利拉鲁肽治疗超重或肥胖超药品说明书用法的循证评价

目的运用循证药学的方法评价利拉鲁肽用于治疗超重或肥胖的临床证据,为超说明书用药循证评价提供参考。方法系统检索Pub Med、EMBASE、Cochrane Library、CNKI、万方数据库,国外药品说明书及MICROMEDEX■循证数据库,由两名评价者独立的根据纳入排除标准筛选文章,评价文献质量,提取数据并分析。结果共纳入FDA与EMA药品说明书、循证数据库MICROMEDEX■、5项国内外指南与6篇系统评价/Meta分析。利拉鲁肽与安慰剂相比可以显著降低肥胖患者的体重和BMI、提高体重减轻至少5%的患者比例。安全性方面利拉鲁肽由于不良反应而停止治疗的比率显著高于安慰剂,其中胃肠道不良反应发生率较高。结论利拉鲁肽用于治疗BMI>27 kg·m^-2合并至少一项肥胖并发症、或者BMI>30 kg·m^-2的单纯性肥胖的患者具有较好的疗效,但是需要注意患者胃肠道不良反应。     

The limits and challenges of antiobesity pharmacotherapy

ABSTRACT

Introduction

Pharmacotherapy is a useful adjunct when patients with obesity are unable to achieve adequate benefit from lifestyle interventions.     

The effect of glucagon-like peptide-1 receptor agonists liraglutide and semaglutide on cardiovascular and renal outcomes across baseline blood pressure categories: Analysis of the LEADER and SUSTAIN 6 trials

It is unknown if the cardioprotective and renal effects of glucagon-like peptide-1 receptor agonists are consistent across blood pressure (BP) categories in patients with type 2 diabetes and at high risk of cardiovascular events. Using data from the LEADER (9340 patients) and SUSTAIN 6 (3297 patients) trials, we evaluated post hoc the cardiorenal effect of liraglutide and semaglutide on major adverse cardiovascular events (MACE) and nephropathy by baseline BP categories using a Cox proportional hazards model (treatment and subgroup as factors; adjusted for cardiorenal risk factors). Data from the two trials were analysed separately. In the LEADER and SUSTAIN 6 trials, the prevalence of stage 1 hypertension was 30% and 31%, respectively, and of stage 2 hypertension 41% and 43%, respectively. There was no statistical heterogeneity across the BP categories for the effects of liraglutide (P = .06 for MACE; P = .14 for nephropathy) or semaglutide (P = .40 for MACE; P = .27 for nephropathy) versus placebo. This implies that liraglutide and semaglutide may be beneficial for patients with type 2 diabetes, irrespective of their baseline BP.     

利拉鲁肽对人胰岛淀粉样多肽聚集性及胰岛细胞毒性的影响

目的:探讨利拉鲁肽对人胰岛淀粉样多肽聚集性及细胞毒性的影响。方法:采用硫磺素T荧光法检测淀粉样纤维聚集的动力学，采用透射电镜检测淀粉样纤维的形态。分离Wistar大鼠胰岛，采用简单随机化分组的方法将大鼠胰岛随机分配成空白对照组、人胰淀素组、人胰淀素+利拉鲁肽组。24 h后采用Annexin-V/PI荧光染色及逆转录聚合酶链反应检测细胞凋亡及炎性因子白细胞介素（IL）-1β、肿瘤坏死因子α（TNFα） 、单核细胞趋化蛋白-1（CCL-2） mRNA的表达。结果:人胰淀素单独孵育时，荧光于1.6 h左右开始上升，并随时间延长逐渐增加，3.4 h后平稳，动力学曲线呈S型曲线；人胰淀素与利拉鲁肽（500 nmol/L）以10∶1分子浓度共同孵育时，荧光信号上升延迟缓慢；以1∶1分子浓度共同孵育时，荧光信号未见明显增加，动力学曲线呈直线型。透射电镜结果显示，人胰淀素单独孵育可见大量长条状纤维聚集，人胰淀素与利拉鲁肽（2 μmol）以10∶1浓度共同孵育后纤维数量明显减少，且短小模糊；1:1（20 μmol利拉鲁肽）浓度共同孵育后，无法找到纤维结构。与空白对照组相比，人胰淀素组IL-1、TNFα、CCL-2基因的mRNA表达均增加，而人胰淀素+利拉鲁肽组表达均下降（F=429.68、48.79、153.39, 均 P＜0.05）。人胰淀素组细胞凋亡率与空白对照组相比明显升高；人胰淀素＋利拉鲁肽组凋亡率比人胰淀素组降低（F=514.34、16.14、18.47，均P＜0.05）。结论:利拉鲁肽抑制胰淀素聚集，减少胰岛细胞炎症及凋亡。     

