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Sodium–glucose co‐transporter 2 inhibitors and acute heart failure

2020; Elsevier BV; Volume: 22; Issue: 4 Linguagem: Inglês

10.1002/ejhf.1759

1879-0844

Amy Groenewegen, Frans H. Rutten,

Neuroendocrine Tumor Research Advances

This article refers to 'Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF)' by K. Damman et al., published in this issue on pages 713–722. Inhibitors of sodium–glucose co-transporter 2 (SGLT2) were initially designed as a new class of hypoglycaemic agents that lowered blood glucose levels in patients with type 2 diabetes. They have become a major focus of interest after three large, Food and Drug Administration-mandated cardiovascular outcome trials suggested that this class of drugs may have profound cardiorenal benefits as well. Compared to placebo, SGLT2 inhibitors unexpectedly and substantially reduced the secondary outcome of hospitalization for heart failure by 25–35% and prevented deterioration of renal function in type 2 diabetes patients.1 Remarkably, the reduction in heart failure hospitalization occurred independently of the glucose-lowering effects. This finding has sparked the idea that SGLT2 inhibition may be therapeutic in patients with heart failure irrespective of diabetes status, which in turn led to a surge in prospective studies evaluating the therapeutic potential of SGLT2 inhibitors across the heart failure spectrum. The recently DAPA-HF trial was the first to show that the SGLT2 inhibitor dapagliflozin indeed reduced the relative risk of the primary composite outcome of worsening heart failure or cardiovascular death by 26%, compared to placebo, in patients with chronic heart failure and a reduced ejection fraction, and that these benefits were similar among patients with and without diabetes (∼60% of participants did not have diabetes).2 Several ongoing trials, including some that involve patients with chronic heart failure with preserved ejection fraction, are expected to read out from 2020 onward. Based on these promising findings in patients with chronic heart failure, Damman and colleagues report in this issue of the Journal the findings of a pilot study evaluating safety and clinical efficacy of the SGLT2 inhibitor empagliflozin in patients with acute decompensated heart failure, the first of its kind. In the multicentre EMPA-RESPONSE-AHF pilot study, 80 patients with acute heart failure (∼50% acutely decompensated heart failure and ∼50% de novo heart failure; overall, ∼30% type 2 diabetes) were randomized to receive either empagliflozin (10 mg/day) or placebo for 30 days, in addition to standard diuretic therapy.3 In this short period of time, empagliflozin did not reduce the primary outcomes of (i) the visual analogue scale dyspnoea score, (ii) diuretic response, (iii) change in N-terminal pro-brain natriuretic peptide (NT-proBNP), or (iv) length of hospital stay. However, taking empagliflozin did confer benefits to patients on the secondary, composite outcome of in-hospital worsening heart failure, rehospitalization for heart failure or death within 60 days, compared to placebo [4 (10%) vs. 13 (33%), P = 0.014]. Although small in number, this finding seems relevant and was mainly driven by a reduction in worsening heart failure, defined as worsening signs and symptoms that require an intensification of intravenous therapy or mechanical support. However, only the composite endpoint reached statistical significance. Acutely decompensated heart failure is the leading cause of hospitalization in the elderly and associated with high risk of (post-discharge and in-hospital) mortality, rehospitalization and health care costs. Unlike in chronic heart failure, there are currently no therapies to convincingly improve clinical outcomes in acute heart failure, apart from those treating underlying causes.4 Despite treatment with loop diuretics, the mainstay for decongestive therapy in acute heart failure, up to 20% of patients is insufficiently recompensated at discharge.5 Residual congestion at discharge is associated with even higher risks of readmission and death, particularly in the case of co-existing renal impairment and poor diuretic response.6 The exact mechanism behind the cardiovascular benefit of SGLT2 inhibitors is yet unclear; postulated pathways include renal enhancement, improved haemodynamics and, most notably, increased natriuresis. Based on these pharmacological effects, SGLT2 inhibitors could indeed be beneficial in acute heart failure patients, as Damman and colleagues hypothesized. At first glance, it seems therefore surprising and somewhat confusing that there was no difference in diuretic response (defined as weight/furosemide dose), dyspnoea severity, and NT-proBNP levels across both groups (empagliflozin vs. placebo) in the current pilot study. This finding is likely at least partly related to the small power caused by the low number of participants in this pilot study and the short-term follow-up, but it may also reflect the imperfection of these surrogate outcome measures for evaluation of the effects of SGLT2 inhibitors in heart failure. Short-term fluid loss is known to poorly correlate