GLP-1受体激动剂应用于肥胖治疗的研究进展

胰高血糖素样肽-1受体激动剂(GLP-1受体激动剂, GLP-1RA)最早用于治疗2型糖尿病,后来在应用过程中发现了其减轻体重的附加作用,其治疗肥胖的作用开始被逐渐认识和开发。GLP-1RA减轻体重的机制包括通过神经系统减少食物摄入以及对脂肪细胞的调控, GLP-1RA在临床试验中已被证明是安全有效的,其中利拉鲁肽和司美格鲁肽已通过临床试验并获美国食品药品监督管理局(FDA)批准作为治疗肥胖的药物上市,目前, GLP-1RA作为有前途的抗肥胖药物获得广泛关注且拥有开阔的发展前景。     

利拉鲁肽治疗胰岛素疗效欠佳的肥胖2型糖尿病的临床观察

目的:探讨利拉鲁肽治疗胰岛素疗效欠佳的肥胖2型糖尿病患者的临床效果。方法:选取皮下注射胰岛素血糖仍控制欠佳的27例肥胖2型糖尿病患者给予利拉鲁肽治疗。入选患者在原有治疗的基础上将胰岛素剂量暂减1/3,加用利拉鲁肽,起始剂量为每次0.6 mg,每日1次,皮下注射,比较患者治疗前及治疗16周后空腹血糖(FBG)、餐后2 h血糖(PBG)、糖化血红蛋白(HBAlc)、总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)、肝肾功能变化,并记录其体重、腰围、身体质量指数(BMI)、血压及加用利拉鲁肽前后胰岛素每日使用单位总数的变化。结果:加用利拉鲁肽治疗后FBG,PBG,HBAlc,TG,体重,BMI较应用原治疗方案明显下降,差异有统计学意义(P<0.05)。胰岛素用量较应用前明显减量,差异有统计学意义。TC,LDL-C和血压、谷丙转氨酶(ALT)、谷草转氨酶(AST)较前有所下降,但差异无统计学意义(P>0.05)。治疗16周后,部分患者皮下注射胰岛素逐渐减量直至停药,完全应用利拉鲁肽治疗,血糖控制达标,且无低血糖事件发生。结论:对肥胖的血糖控制欠佳的2型糖尿病患者给予利拉鲁肽治疗,可有效控制血糖,减轻患者体质量,改善胰岛素抵抗,增强胰岛β细胞功能,不易出现低血糖,利拉鲁肽更适合肥胖2型糖尿病患者。     

利拉鲁肽对肥胖大鼠脂肪组织内质网应激的影响

目的:研究利拉鲁肽对肥胖大鼠脂肪组织内质网应激的影响。方法:取大鼠分别用基础饲料和高脂饲料喂养8周后,分为正常对照组、肥胖组、肥胖-利拉鲁肽组,前2组大鼠腹腔注射0.9%氯化钠注射液,肥胖-利拉鲁肽组大鼠腹腔注射利拉鲁肽100μg/kg,每日2次,连续8周。末次给药后隔夜禁食处死大鼠,称体质量,取肾周及睾周脂肪组织,计算脂体比,检测脂肪组织中类蛋白质激酶激活的双链RNA的内质网激酶(PERK)、肌醇需求激酶1-α(IRE1-α)、C/EBP同源蛋白(CHOP)mRNA的表达和葡萄糖转运蛋白78(GRP78)的表达。结果:与正常对照组比较,肥胖组大鼠体质量、脂体比和脂肪组织中PERK、IRE1-α、CHOP mRNA及GRP78蛋白表达均明显升高(P<0.01);与肥胖组比较,肥胖-利拉鲁肽组大鼠上述指标均明显降低(P<0.01)。结论:利拉鲁肽可显著减轻肥胖大鼠体质量及内脏脂肪组织过度累积,并可缓解脂肪组织内质网应激。     

利拉鲁肽治疗新诊断肥胖2型糖尿病的疗效观察

目的观察利拉鲁肽在新诊断肥胖2型糖尿病中的疗效。方法选择50例新诊断的肥胖2型糖尿病患者用利拉鲁肽治疗12周,比较治疗前后血糖、BMI、血脂及胰岛素水平变化情况。结果利拉鲁肽治疗后,BMI及糖化血红蛋、白血糖、血脂明显降低,胰岛功能明显改善。结论肥胖2型糖尿病用利拉鲁肽治疗能有效控制血糖,减轻体质量,增加胰岛素敏感性,改善脂质代谢,是肥胖2型糖尿病的理想选择。     

