利拉鲁肽对糖尿病心肌病大鼠心功能及心肌代谢异常的改善作用

目的]研究利拉鲁肽对糖尿病心肌病(DCM)大鼠心肌代谢物及相关代谢通路的影响。 [方法]3周龄SPF级雄性SD大鼠60只,随机抽取10只作为正常对照组,其余均采用腹腔注射链脲佐菌素联合高糖高脂饮食法建立DCM大鼠模型。DCM造模成功大鼠36只,随机分为DCM模型组(DCM组)、低剂量利拉鲁肽治疗组(LL组)、高剂量利拉鲁肽治疗组(HL组),每组各12只。LL组(100 μg/kg)和HL组(200 μg/kg)分别给予利拉鲁肽腹腔注射,每日一次,干预12周后,经超声心动图检测心功能后麻醉处死大鼠,并取心脏组织进行代谢组学检测,筛选并富集与利拉鲁肽改善DCM大鼠心肌代谢可能有关的差异代谢物及相关通路。 [结果]超声结果显示,与正常对照组相比,DCM组左心室射血分数(LVEF)、左心室短轴缩短率(LVFS)显著降低,左心室舒张早期最大血流/二尖瓣心房收缩期最大血流比值(E/A)明显升高(P＜0.05)。与DCM组相比,LL组和HL组大鼠LVEF、LVFS明显升高,E/A比值显著降低(P＜0.05),提示LL组和HL组左心室收缩和舒张功能受损明显减轻。代谢组学检测共发现395种代谢物,其中DCM组与正常对照组、LL组与DCM组、HL组与DCM组各自富集出组间差异代谢物分别为239种、116种、187种,代谢通路分别为13条、6条、20条。以上三组共交集出关键差异代谢物29种,主要涉及3条代谢通路(P＜0.05),包括胆碱代谢通路、咖啡因代谢通路以及缬氨酸、亮氨酸和异亮氨酸生物合成通路,其中胆碱代谢通路差异最为显著。 [结论]利拉鲁肽可明显改善DCM大鼠心功能及心肌代谢异常,其中胆碱代谢通路可能在利拉鲁肽改善心肌代谢保护心脏功能过程中起到关键作用。     

利拉鲁肽对2型糖尿病轻度认知功能障碍患者炎性因子及认知功能的影响

目的：探讨利拉鲁肽对2型糖尿病轻度认知功能障碍患者炎性因子及认知功能的影响。方法：选取使用门冬胰岛素30治疗的2型糖尿病（T2DM）伴轻度认知功能障碍（MCI）患者86例，分为治疗组（43例）与对照组（43例），疗程1年。对照组维持原门冬胰岛素30治疗，治疗组改为利拉鲁肽治疗。治疗前和治疗12，24，36，48周末测定患者身高、体质量、血压水平，计算体重指数（BMI），并记录血糖达标[糖化血红蛋白（Hb A1c）≤ 8%]、低血糖情况、实验室检查（血糖、糖化血红蛋白、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、肿瘤坏死因子（TNF-α）水平），并采用简易精神状态量表（MMSE）、蒙特利尔认知量表（MoCA）评估认知功能。结果：对照组和治疗组各完成42例和41例。治疗12，24，36，48周末，治疗组IL-1β、IL-6、TNF-α水平显著低于对照组（P< 0.01），36，48周末HbA1c水平低于对照组（P<0.05），MMSE及MoCA量表评分高于对照组（P<0.05）。对照组和治疗组血糖达标率分别为76.19%（32/42）和82.93%（34/41），痴呆发生率均为0，差异均无显著意义（P>0.05）；低血糖发生率分别为59.52%（25/42）和7.32%（3/41），治疗组低于对照组（P<0.01）。结论：和门冬胰岛素30相比，利拉鲁肽治疗2型糖尿病MCI患者，能更好地控制FPG、2hPG、HbA1c，降低炎性因子水平（IL-1β、IL-6、TNF-α），低血糖发生率更低，并能改善患者认知功能。     

