Heart failure prevention with sodium‐glucose cotransporter 2 inhibitors

The prevalence of type 2 diabetes (T2D) has increased by 60% over the past three decades. Current projections estimate that by 2030 T2D will be the seventh leading cause of death worldwide.1, 2 Despite recent advances in medical care, cardiovascular disease continues to be the leading cause of morbidity and mortality in this cohort.3 Multiple studies have shown that T2D not only increases the risk of stroke and myocardial infarction, but also increases the risk of heart failure (HF). Heart failure is a common complication of T2D, with especially poor outcomes and 5-year survival rates of less than 25%.4 Even asymptomatic diabetic patients with minimal cardiovascular risk factors may develop impaired diastolic function early in the course. Middle-aged diabetic patients may have HF in the absence of a vascular event. Most current preventive therapeutic interventions for this cohort primarily aim to reduce the risk of ischemic cardiovascular events and do not target the pathophysiological mechanisms responsible for the development of diabetic cardiomyopathy and subsequent HF, highlighting the need for novel treatments.5-8 In 2008, the US Food and Drug Administration (FDA) released an industry guidance statement (https://www.fda.gov/downloads/Drugs/Guidances/ucm071627.pdf. Accessed February November 20, 2018) requiring all glucose-lowering drug trials to report major adverse cardiovascular events in patients with T2D. Several trials assessing the cardiovascular effects of novel drug classes, such as glucagon-likepeptide-1(GLP-1) receptor agonists, dipeptidyl peptidase (DPP)-4 inhibitors and sodium-glucose cotransporter 2 (SGLT-2) inhibitors, were completed and published. These studies were designed to demonstrate that the cardiovascular safety of the respective drugs was not inferior to placebo. A network meta-analysis of these trials showed that a 99.6% probability existed of SGLT2 inhibitors being the optimal treatment for reducing the risk of HF hospitalization in T2D, followed by GLP-1 agonists (0.27%) and DPP-4 inhibitors (0.1%).9 These findings suggest that among the novel antihyperglycemic medications, SGLT2 inhibitors are the most beneficial in reducing the risk of HF. The impetus of these results is largely driven by two large scale trials, namely the Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes (CANVAS) and Empagliflozin Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG) trials. Both CANVAS and EMPA-REG trials showed reductions of more than 30% in HF hospitalization among T2D patients, with hazard ratios (HR) of 0.67 (95% confidence interval [CI] 0.52-0.8) and 0.65 (95% CI 0.50-0.85), respectively.10, 11 Recent analyses outlining the comparative effects of SGLT2 inhibitors among patients with and without HF at baseline has broadened our understanding regarding SGLT2 inhibitors for the primary and secondary prevention of HF. Subgroup analysis of the CANVAS and the EMPA-REG OUTCOME trials showed that both canagliflozin and empagliflozin reduce HF admissions in patients with (HR 0.51 [95% CI 0.33-0.79] and 0.75 [95% CI 0.48-1.17], respectively) or without (HR 0.79 [95% CI 0.57-1.09] and 0.59 [95% CI 0.43-0.81], respectively) HF at baseline.12, 13 Consistent with the findings in CANVAS and EMPA-REG OUTCOME, the effect of SGLT2 inhibition on the prevention of HF hospitalization has also been observed in real-world studies, such as CVD-REAL(Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2Inhibitors),14 which reported significant benefit of several SGLT2 inhibitors on mortality and hospitalization for HF (Table 1). Separate analyses investigating dapagliflozin vs other glucose-lowering therapies in a cohort of ≤5% HF at baseline also revealed similar beneficial cardiovascular effects.15, 16 These findings suggest that beneficial effects of SGLT2 inhibitors on the primary prevention of HF may not be limited just to one particular drug, but rather be a class effect. The biology of SGLT2 inhibition from a cardiac perspective is interesting, and many mechanistic bases underlying the beneficial effects of SGLT2 inhibition on HF risk have been put forward (Figure 1). Glycosuria along with natriuresis leads to osmotic diuresis, which