利拉鲁肽临床研究进展

利拉鲁肽是一种胰高血糖素样肽-1(GLP-1)类似物,通过激活GLP-1受体,以葡萄糖依赖性刺激胰岛素分泌并抑制胰高血糖素分泌,临床用于治疗2型糖尿病。本文综述利拉鲁肽的临床研究进展。     

利拉鲁肽在2型糖尿病治疗中的应用进展

胰高血糖素样肽-1(GLP-1)类药物是一种肠促胰岛素,为治疗2型糖尿病的新型药物,为我们提供了治疗糖尿病的新思路。其中,利拉鲁肽为重要代表药物,本文对利拉鲁肽的最新临床研究进行综述。     

利拉鲁肽的药理及临床研究进展

 利拉鲁肽是一种酰化胰高血糖素样肽-1（GLP-1）类似物,通过激活GLP-1受体,以葡萄糖依赖性刺激胰岛素分泌并抑制胰高血糖素分泌,临床用于2型糖尿病的二线治疗,可与其他口服降糖药联合使用,但不用于1型糖尿病的治疗。文中通过Medline对利拉鲁肽进行文献检索,并对其药理作用、药动学、临床研究、安全性和药物相互作用等进行综述。     

糖尿病治疗新药——利拉鲁肽

人胰高糖素样肽-1（GLP-1）是人体内存在的一种生理性多肽，它能根据体内葡萄糖水平高低，按需促进胰岛8细胞分泌胰岛素，抑制胰岛素拮抗激素胰高血糖素的分泌，从而发挥降糖作用。然而，人体产生的GLP-1很不稳定，很快就会被体内的二肽基肽酶Ⅳ（DPP—IV）降解。利拉鲁肽（liraglutide）是诺和诺德公司开发的一种GLP-1类似物，是在天然GLP-1的分子结构上更换了一个氨基酸，并增加了一个16碳棕榈酰脂肪酸侧链，从而在保留天然GLP-1功效的同时克服了其易降解的缺点。通过这种分子改变，利拉鲁肽仅需每日1次注射就能起到良好的降糖作用，     

胰高血糖素样肽1及其类似物治疗2型糖尿病的研究进展

目的:了解胰高血糖素样肽1(GLP-1)及其类似物治疗2型糖尿病的研究进展,为2型糖尿病的药物治疗提供参考。方法:查阅近年来国内外相关文献,就GLP-1及其类似物治疗2型糖尿病的研究进行归纳和总结。结果与结论:GLP-1类似物在2型糖尿病的治疗中使用广泛,其能促进葡萄糖依赖的胰岛素分泌,抑制胰高血糖素的合成,有效改善血糖水平。同时,GLP-1类似物还能够抑制机体餐后胃排空,减少热量摄入,减轻患者体质量。现有的GLP-1类似物中,艾塞那肽降血糖效果明显,患者依从性差,且存在恶心呕吐等不良反应;利拉鲁肽能很好地控制血糖,但存在胃肠道反应;阿必鲁肽降糖效果不及利拉鲁肽;度拉糖肽疗效与利拉鲁肽相当,是最具潜力的2型糖尿病治疗药物;利司那肽在美国还未被批准上市,但具有较好的临床应用前景。     

新型降糖药利拉鲁肽注射液(Ⅰ)

利拉鲁肽属于胰高血糖素样肽-1(glucagon like peptide-1,GLP-1)类似物。利拉鲁肽与天然人GLP-1的同源性高达97%,在充分保留天然人GLP-1生理活性的同时避免了非同源相关的不良效应。利拉鲁肽治疗2型糖尿病,不仅可安全有效     

多重获益——利拉鲁肽联合口服药的临床研究

利拉鲁肽（Liraglutide）是新一代的人GLP-1高度同源长效类似物，其与天然GLP-1的同源性为97％。利拉鲁肽在天然的人GLP-1分子第34位的赖氨酸被精氨酸取代，并在GLP-1分子第26位赖氨酸上，     

