Articles, see p 90 and 100

The serial development of treatments that improve morbidity and mortality in patients with chronic heart failure with reduced ejection fraction (HFrEF) is one of the great success stories of cardiovascular therapeutics. Until recently, the combination of β-blockers, renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), and mineralocorticoid receptor antagonists formed the foundation of triple therapy for heart failure (HF). These agents, each of which provides clear benefits on mortality and morbidity in patients with HFrEF, collectively came to be termed guideline-directed medical therapy (GDMT). This stable foundation of HF therapeutics was upended in 2014 by the stunning results of the PARADIGM-HF study (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), demonstrating substantial improvements in outcomes with the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan above and beyond the benefits provided by the angiotensin-converting enzyme inhibitor enalapril.¹ Now, only a few years later, a remarkable data set has emerged with the sodium-glucose cotransporter-2 inhibitors (SGLT2is) in HF. Initially, the diabetes cardiovascular outcome trials provided evidence of the role of these agents in preventing incident HF in patients with type 2 diabetes mellitus. Last, the recent publication of the primary results of the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) demonstrated substantial benefits in outcomes on top of triple therapy for patients with chronic HFrEF, benefits that are remarkably similar in patients with and without diabetes mellitus.² So is it now time for triple therapy to evolve to quadruple therapy in patients with HFrEF?

The field of HF must now grapple with a number of questions in light of these new data in patients with established HFrEF. Is this a class effect of SGLT2is in general or specific to dapagliflozin? What about other benefits beyond morbidity and mortality? What are the specific mechanisms underlying the observed effects? And last, how should this new class of drugs be implemented, especially in groups of patients (eg, the elderly) where aggressive uptitration of triple therapy has often been a challenge? In that context, the articles by Kosiborod et al³ and Martinez et al⁴ in this issue of Circulation expand the dapagliflozin in HF story and provide greater insights into some of these critical questions.

First, Kosiborod et al³ present a detailed analysis of the effects of dapagliflozin on health-related quality of life in the DAPA-HF study. These data are of critical importance, because improving patient-reported outcomes in HF, especially in highly symptomatic patients, is an important goal in drug development. The reported analysis from DAPA-HF shows a clinically important benefit on health-related quality of life (as measured by the well-validated Kansas City Cardiomyopathy Questionnaire score) with dapagliflozin in comparison with placebo that was sustained >8 months. In a responder analysis, patients randomly assigned to dapagliflozin were more likely to experience a 5-, 10-, or ≥15-point improvement in Kansas City Cardiomyopathy Questionnaire score (consistent with small, medium, and large improvements in health-related quality of life) than were patients on placebo. Although the mean improvement (a 2.8 change in Kansas City Cardiomyopathy Questionnaire total symptom score over placebo at 8 months) may appear modest, it should be noted that this is a similar or greater magnitude of improvement in comparison with Kansas City Cardiomyopathy Questionnaire changes with other effective HF therapies, including sacubitril-valsartan, ivabradine, and cardiac resynchronization therapy. These results confirm and extend the prior results from the DEFINE-HF study (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) in a larger population with longer follow-up.⁵ Dapagliflozin therefore joins a select group of HF interventions that improve mortality, reduce hospitalizations, and improve health-related quality of life in patients with HFrEF: the 3 critical goals of HF treatment.

Another highly relevant question about the potential role of dapagliflozin in HF is how well it works across the spectrum of patients with HFrEF, in particular, groups of patients in whom it is often challenging to optimize GDMT, such as the elderly. Older patients are underrepresented in clinical trials in HF, and aggressive uptitration of GDMT in older patients is often limited by comorbidities, frailty, and polypharmacy. The article by Martinez et al⁴ reports the efficacy and tolerability of dapagliflozin stratified by age group. As expected, the event rate for the primary end point (cardiovascular death or HF event) increased with age, driven primarily by a greater risk of HF events. It is reassuring that, in DAPA-HF, the treatment effect of dapagliflozin was similar across all age groups, including patients >75 years of age. Indeed, the point estimate for the treatment effect of dapagliflozin in the 1149 patients >75 years of age was numerically greatest of all age categories (hazard ratio, 0.68), and the absolute risk reduction in older patients was higher (because of a higher baseline risk than younger patients). In DAPA-HF, older patients were less likely to be aggressively treated with GDMT, consistent with other studies. As anticipated, older patients were more likely to have adverse events and drug intolerance, but this was similar in both the dapagliflozin and placebo groups.

These data emphasize another potentially attractive feature of SGLT2is as HF therapy: in general, these agents play well with others when it comes to overlapping intolerances that often limit (either in reality or in perception) the optimization of GDMT. Although SGLT2i therapy may lead to volume depletion and require adjustment of diuretics, the SGLT2is generally lack some of the other dose-limiting adverse effects (such as renal dysfunction, hyperkalemia, and hypotension) that can make aggressive uptitration of GDMT problematic, in particular, in older patients or those with more advanced disease.