GLP-1 receptor agonists for prevention of cardiorenal outcomes in type 2 diabetes: An updated meta-analysis including the REWIND and PIONEER 6 trials

A meta-analysis of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RAs) and placebo concerning cardiorenal outcomes in patients with type 2 diabetes (T2D) is presented. An electronic search without language restrictions up to June 15, 2019 was conducted to determine eligible trials. A meta-analysis of available trial data was undertaken, using a random-effects model to calculate overall hazard ratios (HRs) and 95% confidence intervals (CIs). Data from seven CVOTs, comprising 56 004 patients (68.9% with established cardiovascular disease) were included. GLP-1RA reduced major cardiovascular events (MACE) by 13% (HR, 0.87; 95% CI, 0.80–0.96; P = 0.011) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (CVD) (P = 0.220). GLP-1RA also reduced the risk of cardiovascular death by 12%, of non-fatal stroke by 16%, of hospitalization for heart failure by 9%, of all-cause mortality by 11%, and the broad composite kidney outcome by 17%; the latter appeared to be driven only by a reduction in macroalbuminuria (HR, 0.76 [0.68–0.86]; P = 0.003). GLP-1RAs have moderate benefits concerning MACE, and also reduce hospitalization for heart failure and all-cause mortality; they also robustly reduce the incidence of macroalbuminuria, without affecting the progression of diabetic renal disease.     

二甲双胍与利拉鲁肽对超重2型糖尿病患者肠道菌群的影响

目的　探究二甲双胍与利拉鲁肽对超重2型糖尿病患者肠道菌群结构和功能的影响。方法　选取2018年1月—2019年6月我院90例超重2型糖尿病患者作为研究对象,采用完全随机原则将其分为治疗方案不同的3组,分别为Met组（单用二甲双胍治疗）、Lira组（单用利拉鲁肽治疗）和Ct组（联合二甲双胍与利拉鲁肽治疗）,采用高通量测序与生物信息学相结合的方法,比较肠道菌群结构和功能的组间差异。结果　Met、Lira、Ct 3组治疗后身体质量指数（body mass index, BMI）分别为（31.48±1.21）kg/m2、（28.92±1.30）kg/m2、（28.29±1.22）kg/m2,均较治疗前有所降低（P均＜0.05）。Lira组和Ct组治疗后BMI、IL-6、TNF-α、TG和TC的下降幅度均大于Met组（P均＜0.05）;Met组、Ct组肠道菌群多样性显著增加,Lira组肠道菌群多样性显著降低（P均＜0.01）。结论　联合二甲双胍与利拉鲁肽治疗超重2型糖尿病患者优于单用利拉鲁肽与单用二甲双胍,但联合用药对肠道菌群影响较大。     

二甲双胍联合利拉鲁肽对多囊卵巢大鼠炎性因子及性激素水平的影响

 目的 研究二甲双胍联合利拉鲁肽对经脱氢表雄酮诱导的多囊卵巢(PCOS)大鼠外周血清炎性因子及性激素水平的影响。方法 将80只PCOS(经脱氢表雄酮诱导)大鼠随机分为对照组(n=40)和干预组(n=40)。对照组大鼠每天给予二甲双胍(270 mg/kg·d)灌胃,干预组大鼠每天给予二甲双胍(270 mg/kg·d)灌胃+利拉鲁肽(5 μg/kg·d)皮下注射, 连续治疗28 d。治疗结束后测定两组大鼠外周血清炎性因子[白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)、C反应蛋白(CRP)]、激素水平[卵泡雌激素(FSH)、黄体生成素(LH)、雌激素(E₂)、睾酮(T)]。结果 治疗后两组大鼠外周血清IL-6(23.88±7.32)pg/ml、TNF-α(13.24±2.23)ng/L、CRP(1.10±0.19)mg/L、LH(6.57±1.37)mIU/ml、LH/FSH(1.17±0.28)、E₂(1.11±0.18)pg/ml、T(12.21±1.32)ng/dL均较治疗前有所降低且差异有统计学意义(P<0.05),干预组低于对照组,差异有统计学意义(P<0.05);治疗后两组大鼠FSH (5.63±0.77) mIU/ml较治疗前升高,差异有统计学意义(P<0.05),干预组高于对照组,差异有统计学意义(P<0.05)。结论 二甲双胍联合利拉鲁肽能很好的降低PCOS大鼠外周血清炎性因子浓度,改善激素水平,为临床实践提供一定的指导。     

