葡萄糖协同转运蛋白2抑制剂防治心力衰竭的研究进展

心力衰竭是合并动脉粥样硬化性心血管疾病(ASCVD)和ASCVD高危因素2型糖尿病(T2DM)患者最常见的并发症之一。临床试验显示葡萄糖协同转运蛋白2抑制剂(SGLT2i)可有效预防心力衰竭住院的发生。新的证据表明SGLT2i治疗确诊的合并和不合并T2DM的心力衰竭患者明显获益,更多的循证医学依据正在积累中。虽然SGLT2i耐受性良好,但应对严重不良作用进行监测。本文主要介绍SGLT2i防治心力衰竭的获益、不良作用和可能机制。     

SGLT2抑制剂对2型糖尿病患者尿酸代谢影响的研究进展

高尿酸血症(HUA)常与2型糖尿病患者的主要不良心血管事件、慢性终末期肾病有关。钠-葡萄糖共转运蛋白2抑制剂(SGLT2i)是一类选择性抑制肾脏近曲小管葡萄糖重吸收的新型口服降糖药物，其兼有降糖之外的获益。本文就SGLT2i对2型糖尿病患者尿酸代谢的影响的研究进展作一综述。     

钠-葡萄糖协同转运蛋白-2抑制剂在射血分数保留的心力衰竭中的作用及机制研究进展

钠-葡萄糖协同转运蛋白-2抑制剂(SGLT2i)是一种新型降糖药物, 可通过抑制近端小管对葡萄糖的重吸收而降低血糖, 广泛用于2型糖尿病的临床治疗。SGLT2i不仅可降低血糖, 还具有多种心血管益处。随着多个大型临床随机对照试验结果的发布, SGLT2i在射血分数保留的心力衰竭(HFpEF)中的安全性和有效性已被证实。现就SGLT2i降低射血分数保留的心力衰竭患者心血管事件的风险其潜在机制的研究进行综述。     

ESC 2019 DAPA-HF研究解读:SGLT2抑制剂的跨界演出

SGLT2抑制剂是近年来诞生的新型降糖药物,在糖尿病领域的几项大型临床研究中证实能减少心血管事件,但获益机制并不能完全归结于血糖的控制。近期ESC上公布的DAPA-HF研究(Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure)证实了SGLT2抑制剂对于未患2型糖尿病的射血分数减低的心力衰竭(HFrEF)患者依然可以显著降低心血管死亡和心力衰竭住院风险,这一里程碑式的研究将开启心力衰竭治疗新的时代。     

钠-葡萄糖共转运蛋白2抑制剂对心律失常影响的研究进展

2型糖尿病与心力衰竭通常会相伴发生,可导致心律失常增加从而使患者预后更差。钠-葡萄糖共转运蛋白2抑制剂(SGLT2i)作为一种新型降糖药物,能降低糖尿病合并心力衰竭患者的心血管疾病死亡率和住院率。越来越多的证据表明SGLT2i有抗心律失常作用。现就SGLT2i对心律失常影响的临床证据以及可能的作用机制进行综述。     

SGLT2抑制剂减少2型糖尿病患者并发心律失常的研究进展

钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）是一种新型降糖药,通过抑制肾脏近端小管对钠及葡萄糖的重吸收降低血糖。研究证实SGLT2i能减少心力衰竭的发生率、住院率及全因死亡率。多项研究提示SGLT2i可以通过减轻心脏负荷、改善离子稳态、调节线粒体功能及抑制交感神经活性等机制减少心律失常的发生。该文介绍SGLT2i通过减少心律失常发生使心血管系统获益的研究进展。     

钠-葡萄糖协同转运蛋白2抑制剂恩格列净的心力衰竭相关研究进展

糖尿病和心力衰竭作为全球疾病负担,与之相关的治疗研究进展一直备受关注。恩格列净是钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）中的一种,不仅作为新型降糖药物近年来广受欢迎,且目前已有相关研究表明其对心力衰竭也同样有获益,是目前被证明可降低心血管死亡发生风险的SGLT-2i。恩格列净的有效性及安全性在得到证实的同时,其治疗心力衰竭的机制也成为如今的研究热点。     