利拉鲁肽前体肽GLP-1(7-37)K34R在大肠埃希菌中的表达与优化

目的 建立利拉鲁肽前体肽GLP-1(7-37)K34R基因工程表达体系,为推进利拉鲁肽生物类似药的产业化开发奠定基础.方法 优化密码子并通过重叠PCR扩增获得GLP-1(7-37)K34R编码基因(glp1a),构建glp1a与GST、Ub、SUMO 3种标签蛋白在大肠埃希菌中融合表达,分别从诱导时机、诱导温度、诱导时...     

从循证证据看德谷胰岛素利拉鲁肽注射液的临床应用

基础胰岛素与胰高血糖素样肽-1受体激动剂（glucagon-like peptide-1 receptor agonist,GLP-1RA）联合用药是近十年糖尿病注射疗法的重要进展之一。新型降糖药物德谷胰岛素利拉鲁肽注射液（Insulin Degludec and Liraglutide Injection,IDegLira）将基础胰岛素类似物（德谷胰岛素）与GLP-1RA受体激动剂（利拉鲁肽）两种药物联合,2022年进入中国市场。现依据IDegLira发表的相关循证证据,介绍作用机制、药效/药代动力学,并且从循证医学角度列举在不同2型糖尿病人群的疗效和安全性及其真实世界研究结果,以帮助临床医生全面了解IDegLira。     

GLP-1类似物利拉鲁肽研究进展

胰高糖素样肽-1类似物(GLP-1类似物)利拉鲁肽是一种全新作用机制的降糖药物,具有降低体重、降低收缩压、改善胰岛细胞功能.本文对利拉鲁肽国内外近期文献进行分析,从其药理作用特点、临床研究、安全性和耐受性等方面阐述其研究进展.其长期应用疗效如何以及能否延缓糖尿病的进展仍需要进一步的研究.     

In Vitro Protein Binding of Liraglutide in Human Plasma Determined by Reiterated Stepwise Equilibrium Dialysis

Liraglutide is a human glucagon-like peptide-1 (GLP-1) analogue approved for the treatment of type 2 diabetes. It is based on human GLP-1 with the addition of a 16-carbon fatty acid, which facilitates binding to plasma proteins, thus prolonging the elimination half-life and allowing once-daily administration. It has not been possible to quantify liraglutide protein binding by ultrafiltration (the usual method of choice), as the lipophilic molecule becomes trapped in the filter membrane. Therefore, the aim of this study was to develop a methodology that could determine the extent of liraglutide binding to plasma proteins in vitro. We report here the details of a novel reiterated stepwise equilibrium dialysis assay that has successfully been used to quantify liraglutide plasma protein binding. The assay allowed quantification of liraglutide binding to proteins in purified plasma protein solutions and human plasma samples and was effective at plasma dilutions as low as 5%. At a clinically relevant liraglutide concentration (10⁴ pM), greater than 98.9% of liraglutide was bound to protein. Specific binding to human serum albumin and α1-acid glycoprotein was 99.4% and 99.3%, respectively. The novel methodology described herein could have an application in the quantification of plasma protein binding of other highly lipophilic drug molecules. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2882–2888, 2013     