may result in reduced preload.19 This condition, coupled with modification of the intrarenal renin-angiotensin axis, reduction in arterial stiffness, and systemic blood pressure lowering, may contribute to optimize loading conditions of the myocardium.20-22 There may also be a direct positive effect of SGLT2 inhibition on cardiac metabolism; an established effect of SGLT2 inhibitors is increased hepatic neogenesis of ketone bodies, which are an essential alternative fuel source for the hypertrophied and failing heart.21 Recent studies have also shown that SGLT2 inhibitors may hinder myocardial sodium-hydrogen exchange and thus modify intracellular calcium and sodium handling, which may prevent HF-associated remodeling.22 Finally, the preservation of renal function and regulation of interstitial volume status may be particularly useful in the reduction of HF risk.23 Although current data support the use of SGLT2 inhibitors for primary prevention, data related to secondary prevention of adverse outcomes in those with prevalent HF must be interpreted with care where the evidence is largely based on subgroup analysis of trials that are smaller and accrued fewer events. Furthermore, in the vast majority of studies, patients were categorized based on investigator-reported criteria, and none of these studies measured cardiac function, such as left ventricular ejection fraction, or biomarkers, like N-terminal pro B-type natriuretic peptide, at baseline.24 Ongoing trials with these drugs in patients with manifest HF will shed further light in that regard.25-28 在过去的三十年中2型糖尿病(T2D)的患病率已经增加了60%。目前预测，估计到2030年时T2D将成为全球第七大死因1,2。尽管近年来在医疗保健方面取得了一些进展，但是在T2D人群中心血管疾病仍然是发病率与死亡率最多的病因3。多项研究结果表明，T2D不但可以导致中风与心肌梗死的风险增加，而且也增加了心力衰竭(HF)的风险。心力衰竭是一种常见的T2D并发症，预后特别差，5年生存率低于25%4。即使是心血管危险因素最低的无症状糖尿病患者也可能在病程早期出现心脏舒张功能受损。中年糖尿病患者在没有血管事件的情况下也可能出现HF。目前大多数针对这个人群的预防性干预治疗主要是为了降低缺血性心血管事件的风险，并不是针对糖尿病性心肌病以及随后发生HF的病理生理机制，因此显示出新的治疗方法的必要性5-8。 在2008年，美国食品药品监督管理局(FDA)发布了一项行业指导声明(https://www.fda.gov/downloads/Drugs/Guidances/ucm071627.pdf. Accessed February November 20, 2018)，要求所有的降糖药物试验都要报告T2D患者的主要不良心血管事件。有一些评估新类别药物(如胰高血糖素肽-1[GLP-1]受体激动剂、二肽基肽酶[DPP]-4抑制剂以及钠-葡萄糖共转运体2[SGLT-2]抑制剂)对心血管影响的试验已经完成并且发表。这些研究的目的是要证明各个药物的心血管安全性不亚于安慰剂。针对这些试验的网络mata分析结果表明，使用SGLT2抑制剂治疗是减少T2D患者HF住院风险的最佳治疗方法，治疗有效的可能性达到了99.6%，接着是GLP-1激动剂(0.27%)与DPP-4抑制剂(0.1%)9。这些研究结果表明，在这些新型的降糖药物中SGLT2抑制剂是最有益于减少HF风险的药物。促进这些结果主来自两项大规模试验，即评估2型糖尿病患者使用坎格列净治疗后心血管与肾脏事件(Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes，CANVAS)的试验以及评估2型糖尿病患者使用恩格列净治疗后心血管结果与死亡率(Empagliflozin Cardiovascular Outcomes, and Mortality in Type 2 Diabetes，EMPA-REG)的试验。CANVAS与EMPA-REG试验结果都表明，T2D患者的HF住院减少了30%以上，风险比(HR)分别为0.67(95%置信区间[CI]为0.52-0.8)与0.65(95% CI为0.50-0.85)10,11。 最近有研究列出了基线时合并或者不合并HF患者使用SGLT2抑制剂治疗后的对比结果，这加深了我们对SGLT2抑制剂一级预防与二级预防HF的理解。CANVAS与EMPA-REG试验的亚组分析结果表明，坎格列净与恩格列净都可以减少患者的HF住院，无论他们在基线时合并(HR分别为0.51[95% CI为0.33-0.79]与0.75[95% CI 0.48-1.17])或不合并(HR分别为0.79 [95% CI为0.57-1.09]与0.59 [95% CI为0.43-0.81])HF12,13。与CANVAS以及EMPA-REG OUTCOME试验研究结果相一致的是，在真实世界研究中也观察到了SGLT2抑制剂具有预防HF住院的结果，例如在初次使用SGLT-2抑制剂的患者中比较它们对心血管结果的疗效研究(Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2-Inhibitors，CVD-REAL)中14，报告了患者使用几种SGLT-2抑制剂治疗后的死亡率以及HF住院都有显著减少。在基线时HF≤5%的队列中，单独分析达格列净与其他降糖治疗药物对心血管的影响，结果也显示了达格列净具有类似的获益15,16。这些研究结果表明，SGLT2抑制剂有益于HF的一级预防治疗，这可能并不仅仅局限于某一种特定的药物，而是种类效应。 从保护心脏的角度来看，抑制SGLT2的生物学效应非常有趣，目前已经有人提出了许多潜在的SGLT2抑制后可以减少HF风险的相关作用机制。尿糖与尿钠同时增多会导致渗透性利尿，这可能会导致心脏前负荷降低19。这种情况加上肾脏内的肾素-血管紧张素轴改变、动脉僵硬度的降低以及全身血压的降低，这些可能都有助于改善心肌的负荷程度20-22。SGLT2抑制后对心脏的代谢也可能会有直接的有益影响；SGLT2抑制剂有一个明确作用是增加肝脏的酮体再生，而酮体对于肥大与衰竭的心脏来说是一种重要的替代能量来源21。最近的研究也表明，SGLT2抑制剂可能会抑制心肌的钠-氢交换，从而影响细胞内钙与钠的处理，而这可以预防HF相关的心肌重塑22。最后，维持肾功能与调节间质容量状态对于降低HF风险来说特别有益23。 虽然目前的数据支持使用SGLT2抑制剂治疗来一级预防HF的发生，但是对于普通的HF患者来说，我们必须谨慎地解释与二级预防不良结果相关的数据，因为这些证据主要来源于规模较小并且累积事件较少的试验亚组分析。此外，在绝大多数研究中，患者都是根据研究者报告的标准来分类，而在这些研究中没有一项在基线时测量过心脏功能如左心室射血分数或生物标志物如N末端B型尿钠肽原24。目前正在进行的使用这些药物治疗严重HF患者的试验将有助于进一步阐明这种关系25-28。 Muhammad Shahzeb Khan has no disclosures. Javed Butler has received research support from the National Institutes of Health, Patient Centered Outcomes Research Institute (PCORI), and the European Union, and serves as a consultant for Amgen, Array, AstraZeneca, Bayer, BoehringerIngelheim, Bristol Myers Squib, CVRx, G3 Pharmacauticals, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Relypsa, StealthPeptide, SC Pharma, Vifor, and ZS Pharma.