香砂六君子汤治疗利拉鲁肽引起胃潴留的临床疗效

目的 观察香砂六君子汤治疗利拉鲁肽引起胃潴留的临床疗效.方法 选取2020年1—6月于杭州市临安区中医院内分泌科住院治疗的2型糖尿病(T2DM)肥胖患者46例,均使用利拉鲁肽治疗2周后胃镜检查提示胃潴留,根据随机数字表法分为观察组和对照组,各23例.对照组给予枸橼酸莫沙必利分散片和常规治疗,观察组在对照组基础上给予香砂...     

利拉鲁肽对2型糖尿病肥胖脂肪肝患者肝脏脂肪沉积的疗效分析

目的:研究利拉鲁肽对2型糖尿病肥胖脂肪肝患者肝脏脂肪沉积的疗效。方法:选取2017年3月～2018年12月某院收治的2型糖尿病肥胖脂肪肝患者75例作为研究对象,所有患者均给予利拉鲁肽注射剂治疗半年,观察患者治疗前、治疗12周后血糖、血脂及血压等相关指标、脂肪受控衰减参数(CAP)与肝脏硬度(LSM)等肝脂肪沉淀指标。结果:治疗后患者FPG、2hPBG、HbAle、TG、TC及LDL-C、SBP及DBP指标、CAP、LSM等指标明显下降,均低于治疗前,差异具有统计学意义(P0.05)。结论:利拉鲁肽治疗2型糖尿病肥胖脂肪肝患者能下调血糖、血脂与血压,且明显缓解患者肝脏脂肪沉淀。     

利拉鲁肽治疗2型糖尿病合并肥胖患者对胰岛素抵抗的影响

目的观察利拉鲁肽及胰岛素治疗2型糖尿病合并肥胖患者对胰岛素抵抗的影响。方法将本研究中70例2型糖尿病合并肥胖患者随机分为试验组和对照组各35例,试验组在利拉鲁肽治疗下和对照组在胰岛素治疗下,通过增加利拉鲁肽的使用量及胰岛素的使用量使两组患者在1个月内血糖控制达标,继续治疗6个月时为观察点1(即治疗6个月时),停试验组利拉鲁肽治疗,若患者血糖仍高,仍继续利拉鲁肽治疗,对照组持续胰岛素治疗1年后为观察终点(即治疗1.5年时)。对比治疗6个月时、1.5年后两组患者胰岛素抵抗的差异。观察指标有:HOMA-IR、HOMA-β、FINS、FBG、2h PG、Hb A1C、BMI、TG、LDL-C。结果试验组在治疗6个月后、1.5年后HOMA-IR水平较治疗前下降(P<0.05)。对照组在治疗6个月后、1.5年后HOMA-IR水平较治疗前无统计学意义(P>0.05)。试验组在治疗6个月后、1.5年后HOMA-IR水平差值较对照组变化显著(P<0.05)。结论利拉鲁肽治疗2型糖尿病合并肥胖患者对胰岛素抵抗减轻明显,减轻体重,改善BMI、血糖、血脂,不发生低血糖风险。     

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     

利拉鲁肽对初发2型糖尿病伴肥胖患者疗效及微炎症状态的影响研究

目的探究在初发2型糖尿病伴肥胖患者中应用利拉鲁肽对其的临床效果以及微炎症状态的改善。方法择取我院初发2型糖尿病并伴随肥胖的患者75例进行研究,按数字表法分为2组,对照组37例给予二甲双胍进行治疗,研究组38例应用利拉鲁肽进行治疗,观察两组患者治疗后机体指标改善情况与微炎症状态缓解情况。结果研究组与对照组治疗后微炎症状态均有改善,且研究组IL-6、TNF-α、ASAA等指标均明显低于对照组,差异显著,存在统计学差异(P<0.05);研究组治疗后Hb A1c、FBG、BMI等指标水平与对照组比较,均有明显降低,差异具有统计学意义(P<0.05)。结论应用利拉鲁肽治疗初发2型糖尿病伴有肥胖的患者,不仅能改善其空腹血糖水平与体质量指数,对其微炎症状态治疗效果也十分显著。     

