糖-钠协同转运蛋白2抑制剂对心力衰竭合并糖尿病小鼠治疗效果及左心室重构影响的实验研究

摘要 目的：探究糖-钠协同转运蛋白2（Sodium-glucose cotransporter2,SGLT2）抑制剂对心力衰竭合并糖尿病小鼠治疗效果及左心室重构影响的实验研究。方法：选择4周龄雄性C57BL/6J小鼠,通过高脂饮食和免疫抑制剂他克莫司(Tacrolimus,TAC)诱导心力衰竭建立心衰合并糖尿病模型,分为三组：对照组（正常脂肪饮食）、模型组（高脂饮食第2周,TAC诱导心力衰竭）、SGLT2抑制剂组（高脂饮食+恩格列净灌胃第2周,同时TAC诱导心力衰竭）。治疗6周后,记录并比较各组小鼠死亡案例和生存率;酶联免疫吸附实验检测各组小鼠的白细胞介素-6(interleukin 6,IL-6)、IL-10、肿瘤坏死因子--α（tumor necrosis factor-α,TNF-α）的含量;50 MHz传感器耦合的Vevo 2100系统进行超声心动图评估;逆转录聚合酶链式反应(reverse transeription-polymerase chain reaction,RT-PCR)实时分析p53、p21和p16的mRNA表达;蛋白印迹分析组织因子血管细胞黏著因子(Vascular cell Adhesion Molecule-1,VCAM-1)、SGLT1、SGLT2、一氧化氮合酶(endothelial nitric oxide synthase,eNOS)蛋白表达。结果：10天内模型组较对照组和SGLT2抑制剂组生存率降低（P<0.05）,第20天、40天时模型组较对照组大鼠生存率降低,SGLT2抑制剂组较模型组的生存率升高（P<0.05）。模型组较对照组IL-6和TNF-α含量、右心室收缩压（right Ventricular Systolic Pre-ssure,RVSP）和平均肺动脉压（mean Pulmonary Artery Pressure,mPAP）水平、p53、p21和p16的mRNA表达量、VCAM-1、SGLT1、SGLT2的蛋白表达量以及左心室收缩末前后径(left ventricular end-systolic diameter,LVESD)、左心室舒张末前后径(left ventricular end-diastolic diameter,LVEDD)、左心室收缩末容量(left ventricular end-systolic volume,LVESV)均显著升高,IL-10含量、肺动脉血流加速时间(Pulmonary artery acceleration time,PAAT)水平、eNOS蛋白表达量以及左心室射血分数(left ventricular ejection fraction,LVEF)均显著降低（P<0.05）,SGLT2抑制剂组较对照组以上指标变化均与上述相反,且差异具有统计学意义（P<0.05）。结论：选择性SGLT2抑制剂恩格列净改善了心衰合并糖尿病小鼠的收缩压,心脏重塑和内皮功能障碍。促进心脏的保护作用,同时改善左心室重量和体积及后壁厚度。     

Determining the role of SGLT2 inhibition with Empagliflozin in the development of diabetic retinopathy

Diabetes mellitus is a chronic metabolic disease that occurs when the pancreas is not producing enough insulin or when the insulin that it does produce is not able to be used effectively in the body. This results in hyperglycemia and if the blood sugars are not controlled, then it can lead to serious damage of various body systems, especially the nerves and the blood vessels. Uncontrolled diabetes is a major cause of kidney failure, heart attacks, stroke and amputation. One of the most devastating complications for patients is diabetic retinopathy (DR) which represents the leading cause of preventable vision loss in people between 20 and 65 years of age. Sodium glucose transporter 2 (SGLT2) inhibitors have been shown to reduce the risk for cardiovascular and renal events, however literature highlighting their potential role to prevent DR is limited. We therefore used a relevant mouse model (Akimba) to explore the effects of the SGLT2 inhibitor, Empagliflozin (EMPA), on the development of diabetic retinal changes. Here we show that when given in the early stages of type 1 diabetes (T1D), EMPA reduced the weight loss usually associated with T1D, decreased diabetes-associated polydipsia, lowered fasting blood glucose levels, decreased kidney-to-body weight ratios and, most importantly in the current context, substantially reduced retinal abnormalities associated with DR. We show that EMPA reduces vascular leakage indicated by lower albumin staining in the vitreous humor and diminishes expression of the pathogenic factor VEGF in the retina. Additionally, EMPA significantly alters the retinal genetic signature. Our findings suggest that SGLT2 inhibition may be a useful therapeutic approach to prevent the development of DR and its severity if given early in the disease process.     

