Treatment of heart failure: the dawn of the era of sodium–glucose co-transporter-2 inhibitors

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on heart failure (HF) provides novel clinically relevant information on sodium–glucose co-transporter-2 (SGLT2) inhibitors which, initially proposed for the treatment of type 2 diabetes mellitus (T2D), have been found to improve the outcome of HF with reduced ejection fraction (HFrEF) when administered on the top of drugs known to improve the outcome of HF and are recommended in current European Guidelines.1,2 Acording to modelling estimates, when compared with no neurohormonal blockade, the use of a broad-based combination of disease-modifying drugs at target doses in patients with HF may reduce the risk of death by as much as 75%. It is surprising that in spite of this powerful therapeutic armamentarium, <1% of patients with chronic HF are currently receiving recommended drugs at doses that have been shown to prolong life.3 The issue opens with a Current Opinion article entitled ‘Totality of evidence in trials of sodium–glucose co-transporter-2 inhibitors in the patients with heart failure with reduced ejection fraction: implications for clinical practice’ by Milton Packer from the Baylor University Medical Center at Dallas in Texas, USA and colleagues. The authors provide a perspective on the totality of evidence with SGLT2 inhibitors in patients with HFrEF.4 This paper is the first to issue a call for a major change in clinical practice based on the concordant results of DAPA-HF and EMPEROR-Reduced trials. The analyses and interpretations that are presented in this manuscript will undoubtedly generate considerable discussion and debate for a long time. Concern about hypotension often leads to withholding of beneficial therapy in patients with HFrEF. In a clinical research manuscript entitled ‘Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF)’ John McMurray from the Western Infirmary in Glasgow, UK and colleagues on behalf of the DAPA-HF Investigators and Committees evaluated the efficacy and safety of dapagliflozin according to baseline systolic blood pressure (SBP) in DAPA-HF trial.5 Key inclusion criteria were: New York Heart Association (NYHA) class II–IV, left ventricular ejection fraction (LVEF) ≤40%, elevated N-terminal probrain natriuretic peptide (NT-proBNP) level, and SBP ≥95 mmHg. The primary outcome was a composite of worsening HF or cardiovascular death. The efficacy and safety of dapagliflozin was examined using SBP as both a categorical and a continuous variable. The placebo-corrected reduction in SBP from baseline to 2 weeks with dapagliflozin was –2.54 mmHg. The benefit and safety of dapagliflozin were consistent across the range of SBP. Study drug discontinuation did not differ between dapagliflozin and placebo across the SBP categories examined. The authors conclude that dapagliflozin had a small effect on SBP in patients with HFrEF and was superior to placebo in improving outcomes, and well tolerated, across the range of SBP included in DAPA-HF. The manuscript is accompanied by an Editorial by Francesco Cosentino from the University Hospital Solna in Stockholm, Sweden who comments that altogether, the results of the current post-hoc analysis demonstrating efficacy and safety of dapagliflozin regardless of SBP values might significantly contribute to foster the implementation of dapagliflozin use in HF clinical practice by dissipating any potential safety concern linked with its hypotensive effects.6 In a clinical research article entitled ‘A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes: the DAPA-LVH trial’, Chim Lang from the University of Dundee in the UK and colleagues tested the hypothesis that dapagliflozin may regress left ventricular hypertrophy (LVH) in people with T2D.7 The authors randomly assigned 66 patients with T2D, LVH, and controlled blood pressure to receive dapagliflozin 10 mg once daily or placebo for 12 months. The primary endpoint was change in absolute left ventricular mass (LVM), assessed by cardiac magnetic resonance imaging (MRI). In the intention-to-treat analysis, dapagliflozin significantly reduced LVM compared with placebo, with an absolute mean change of –2.82 g. Additional sensitivity analysis adjusting for baseline LVM, baseline blood pressure, weight, and SBP change showed the LVM change to remain statistically significant. Dapagliflozin significantly reduced pre-specified secondary endpoints including ambulatory 24-h SBP, nocturnal SBP, body weight, visceral adipose tissue, subcutaneous adipose tissue, insulin resistance, and high-sensitivity C-reactive protein. Column bar charts showing the mean regression of left ventricular mass following dapagliflozin treatment compared to placebo (from Brown AJM, Gandy S, McCrimmon R, Houston JG, Struthers AD, Lang CC. A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes: the DAPA-LVH trial. See pages 3421–3432). Lang and colleagues conclude that dapagliflozin treatment significantly reduced LVM in patients with T2D and LVH. The regression