口服降糖药治疗不佳肥胖2型糖尿病疗效观察

目的探讨对于口服降糖药治疗不佳的肥胖2型糖尿病患者采用利拉鲁肽进行治疗的临床效果。方法选择2010年12月至2012年1月收治的肥胖2型糖尿病住院患者31例。对所有患者在原口服降糖药治疗的基础上追加利拉鲁肽进行治疗。结果该组患者治疗后患者各项身体及血糖指标均较治疗前对比有显著差异,且结果（P〈0．05）具有统计学意义。结论对口服降糖药治疗不佳的肥胖2型糖尿病患者采用利拉鲁肽进行治疗其疗效显著。     

An evaluation of liraglutide including its efficacy and safety for the treatment of obesity

ABSTRACT

Introduction: The prevalence of obesity is increasing worldwide and associated conditions, particularly type 2 diabetes mellitus (T2DM), also show increasing prevalence. Lifestyle intervention should be the first line of management for obesity but additional pharmacotherapy is often required and bariatric surgery is appropriate in more severe cases. Drugs acting as glucagon-like peptide-1 receptor agonists (GLP-1RAs) developed for the management of T2DM reduce body weight and liraglutide is the first GLP-1RA to be approved for the treatment of obesity in patients with and without T2DM.

Areas covered: In this review of relevant published material, the authors summarize the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of liraglutide for the treatment of obesity.

Expert opinion: Liraglutide effectively reduces body weight and body fat through mechanisms involving reduced appetite and lowered energy intake, independent of its glucose-lowering effects. Like most of the other medications currently available for obesity, liraglutide has some common adverse effects, although generally not serious ones. Liraglutide has additional benefits in reducing cardiovascular events in patients with T2DM but the cost and the need for daily injections may limit its use in obesity. Newer GLP-1RAs, such as semaglutide, or other drugs in development for obesity may have advantages over liraglutide.     

Fixed-ratio combination therapy with GLP-1 receptor agonist liraglutide and insulin degludec in people with type 2 diabetes

Introduction: A fixed combination of basal insulin degludec and glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide (IDegLira; 50 units degludec/1.8 mg liraglutide) has been developed as a once daily injection for the treatment of type 2 diabetes (T2D). In the phase 3a trial programme ‘Dual action of liraglutide and insulin degludec in type 2 diabetes’ (DUAL?), five trials of 26 weeks duration and one trial of 32 weeks duration have evaluated the efficacy and safety of IDegLira compared with administration of insulin degludec, insulin glargine, liraglutide alone or placebo.

Areas covered: Combination therapy with IDegLira reduces HbA1c more than monotherapy with a GLP-1RA (liraglutide) or insulin (degludec or glargine). Combination therapy leads also to weight loss, or a stable body weight, with no increase in hypoglycaemia. Rates of adverse events did not differ between treatment groups; however, gastrointestinal side effects were fewer with IDegLira compared with liraglutide treatment alone. A limitation of the DUAL? development programme is that patients receiving basal insulin doses in excess of 50 units were excluded from the studies.

Expert commentary: In conclusion, IDegLira combines the clinical advantages of basal insulin and GLP-1RA treatment, and is a treatment strategy that could improve the management of patients with T2D.     

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.     

