Liraglutide treatment improves endothelial function in the Ldlr−/− mouse model of atherosclerosis and affects genes involved in vascular remodelling and inflammation

Recent clinical intervention studies have shown that the GLP1 analogue liraglutide lowers cardiovascular risk, but the underlying mechanism has not yet been fully elucidated. This study investigated the effects of liraglutide on endothelial function in the Ldlr?/? mouse model. Mice (n = 12/group) were fed Western diet (WD) or chow for 12 weeks followed by 4 weeks of treatment with liraglutide (1 mg/kg/day) or vehicle subcutaneously. Weight loss, blood lipid content, plaque burden, vasomotor function of the aorta and gene expression pattern in aorta and brachiocephalic artery were monitored. Liraglutide treatment significantly induced weight loss (P < .0001), decreased blood triglycerides (P < .0001) and total cholesterol (P < .0001) in WD‐fed mice but did not decrease plaque burden. Liraglutide also improved endothelium‐mediated dilation of the distal thoracis aorta (P = .0067), but it did not affect phenylephrine or sodium nitroprusside responses. Fluidigm analyses of 96 genes showed significantly altered expression of seven genes related to inflammation, vascular smooth muscle cells and extracellular matrix composition in liraglutide‐treated animals. We conclude that treatment with liraglutide decreased endothelial dysfunction and that this could be linked to decreased inflammation or regulation of vascular remodelling.     

利拉鲁肽对大鼠心肌微血管内皮细胞缺氧复氧损伤的影响

 目的 探究胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)类似物利拉鲁肽(GLP-1 analogue,Liraglutide)对大鼠心肌微血管内皮细胞(cardiac microvascular endothelial cells, CMEC)缺氧复氧损伤的影响。方法 双酶消化法体外分离培养SD大鼠CMEC,实验的细胞分为正常对照组、Liraglutide(0~100 nM)组、H/R组、H/R+Liraglutide组。建立缺氧复氧模型(hypoxia/reoxygenation model,H/R)诱导的细胞氧化应激凋亡模型,流式细胞学检测细胞凋亡率,DCFHDA荧光探针检测胞内ROS的变化免疫荧光染色和Western Blot检测XO、caspase3等蛋白分子的表达情况,通过比较各组中XO、ROS以及凋亡相关蛋白caspase3的表达情况阐明Liraglutide在抗细胞氧化应激过程中的保护作用机制。结果 与正常对照组细胞相比,H/R模型条件诱导细胞中XO表达增加,生成过量ROS及凋亡蛋白的表达,最终导致凋亡细胞数量显著提高至20.66%±1.30%。Liraglutide预处理12 h抑制了H/R诱导的XO的激活,最终降低胞浆过量ROS并将细胞的凋亡数量降低至8.36±1.19%。结论 H/R模型导致XO-ROS激活,生成过量胞浆ROS,最终介导了CMEC的线粒体凋亡通路激活,而予以Liraglutide预处理可以逆转上述过程。     

影响患者利拉鲁肽降糖疗效因素的回顾分析

目的：为促进利拉鲁肽合理应用提供依据,回顾性分析影响2型糖尿病（type 2 diabetic mellitus,T2DM）患者使用利拉鲁肽降糖疗效的因素。方法：以华东医院2019年1月至2020年8月间使用利拉鲁肽的T2DM患者为研究对象,采用回顾性分析方法,观察和比较患者首次使用利拉鲁肽3个月及以上前后的糖化血红蛋白（HbA1c）、BMI （身体质量指数）和体质量的差异,分成疗效达标（治疗后HbA1c<7%或下降幅度>1%）和疗效未达标组。通过独立样本t检验和卡方检验分析组间基线数据差异,包括基本信息、检验指标,还有合并用药情况,Logistic回归法筛选出降糖疗效的影响因素。结果：在所有纳入研究的患者中,HbA1c、BMI和体质量指标分别下降（1.13±2.04）%、（0.77±1.48） kg·m^-2、（2.41±4.04） kg。140例（60.9%）患者达到预期的降糖目标,90例（39.1%）未达标。研究还发现2组患者的年龄、DM病程、体质量、性别和联用胰岛素的差异具有统计学意义（P=0.005、P=0.000、P=0.044、P=0.016、P=0.011）,Logistic回归分析显示年龄和联用胰岛素对利拉鲁肽降糖疗效影响有显著意义[P=0.004,OR=0.907,95% CI （0.848,0.969）;P=0.000,OR=0.151,95% CI （0.058,0.396）]。结论：首次使用利拉鲁肽时,患者的年龄、DM病程、体质量、性别和联用胰岛素与其降糖疗效达标相关,年龄和联用胰岛素是影响利拉鲁肽疗效的主要因素。临床个体化用药时,可评估以上因素对疗效的影响。     