Different Sodium-Glucose Cotransporter-2 Inhibitors: Can They Prevent Death?

ObjectiveSodium-glucose cotransporter-2 inhibitors (SGLT2is) in cardiovascular outcome trials (CVOTs) demonstrate cardiovascular (CV) safety and benefits. Some dedicated randomized controlled trials (RCTs) demonstrate benefit in terms of renal outcomes and hospitalization due to heart failure (HF). RCTs report differences in the secondary outcomes with respect to mortality (CV and/or all-cause). We undertook a meta-analysis of all SGLT2is for which in addition to CVOT, HF outcome/renal outcome studies are available to establish whether individual SGLT2is were able to prevent death.MethodsWe included available event-driven randomized, placebo-controlled CVOTs and dedicated RCTs of SGLT2is exploring renal outcomes and HF. We included 3 trials of empagliflozin, 3 of dapagliflozin, 2 of canagliflozin, and 2 of sotagliflozin. The efficacy outcomes included all-cause mortality and CV mortality. Hazard ratios (HRs) with 95% CIs were pooled for individual molecules.ResultsThe HR for all-cause mortality including all trials was 0.86 (0.80-0.93). The HRs for all-cause mortality in empagliflozin (N = 16 738), dapagliflozin (N = 26 208), canagliflozin (N = 14 543), and sotagliflozin (N = 11 806) were 0.86 (0.69-1.08), 0.83 (0.72-0.97), 0.86 (0.75-0.97), and 0.95 (0.81-1.11), respectively. The HR for CV mortality including all trials was 0.85 (0.78-0.92). The HRs for CV mortality in empagliflozin, dapagliflozin, sotagliflozin, and canagliflozin were 0.81 (0.63-1.03), 0.88 (0.78-1.00), 0.89 (0.74-1.07), and 0.84 (0.72-0.98), respectively.ConclusionSGLT2is as a class reduce both all-cause mortality and CV mortality. Canagliflozin possibly reduces both all-cause mortality and CV mortality, whereas dapagliflozin may reduce all-cause mortality but not CV mortality. Empagliflozin and sotagliflozin may reduce neither.     

Cost-Effectiveness of Empagliflozin and Metformin Combination Versus Standard Care as First-Line Therapy in Patients With Type 2 Diabetes Mellitus

ObjectiveSodium-glucose cotransporter 2 inhibitors have been shown to reduce cardiovascular events but are currently not used as the first-line therapy. This study was conducted to evaluate the cost-effectiveness of first-line empagliflozin plus metformin versus metformin monotherapy among Australians with type 2 diabetes mellitus (T2DM) and existing cardiovascular disease (CVD).MethodsA Markov model with 1-year cycles and a 5-year time horizon was constructed to simulate the occurrence of recurrent cardiovascular events among Australians aged 50 to 84 years with T2DM and CVD. Efficacy results were derived from the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose trial. Costs and utilities were drawn from published sources. The evaluation adopted both health care and societal perspectives, with the latter ascribing the Australian government’s “value of statistical life year” (A$213 000) to each year lived by a person. Future outcomes were discounted at 5% annually. Sensitivity analyses were conducted to enhance the robustness of conclusions.ResultsCompared with metformin monotherapy, first-line empagliflozin plus metformin reduced overall cardiovascular events by 0.82% and overall deaths by 7.72% over 5 years. There were 0.2 years of life saved per person and 0.16 quality-adjusted life years gained, at a net health care cost of A$4408. These equated to incremental cost-effectiveness ratios of A$22 076 per year of life saved and A$28 244 per quality-adjusted life year gained. The gains in the value of statistical life year equated to A$42 530 per person, meaning that from a societal perspective, the intervention was cost-saving.ConclusionFirst-line empagliflozin plus metformin may represent a cost-effective strategy for the management of T2DM and CVD in Australia.