of LVM suggests that dapagliflozin can initiate reverse remodelling and changes in left ventricular structure that may partly contribute to cardioprotective effects of dapagliflozin. This manuscript is accompanied by an Editorial by Francesco Paneni from the University of Zurich in Switzerland and colleagues.8 They note that the above-mentioned effects of SGLT2 inhibitors set the ground for a possible beneficial effect of these drugs in patients with HFpEF, where microvascular dysfunction, cardiomyocyte inflammation, and cardiometabolic alterations take centre stage. While several landmark studies have long established that implantable cardioverter-defibrillator (ICD) therapy improves survival for primary prevention of sudden cardiac death ,9 risk stratification parameters and methods for this purpose are clinically underused. In a clinical research article entitled ‘Clinical effectiveness of primary prevention implantable cardioverter-defibrillators: results of the EU-CERT-ICD controlled multicentre cohort study’ Markus Zabel from the Universitätsmedizin Göttingen in Germany and colleagues from the EU-CERT-ICD Study Investigators assessed the current clinical effectiveness of primary prevention by ICD therapy in a prospective investigator-initiated, controlled cohort study, conducted in 44 centres and 15 European countries. The study sought to assess current clinical effectiveness of primary prophylactic ICD implantation.10 The authors recruited 2327 patients with ischaemic or dilated cardiomyopathy and guideline indications for prophylactic ICD implantation. The primary endpoint was all-cause mortality. Baseline and follow-up data from 2247 patients were analysable: 1516 patients with first ICD implantation (ICD group) and 731 patients without ICD serving as controls. Multivariable models and propensity scoring for adjustment were used to compare the two groups for mortality. Adjusted mortality associated with ICD vs. control was significantly lower (hazard ratio 0.731). Subgroup analyses indicated no ICD benefit in diabetics or in those aged ≥75 years. Secondary efficacy endpoints comparing cardiosphere-derived cells and placebo at 6 months. Change in (A) left ventricular end-diastolic volume; (B) left ventricular end-systolic volume; and (C) N-terminal pro b-type natriuretic peptide levels; at 6 months. CDC, cardiosphere-derived cell; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; NT-proBNP, N-terminal pro b-type natriuretic peptide (from Makkar RR, Kereiakes DJ, Aguirre F, Kowalchuk G, Chakravarty T, Malliaras K, Francis GS, Povsic TJ, Schatz R, Traverse JH, Pogoda JM, Smith RR, Marbán L, Ascheim DD, Ostovaneh MR, Lima JAC, DeMaria A, Marbán E, Henry TD. Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial. See pages 3451--3458). The authors conclude that in contemporary ischaemic/dilated cardiomyopathy patients (LVEF ≤35%, narrow QRS), primary prophylactic ICD treatment was associated with a substantial reduction in mortality, although this improvement was not consistent across the whole population. The manuscript is accompanied by an Editorial by N.A. Mark Estes III from the Heart and Vascular Institute UPMC in Pittsburgh, Pennsylvania, USA.11 The authors note that clinicians should be mindful of available risk stratification models and subgroup analyses from the EU-CERT-ICD and other studies. It follows that the process of shared decision-making should include careful consideration of the patient’s wishes and values, with an individualized assessment of potential benefit and risks of primary prevention of sudden death by ICD implantation. Cardiosphere-derived cells (CDCs) are cardiac progenitor cells which exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy.12,13 In a clinical research article entitled ‘Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial’, Raj Makkar from the Cedars-Sinai Heart Institute in Los Angeles, California, USA and colleagues assessed the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blind, placebo-controlled, intracoronary ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration (ALLSTAR) trial.14 The authors enrolled patients 4 weeks to 12 months after MI, with LVEF ≤45% and left ventricular LV scar size ≥15% of LVM by MRI. A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by the stop–flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for HF or non-fatal MI). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. Makkar and colleagues randomly allocated 90 patients to the CDC group and 44 to the placebo group. The mean baseline LVEF was 40% and the mean scar size was 22% of the LVM. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size between CDC and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume, LV end-systolic volume, and NT-proBNP at 6 months in CDC-treated patients. The authors conclude that intracoronary infusion of allogeneic CDCs in patients with post-MI left ventricular dysfunction was safe but did not reduce scar size relative to placebo at 6 months. The manuscript is accompanied by an Editorial by Francisco Fernandez-Aviles from the Hospital General Universitario Gregorio Marañón in Madrid, Spain and colleagues.15 The authors feel that various points need to be better addressed before proceeding again to clinical trials, if we want to move the field of cardiovascular regenerative and reparative medicine forward, for the sake of the cardiovascular health of millions of patients. Treatment of pathological cardiac remodelling and subsequent HF represents an unmet clinical need. Long non-coding RNAs (lncRNAs) are emerging as crucial molecular orchestrators of disease processes including that of heart diseases.16,17 In a Basic Science article entitled ‘Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy’, Thomas Thum from the Hannover Medical School in Germany, and colleagues report on the powerful therapeutic potential of the conserved lncRNA H19 in the treatment of pathological cardiac hypertrophy.18 Pressure overload-induced left ventricular cardiac remodelling revealed an up-regulation of H19 in the early phase, but a strong sustained repression upon reaching the decompensated phase of HF. The translational potential of H19 was highlighted by its repression in a large animal (pig) model of LVH, in diseased human heart samples, in human stem cell-derived cardiomyocytes, and in human engineered heart tissue in response to afterload enhancement. Pressure overload-induced cardiac hypertrophy in H19 knockout mice was aggravated compared with wild-type mice. In contrast, vector-based, cardiomyocyte-directed gene therapy using murine but also human H19 strongly attenuated HF even when cardiac hypertrophy was already established. Mechanistically, using microarray, gene set enrichment analyses, and chromatin immunoprecipitation-DNA sequencing, the authors identified a link between H19 and prohypertrophic nuclear factor of activated T cells (NFAT) signalling. H19 physically interacts with the polycomb repressive complex 2 to suppress H3K27 tri-methylation of the antihypertrophic Tescalcin locus which in turn leads to reduced NFAT expression and activity. Thum and colleagues conclude that H19 is highly conserved and down-regulated in failing hearts from mice, pigs, and humans. H19 gene therapy prevents and reverses experimental pressure overload-induced HF. H19 acts as an antihypertrophic lncRNA and represents a promising therapeutic target to combat pathological cardiac remodelling. The manuscript is accompanied by an Editorial by Gianluigi Condorelli from the Humanitas University in Rozzano, Italy and colleagues. The authors note that dysregulation of epigenetic mechanisms leading to aberrant loss of cardiomyocyte homeostasis is a critical point to consider in understanding the onset of cardiovascular pathologies. Thus exploiting lncRNAs as therapeutic agents in myocardial disease could pave the way for efficaciously combatting one of the greatest healthcare burdens worldwide.19 With the advent of omics, an innovative inductive method has provided researchers with possible ways new to monitor health and disease. This approach incorporates data from studies of the genome, transcriptome, proteome, and metabolome to focus on the assessment of a varied range of biomolecules.20 In a clinical review article entitled ‘Omics phenotyping in heart failure: the next frontier’ Antoni Bayes-Genis from the Cardiology Service, Hospital Universitari Germans Trias i Pujol in Badalona, Spain and colleagues provide a state-of-the-art review aiming to provide an up-to-date look at breakthrough omic technologies that are helping to unravel HF disease mechanisms and heterogeneity.21 Genomics, transcriptomics, proteomics, and metabolomics in HF are reviewed in depth. In addition, there is a thorough, expert discussion regarding the value of omics in identifying novel disease pathways, advancing understanding of disease mechanisms, differentiating HF phenotypes, yielding biomarkers for diagnosis or prognosis, or identifying new therapeutic targets in HF. The combination of multiple omics technologies may create a more comprehensive picture of the factors and pathophysiology involved in HF than achieved by either one alone, and provides a rich resource for predictive phenotype modelling. However, the successful translation of omics tools as solutions to clinical HF requires that the observations are robust and reproducible, and can be validated across multiple independent populations to ensure confidence in clinical decision-making. This issue is also complemented by a Discussion Forum contribution. In a contribution entitled ‘Heart failure development in obesity: mechanistic pathways’ Kristjan Karason from the Sahlgrenska University Hospital in Gothenburg, Sweden and colleagues provide a reply to a recent comment entitled ‘Incident heart failure risk after bariatric surgery: the role of epicardial fat’.22,23 The editors hope that this issue of the European Heart Journal will be of interest to its readers. With thanks to Amelia Meier-Batschelet, Johanna Hugger, and Martin Meyer for help with compilation of this article.