Where do we go from here? It is important to acknowledge that, although well-conducted and convincing, DAPA-HF is only a single trial. Multiple ongoing studies will continue to fill out the picture of the role of SGLT2is as a class in the treatment of HF, including studies with other SGLT2s, and trials in patients with HF and preserved ejection fraction and those hospitalized with HF, as well. Although the accumulated data on this class to date certainly seem hopeful, definitive answers to some of these questions await the results of ongoing studies.

Assuming that future data confirm the benefits of SGLT2is in HF, the next critical step is implementation, a challenge that has been well documented in other aspects of GDMT despite most therapies being available as low-cost generic drugs.⁶ On the basis of the recent experience with sacubitril-valsartan, it is clear that evidence generation alone is insufficient to move the needle for the uptake of new efficacious treatments.⁷ Gaps in implementation can result from a combination of knowledge deficits, clinical inertia, patient reluctance to take additional medications, and barriers to access from payers. As we stand at the beginning of a new era of quadruple therapy for HFrEF with β-blockers, angiotensin receptor-neprilysin inhibitor, mineralocorticoid receptor antagonists, and SGLT2is, it is incumbent on the field to realize that the real work of getting the right drug to the right patient at the right time has only just begun.

Dr Felker has received research grants from the National Heart, Lung, and Blood Institute, American Heart Association, Amgen, Merck, Cytokinetics, and Roche Diagnostics; he has acted as a consultant to Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Relypsa, V-Wave, Myokardia, Innolife, EBR Systems, Arena, Abbott, Sphingotec, Roche Diagnostics, Alnylam, LivaNova, Windtree Therapeutics, Rocket Pharma, and SC Pharma.

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

https://www.ahajournals.org/journal/circ

文章，请参阅第90和100页

The serial development of treatments that improve morbidity and mortality in patients with chronic heart failure with reduced ejection fraction (HFrEF) is one of the great success stories of cardiovascular therapeutics. Until recently, the combination of β-blockers, renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), and mineralocorticoid receptor antagonists formed the foundation of triple therapy for heart failure (HF). These agents, each of which provides clear benefits on mortality and morbidity in patients with HFrEF, collectively came to be termed guideline-directed medical therapy (GDMT). This stable foundation of HF therapeutics was upended in 2014 by the stunning results of the PARADIGM-HF study (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), demonstrating substantial improvements in outcomes with the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan above and beyond the benefits provided by the angiotensin-converting enzyme inhibitor enalapril.¹ Now, only a few years later, a remarkable data set has emerged with the sodium-glucose cotransporter-2 inhibitors (SGLT2is) in HF. Initially, the diabetes cardiovascular outcome trials provided evidence of the role of these agents in preventing incident HF in patients with type 2 diabetes mellitus. Last, the recent publication of the primary results of the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) demonstrated substantial benefits in outcomes on top of triple therapy for patients with chronic HFrEF, benefits that are remarkably similar in patients with and without diabetes mellitus.² So is it now time for triple therapy to evolve to quadruple therapy in patients with HFrEF?

鉴于已建立HFrEF的患者的这些新数据，HF领域现在必须解决许多问题。这是SGLT2的类效应是一般还是特定于dapagliflozin？除了发病率和死亡率之外，其他好处又如何呢？观察到的影响的具体机制是什么？最后，应该如何实施这种新型药物，特别是在积极地采用三联疗法挑战的患者群体中（例如，老年人）？在这种情况下，Kosiborod等人³和Martinez等人⁴在本期《循环》上的文章扩展了dapagliflozin在HF方面的应用，并为其中一些关键问题提供了更深刻的见解。

首先，Kosiborod等人³在DAPA-HF研究中，对达格列净对健康相关生活质量的影响进行了详细分析。这些数据具有至关重要的意义，因为改善心力衰竭患者报告的结局，尤其是对有症状的患者而言，是药物开发的重要目标。DAPA-HF的报告分析显示，与持续时间超过8个月的安慰剂相比，使用dapagliflozin对健康相关的生活质量具有临床重要意义（通过经过验证的堪萨斯城心肌病问卷调查评分）。在回应者分析中，随机分配达格列净的患者更有可能在堪萨斯城心肌病问卷调查中获得5分，10分或≥15分的改善（与小，中，并且与健康相关的生活质量得到了极大的改善）。尽管平均改善（在8个月时，堪萨斯城心肌病问卷调查的总症状评分较安慰剂高2.8个变化）可能看起来不大，但应注意的是，与堪萨斯城心肌病问卷的其他改善相比，这是一个相似或更大的改善幅度有效的高频疗法，包括屈比特尔-缬沙坦，伊伐布雷定和心脏再同步化疗法。这些结果证实并扩大了DEFINE-HF研究的先前结果（达格列净对射血分数降低的HF患者的生物标志物，症状和功能状态的影响），且随访时间更长。在8个月时，堪萨斯城心肌病问卷总症状评分超过安慰剂的8个变化可能看起来不大，应该指出的是，与堪萨斯城心肌病问卷与其他有效的HF治疗方法（包括屈比特利特）相比，其改善程度相似或更高-缬沙坦，伊伐布雷定和心脏再同步治疗。这些结果证实并扩大了DEFINE-HF研究的先前结果（达格列净对射血分数降低的HF患者的生物标志物，症状和功能状态的影响），且随访时间更长。在8个月时，堪萨斯城心肌病问卷调查总症状评分超过安慰剂的8个变化可能看起来不大，应注意的是，与堪萨斯城心肌病问卷调查与其他有效的HF治疗方法（包括屈比特利特）相比，改善程度相似或更大-缬沙坦，伊伐布雷定和心脏再同步治疗。这些结果证实并扩大了DEFINE-HF研究的先前结果（达格列净对射血分数降低的HF患者的生物标志物，症状和功能状态的影响），且随访时间更长。包括沙比特尔-缬沙坦，伊伐布雷定和心脏再同步治疗。这些结果证实并扩大了DEFINE-HF研究的先前结果（达格列净对射血分数降低的HF患者的生物标志物，症状和功能状态的影响），且随访时间更长。包括沙比特尔-缬沙坦，伊伐布雷定和心脏再同步治疗。这些结果证实并扩大了DEFINE-HF研究的先前结果（达格列净对射血分数降低的HF患者的生物标志物，症状和功能状态的影响），且随访时间更长。⁵ Dapagliflozin因此加入了一系列的HF干预措施，这些措施可改善HFrEF患者的死亡率，减少住院治疗并改善健康相关的生活质量：HF治疗的三个关键目标。

