SGLT-2抑制剂及GLP-1受体激动剂治疗2型糖尿病的心血管获益：一项系统回顾和网状Meta分析

目的 通过贝叶斯网状Meta分析系统评价上市的11种钠-葡萄糖共转运蛋白-2（SGLT-2）抑制剂和胰高血糖素样多肽-1（GLP-1）受体激动剂治疗2型糖尿病患者的心血管获益。方法 检索Medline、Embase和Cochrane 数据库,检索日期为建库至2020年7月18日。研究终点为心血管不良事件,效应指标为风险比（hazard ratios, HR）及其95%可信区间（95% CI）。结果 与安慰剂相比,恩格列净、卡格列净、达格列净、阿必鲁肽、度拉糖肽、艾塞那肽、利拉鲁肽和索马鲁肽可降低2型糖尿病患者主要心血管不良事件的发生风险,HR及95%CI为0.75(0.60-0.95) ~0.90(0.82-0.99);恩格列净、卡格列净、达格列净和艾托格列净可降低心力衰竭的发生风险,HR及95%CI为0.64(0.49-0.82) ~0.74(0.65-0.85);恩格列净、卡格列净、达格列净、艾塞那肽、利拉鲁肽和口服索马鲁肽可降低全因死亡的发生风险,HR及95%CI为0.52(0.33-0.84)~0.89(0.80-0.99);恩格列净、卡格列净、利拉鲁肽和口服索马鲁肽可降低心血管死亡事件的发生风险,HR及95%CI为0.54(0.30-0.95) ~0.83(0.71-0.96) 。结论 应用SGLT-2抑制剂或GLP-1受体激动剂,对2型糖尿病合并动脉粥样硬化性心血管疾病患者的心血管获益依次是：卡格列净、恩格列净、度拉糖肽、利拉鲁肽;对2型糖尿病合并心衰的患者,心血管获益依次是：恩格列净、卡格列净、艾托格列净、达格列净。     

钠-葡萄糖共转运蛋白2抑制剂在心血管疾病中的抗炎作用及机制

钠-葡萄糖共转运蛋白(SGLT)-2抑制剂是一类新型口服降血糖药,主要通过抑制肾脏近端小管葡萄糖的重吸收,促进尿糖排泄,降低血糖。大量临床研究发现SGLT-2抑制剂具有良好的心血管保护作用。同时,众多基础研究发现多种SGLT-2抑制剂在细胞及动物模型中表现出良好的抗炎活性,SGLT-2抑制剂的心血管保护机制可能与抑制炎症反应密切相关。如卡格列净通过提高AMP活化蛋白激酶(AMPK)、内皮型一氧化氮合酶(eNOS)等抗炎信号传导抑制炎症反应;达格列净可显著降低白细胞介素(IL)-1β、IL-6及肿瘤坏死因子(TNF)-α等炎症因子的表达,促进巨噬细胞向抗炎表型的极化;恩格列净可以减少糖尿病心肌病、高血压和心力衰竭模型中的心脏炎症。     

钠-葡萄糖共转运酶2抑制剂降低心血管和肾病风险

心血管疾病(Cardiovascular disease,CVD)是2型糖尿病(Type 2 diabetes mellitus,T2DM)患者发病和死亡的主要原因,因此,合理利用降糖药物积极进行糖尿病管理的同时,最大限度降低CVD不良结果风险是非常重要的。T2DM患者发生CVD的风险很高,而且糖尿病引发的糖尿病肾病使CVD风险增加,糖尿病肾病患者更有可能死于CVD,而不是死于慢性肾衰竭或终末期肾病,使用对CVD和肾功能有双重保护作用的药物对于T2DM患者是有益的。钠-葡萄糖共转运蛋白-2(SGLT-2)抑制剂是目前较为新型的治疗T2DM的药物,研究显示,SGLT-2抑制剂对CVD有良好的预防作用,同时可降低肾病风险,给糖尿病患者带来了新的希望。本文梳理了当前我国上市的3种SGLT-2抑制剂相关的临床数据,对SGLT-2抑制剂预防T2DM患者CVD和肾病的临床疗效和安全性,以及不同的SGLT-2抑制剂对心血管和肾病的风险收益之间的异同进行综述,为临床用药提供参考。     

