Dapagliflozin in Heart Failure: New Frontiers (2019)

This article refers to ‘The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial: baseline characteristics’, by J.J.V. McMurray et al., published in this issue on pages 1402–1411. Diabetes and heart failure (HF) are inextricably linked to one another.1 Diabetes is an important risk factor for developing HF and among patients with HF, diabetes is one of the most important adverse prognostic factors.1-3 More recently, the Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) confirmed earlier results from the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and the Canagliflozin Cardiovascular Assessment Study (CANVAS) trials, by showing patients with type 2 diabetes at risk for atherosclerotic cardiovascular disease treated with sodium–glucose co-transporter 2 (SGLT2) inhibitors were less likely to be hospitalized for HF compared to placebo.4 Importantly, the cardiovascular mortality and HF hospitalization curves in previous trials have demonstrated early separation, suggesting a unique mechanistic component of SGLT2 inhibitors that may confer specific cardiovascular and HF benefit. This raises the interesting question whether SGLT2 inhibitors might reduce cardiovascular mortality in patients with HF, even in patients without diabetes. There is some early evidence that SGLT2 inhibitors not only prevent HF, but might also serve as potential treatment for patients with prevalent HF—in both the CANVAS and DECLARE-TIMI-58 trials treatment with SGLT2 inhibitors reduced cardiovascular death with a potentially greater magnitude in patients with HF at baseline.5, 6 Subsequent analyses suggested the risk reduction is present in patients with chronic kidney disease and across a spectrum of cardiovascular risk. In addition to diabetes, many HF patients have prevalent and active co-morbidities such as these, thus a therapy that may reduce the risk of readmission and mortality when faced with these co-morbidities would be a significant advancement. Furthermore, in the EMPA-REG OUTCOME trial, use of empagliflozin was associated with a reduction in deaths from pump failure, while cardiovascular deaths relating to atherosclerotic events were seemingly not affected.7 Lastly, in the DECLARE-TIMI 58 trial, this reduction was stronger in patients with a history of HF with reduced ejection fraction (HFrEF) compared to patients with HF without a known history of HFrEF.6 In the current issue of the Journal, McMurray et al. present the baseline characteristics of 4744 patients with HFrEF enrolled in the international, multicentre, parallel group, randomized, double-blind Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) study.8, 9 The authors demonstrate that the population enrolled in DAPA-HF is generally similar compared to other recent trials with ambulant HFrEF, including the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial and the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure (ATMOSPHERE). Patients are of similar age compared to the populations of these earlier two trials and the proportion of patients treated with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor–neprilysin inhibitor (94%), beta-blocker (96%), and mineralocorticoid receptor antagonist (71%) is high. The rate of implantable cardioverter-defibrillator implementation was higher (26%) compared to PARADIGM-HF (15%) and ATMOSPHERE (15%) but could be accounted for by differences in regional enrolment according to the authors, particularly the greater proportion of patients from North America. Despite similar inclusion and exclusion criteria, patients in DAPA-HF had a greater number of co-morbidities, a greater proportion of patients with estimated glomerular filtration rate < 60 mL/min/1.73 m2, much higher concomitant use of mineralocorticoid receptor antagonists, and were more reflective of patients enrolled in A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure (COMMANDER-HF) than PARADIGM-HF or ATMOSPHERE. This may be reflective of willingness and enthusiasm of investigators to enrol and randomize a more advanced HF patient population when the investigational drug is not a HF-specific vasoactive agent. The overall prevalence of a history of diabetes was comparatively higher in patients enrolled in DAPA-HF (42%) compared to PARADIGM-HF (35%) and ATMOSPHERE (28%), although in the latter study inclusion of patients with diabetes was halted by European regulators due to safety concerns.10, 11 The prevalence of a history of diabetes in DAPA-HF more closely resembled patient characteristics seen in the recent COMMANDER-HF trial (41%). However COMMANDER-HF only included patients with a history of coronary artery disease, which might have led to a greater proportion of patients with a history of diabetes included in this study.12 The authors rightly point out that the prevalence of diabetes was similar to several contemporary registries such as Change the Management of Patients with Heart Failure (CHAMP-HF); however, these are either single country or regional registries performed in the West, where the prevalence of obesity and concomitant diabetes are considerably higher compared to non-western regions. Variable definitions of diabetes and pre-diabetes between these trials may impact extrapolation of the impact of dapagliflozin from DAPA-HF to other populations of patients with diabetes and pre-diabetes. However, if SGLT2 inhibitors improve outcomes in patients with HF both with and without diabetes, these variable definitions may be less important. Importantly, it is encouraging to see that the clinical characteristics of patients without a history of diabetes are largely similar to those of patients without a history of diabetes enrolled in ATMOSPHERE and PARADIGM-HF.10, 11 The possible mechanisms underlying the potential cardioprotective effects of SLGT2 inhibitors have been much debated. The potential beneficial effects of SGLT2 inhibitors might be mediated through their natriuretic effects and subsequent decrease in afterload13, 14; a recent secondary analysis in the EMPA-REG OUTCOME study suggests changes in markers of plasma volume were the most important mediators of the reduction in risk of cardiovascular death with empagliflozin vs. placebo without negative renal effects.14 Their impact on the proximal tubule to promote diuresis suggests they may be of benefit in patients with acute HF. The cardiorenal syndrome and diuretic resistance can prevent adequate decongestion in acute HF. The synergy provided by combining an SGLT2 inhibitor with a loop diuretic may be of potential benefit. Further, the hypothesis of their utility in HF patients regardless of the presence of diabetes is further supported by recent results from the EMPA-HEART CardioLink-6 trial, where among 97 patients with type 2 diabetes randomized to empagliflozin vs. placebo, there was a greater reduction in left ventricular mass and systolic blood pressure after 6 months in the group treated with empagliflozin compared to placebo.13 A recent experimental study in non-diabetic rats undergoing permanent coronary artery ligation to induce myocardial infarction compared to sham surgery supports the hypothesis of a unique cardiac effect of SGLT2 inhibitors.15, 16 Rats were given empagliflozin saturated chow vs. control either before or 2 weeks after surgery. In rats (pre-)treated with empagliflozin, diuresis was increased without affecting renal function. Empagliflozin also improved cardiac function post-myocardial infarction, increased ATP availability, and attenuated pathological cardiomyocyte hypertrophy and cardiac fibrosis in both rats treated with empagliflozin before the infarct as well as in rats receiving empagliflozin 2 weeks after surgery.15 Clearly, with the great expectations for SGLT2 inhibitors in the treatment of prevalent HF, DAPA-HF provides important insights, which, combined with data from other ongoing trials testing the use of SGLT2 inhibitors in prevalent HFrEF, provide more conclusive evidence regarding the safety and efficacy of SGLT2 inhibitors in patients with HFrEF. However, perhaps the most important question that DAPA-HF answered is the impact of SGLT2 inhibitors on reducing cardiovascular mortality in patients with HFrEF without diabetes.17 This suggests there may be other opportunities to study SGLT2 inhibitors in other stages of HF, such as those with acute HF or HF with preserved ejection fraction. Conflict of interest: S.C. received research support from NIH, AHRQ, AHA, PCORI, BMS, and consulting fees from Novartis, Medtronic, Ortho Clinical, Boehringer Ingelheim, Vixiar. J.T. declares no conflict of interest.