关于达格列净在HF中潜在作用的另一个高度相关的问题是，它在HFrEF患者的整个频谱中如何发挥良好的作用，尤其是在老年人中优化GDMT常常面临挑战的患者群体。老年患者在HF的临床试验中代表性不足，并且老年患者中GDMT的激增通常受到合并症，虚弱和多药治疗的限制。Martinez等人的文章⁴报告按年龄组分层的达格列净的疗效和耐受性。正如预期的那样，主要终点事件的发生率（心血管死亡或HF事件）随着年龄的增长而增加，这主要是由HF事件的更大风险所驱动。令人放心的是，在DAPA-HF中，达格列净的治疗效果在所有年龄组中均相似，包括> 75岁的患者。的确，达格列净在超过75岁的1149例患者中治疗效果的点估计值在所有年龄段中均达到数字最大（危险比，0.68），而老年患者的绝对风险降低更高（因为基线更高）风险要比年轻患者高）。与其他研究一致，在DAPA-HF中，老年患者不太可能接受GDMT积极治疗。不出所料

这些数据强调了SGLT2的另一个潜在诱人特征是HF治疗：总的来说，当涉及到不耐受的重叠不耐受时，这些药物通常与其他药物一起发挥良好作用，而这些不耐受通常会限制（无论是在现实中还是在感知上）GDMT的优化。尽管SGLT2i治疗可能会导致容量减少并需要调整利尿剂，但SGLT2通常缺乏其他一些剂量限制的不良反应（例如肾功能不全，高钾血症和低血压），这些不良反应会导致GDMT的主动调高成为问题，特别是，在年龄较大的患者或患有较晚期疾病的患者中。

我们从这里去哪里？重要的是要承认，尽管操作合理且令人信服，但DAPA-HF只是一个单独的试验。正在进行的多项研究将继续充实SGLT2is作为一类在HF治疗中的作用的图景，包括与其他SGLT2s的研究，以及在HF和射血分数保留的患者以及HF住院患者中进行的试验。尽管迄今为止在该课程上积累的数据肯定是希望的，但是对其中一些问题的确切答案仍在等待进行中的研究结果。

假设未来的数据证实了SGLT2在HF中的益处，那么下一个关键步骤就是实施，尽管大多数疗法都是低成本的仿制药，但这一挑战已在GDMT的其他方面得到了充分证明。^[6]根据最近使用沙必比尔-缬沙坦的经验，很明显，仅凭证据产生不足以推动人们采用新的有效疗法。⁷实施方面的差距可能是由于知识不足，临床惯性，患者不愿服用其他药物以及付款人难以获得药品等综合因素造成的。正当我们站在使用β-受体阻滞剂，血管紧张素受体-中性溶酶抑制剂，盐皮质激素受体拮抗剂和SGLT2的HFrEF四联疗法新时代的开始时，该领域有责任认识到获得正确药物的真正工作在适当的时间为适当的患者服务才刚刚开始。

Felker博士已获得美国国家心脏，肺和血液研究所，美国心脏协会，安进公司，默克公司，细胞动力学和罗氏诊断公司的研究资助；他曾担任诺华，安进，BMS，细胞动力学，美敦力，心律，Relypsa，V-Wave，Myokardia，Innolife，EBR Systems，Arena，Abbott，Sphingotec，Roche Diagnostics，Alnylam，LivaNova，Windtree Therapeutics，Rocket Pharma的顾问和SC Pharma。

本文表达的观点不一定是编辑者或美国心脏协会的观点。

https://www.ahajournals.org/journal/circ