% of treated patients in randomized studies) and is contraindicated in patients with renal insufficiency or severe liver disease. Patients treated with a sulphonylurea are at increased risk for hypoglycaemia and moderate weight gain, whereas those receiving a thiazolidinedione are subject to an increased risk of weight gain, oedema, heart failure or fracture. Weight gain and hypoglycaemia are associated with insulin use. Thus, there is an unmet need for a safe and efficacious add-on agent after initial-therapy failure. Evidence suggests that incretin-based agents, such as GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, can successfully achieve glycaemic targets and potentially provide cardiovascular and β-cell-function benefits. This review will examine current approaches for treating type 2 diabetes and discuss the place of incretin therapies, mainly GLP-1 agonists, in the type 2 diabetes treatment spectrum.     

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。     

Targeting Incretins in Type 2 Diabetes: Role of GLP-1 Receptor Agonists and DPP-4 Inhibitors

Until recently, the pathogenesis of type 2 diabetes mellitus (T2DM) has been conceptualized in terms of the predominant defects in insulin secretion and insulin action. It is now recognized that abnormalities in other hormones also contribute to the development of hyperglycemia. For example, the incretin effect, mediated by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), is attenuated in T2DM. Intravenous administration of GLP-1 ameliorates hyperglycemia in patients with T2DM, but an extremely short half-life limits its utility as a therapeutic agent. Strategies to leverage the beneficial effects of GLP-1 include GLP-1 receptor agonists or analogs or dipeptidyl peptidase-4 (DPP-4) inhibitors-agents that act by slowing the inactivation of endogenous GLP-1 and GIP. The GLP-1 agonist exenatide has been shown to improve HbA1c and decrease body weight. However, exenatide is limited by its relatively short pharmacologic half-life, various gastrointestinal (GI) side effects, and the development of antibodies. Studies of a long-acting exenatide formulation suggest that it has improved efficacy and also promotes weight loss. Another prospect is liraglutide, a once-daily human GLP-1 analog. In phase 2 studies, liraglutide lowered HbA1c by up to 1.7% and weight by approximately 3 kg, with apparently fewer GI side effects than exenatide. DPP-4 inhibitors such as sitagliptin and vildagliptin result in clinically significant reductions in HbA1c, and are weight neutral with few GI side effects. This review will provide an overview of current and emerging agents that augment the incretin system with a focus on the role of GLP-1 receptor agonists and DPP-4 inhibitors.     

Adverse drug reactions associated with the use of liraglutide in patients with type 2 diabetes – focus on pancreatitis and pancreas cancer

Introduction: The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, is a widely used drug for the treatment of type 2 diabetes. Liraglutide is one of several incretin-based agents that have been suggested to be associated with pancreatitis and pancreas cancer. The suspicion accelerated after publication of an autopsy study claiming increased incidences of several pathological changes in pancreata from patients with diabetes treated with incretin-based drugs.

Areas covered: The aim of the present review is to give an overview of the pharmacology of liraglutide and provide a review of adverse reactions associated with liraglutide with a focus on the risk of pancreatitis and pancreas cancer.

Expert opinion: When comprehensively reviewing the available literature, no clear and significant associations between liraglutide and pancreatitis and/or pancreas cancer seem evident. However, a recently published analysis suggests a trend toward a slightly elevated risk of pancreatitis with GLP-1 receptor agonists (including liraglutide), which may become statistical significant as more data become available. Well-established side effects are of gastrointestinal origin, typical mild-to-moderate and of transient character. The risk of hypoglycemia associated with liraglutide treatment is low.     

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.