Liraglutide: clinical pharmacology and considerations for therapy

Liraglutide is a United States Food and Drug Administration (FDA)-approved glucagon-like peptide-1 (GLP-1) analog that is 97% homologous to native human GLP-1. The additional 16-carbon fatty acid chain causes noncovalent binding to albumin, which slows absorption from the injection site and protects the molecule from degradation by the enzyme dipeptidyl peptidase-4, allowing for protraction of action. Albumin binding and an elimination half-life of 13 hours combine to allow for once-daily dosing. Liraglutide 1.2 and 1.8 mg/day given as monotherapy for up to 52 weeks produced mean reductions in hemoglobin A1c (A1C) of 0.6-1.6%; combination therapy of liraglutide with oral antidiabetic agents demonstrated mean A1C reductions up to 1.5%. The satiety effect of GLP-1 receptor agonists and documented weight loss as great as 3.38 kg in clinical trials may make liraglutide ideal for obese patients with type 2 diabetes mellitus. Like other incretin-based agents, preliminary studies suggest liraglutide may also increase β-cell mass and function. Hypoglycemia is rare with liraglutide and tends to occur when used in combination with sulfonylureas; liraglutide in combination with insulin is not yet FDA approved. The pharmacokinetic parameters of liraglutide are unaffected by age, sex, race, or ethnicity, and no special recommendations for altered dosing of liraglutide need apply to populations with hepatic or renal impairment. Results from clinical trials have not shown an increased risk of medullary thyroid cancer, pancreatitis, or poor cardiovascular outcomes with liraglutide treatment. Ongoing, long-term monitoring studies continue to evaluate the safety of liraglutide treatment in these outcomes.     

利拉鲁肽治疗非酒精性脂肪性肝病的作用机制及研究进展

非酒精性脂肪性肝病（NAFLD）是我国最常见的慢性肝脏疾病之一。大多数病人的肝脂肪变性的发展与饮食中的脂肪摄入有关,其特征为自由脂肪酸摄入增加和肝脏脂肪重新生成,肝细胞中三酰甘油过度积聚。非酒精性脂肪性肝炎是一种由单纯性肝脂肪性变进展为肝细胞死亡、炎症浸润和纤维化状态的代谢性肝病,是NAFLD较严重的状态,是肝硬化、肝癌的重要危险因素。胰高血糖素样肽-1(GLP-1)是回肠内分泌细胞分泌的一种脑肠肽,进餐后血糖升高刺激胰高血糖素样肽-1分泌,抑制α细胞分泌胰高血糖素,防止餐后高血糖。以往的研究中,GLP-1受体激动剂被明确批准用于治疗糖尿病和肥胖症。其中,GLP-1受体激动剂利拉鲁肽除了其降血糖效果外,还对NAFLD存在有益的影响。该文对利拉鲁肽在NAFLD中的作用及机制研究进展做一综述。     

Potential Role of Glucagon-Like Peptide-1 (GLP-1) in Neuroprotection

The current understanding of neurodegenerative processes in sporadic diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) or multiple sclerosis is very limited. Several risk factors have been identified that may shed light on the underlying mechanisms that initiate the neurodegeneration. Type 2 diabetes mellitus has been identified as a risk factor for AD and PD. In AD patients, desensitization of insulin receptors in the brain has been shown, even in non-diabetic patients. Insulin acts as a growth factor in the brain and supports neuronal repair, dendritic sprouting and synaptogenesis, and protection from oxidative stress. Importantly, several drugs have been developed to treat type 2 diabetes that re-sensitize insulin receptors and may be of use to prevent neurodegenerative processes. Glucagon-like peptide-1 (GLP-1) is a hormone that facilitates insulin release under high blood sugar conditions. Interestingly, GLP-1 also has very similar growth factor-like properties to insulin, and has been shown to reduce a range of degenerative processes. In pre-clinical studies, GLP-1 and longer-lasting protease-resistant analogues cross the blood-brain barrier, protect memory formation (AD) or motor activity (PD), protect synapses and synaptic functions, enhance neurogenesis, reduce apoptosis, protect neurons from oxidative stress, and reduce plaque formation and the chronic inflammation response in the brains of mouse models of AD, PD, amyotrophic lateral sclerosis, stroke and other degenerative diseases. GLP-1 signalling does not affect blood sugar levels in non-diabetic people and therapies that affect GLP-1 signalling have a good safety profile as shown by the chronic application of drugs currently on the market (liraglutide, Victoza?; NovoNordisk, Copenhagen, Denmark, and exendin-4, Byetta?; Amylin, San Diego, CA, USA). Based on the extensive evidence, several clinical trials are currently underway, testing liraglutide and exendin-4 in AD and PD patients. Therefore, GLP-1 analogues show great promise as a novel treatment for AD or other neurodegenerative conditions.     

