The far-reaching beneficial effects of sodium–glucose co-transporter 2 inhibitors in heart failure

With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article. For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Issue opens with the State of the Art Review article entitled ‘Critical appraisal of artificial intelligence-based prediction models for cardiovascular disease’1 by Maarten van Smeden from the University Medical Center Utrecht in the Netherlands, and colleagues. The authors note that the medical field has seen a rapid increase in the development of artificial intelligence (AI)-based prediction models.2–8 With the introduction of such AI-based prediction model tools and software in cardiovascular (CV) patient care, the CV researcher and healthcare professional are challenged to understand the opportunities as well as the limitations of the AI-based predictions. In this article, 12 critical questions for CV health professionals to ask when confronted with an AI-based prediction model are presented. The authors aim to support medical professionals to distinguish the AI-based prediction models that can add value to patient care from those that do not. The Issue continues with a focus on heart failure (HF) and cardiomyopathies. The State of the Art Review article entitled ‘Non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease’ is authored by Arjun Pandey from McMaster University in Hamilton, ON, Canada, and colleagues.9 Cardiorenal syndrome characterizes the complex interplay between chronic kidney disease (CKD) and HF, and affects millions of people worldwide. Patients remain at persistently high risk for progression to end-stage disease even with existing treatments. Despite being launched over eight decades ago and demonstrating substantial mortality benefit in HF over two decades ago, clinical use of mineralocorticoid receptor antagonists (MRAs) has been limited by the perceived risk of hyperkalaemia and adverse hormonal side effects.10,11 The discovery of non-steroidal MRAs represents an important new dimension in the treatment of cardiorenal disease. This review summarizes the mechanisms and clinical evaluation of non-steroidal MRAs, as well as future perspectives on their role in the treatment of cardiorenal disease. Similar to their steroidal counterparts, they have beneficial anti-inflammatory, antiremodelling, and antifibrotic properties in the kidneys, heart, and vasculature. There are several non-steroidal MRAs under development and clinical assessment; of these, only esaxerenone and finerenone are approved for treatment globally. In Japan, esaxerenone is approved for essential hypertension and has been studied in diabetic nephropathy. Compared with steroidal MRAs, finerenone more potently inhibits MR co-regulator recruitment and fibrosis, and distributes more evenly between the heart and kidneys. The landmark Phase III trials FIGARO-DKD and FIDELIO-DKD demonstrated that finerenone reduced major kidney and CV events on top of maximally tolerated renin–angiotensin–aldosterone system inhibition in patients with CKD associated with type 2 diabetes. Non-steroidal MRAs are currently under evaluation in HF and for synergistic treatment with sodium–glucose co-transporter 2 inhibitors (SGLT2is). These ground-breaking agents could become an important therapy across the spectrum of cardiorenal disease. Anti-interleukin (IL)-1 agents have been developed for the treatment of autoinflammatory and rheumatic conditions, where overproduction of IL-1 is an important pathophysiological process. IL-1α and IL-1β are the most studied members of the IL-1 family of cytokines and have the strongest proinflammatory effects. In the State of the Art Review article ‘Anti-interleukin-1 agents for pericarditis: a primer for cardiologists’, Massimo Imazio from the University Hospital ‘Santa Maria della Misericordia’ in Udine, Italy and colleagues indicate that overproduction of both IL-1α (released by inflamed/damaged pericardial cells) and IL-1β (released by inflammatory cells) is now a well-recognized therapeutic target in patients with recurrent idiopathic pericarditis.12 Currently, there are three available anti-IL-1 agents: anakinra (recombinant human IL-1Ra), rilonacept (a soluble decoy receptor ‘trap’, binding both IL-1α and IL-1β), and canakinumab (human monoclonal anti-IL-1β antibody). For patients with corticosteroid-dependent and colchicine-resistant recurrent pericarditis with evidence of systemic inflammation, as evidenced by elevated C-reactive protein, the efficacy and safety of anakinra (2 mg/kg/day up to 100 mg/day s.c. usually for at least 6 months, then tapered) and rilonacept (320 mg s.c. for the first day followed by 160 mg s.c. weekly) have been clearly demonstrated in observational studies and randomized controlled clinical trials. Severe side effects are rare and discontinuation rates are very low (<4%). The most common reported side effect is injection site reactions (>50% of patients). In this