低碳水化合物饮食结合利拉鲁肽治疗2型糖尿病合并肥胖症的临床疗效

目的 探讨低碳水化合物饮食结合利拉鲁肽治疗2型糖尿病合并肥胖症的临床疗效.方法 将入组的60例2型糖尿病合并肥胖症患者随机分为2组,A组给予低碳水化合物饮食+利拉鲁肽干预治疗;B组给予低碳水化合物饮食,比较治疗后两组患者的体重、体重指数(BMI)、腰围、血脂(TC、TG、LDL、HDL)、脂肪率、内脏脂肪、空腹血糖(FBG)、餐后2小时血糖(2hPBG)、糖化血红蛋白(HbA1c)、空腹胰岛素(FINS)、胰岛素抵抗指数(HOMA-IR)等指标的变化情况.结果 A组治疗后体重降至(79.00±11.95) kg,腰围降至(97.48±10.78) cm,BMI降至(27.72±3.10) kg/m2,TC、TG、LDL分别降至[(4.42±0.86)、(1.57±0.54)、(3.12±0.61)mmol/L],FBG、2hPBG分别为[(5.42±0.86)、(7.26±0.84)mmol/L],HbA1c降至(5.93±0.63)％,FINS为(13.72±4.20)μIU/nl;B组治疗后体重降至(81.04±8.78)kg,腰围降至(99.32±8.08) cm,BMI降至(28.84±2.35) kg/m2,TC、TG、LDL分别降至[(4.74±0.72)、(1.72±1.09)、(3.25±0.84) mmol/L],FBG、2hPBG分别为[(5.84±0.79)、(7.99±1.04) mmol/L],HbAIc降至(6.11±0.87)％,FINS为(15.71±3.27)μIU/ml,A、B组两组治疗后比较,体重、BMI、腰围、TC、TG、LDL、脂肪率、内脏脂肪FBC、2hPBG、HbA1c、FINS、HOMA-IR比较差异有统计学意义(P＜0.05),但HDL干预后改善不显著(P＞0.05).结论 低碳水化合物饮食结合利拉鲁肽可明显降低患者体重,改善肥胖相关指标、降低血糖、改善胰岛素抵抗,且效果优于单纯低碳水化合物饮食.     

Rimonabant: new drug. Obesity: loss of a few kilos, many questions

(1) The treatment of obesity is based on calorie reduction and moderate physical activity. (2) Rimonabant, a CB1 cannabinoid receptor antagonist, is marketed in Europe for the adjuvant treatment of obesity, in combination with a low-calorie diet and physical exercise. (3) Four double-blind placebo-controlled trials involving about 6500 patients show that, when combined with a low-calorie diet, rimonabant 20 mg/day leads to an average weight loss of 4 or 5 kg more than placebo after one year of treatment. This is similar to the weight loss reported with orlistat (indirect comparison). Effects on the lipid profile are similar to those reported with sibutramine. (4) Rimonabant has not been shown to reduce morbidity or mortality. Patients regain the weight they lost within about 9 months after rimonabant withdrawal. (5) Three placebo-controlled trials have evaluated rimonabant in smoking cessation. The available results (a single conference abstract) are inconclusive. In early 2006 the FDA and the European Medicines Agency refused to approve rimonabant for this use. (6) Adverse effects mentioned in published clinical trials of rimonabant include mental disorders (anxiety, depression), neurological disorders (dizziness) and gastrointestinal disorders (nausea, diarrhoea). No postmarketing safety data are available. The possible long-term adverse effects of rimonabant are unknown. (7) In practice, when drug therapy is considered for weight loss, it seems unwise to prescribe rimonabant: this new drug has only limited symptomatic effects and its adverse effects, especially in the long term, are poorly documented.     

Effects of liraglutide and sibutramine on food intake,palatability, body weight and glucose tolerance in the gubra DIO-rats

Aim:

To validate the gubra DIO-rats as a useful animal model of human obesity.

Methods:

The gubra diet-induced obesity (DIO) rat model was based on male Sprague-Dawley rats with ad libitum access to regular chow and a palatable diet rich in fat and sugar. To evaluate the versatility of the gubra DIO-rats as a valid model of human obesity syndrome, the efficacy of 2 weight loss compounds liraglutide and sibutramine with different mechanisms of action were examined in 7-month-old gubra DIO-rats. Liraglutide (200 μg/kg, sc) was administered bi-daily, and sibutramine (5 mg/kg, po) was administered once daily for 23 d.

Results:

Both the compounds effectively reduced the food intake, body weight and total fat mass as measured by nuclear magnetic resonance. Whereas the 5-HT reuptake inhibitor/5-HT receptor agonist sibutramine reduced the intake of both chow and the gubra-diet, the GLP-1 analogue liraglutide predominantly reduced the intake of the highly palatable diet, indicating a shift in food preference. Sibutramine lowered the insulin sensitivity index, primarily via reductions in glucose-stimulated insulin secretion.