The pharmacokinetics, pharmacodynamics, and tolerability of liraglutide, a once-daily human GLP-1 analogue, after multiple subcutaneous administration in healthy Chinese male subjects

In this single-center, randomized, double-blind, within dose group, placebo-controlled, dose escalation trial, the pharmacokinetics, pharmacodynamics, tolerability, and safety of liraglutide were evaluated in 37 healthy Chinese subjects. Subjects were randomized to 1 of 3 dose groups (0.6, 1.2, or 1.8 mg), and within each group, randomized to liraglutide or placebo (3:1). All subjects started at 0.6 mg liraglutide (or placebo) once daily for 1 week, and the dose was increased for dose groups 1.2 mg and 1.8 mg in weekly steps of 0.6 mg to the predefined dose targets. Liraglutide or placebo was administered once daily by subcutaneous injection for 21 consecutive days. The dose relationships of AUC(0-24h), C(max), and C(trough) at steady state do not deviate in a relevant way from dose proportionality. t(max) and t(1/2) were 8 hours (median) and 11.2 to 12.2 hours (geometric mean), respectively. The plasma glucose levels in all liraglutide groups were decreased, while reduced serum insulin level was observed in the 1.2- and 1.8-mg groups after liraglutide treatment. The most common adverse events were of gastrointestinal origin. Other adverse events were comparable between the liraglutide and placebo groups. Liraglutide was well tolerated in healthy Chinese subjects. No major safety concerns were identified.     

CORE糖尿病模型预测利拉鲁肽联合二甲双胍治疗2型糖尿病的长期健康结果

目的预测利拉鲁肽联用二甲双胍治疗2型糖尿病的长期健康结果。方法临床数据来源于国际多中心随机对照双盲临床试验NCT00614120,入组对象为来自中国、印度和韩国的2型糖尿病患者。选取利拉鲁肽1.2 mg·d~(-1)组(n=233)、利拉鲁肽1.8 mg·d~(-1)组(n=234)和格列美脲4.0 mg·d~(-1)组(n=231)的患者作为研究对象,每组患者均联用二甲双胍1.5～2.0 g·d~(-1),3组完成试验分别为187例、175例和215例。应用CORE糖尿病模型,输入16 wk临床试验前后患者机体参数改变值,模拟患者终身(30年)治疗健康结果。结果与格列美脲4.0 mg·d~(-1)组相比,利拉鲁肽1.2 mg·d~(-1)组患者背景型视网膜病变、终末期肾病、首次足溃疡和充血性心力衰竭死亡的累积发病率分别降低0.195%、0.086%、0.020%和0.528%,存活率增加了0.32%,预期寿命增加0.018年,质量调整生命年增加0.11年;利拉鲁肽1.8 mg·d~(-1)组以上4种并发症的累积发病率分别降低0.607%、0.116%、0.337%和0.626%,存活率增加了0.42%,预期寿命增加0.051年,质量调整生命年增加0.108年。敏感度分析结果显示,当模拟时间跨度分别设为10年、20年、35年,贴现率分别设置为0和5%时,与格列美脲4.0 mg·d~(-1)组的模拟结果相比,利拉鲁肽1.2 mg·d~(-1)组和1.8 mg·d~(-1)组均获得较长的存活率、预期寿命和质量调整生命年。结论与格列美脲联用二甲双胍相比,利拉鲁肽联用二甲双胍能够延缓并减少2型糖尿病患者并发症的发生,增加存活率、预期寿命与质量调整生命年。     