article, Imazio and colleagues describe the historical and pathophysiological background and provide a comprehensive review of these agents, which appear to be the most significant advance in medical therapy of recurrent pericarditis in the last 5 years. In the DECLARE–TIMI 58 trial, patients with type 2 diabetes mellitus and higher body mass index were more likely to be hospitalized for heart failure and atrial fibrillation or flutter, and obese patients tended to derive greater absolute risk reduction in obesity-related outcomes, hospitalization for heart failure, and atrial fibrillation or flutter from dapagliflozin, although relative risk reductions in all the outcomes were consistent across the range of body mass index. AF/AFL, atrial fibrillation or atrial flutter; BMI, body mass index; HF, heart failure; HR, hazard ratio.19 The growing incidence and prevalence of obesity and type 2 diabetes mellitus (T2DM) is widely recognized as one of the most challenging contemporary threats to global public health.13–18 Obesity has a crucial role in the development and progression of T2DM, which, in turn, is strongly and independently related to the risk of coronary artery disease, HF, stroke, other CV diseases, and diabetic kidney disease. Obesity is also an independent risk factor for the development of HF, coronary artery disease, and atrial fibrillation (AF) as well as CKD, in part through its influence on the development and severity of comorbidities such as hypertension, dyslipidaemia, and glucose intolerance or diabetes. In a Clinical Research article entitled ‘Obesity and effects of dapagliflozin on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus in the DECLARE–TIMI 58 trial’, Kazuma Oyama from Harvard Medical School in Boston, MA, USA, and colleagues investigated the associations between obesity, cardiorenal events, and benefits of dapagliflozin in patients with T2DM.19 DECLARE–TIMI 58 randomized patients with T2DM and either atherosclerotic CV disease or multiple risk factors to dapagliflozin vs. placebo. Patients were stratified by body mass index (BMI, kg/m2): normal (18.5 to <25), overweight (25 to <30), moderately obese (30 to <35), severely obese (35 to <40), and very severely obese (≥40). Outcomes analysed were CV death, hospitalization for HF (HHF), renal-specific composite outcome, and AF or flutter (AFL). Of 17 134 patients, 9.0% had a normal BMI, 31.5% were overweight, 32.4% were moderately, 17.2% severely, and 9.8% were very severely obese. Higher BMI was associated with a higher adjusted risk of HHF and AF/AFL [hazard ratio (HR) 1.30 and 1.28, respectively, per 5 kg/m2; P < 0.001 for all]. Dapagliflozin reduced body weight by similar relative amounts consistently across BMI categories (percentage difference: −1.9% to −2.4%). Although relative risk reductions in CV and renal-specific composite outcomes with dapagliflozin did not significantly differ across the range of BMI (P for interaction ≥0.20 for all outcomes), obese patients (BMI ≥ 30 kg/m2) tended to derive greater absolute risk reduction in HHF and AF/AFL (P for interaction 0.02 and 0.09, respectively) than non-obese patients (Figure 1). Oyama et al. conclude that in DECLARE–TIMI 58, patients with T2DM and higher BMI were more likely to have HHF and AF/AFL. Whereas relative risk reductions in CV and renal outcomes with dapagliflozin were generally consistent across the range of BMI, absolute risk reduction in obesity-related outcomes including HHF and AF/AFL tended to be larger in obese patients. The manuscript is linked to an Editorial by Naveed Sattar from the University of Glasgow in Scotland, UK, and colleagues.20 Sattar and colleagues conclude that the results of this trial and others will help us better determine the value of large-scale weight loss to both prevent and treat HF and related conditions such as AF. Targeting obesity in heart failure with preserved ejection fraction (HFpEF) is of particular interest, given the large body of evidence suggesting a potential causal role for adiposity in its pathogenesis. However, for the time being, it is reassuring to know that SGLT2is reduce incident HF risk regardless of baseline BMI but may do so better in those with higher levels of obesity. The ability of SGLT2is to prevent and treat HF and CKD in people with and without diabetes truly represents one of the most formidable pharmacological advances of modern cardiovascular medicine. Cumulative rates of heart failure hospitalization after non-cardiac surgery, stratified by status of atrial fibrillation. Cumulative rates differed significantly among groups (P < 0.001 by log-rank test).21 Post-operative AF (POAF) is associated with stroke and mortality. It is unknown if POAF is associated with subsequent HHF. In a Clinical Research article entitled ‘Post-operative atrial fibrillation and risk of heart failure hospitalization’, Parag Goyal from Weill Cornell Medicine in New York, USA, and colleagues examined the association between POAF and