with weight loss and with dyspnoea relief.7, 8 Indeed, subgroup analysis of the EMPA-RESPONSE-AHF study showed that empagliflozin compared to placebo was associated with a clinically relevant and significantly greater cumulative urine output (difference 3449 mL, 95% confidence interval 578–6320 mL, P < 0.01, n = 28 for this outcome) after 4 days and higher net fluid loss (−2163 mL vs. −1007 mL, P < 0.01, n = 53) after 1 day, although numbers are too low to support robust conclusion. This study calls for rethinking hypotheses about the main mechanisms by which SGLT2 inhibitors might exert their benefits. Recent pathophysiological studies suggest important differences between SGLT2 inhibitors and loop diuretics. For example, in EMPA-REG OUTCOME, no significant changes were observed in serum electrolytes, especially sodium and potassium, with empagliflozin.9 Conversely, loop diuretics generally cause potassium loss and are known to increase the risk of sudden cardiac death, whereas SGLT2 inhibitors significantly reduce this risk of sudden death.2 In another comparative study, both dapagliflozin and bumetanide reduced sodium and interstitial fluid, but while bumetanide simultaneously lowered intravascular volume, dapagliflozin did not or only a bit.10 This differential regulation of interstitial and intravascular compartments is of particular interest to heart failure patients, whose symptoms are caused by excess fluid in the venous system and interstitial space, but who simultaneously suffer from arterial underfilling as a result of low cardiac output. Unlike loop diuretics, which generally aggravate arterial underfilling, SGLT2 inhibitors are not associated with the typical signs of intravascular dehydration, such as increased sympathetic activity or a decrease in glomerular filtration rate (GFR) if blood pressure falls to levels that are too low to maintain sufficient filtration pressure. It may also explain why the decline in NT-proBNP was only modest (10–15%) in DAPA-HF and absent in the current study. If arterial fluid pressure is not reduced, left ventricular wall tension will not decrease either, according to LaPlace's law (wall tension = pressure x volume/mass). Because NT-proBNP is a direct measure of wall tension, it may not be a suitable surrogate outcome for SGLT2 benefits, at least not in studies with short follow-up. All together, the findings in the EMPA-RESPONSE-AHF study are good omens for acute heart failure patients, who thus far have mainly had to rely on loop diuretics, which are remarkably effective for symptom reduction but come with associated problems of hypokalaemia, hyponatraemia and (at least initially) decreasing renal function. Large trials including extensive biomarker studies in chronic heart failure with reduced or preserved ejection fraction patients are nearing completion, and will provide more insight on the working mechanism of SGLT2 inhibitors in heart failure. Although EMPA-RESPONSE-AHF lacks the numbers to support robust conclusions on benefits, and the low inclusion rate may raise questions on generalizability, this pilot study showed that empagliflozin is likely safe to use even in the first vulnerable days after hospitalization for acute heart failure. Numbers of adverse events were comparable across groups and empagliflozin had no major effects on heart rate, blood pressure or kidney function in the short term; an important finding, as SGLT2 inhibitors are known to induce a short-lived but acute reduction in GFR by enhancing tubuloglomerular feedback and increasing afferent arteriole tone, before preserving GFR in the long term.11 Although reversible, such an acute reduction in GFR could have had serious negative effects in acutely decompensated patients, but this did not occur in the EMPA-RESPONSE-AHF study. Lastly, in the EMPA-RESPONSE-AHF study, similarly to the results in the DAPA-HF trial, no (serious) adverse events regarding glucose regulation occurred among those with (∼30%) or without type 2 diabetes (∼70%). These safety results thus provide the necessary groundwork for larger efficacy trials in acute heart failure patients. However, as highlighted by other authors,12 the impressive results of DAPA-HF and other SGLT2 inhibitor trials should not distract us from the fact that the benefits of any new therapeutic option will fall into insignificance unless we manage to improve guideline-recommended therapy use and adherence. The uptake of some medication known to reduce heart failure hospitalization is still poor.13 For example, angiotensin receptor–neprilysin inhibitors, which were proven to be beneficial for the majority of heart failure patients with a reduced ejection fraction in 2014,14 are used by a mere 15% of patients with a clinical indication for their use.15 The EMPA-RESPONSE-AHF pilot study is no exception: only 5% of the patients presenting with acute decompensated heart failure used an angiotensin receptor–neprilysin inhibitor at baseline. That being said, the field of acute heart failure care has not seen pharmacological advances in many years despite no lack of effort,16-18 and SGLT2 inhibitors are a welcome surprise. Conflict of interest: none declared.