SGLT2抑制剂和GLP-1受体激动剂对2型糖尿病患者心血管保护作用研究进展

大量研究表明钠-葡萄糖共转运体2(SGLT2)抑制剂和胰高血糖素样肽1(GLP-1)受体激动剂(GLP-1RA)在降低2型糖尿病(T2DM)患者的死亡率和心血管风险方面显示出积极的效果。本文综述了SGLT2抑制剂和GLP-1RA对T2DM患者心血管获益有关的临床研究。以期针对T2DM合并心血管疾病患者的不同临床受益情况，提供个体化用药选择思路。     

SGLT2抑制剂的心血管获益及治疗心力衰竭的研究综述

心力衰竭（心衰）是多种心血管疾病的严重终末阶段,尽管其药物治疗已取得很大进步,但其预后仍不乐观,接受标准治疗的心衰患者仍存在高死亡和再住院风险。目前已有多项大型随机对照研究证实降糖药物钠-葡萄糖共转运蛋白2（SGLT2）抑制剂有明显的心血管获益,可以明显降低心衰患者心血管死亡率,降低心衰恶化风险,且无论是否伴有糖尿病均可获益。本文就SGLT2抑制剂的心血管获益和治疗心衰的研究和机制进行综述,期待SGLT2抑制剂可以打破传统心衰治疗的金三角（血管紧张素转化酶抑制剂/血管紧张素II受体拮抗剂/血管紧张素受体脑啡肽酶抑制剂、盐皮质激素受体拮抗剂和β受体阻滞剂）,实现与金三角使用的四联治疗。     

钠-葡萄糖协同转运蛋白2抑制剂对心血管保护作用机制的研究进展

糖尿病是心血管疾病(CVD)的主要危险因素之一,糖尿病合并CVD在我国有着极高的发病率。糖尿病患者治疗的核心目标是在降糖达标的基础上产生心脏保护作用,从而改善患者预后。近年来,新上市的钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂被证实有着显著的心血管获益。本文就SGLT2抑制剂心血管获益的相关研究结果及可能的机制进行综述。     

Sodium glucose cotransporter 2 inhibitors: New horizon of the heart failure pharmacotherapy

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have gained momentum as the latest class of antidiabetic agents for improving glycemic control. Large-scale clinical trials have reported that SGLT2 inhibitors reduced cardiovascular outcomes, especially hospitalization for heart failure in patients with type 2 diabetes mellitus who have high risks of cardiovascular disease. Accumulating evidence has indicated that beneficial effects can be observed regardless of the presence or absence of type 2 diabetes mellitus. Accordingly, the Food and Drug Administration approved these agents specifically for treating patients with heart failure and a reduced ejection fraction. It has been concluded that canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin can be recommended for preventing hospitalization associated with heart failure in patients with type 2 diabetes and established cardiovascular disease or those at high cardiovascular risk. In the present review, we explore the available evidence on SGLT2 inhibitors in terms of the cardioprotective effects, potential mechanisms, and ongoing clinical trials that may further clarify the cardiovascular effects of the agents.     

The cardiovascular outcomes,heart failure and kidney disease trials tell that the time to use Sodium Glucose Cotransporter 2 inhibitors is now

Sodium glucose contrasporter 2 inhibitors (SGLT2i) were initially introduced as a novel class of modestly effective antiglycemics. Over the last 5 years, multiple members of this class have been examined for their cardiovascular safety, effects on heart failure with reduced ejection fraction (HFrEF) and chronic kidney disease (CKD) in diverse populations with or without diabetes type 2. The plethora of studies and outcomes examined make it difficult for the practitioner to track the entirety of the evidence. SGLT2i improve cardiorenal outcomes and have a beneficial risk benefit ratio across populations with cardiovascular disease, HFrEF and kidney disease. In this quantitative review, we synthesize the data from the large outcomes trials about the benefits and risks of SGLT2i. SGLT2i reduce all cause, cardiovascular mortality, heart failure hospitalizations, need for dialysis and acute kidney injury as a class effect across a broad range of populations with diabetes Type 2 at risk for cardiovascular disease, patients with HFrEF or CKD with or without diabetes. While certain adverse events for example, diabetic ketoacidosis and genital mycotic infections are reproducibly increased by SGLT2i, the absolute increase in the risk of these complications is smaller than the absolute risk reductions conferred by SGLT2i. Other complications such as amputations, fractures and urinary tract infections are increased to a lesser degree, or not at all (e.g., hypoglycemia). Overall, SGLT2is appear to have a favorable safety profile and thus should be used by cardiologists, nephrologists, endocrinologists, primary care physicians when managing the cardiorenal risk of their patients.     