Liraglutide 3.0 mg for weight management: weight-loss dependent and independent effects

Objective: As an adjunct to a reduced-calorie diet and increased physical activity, treatment with liraglutide 3.0?mg for weight management provides a statistically significant and clinically meaningful weight loss of 5.7%–8.0% compared to 1.6%–2.6% with placebo. The objective of this post hoc analysis was to quantify the relative contribution of weight loss to the treatment effects of liraglutide 3.0?mg on key efficacy endpoints.

Methods: The analysis utilized data from 4725 participants across three randomized, placebo-controlled, double-blind trials that evaluated the efficacy and safety of liraglutide 3.0?mg versus placebo, as an adjunct to a reduced-calorie diet and increased physical activity (ClinicalTrials.gov identifiers: NCT01272219, NCT01272232 and NCT01557166). The duration of two of the trials was 56 weeks; one trial was of 32 weeks’ duration. A mediation analysis was performed, which ranked the relative contribution of weight loss to the treatment effects of liraglutide 3.0?mg on key cardiometabolic efficacy endpoints, Apnea–Hypopnea Index (AHI) and health-related quality of life (QoL). A limitation of this type of analysis is that it cannot conclusively prove a causal relationship.

Results: In individuals without type 2 diabetes mellitus (T2DM), endpoints predominantly driven by liraglutide-induced weight loss included waist circumference, diastolic blood pressure, triglycerides, high density lipoprotein cholesterol, AHI, and Impact of Weight on Quality of Life–Lite total and physical function scores. Endpoints predominantly independent of weight loss included the glycemic endpoints hemoglobin A1c and fasting plasma glucose in individuals with and without T2DM. Regardless of the degree of dependence on weight loss according to the mediation analysis, greater weight loss was associated with greater improvement in all endpoints.

Conclusion: Treatment with liraglutide 3.0?mg contributes to improved cardiometabolic parameters, AHI and health-related QoL through both weight-loss dependent and weight-loss independent mechanisms.     

Cardiovascular safety of liraglutide for the treatment of type 2 diabetes

Introduction: Liraglutide is a GLP-1 RA that is an option for treatment of T2DM. Typical of all new glucose-lowering agents, its CV safety profile is of great interest.

Areas covered: This article outlines the efficacy of the GLP-1 RA liraglutide from RCTs, moving through the pivotal phase 3 LEAD trials, and subsequent meta-analyses to assess CV safety. This review describes evolution of regulatory requirements to obtain safety information through dedicated CVOTs.

Expert opinion: Since the FDA mandated that CV outcomes for new diabetes therapies should be assessed via a dedicated CVOT, opinion of their utility in T2DM evolved from cynicism through to enthusiasm. In LEADER, liraglutide became the second modern glucose-lowering agent to demonstrate significant CV benefit. CVOTs are now providing important answers, highlighting the CV benefits of modern glucose-lowering agents, but also raising several questions, notably whether the effects seen with liraglutide and empagliflozin are class-effects or are unique to these molecules. Furthermore it is unknown if these results in patients with high CV risk are applicable to all patients with T2DM, and should be incorporated into new treatment guidelines. In our view it’s prudent to suggest that CVOT findings cannot currently be extrapolated to the whole T2DM population.     

Efficacy and safety of fixed-ratio combination of insulin degludec and liraglutide (IDegLira) for the treatment of type 2 diabetes

Introduction: Type 2 diabetes (T2D) is a progressive disease with increasing prevalence in most countries. The majority of patients with T2D have inadequate glycaemic control, which increases the risk of diabetic complications later in life. New therapies with improved safety profiles are required to tackle the progressive nature of T2D.