从心血管结局看钠-葡萄糖共转运蛋白2抑制剂——糖尿病药物治疗的新机制、新选择

钠-葡萄糖共转运蛋白2（SGLT-2）抑制剂通过高选择性抑制SGLT-2,减少肾小管对葡萄糖重吸收,通过尿排出多余糖分,降低血糖的新型降糖药。本文主要对该类药物的降糖机制及多个高级别的相关心血管结局研究进行概述,助力临床决策。     

SGLT-2抑制剂与2型糖尿病心血管风险的研究进展

回顾评估钠-葡萄糖协同转运蛋白2(SGLT-2)抑制剂对糖尿病并发心血管疾病的作用,从临床试验数据和基础研究结果中获得证据,以阐明SGLT-2抑制剂对心血管系统疾病的危险因素以及预后的影响。对已发表在PubMed上的出版物、临床试验资料库注册的试验以及相关指南共识等进行全面系统的检索。SGLT-2抑制剂诱导多效应作用,可降低糖尿病患者并发心血管相关疾病的风险。SGLT-2抑制剂应被视为合并心血管疾病高风险的糖尿病患者进行血糖控制的临床一线药物。     

SGLT-2抑制剂治疗2型糖尿病的研究进展

钠-葡萄糖协同转运蛋白2抑制剂(SGLT-2i)类药物为近年来出现的一种新型口服糖尿病药物,由于其不依赖于胰岛素的独特降糖机制而日益受到关注。该类药物通过抑制肾脏肾小管中负责从尿液中重吸收葡萄糖的SGLT-2来降低肾糖阈,排出多余的葡萄糖,从而降低血液循环中葡萄糖水平。此外,该类药物还具有降压、减重、减轻尿蛋白等额外获益,在中国2型糖尿病治疗指南(2017版)中被推荐作为单一口服降糖药物效果不佳而采用的二联或三联治疗用药之一。目前,我国临床常见的SGLT-2i抑制剂类药物包括国内批准上市的恩格列净、达格列净和卡格列净。本文对SGLT-2抑制剂类药物的作用机制、降糖效果、降糖外获益等方面进行综述,为临床医师和药师合理用药提供参考。     

钠-葡萄糖共转运蛋白-2抑制剂的药理学与临床评价

目的：探讨钠-葡萄糖共转运蛋白-2（SGLT-2）抑制剂的药理学作用与临床应用。方法：采用文献分析方法,对国内外SGLT-2抑制剂相关文献进行检索,评价SGLT-2抑制剂的临床疗效与安全性。结果与结论：SGLT-2抑制剂为一类新型抗糖尿病药,临床上用于饮食和运动控制治疗后效果不佳的2型糖尿病者。SGLT-2抑制剂的作用机制与口服降糖药截然不同,其非在于促进胰岛β细胞分泌胰岛素,作用不依赖胰岛素,可延缓糖尿病的进程,发生低血糖的风险小,具有良好的应用前景,但其安全性、经济性、临床获益有待更长期的临床研究来证明。     

钠-葡萄糖共转运蛋白2抑制剂相关的药物相互作用

钠-葡萄糖共转运蛋白2(sodium-glucose cotransporter 2,SGLT-2)抑制剂是治疗2型糖尿病的新型口服药物。SGLT-2抑制剂通过降低肾糖阈,增加尿葡萄糖排泄,同时排出部分能量;由于SGLT-2抑制剂的降糖机制依赖于血液和尿液中葡萄糖的浓度差,因此,在血糖较低的时候其效用就大大减弱,从而降低了低血糖发生风险。在降血糖外,SGLT-2抑制剂还有诸多获益,包括降低收缩压、舒张压,改变血液动力学,提高血细胞比容;降低体质量,减少内脏脂肪和皮下脂肪;降低尿酸;对心脏、肾脏还有保护作用。本文就我国批准使用的SGLT-2抑制剂恩格列净、达格列净和卡格列净的药物相互作用进行综述,以期为临床医师和药师合理用药提供参考。     