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.     

2型糖尿病肾病患者利拉鲁肽干预后血清Vaspin、Nesfatin-1水平变化及与炎症因子水平的关系

目的 探讨分析2型糖尿病（T2DM）肾病患者利拉鲁肽干预后血清Vaspin、Nesfatin-1水平变化及与炎症因子水平的关系。方法 回顾性分析2020年4月—2022年8月广西壮族自治区民族医院收治的214例DN患者的临床资料。其中进行常规治疗措施的105例DN患者作为对照组,利拉鲁肽联合常规治疗措施的109例DN患者作为研究组,两组均治疗3个月后观察疗效。对比两组治疗前后血糖、血脂、肾功能代谢指标,比较两组治疗前后血清Vaspin、Nesfatin-1水平及炎症因子的变化,采用Pearson法分析血清Vaspin、Nesfatin-1水平与炎症因子水平的相关性。结果 研究组治疗前后空腹血糖、餐后2 h血糖、糖化血红蛋白、胰岛素抵抗指数、胰岛β-细胞功能指数的差值高于对照组（P <0.05）。研究组治疗前后的甘油三酯、总胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇的差值高于对照组（P <0.05）。研究组治疗前后血肌酐、血尿素氮、尿白蛋白/肌酐比值的差值高于对照组（P <0.05）。研究组治疗前后的Vaspin、Nesfatin-1的差值高于对照组（P <0...     

Liraglutide and cardiovascular outcomes in adults with overweight or obesity: A post hoc analysis from SCALE randomized controlled trials

The cardiovascular safety of liraglutide, a glucagon‐like peptide‐1 receptor agonist approved for weight management at a dose of 3.0 mg, was evaluated post hoc using data from 5908 participants in 5 randomized, double‐blind, placebo‐controlled clinical trials. Participants were randomized to liraglutide or a comparator group (placebo or orlistat). The objective was to evaluate whether cardiovascular risk was increased with liraglutide treatment. The primary composite outcome of this time‐to‐event analysis was the first occurrence of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke. These cardiovascular events were adjudicated prospectively for three of the trials and retrospectively for two trials by an event adjudication committee. The primary outcome was analyzed using a Cox proportional hazards model, stratified by trial. With liraglutide 3.0 mg, 8 participants had positively adjudicated cardiovascular events (1.54 events/1000 person‐years) compared to 10 participants in the comparators group (3.65 events/1000 person‐years). The hazard ratio for liraglutide 3.0 mg compared to comparators was 0.42 (95% confidence interval, 0.17‐1.08). In this analysis, liraglutide 3.0 mg treatment was not associated with excess cardiovascular risk. However, the wide confidence intervals and retrospective adjudication of events in two of the trials are limitations of the analysis.     