incident HHF among patients undergoing cardiac and non-cardiac surgeries.21 A retrospective cohort study was conducted using all-payer administrative claims data that included all non-federal emergency department visits and acute care hospitalizations across 11 states in the USA. The study population included adults aged at least 18 years hospitalized for surgery without a prior diagnosis of HF. Cox proportional hazards regression models were used to examine the association between POAF and incident HF hospitalization after making adjustment for socio-demographics and comorbid conditions. Among 76 536 patients who underwent cardiac surgery, 14 365 (18.8%) developed incident POAF. In an adjusted Cox model, POAF was significantly associated with incident HHF (HR 1.33). In a sensitivity analysis excluding HF within 1 year of surgery, POAF remained significantly associated with incident HF hospitalization (HR 1.15). Among 2 929 854 patients who underwent non-cardiac surgery, 23 763 (0.8%) developed incident POAF. In an adjusted Cox model, POAF was again significantly associated with incident HF hospitalization (HR 2.02), including in a sensitivity analysis excluding HF within 1 year of surgery (HR 1.49) (Figure 2). The authors conclude that post-operative AF is associated with incident HHF among patients without prior history of HF undergoing cardiac or non-cardiac surgeries. These findings reinforce the adverse prognostic impact of POAF and suggest that POAF may be a marker for identifying patients with subclinical HF and those at elevated risk for HF. The manuscript is accompanied by an Editorial by Melissa Middeldorp and Christine Albert from Cedar-Sinai Smidt Heart Institute in Los Angeles, CA, USA.22 The authors conclude that having patient-specific data, inclusive of imaging and complete risk factor and comorbidity profiles, may provide the tools needed to evaluate some of the ambiguities that hinder progress on reducing the burden of POAF and its associated adverse outcomes. With a greater understanding of a patient's full risk factor profile, we may advocate for early aggressive intervention at the initial manifestation of POAF, to improve outcomes and reduce rehospitalization following cardiac and non-cardiac surgery. Hyperkalaemia frequently leads to interruption and discontinuation of neurohormonal antagonists, which may worsen HF prognosis. In a Clinical Research article entitled ‘Empagliflozin and serum potassium in heart failure: an analysis from EMPEROR-Pooled’, João Pedro Ferreira from the Faculty of Medicine of the University of Porto in Portugal, and colleagues note that some studies suggested that SGLT2is reduce hyperkalaemia, an effect that may have important clinical implications.23 This analysis evaluates the effect of empagliflozin on the occurrence of hyper- and hypokalaemia in HF. EMPEROR-Pooled (i.e. EMPEROR-Reduced and EMPEROR-Preserved combined) included 9583 patients with available serum potassium levels at baseline (98.6% of the total EMPEROR-Pooled population, n = 9718). The main outcome was a composite of investigator-reported hyperkalaemia or initiation of potassium binders. Patients with high potassium at baseline were more frequently diagnosed with diabetes and ischaemic HF aetiology and had lower left ventricular ejection fraction and estimated glomerular filtration rate, but were more frequently treated with sacubitril/valsartan or MRAs. Empagliflozin (compared with placebo) significantly reduced the composite of investigator-reported hyperkalaemia or initiation of potassium binders (6.5% vs. 7.7%, HR 0.82). Empagliflozin reduced hyperkalaemia rates regardless of the definition used (serum potassium >5.5 mmol/L: 8.6% vs. 9.9%, HR 0.85, P = 0.017; serum potassium >6.0 mmol/L: 1.9% vs. 2.9%, HR 0.62, P < 0.001). The incidence of hypokalaemia (investigator-reported or serum potassium <3.0 mmol/L) was not significantly increased with empagliflozin. The authors conclude that empagliflozin reduces the incidence of hyperkalaemia without a significant increase in hypokalaemia. The contribution is accompanied by an Editorial by Subodh Verma from the University of Toronto in Canada, and colleagues.24 The authors highlight that hyperkalaemia represents a significant clinical problem amongst patients with HF through its association with clinical endpoints and reduced uptake of renin–angiotensin–aldosterone system inhibitors and MRAs. SGLT2is have consistently been shown to reduce the risk of this adverse HF outcome, with the most recent evidence being provided by Ferreira and colleagues’ present analysis of the EMPEROR-Pooled dataset. Emerging therapies including patiromer may join SGLT2is as important facets in the clinician's armamentarium for managing hyperkalaemia in HF. The editors hope that readers of this issue of the European Heart Journal will find it of interest. Dr. Crea reports speaker fees from Amgen, Astra Zeneca, Servier, BMS, other from GlyCardial Diagnostics, outside the submitted work.