3类降糖药物在2型糖尿病合并动脉粥样硬化性心血管疾病中的应用

目的:为2型糖尿病(T2DM)合并动脉粥样硬化性心血管疾病(ASCVD)患者降糖药物的选择提供参考。方法:以“2型糖尿病”“动脉粥样硬化性心血管疾病”“二甲双胍”“人胰高血糖素样肽1受体激动剂(GLP-1 RA)”“钠-葡萄糖协同转运蛋白2抑制剂(SGLT2I)”的中英文为检索词,通过计算机检索PubMed、Cochrane Library、Embase、ClinicalTrials、中国知网、万方数据库和维普数据库,检索时限为建库至2020年6月,收集降糖药物在T2DM合并ASCVD患者中的应用案例,从临床获益证据、作用机制和安全性方面逐一阐述。结果:二甲双胍、GLP-1 RA和SGLT2I均能显著改善心血管结局,且SGLT2I可以显著降低心衰住院风险,预防和延缓心衰的发生。3类药物心血管保护作用机制有所不同,但均通过多种途径(包括减少肝糖生成、促进胰岛素分泌、抑制葡萄糖吸收等)达到改善心血管结局的目的。在安全性方面,二甲双胍和GLP-1 RA类药物应注意其胃肠道不适等不良反应;SGLT2I类药物应注意其泌尿生殖系统感染以及糖尿病酮症酸中毒等。结论:3类降糖药物均具有心血管保护作用且安全性良好,适用于T2DM合并ASCVD患者;SGLT2I还适用于心衰患者。     

钠-葡萄糖共转运蛋白2抑制剂在心血管领域的临床应用进展

钠-葡萄糖共转运蛋白2抑制剂(sodium-glucose cotransporter 2 inhibitor, SGLT2i)是一类新型口服降糖药物,其作用机制是抑制近端肾小管钠-葡萄糖重吸收,促进尿糖排泄,从而降低血糖浓度。多项研究表明SGLT2i的使用可以降低心血管不良事件发生的风险,改善T2DM合并心血管风险高危甚至心力衰竭患者的预后。本文通过对SGLT2i心血管系统的保护机制、循证医学证据和药物使用进展进行综述,探讨SGLT2i在心血管领域的临床应用。     

The effect of SGLT2 inhibitors on cardiovascular events and renal function

Introduction: Sodium-glucose co-transporters-2inhibitors have emerged as a very promising antidiabetic drug class, with data from the two available cardiovascular trials of this class suggesting remarkable benefits in terms of cardiovascular events, total mortality and renal outcomes.

Areas covered: Data point toward clinically meaningful benefits from SGLT-2inhibition on a variety of cardiovascular risk factors. Empagliflozin, and to a lesser extent canagliflozin, resulted in significant reductions of an abundance of cardiovascular mortality and morbidity endpoints. SGLT-2inhibitors were also found to reduce the incidence of heart failure events and ameliorate the progression of diabetic kidney disease. However, empagliflozin was associated with a trend for stroke risk increase, that could be partially attributed to the drug-induced hematrocrit increases, while canagliflozin was related with higher amputations risk.

Expert commentary: The beneficial impact of SGLT-2inhibitors on cardiovascular risk factors seem to be manifested in significant morbidity and mortality benefits. The bright future of SGLT-2inhibitors in diabetes therapeutics is overshadowed by the higher amputations risk and the potential harms in terms of stroke incidence. Further analyses of the data and future studies could unveil patients subgroups that might be more prone to such events or put to rest the concerns for this otherwise promising class of drugs.     

Sodium–glucose cotransporter 2 inhibitors: an evidence-based practice approach to their use in the natural history of type 2 diabetes

Objective The sodium–glucose cotransporter 2 (SGLT-2) inhibitors are an important addition to available treatments for patients with type 2 diabetes (T2D) as an adjunct to modifications in diet and exercise. SGLT-2 inhibitors may be prescribed alone or as add-on treatment in patients receiving metformin, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and/or insulin across the natural history of the disease. Inhibition of SGLT-2, which is responsible for approximately 90% of renal glucose reabsorption, increases urinary glucose excretion and lowers blood glucose concentrations. The objective of this review is to discuss the pathophysiology of diabetes and the contribution of the kidney to glucose homeostasis and to provide an evidence-based practice approach to clinical applications of SGLT-2 inhibitors in the treatment of T2D.

Methods PubMed and Google Scholar databases were searched to identify literature published from 1990 through September 2015 examining the pathophysiology of T2D, the role of the kidney in regulating glucose concentrations, and clinical evidence for the efficacy and safety of SGLT-2 inhibitors in T2D.

Results There is a need for early treatment in patients with T2D to minimize the risk of cardiovascular complications that increase morbidity and mortality. SGLT-2 inhibitors improve glycemic control, reduce body weight and blood pressure, and are associated with a low risk of hypoglycemia. Adverse events associated with SGLT-2 inhibitors include mild to moderate urinary tract and genital infections and mild dehydration potentially leading to orthostatic hypotension.