Conclusion:

This animal model responds well to 2 weight loss compounds with different mechanisms of action. Moreover, the gubra DIO-rat can be particularly useful for the testing of compounds with potential effects on diet preference.     

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.     

Anti-obesity drugs: a review about their effects and their safety

INTRODUCTION: Amphetamines, rimonabant and sibutramine licenses as anti-obesity drugs have been withdrawn because of their adverse effects. In fact, orlistat is the only available long-term treatment for obesity. AREAS COVERED: The efficacy and safety of long-term drug therapy is very important in the management obesity; for this reason, the authors decided to conduct a review on the efficacy and safety of current, past and future pharmacotherapies for weight loss. EXPERT OPINION: Orlistat is a good choice for the treatment of obesity, because of its safety on cardiovascular events and its positive effects on diabetic control, even if it is not as effective as rimonabant or sibutramine in reducing body weight. Regarding emerging anti-obesity therapies in diabetic people, we currently have drugs that have already been marketed including the glucagon-like peptide-1 (GLP-1) receptor agonists exenatide and liraglutide; other than improving glycemic control, they also suppress appetite reducing body weight. Moreover, some other drugs are currently in study such as tesofensine, phentermine + topiramate, bupropion + naltrexone and bupropion + zonisamide. Furthermore, several additional gut hormone-based treatments for obesity are under investigation in Phase II and III clinical trials, with particular focus on ghrelin, peptide YY, pancreatic polypeptide, amylin and oxyntomodulin.     

Liraglutide: a review of its use in the management of type 2 diabetes mellitus

Liraglutide (Victoza?) is a subcutaneously administered glucagon-like peptide-1 (GLP-1) receptor agonist produced by recombinant DNA technology and used as an adjunct to diet and exercise in the treatment of adults with type 2 diabetes mellitus. This article reviews the clinical efficacy and tolerability of liraglutide in adults with type 2 diabetes, and provides a summary of its pharmacological properties. Recently published pharmacoeconomic studies of liraglutide are also reviewed. Administered subcutaneously, liraglutide (usually 1.2 or 1.8?mg once daily) generally produced greater improvements in glycaemic control than active comparators or placebo when administered as monotherapy or in combination with one or two oral antidiabetic drugs (OADs) to adults with type 2 diabetes in numerous randomized, controlled phase III trials. These included six trials in the LEAD trial programme that was designed to evaluate the efficacy and safety of liraglutide across a continuum of antihyperglycaemic management for patients with type 2 diabetes. Liraglutide was generally well tolerated, with a low risk of hypoglycaemia evident, in the phase III trials. The most common adverse events were gastrointestinal and included nausea and diarrhoea; most events were mild to moderate in severity and decreased in incidence over time. In conclusion, liraglutide has an important place in the management of adults with type 2 diabetes across a continuum of care. As well as providing effective glycaemic control, liraglutide improves pancreatic β-cell function and leads to bodyweight loss, thereby addressing some of the unmet needs of patients treated with traditional OADs.     

利拉鲁肽治疗腹型肥胖2型糖尿病患者的临床观察

目的：观察腹型肥胖的2型糖尿病患者应用利拉鲁肽治疗的疗效及其安全性。方法筛选20例符合入选标准的腹型肥胖2型糖尿病患者,在原有降糖药物基础上,加用利拉鲁肽0.6~1.8 mg皮下注射,1次/d。治疗随访观察12周,比较治疗前后空腹血糖（FPG）、餐后2 h血糖（2 hPG）、空腹及餐后2 h胰岛素及C肽、糖化血红蛋白（HbA1c）、体重指数（BMI）、腰围、血压、血脂的变化情况。观察并记录其不良反应。结果对采用利拉鲁肽治疗患者前后的空腹血糖、餐后2h血糖、糖化血红蛋白、体重、BMI、腰围、HOMA-β及HOMA-IR指数相互比较,其差异有统计学意义（ P〈0.05）。观察到有少数患者出现不良反应,但均能耐受治疗。结论在原有口服降糖药物基础上加用利拉鲁肽能有效降低血糖,显著降低患者体重,并能改善胰岛β细胞功能,降低血脂、血压,且发生低血糖的风险低,是2型糖尿病患者治疗的新选择。