利拉鲁肽极化M2型巨噬细胞改善非酒精性脂肪肝的机制

目的：探讨利拉鲁肽改善2型糖尿病伴随的非酒精性脂肪肝（NAFLD）的作用机制。方法：小鼠随机分为正常组、模型组和利拉鲁肽组3组,每组15只。模型组和利拉鲁肽组采用高糖高脂饲料联合小剂量链脲佐菌素的方法,构建2型糖尿病NAFLD的小鼠模型,利拉鲁肽组皮下注射利拉鲁肽（100 μg/kg）,每日1次,连续4周。检测各组小鼠的体质量、肝指数、ALT、AST和TG指标;HE染色及油红O染色观察肝组织病理改变;ELISA法检测血清中IL-4和IL-10的含量;流式细胞术检测M2型巨噬细胞比例;RT-PCR检测IL-4、IL-10、CD206、CD301、MGL-1、MGL-2和Arg-1 mRNA表达。结果：与模型组比,利拉鲁肽组小鼠体质量、肝指数、TG、AST和ALT均明显下降,肝组织中脂肪变性减轻,M2型巨噬细胞比例显著上升（P＜0.001）,IL-4、IL-10蛋白表达显著上升（P＜0.05）,IL-4、IL-10、CD206、CD301、MGL-1、MGL-2和Arg-1 mRNA表达也显著上升（P＜0.01）。结论：利拉鲁肽对2型糖尿病NAFLD具有保护作用,其机制可能与促进IL-4和IL-10的表达,极化M2型巨噬细胞有关。     

Liraglutide: once-daily GLP-1 agonist for the treatment of type 2 diabetes

What is known and Objective: The prevalence of diabetes is increasing worldwide. Over the recent years, new discoveries have led to the development of new pharmacological agents targeting the incretin hormones gastric inhibitory peptide (GIP) and glucagon‐like peptide‐1 (GLP‐1). These agents, called incretin‐mimetics, are the newest agents added to the diabetes treatment options. The purpose of this article is to review the relevant literature on the chemistry, pharmacology, pharmacokinetics, metabolism, clinical trials, safety, drug interactions and place in therapy of liraglutide in the treatment of type 2 diabetes. Methods: An extensive search of the literature was performed with liraglutide and NN2211 as key terms. This article presents a review of the literature related to the chemistry, pharmacology, pharmacokinetics, drug interactions and safety and efficacy of liraglutide. Results and Discussion: Liraglutide, a subcutaneously administered GLP‐1 agonist, displays phamacodynamic and pharmacokinetic properties that allow for once‐daily administration. The agent has been shown to be efficacious as monotherapy, as well as in combination with glimperide, metformin and/or rosiglitazone, reducing glycoslyated haemoglobin (A1C) between 0·84% and 1·5%. The primary adverse event reported with liraglutide is transient nausea. What is new and conclusion: Liraglutide has been well studied in dual and triple combination therapies with sulfonylureas, metformin and rosiglitazone and appears safe and effective. For patients who cannot tolerate first‐line agents, metformin, insulin and sulfonylureas, liraglutide is a reasonable treatment option.     

Effects of liraglutide on cardiovascular risk factors in patients with type 1 diabetes

We investigated the short‐term effect of adding liraglutide 1.8 mg once daily to insulin treatment on cardiovascular risk factors in patients with type 1 diabetes. In total, 100 overweight (BMI ≥25 kg/m²) adult patients (age ≥18 years) with type 1 diabetes and HbA1c ≥ 8% (64 mmol/mol) were randomized to liraglutide 1.8 mg or placebo added to insulin treatment in a 24‐week double‐blinded, placebo‐controlled trial. At baseline and after 24 weeks of treatment, 24‐hour blood pressure and heart rate, pulse pressure, pulse wave velocity and carotid intima‐media thickness were evaluated. Compared with placebo, liraglutide increased 24‐hour heart rate by 4.6 beats per minute (BPM); P = .0015, daytime heart rate by 3.7; P = .0240 and night‐time heart rate by 7.5 BPM; P < .001 after 24 weeks. Diastolic nocturnal blood pressure increased by 4 mm Hg; P = .0362 in the liraglutide group compared with placebo. In conclusion, in patients with long‐standing type 1 diabetes, liraglutide as add‐on to insulin increased heart rate and did not improve other cardiovascular risk factors after 24 weeks of treatment.