Weight loss with liraglutide, a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes treatment as monotherapy or added to metformin, is primarily as a result of a reduction in fat tissue

Aim: The effect on body composition of liraglutide, a once-daily human glucagon-like peptide-1 analogue, as monotherapy or added to metformin was examined in patients with type 2 diabetes (T2D).
Methods: These were randomized, double-blind, parallel-group trials of 26 [Liraglutide Effect and Action in Diabetes-2 (LEAD-2)] and 52 weeks (LEAD-3). Patients with T2D, aged 18–80 years, body mass index (BMI) ≤40 kg/m² (LEAD-2), ≤45 kg/m² (LEAD-3) and HbA1c 7.0–11.0% were included. Patients were randomized to liraglutide 1.8, 1.2 or 0.6 mg/day, placebo or glimepiride 4 mg/day, all combined with metformin 1.5–2 g/day in LEAD-2 and to liraglutide 1.8, 1.2 or glimepiride 8 mg/day in LEAD-3. LEAD-2/3: total lean body tissue, fat tissue and fat percentage were measured. LEAD-2: adipose tissue area and hepatic steatosis were assessed.
Results: LEAD-2: fat percentage with liraglutide 1.2 and 1.8 mg/metformin was significantly reduced vs. glimepiride/metformin (p < 0.05) but not vs. placebo. Visceral and subcutaneous adipose tissue areas were reduced from baseline in all liraglutide/metformin arms. Except with liraglutide 0.6 mg/metformin, reductions were significantly different vs. changes seen with glimepiride (p < 0.05) but not with placebo. Liver-to-spleen attenuation ratio increased with liraglutide 1.8 mg/metformin possibly indicating reduced hepatic steatosis. LEAD-3: reductions in fat mass and fat percentage with liraglutide monotherapy were significantly different vs. increases with glimepiride (p < 0.01).
Conclusion: Liraglutide (monotherapy or added to metformin) significantly reduced fat mass and fat percentage vs. glimepiride in patients with T2D.     

Effects of liraglutide versus sitagliptin on circulating cardiovascular biomarkers,including circulating progenitor cells,in individuals with type 2 diabetes and obesity: Analyses from the LYDIA trial

The mechanisms behind the beneficial cardiovascular effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) compared with dipeptidyl peptidase-4 inhibitors (DPP4is) remain largely unknown, despite both targeting the incretin pathway to improve glycaemic control. In these prespecified secondary analyses of the LYDIA trial, we examined the impact of the GLP-1RA liraglutide (1.8 mg once-daily) and the DPP4i sitagliptin (100 mg once-daily) on circulating cardiovascular biomarkers associated with atherosclerotic risk, including circulating progenitor cells (CPCs). LYDIA was a 26-week, randomized, active-comparator trial in 61 adults with type 2 diabetes and obesity (mean ± SD: age 43.8 ± 6.5 years, body mass index 35.3 ± 6.4 kg/m², HbA1c 7.5% ± 0.83% [58.5 ± 9.1 mmol/mol]). Vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1-alpha (SDF-1ɑ), both of which are implicated in endothelial function, were higher at 26 weeks with liraglutide therapy compared with sitagliptin (mean between-group difference [95% CI]: 77.03 [18.29, 135.77] pg/mL, p = .010; and 996.25 [818.85, 1173.64] pg/mL, p < .001, respectively). There were no between-group differences in CPCs, nitric oxide, C-reactive protein, interleukin-6, tumour necrosis factor alpha and advanced glycation end-products. These analyses suggest a favourable impact of liraglutide on VEGF and SDF-1ɑ levels compared with sitagliptin. These factors may therefore be implicated in the differential cardiovascular effects observed between these agents in large cardiovascular outcome trials. However, these are secondary analyses from a previous trial and thus hypothesis-generating. Purposive trials are required to examine these findings further.