Mechanisms of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors: JACC State-of-the-Art Review

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class approved for treatment of diabetes, have been shown to possess a favorable metabolic profile and to significantly reduce atherosclerotic events, hospitalization for heart failure, cardiovascular and total mortality, and progression of chronic kidney disease. Although initially considered to be only glucose-lowering agents, the effects of SGLT2i have expanded far beyond that, and their use is now being studied in the treatment of heart failure and chronic kidney disease, even in patients without diabetes. It is therefore critical for cardiologists, diabetologists, nephrologists, and primary care physicians to be familiar with this drug class. This first part of this 2-part review provides an overview of the current understanding of the mechanisms of the cardio-metabolic-renal benefits of SGLT2i. The second part summarizes the recent clinical trials of SGLT2i.     

Sodium–glucose cotransporter 2 inhibitors represent a paradigm shift in the prevention of heart failure in type 2 diabetes patients

Recent major clinical trials of the use of sodium–glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes have shown that they reduce three-point major adverse cardiovascular events, cardiovascular death, hospitalization for heart failure (HF) and a composite renal outcome. These beneficial effects of SGLT2 inhibitors are also evident in type 2 diabetes patients with a previous history of atherosclerotic cardiovascular disease or advanced renal disease. HF is a major determinant of the prognosis of diabetes patients. Although HF with low ejection fraction can be effectively treated with antihypertensive drugs, these treatments do not reduce mortality in HF patients with preserved ejection fraction (HFpEF). HFpEF is clinically characterized by left ventricular diastolic dysfunction, perivascular fibrosis and stiffness of cardiomyocytes, defined as “cardiomyopathy”. Therefore, HFpEF is considered to be an entirely separate entity to HF with low ejection fraction. Recent studies have suggested that HFpEF might be treatable using SGLT2 inhibitors, which ameliorate visceral adiposity, insulin resistance, hyperglycemia, hyperlipidemia, volume overload, hypertension and cardiac inflammation. In the final part of the present review, we discuss the biochemical and molecular mechanisms of the effects of SGLT2 inhibitors in type 2 diabetes patients with HFpEF. These involve amelioration of the low nitric oxide production and oxidative stress, a reduction in cardiac inflammatory cytokine signaling, inhibition of Ca²⁺ overload, and an improvement in cardiac energy metabolism as a result of ketone body production. Investigations of the beneficial effects of SGLT2 inhibitors on cardiorenal outcomes, including hospitalization for HF, are now being carried out in preclinical and clinical studies.     

Evaluation of the effect of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR‐Reduced trial

Drugs that inhibit the sodium–glucose co‐transporter 2 (SGLT2) have been shown to reduce the risk of hospitalizations for heart failure in patients with type 2 diabetes. In populations that largely did not have heart failure at the time of enrolment, empagliflozin, canagliflozin and dapagliflozin decreased the risk of serious new‐onset heart failure events by ≈30%. In addition, in the EMPA‐REG OUTCOME trial, empagliflozin reduced the risk of both pump failure and sudden deaths, the two most common modes of death among patients with heart failure. In none of the three trials could the benefits of SGLT2 inhibitors on heart failure be explained by the actions of these drugs as diuretics or anti‐hyperglycaemic agents. These observations raise the possibility that SGLT2 inhibitors could reduce morbidity and mortality in patients with established heart failure, including those without diabetes. The EMPEROR‐Reduced trial is enrolling ≈3600 patients with heart failure and a reduced left ventricular ejection fraction (≤ 40%), half of whom are expected not to have diabetes. Patients are being randomized to placebo or empagliflozin 10 mg daily, which is added to all appropriate treatment with inhibitors of the renin–angiotensin system and neprilysin, beta‐blockers and mineralocorticoid receptor antagonists. The primary endpoint is the time‐to‐first event analysis of the combined risk of cardiovascular death and hospitalization for heart failure, but the trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all‐cause mortality, and recurrent hospitalization events. By adjusting eligibility based on natriuretic peptide levels to the baseline ejection fraction, the trial will preferentially enrol high‐risk patients. A large proportion of the participants is expected to have an ejection fraction < 30%, and the estimated annual event rate is expected to be at least 15%. The EMPEROR‐Reduced trial is well‐positioned to determine if the addition of empagliflozin can add meaningfully to current approaches that have established benefits in the treatment of chronic heart failure with left ventricular systolic dysfunction.     