利拉鲁肽血药浓度变化对2型糖尿病合并动脉粥样硬化患者的临床影响评价

目的：探究2型糖尿病合并动脉粥样硬化患者血药利拉鲁肽浓度与其不良反应相关性,确定最佳利拉鲁肽血药浓度。方法：选取2018年2月至2019年2月在巴中市中心医院接受利拉鲁肽药物治疗的80例2型糖尿病合并动脉粥样硬化患者为研究对象。患者均在用药过程中检测利拉鲁肽血药浓度;治疗时间1年,根据血糖临床控制疗效标准确定显效、有效及无效组。分别统计各组患者治疗前、治疗后12个月不良反应及相关因子指标;ROC曲线分析降低患者不良反应的最佳血药利拉鲁肽的浓度。结果：HPLC检测利拉鲁肽血药浓度色谱图基线平稳,回归方程线性良好;显效患者42例,有效患者25例,无效患者13例,3组患者中位利拉鲁肽谷浓度分别为116.40,102.58,82.33 ng·mL^-1,显效组中位利拉鲁肽谷浓度最高,有效组次之,无效组最后,各组之间差异有统计学意义（P<0.05）。利拉鲁肽分成A组（<100 ng·mL^-1）、B组（100~120 ng·mL^-1）、C组（120~140 ng·mL^-1）及D组（>140 ng·mL^-1）4个浓度区间;当高于120 ng·mL^-1时,易发生低血糖症,差异有统计学意义（P<0.05）。利拉鲁肽血药浓度对FPG、PBG、HbA1c、TC、TG、LDL-C、ALT、Cr、AIP、IMT厚度、sICAM-1、sVCAM-1及颈动脉粥样硬化面积影响性大,差异有统计学意义（P<0.05）。ROC曲线分析利拉鲁肽最佳浓度为108.44 ng·mL^-1,差异有统计学意义（P<0.05）。结论：适度调整糖尿病合并动脉粥样硬化患者血液中利拉鲁肽浓度可以降低药物不良反应,提高临床疗效。     

Tolerability, pharmacokinetics and pharmacodynamics of the once-daily human GLP-1 analog liraglutide in Japanese healthy subjects: a randomized, double-blind, placebo-controlled dose-escalation study

OBJECTIVES: Liraglutide is a once-daily human GLP-1 analog being developed as a Type 2 diabetes therapy. A dose-finding study in Japanese patients with Type 2 diabetes showed liraglutide to produce dose-dependent decreases in HbA(1C). Studies have also shown that, with stepped dose titration, liraglutide is well tolerated. This double-blind trial in 24 healthy Japanese men assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of once-daily subcutaneous (s.c.) liraglutide using doses exceeding those previously studied, and using the stepped titration approach. MATERIALS AND METHODS: Subjects were randomized to three groups in each of which 6 received liraglutide, and 2 placebo for 35 consecutive days. The daily dose of liraglutide was stepped from 5 microg/kg (s.c. abdomen, morning) to 10 and then 15 microg/kg at 7-day intervals. One group remained at this dose, the others titrating further to 20 and 25 microg/kg, respectively. Subjects remained at the study site from Day 21 until the end of the trial, with standard meals served during inhouse periods. RESULTS: No safety issues, hypoglycemia, gastrointestinal or any other adverse events were observed. Liraglutide showed dose-dependent increases in the pharmacokinetic parameters of AUC0-24 h, C(max) and C(trough), while t(max), t(1/2) and V(d/F) were constant. Mean plasma glucose concentrations were similar across all treatment groups at baseline, but dose-dependent decreases in mean and postprandial plasma glucose were seen with liraglutide, although all values remained within normal ranges. There was a tendency for weight to decrease with liraglutide in comparison to placebo. CONCLUSIONS: Liraglutide appears to be well tolerated at doses of up to 25 microg/kg in Japanese subjects. Despite clear pharmacodynamic effects in this euglycemic cohort, a low risk for hypoglycemia was suggested together with good gastrointestinal tolerability.