Conclusions An evidence-based practice approach to examining the importance of early, proactive treatment of T2D using SGLT-2 inhibitors from initiation of pharmacotherapy to increasingly more complicated combination therapy regimens, including insulin, suggests that this treatment strategy maximizes benefits and minimizes potential side effects. The SGLT-2 inhibitors augment the arsenal of available antidiabetes agents, facilitating the ability of clinicians to design tailored treatment regimens that help patients achieve therapeutic goals.     

Pharmacoeconomic evaluation of sodium-glucose transporter-2 (SGLT2) inhibitors for the treatment of type 2 diabetes

Introduction: Clinicians have many safe and effective options for the treatment of type 2 diabetes that can improve glycemic control and effect other cardio-metabolic parameters. Sodium-glucose transporter-2 inhibitors (SGLT-2) are the most recent class of therapies, have a novel mechanism of action, and provide good glycemic efficacy and a favorable cardiovascular risk profile. Cost-effectiveness data can play an important role in assessing the benefits of this class of therapy in anti-diabetes treatment regimens.

Areas covered: This review summarizes all the available evidence regarding the cost-effectiveness of SGLT-2 inhibitors. For the purposes of this article, the authors have performed a systematic review of pharmacoeconomic analyses through a non-restricted literature until June 2018.

Expert opinion: The available analyses demonstrate that SGLT-2 inhibitors are a more cost-effective option compared to other oral anti-diabetes therapies and insulin in the treatment of individuals with uncontrolled type 2 diabetes. Future studies should examine populations with renal and liver disease and expand data of some SGLT-2 inhibitors to patients at high cardiovascular risk and hard endpoint data.     

Cardiovascular effects of anti-diabetes drugs

ABSTRACT

Introduction: Cardiovascular disease remains the major contributor to morbidity and mortality in diabetes. From the need to reduce cardiovascular risk in diabetes and to ensure that such risk is not exacerbated by drug treatments, governmental regulators and drug manufacturers have focused on clinical trials evaluating cardiovascular outcomes.

Areas covered: Findings from mechanistic and clinical trials of biguanides, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose co-transporter 2 (SGLT-2) inhibitors will be reviewed. These drug classes will be compared within the context of available cardiovascular outcomes data. Clinical implications of new study regulations will be examined.

Expert opinion: Recent cardiovascular studies provide a more comprehensive evaluation of specific anti-diabetes therapy in individuals with high cardiovascular risk. Long-term effects of anti-hyperglycemic agents in patients with lower cardiovascular risk are still speculative. Historical data supports continued use of metformin as a first-line agent. DPP-4 inhibitors and GLP-1 receptor agonists appear to have neutral effects on cardiovascular outcomes. The significantly decreased cardiovascular risk associated with empagliflozin SGLT-2 inhibitor therapy is impressive and may change how practitioners prescribe add-on therapy to metformin.     

Weight loss differences seen between glucagon-like peptide–1 receptor agonists and sodium–glucose cotransporter–2 inhibitors for treatment of type 2 diabetes

BackgroundWeight loss is an advantageous quality for diabetic medications because it can improve insulin sensitivity and glucose control and reduce cardiovascular risk factors and comorbidities. Glucagon-like peptide–1 (GLP-1) receptor agonists and sodium–glucose cotransporter–2 (SGLT-2) inhibitors are both preferred agents for use after metformin therapy, and both cause modest weight loss.ObjectiveThe aim of this study was to evaluate the difference in weight loss between GLP-1 receptor agonists and SGLT-2 inhibitors in patients with type 2 diabetes (T2D).MethodsThis was a retrospective study that was conducted at a level 3 patient-centered medical home in Buffalo, NY. The participants were adults with T2D treated with either a GLP-1 receptor agonist or an SGLT-2 inhibitor, in addition to background diabetes medications, between January 1, 2012, and September 20, 2017. The outcome measures included the median weight loss after 6 months of consecutive therapy compared between the 2 antidiabetic classes and the median differences in blood pressure, glycosylated hemoglobin (A1C) levels, and renal function markers compared between the 2 classes.ResultsA total of 73 patients were included in the final analysis, with 31 receiving SGLT-2 inhibitors and 42 receiving therapy with GLP-1 receptor agonists. The SGLT-2 inhibitor cohort presented a median weight loss of –2.80 kg (interquartile range [IQR] –5.40 to –1.50), and the GLP-1 receptor agonist cohort presented a median weight loss of –1.15 kg (IQR –3.38 to 0.975) (P = 0.014). There were no statistically significant differences in A1C levels, blood pressure, or renal function markers.ConclusionSGLT-2 inhibitors, when used in combination with background diabetes regimens, can lead to more statistically significant weight loss than GLP-1 receptor agonists without compromising renal function.     