When and How to Use Sodium-Glucose Cotransporter 2 Inhibitors in Patients With Heart Failure With Reduced Ejection Fraction or Chronic Kidney Disease

The role of sodium-glucose cotransporter 2 (SGLT2) inhibitors in preventing heart failure (HF) in people with type 2 diabetes (T2DM) is now part of current treatment recommendations. Two large clinical trials (DAPA-HF and EMPEROR-Reduced) have recently highlighted the important impact of SGLT2 inhibitors in patients with HF and a reduced ejection fraction (HFrEF), with significant outcome benefits on HF hospitalisations and cardiovascular mortality, and similar effects in patients with and without T2DM. These benefits were observed on top of excellent background HF therapy, and there were no treatment interactions between SGLT2 inhibitors and background HF therapy. There were no increases in adverse events of interest in the SGLT2 inhibitor arm, including volume depletion, adverse renal events, hypoglycemia, amputation, and ketoacidosis, demonstrating the favourable safety profile of this treatment in HFrEF. Approximately 40%-50% of patients with HFrEF have chronic kidney disease (CKD), and the recently reported results of the DAPA-CKD trial indicate that dapagliflozin can prevent renal and cardiovascular outcomes in patients with established CKD, whether diabetes is present or not. Although the mechanisms of action of SGLT2 inhibitors are not fully understood, the hypotheses that have been proposed for their HF outcome benefits include a reduction of preload via osmotic diuresis, lowering of afterload, reduction in myocardial mass, alteration of myocardial energy substrate toward a more efficient glucose metabolism, modulation of renal sympathetic afferent tone, and increased erythropoiesis. We here present a summary of the evidence as well as a practical perspective on prescribing SGLT2 inhibitors in patients with HFrEF, with or without diabetes.     

When metformin is not enough: Pros and cons of SGLT2 and DPP‐4 inhibitors as a second line therapy

The newer oral therapies for type 2 diabetes mellitus, dipeptidyl peptidase‐4 (DPP‐4) inhibitors and sodium glucose cotransporter 2 (SGLT2) inhibitors, have advantages over older agents. Dipeptidyl peptidase‐4 inhibitors are weight neutral and have few adverse effects. Sodium glucose cotransporter 2 inhibitors have additional benefits: weight loss, blood pressure reduction, cardiovascular risk reduction, and renoprotective effects. Sodium glucose cotransporter 2 inhibitors have increased risk of urogenital infections and possible risk of “euglycaemic” diabetic ketoacidosis. It is important to balance the benefits over the older‐oral therapies as these agents are more expensive; yet some analyses suggest that they are within the limits of what is considered cost‐effective in health care. We discuss the relative merits and drawbacks of these 2 classes and consider their roles in the treatment of type 2 diabetes mellitus. We suggest a number of patient profiles where early use of these agents could be used. We favour the use of SGLT2 inhibitors over DPP‐4 inhibitors as add on therapy to metformin when glycaemic targets have not been achieved given their similar glycaemic efficacy and the additional benefits of SGLT2 inhibitors. We particularly favour SGLT2 inhibitors in those where additional weight loss and blood pressure reductions are desired, and in patients with heart failure or cardiovascular disease. Care should be taken to warn patients about genital fungal infections and to avoid use in people with risk factors for SGLT2 associated ketoacidosis. We favour DPP‐4 inhibitors in those where side effects of other agents are of concern, the frail elderly population, and those with renal disease precluding SGTL2 inhibitor use.     

Tolerability and efficacy of sodium–glucose co-transporter-2 inhibitors in Australian Aboriginal and Torres Strait Islanders with type 2 diabetes mellitus: an observational study

Sodium–glucose co-transporter-2 inhibitors (SGLT2i) have renal and cardiovascular benefits in addition to their glucose-lowering potential. Data on the efficacy and safety of SGLT2i in Australian Aboriginal and Torres-Strait Islanders are lacking. We conducted a single-centre retrospective study assessing the safety and effects on glycaemic control and albuminuria of SGLT2i in Aboriginal and Torres Strait Islander patients with type 2 diabetes mellitus.