Areas covered: The efficacy and safety profile of IDegLira – a once-daily, fixed-ratio combination of insulin degludec and liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), for the treatment of T2D – has been extensively evaluated. IDegLira’s phase 3 clinical trial programme builds upon the clinical programmes of its mono-components, and their cardiovascular outcomes trials. The results are described here, focusing on different patient populations and compared with alternative insulin regimens.

Expert opinion: IDegLira provides superior glycaemic control and mitigates the primary adverse effects associated with insulin therapy (weight gain and hypoglycaemia) and GLP-1RAs (gastrointestinal side effects) with no indication of additive effects. Accordingly, co-formulations such as IDegLira are likely to be increasingly preferred over stepwise addition and titration of the individual agents in the management of T2D.     

脂联素45 T/G基因多态性对利拉鲁肽治疗2型糖尿病患者的临床疗效

目的:研究脂联素45(APM1-45)T/G基因遗传变异对利拉鲁肽治疗2型糖尿病(T2DM)患者的临床疗效以及对T2DM易感性的影响。方法:选取2017年7月至2019年11月期间海口市第三人民医院收治的T2DM患者共95例作为研究对象,均给予利拉鲁肽进行为期14周的治疗,记录不同基因型患者治疗前后的血糖水平、BMI指数和mRNA相对表达等指标变化,统计不良反应的发生情况。结果:APM1-45(rs2241766)位点在研究人群中的基因分布频率为:TT型46例(48.42%),TG型43例(45.26%),GG型6例(6.32%),三种基因型分布频率符合哈迪温伯格平衡(P=0.328)。治疗后,各组患者的餐后2小时血糖(2h PG)、糖化血红蛋白(HbA1c)、空腹血糖(FPG)和BMI相关指标相比治疗前均下降明显,且存在统计学差异(P<0.05);TT基因型患者的各项指标与TG/GG基因型患者相比,下降更多,但二者相比不存在统计学差异(P>0.05)。mRNA相对表达方面,相对于TG/GG基因型患者,TT基因型患者的mRNA的相对表达明显偏低,二者差异具有统计学意义(P<0.05)。患者整体不良反应发生情况较少,各组之间无统计学差异。结论:对2型糖尿病患者,利拉鲁肽进行治疗具有明显效果,在显著降低血糖水平、控制体质量的同时,不良反应发生率较低,G等位基因与T2DM易感性存在一定的相关性,而T等位基因携带者对利拉鲁肽的治疗表现出更优的效果。     

Pharmacotherapy in obesity: a systematic review and meta-analysis of randomized controlled trials of anti-obesity drugs

ABSTRACT

Introduction: Obesity poses a significant increase in morbidity and mortality and thus five anti-obesity drugs have been approved currently by US FDA. Several phase 3 trials have shown a significant improvement in cardio-metabolic profile including significant weight reduction with these agents compared to placebo.

Areas covered: We systematically searched the database of PubMed, Embase, The Cochrane Library and The ClinicalTrials.gov up to 30 September 2019 and retrieved all the randomized controlled trials (RCTs) that were conducted with these five drugs for ≥1 year and explicitly reported their efficacy versus placebo. Subsequently, we have conducted the meta-analysis to primarily study the effect of these anti-obesity drugs on weight reduction. We additionally reviewed the effect of these drugs on other cardio-metabolic parameters including key adverse events.

Expert opinion: This meta-analysis finds a significant reduction in body weight with orlistat (N = 10,435; ? ?3.07 Kg, 95% CI, ?3.76 to ?2.37), phentermine plus topiramate (N = 2985; ? ?9.77 Kg; 95% CI, ?11.73 to ?7.81), lorcaserin (N = 16,856; ? ?3.08 Kg; 95% CI, –3.49 to –2.66), naltrexone plus bupropion (N = 3239; ? ?4.39 Kg; 95% CI, ?5.05 to ?3.72) and liraglutide (N = 4978; ? ?5.25 Kg; 95% CI, ?6.17 to ?4.32), compared to placebo (all p < 0.00001).