The role of sodium glucose cotransporter-2 (SGLT-2) inhibitors in heart failure and chronic kidney disease in type 2 diabetes

Background: Heart failure (HF) and chronic kidney disease (CKD) are responsible for substantial morbidity and mortality in individuals with type 2 diabetes (T2D).

Methods: This review discusses the significance of these comorbidities of T2D and current options for managing them, with a focus on sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Based on a focused literature search of cardiovascular outcomes trials (CVOTs), this review assessed the effects of SGLT-2 inhibitors in individuals with T2D with or without established cardiovascular disease (CVD).

Results: In addition to effective glycemic control and weight loss, SGLT-2 inhibitor treatment of T2D prevents adverse cardiovascular and renal outcomes in individuals with and without these comorbidities. Reduced rate of hospitalization due to HF (HHF) and improved renal outcomes appear to be class effects of SGLT-2 inhibitors. Reduction in CV events may be more significant in individuals with established cardiovascular disease.

Conclusions: CVOTs and other studies confirm that the SGLT-2 inhibitors, mostly used in combination with other glucose-lowering drugs, offer several clinical benefits beyond improved glycemic control. These include reducing HHF risk and improving renal outcomes. HF and renal benefits are observed in individuals with and without established CVD, which may simplify therapeutic selection. Ongoing SGLT-2 inhibitor CVOTs will help clarify the potential of these drugs to treat T2D comorbid with different forms of HF (HF with preserved vs reduced ejection fraction) and different degrees of renal dysfunction, and in individuals with T2D vs pre-diabetes or normal glucose metabolism.     

An evaluation of the efficacy and safety of Tofogliflozin for the treatment of type II diabetes

Introduction: Accumulating data from recent studies has altered the gold standard of care for diabetes treatment. In patients with type 2 diabetes (T2D) and established cardiovascular disease (CVD) or those at high risk for CVD, subsequently to lifestyle changes and metformin therapy, the administration of an SGLT-2 inhibitor with established benefits for cardiovascular outcome (CVOT) should be considered.

Areas covered: Tofogliflozin is the most selective SGLT-2 inhibitor and has been approved for the treatment of T2D in Japan. This review summarizes the available data on Tofogliflozin as compared to other SGLT-2 inhibitors, and primarily the three SGLT-2 inhibitors with published CVOT: Empagliflozin, Canagliflozin and Dapagliflozin.

Expert opinion: Tofogliflozin’s higher selectivity profile increases the positive effects on cardiovascular (CV) outcomes and death and reduces side effects. However, the clinical data on Tofogliflozin from both clinical and real-world studies remain sparse and much less abundant than the other main 3 SGLT-2 inhibitors, thus calling for caution and underscoring the need for further research.     

A safety evaluation of empagliflozin plus linagliptin for treating type 2 diabetes

Introduction: Dipeptidyl-peptidase-IV inhibitors (DPP-4i) and sodium-glucose-transporter-2 inhibitors (SGLT-2i) are oral antidiabetic drugs that improve glycemic parameters and possess a very low intrinsic hypoglycemia risk and favorable cardiovascular data.

Areas covered: An overview on the clinical studies investigating the combination therapy with the DPP-4i linagliptin and the SGLT-2i empagliflozin is given. The clinical evidence for the efficacy and safety of free combinations as well as for their fixed dose combinations is presented. Empagliflozin has recently proved to reduce cardiovascular risk in type 2 diabetes and cardiovascular high risk situations. A fixed dose combination (FDC) of empagliflozin and linagliptin as add on therapy to metformin or as initial treatment lowered the HbA1c by approximately 1.1% and reduced the body weight by 2.0–3.0 kg. The hypoglycemia risk was not significantly increased. The relevant studies were identified by a search in Medline and in clinicaltrials.gov.

Expert opinion/commentary: A DPP-4i/SGLT-2i FDC may be especially useful to simplify treatment, to reduce the tablet burden and to increase medication adherence. This FDC may be particularly beneficial for patients where the reduction of body weight, blood pressure and cardiovascular risk are important and in whom hypoglycemia should be avoided.