Sodium–glucose co‐transporter 2 inhibitors in heart failure with preserved ejection fraction: reasons for optimism
Authors: Stefan D. Anker, Muhammad Shahzeb Khan, Izza Shahid, Gerasimos Filippatos, Andrew J.S. Coats, Javed Butler
Journal: European Journal of Heart Failure (2021)

Over the last three decades, several lifesaving therapies for the treatment of heart failure with reduced ejection fraction (HFrEF) have emerged; however, this is not the case for heart failure with preserved ejection fraction (HFpEF). Sodium–glucose co-transporter 2 (SGLT2) inhibitors have emerged as a novel foundational therapy in patients with HFrEF.1, 2 Initially developed as a treatment for diabetes, accumulating evidence from the DAPA-HF (Dapagliflozin and Prevention of Adverse outcomes in Heart Failure) and EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction) trials have proven that the benefits of SGLT2 inhibitors extend to patients beyond type 2 diabetes mellitus to those with HFrEF as well, irrespective of diabetes status.1, 2 It remains uncertain, however, if SGLT2 inhibitors will confer similar benefits in patients with HFpEF. While trials in this patient population are ongoing, the current models of HFpEF pathophysiology, the pharmacodynamic profile of SGLT2 inhibitors, and secondary analyses of previous trials, all provide hope that these drugs may indeed benefit patients with HFpEF. The pathophysiology of HFpEF is complex, multifactorial with a variety of aetiologies, and remains hotly debated. Although the exact pathophysiological mechanisms involved in HFpEF remain uncertain, prevalent theories centre around derangements in four organ systems with overlapping systemic pathophysiologic underpinnings that are thought to play a key role in the development and progression of HFpEF.3 Multiple cardiac structural and functional abnormalities are seen commonly in patients with HFpEF. Increased passive myocardial stiffness due to impaired titin phosphorylation states has been proposed as a mechanistic process for the development of HFpEF.4 Impaired left ventricular (LV) stiffness and relaxation, which cause elevated LV filling pressures, contribute to dyspnoea and impaired exercise capacity in patients with HFpEF.5 The underlying myocardial inflammation also triggers LV hypertrophy and diastolic dysfunction.6 While LV ejection fraction (LVEF) is normal in HFpEF, myocardial contractility and LV systolic mechanics are impaired and associated with worse prognosis in HFpEF.5 Impaired chronotropic response of the heart has also been observed in some patients with HFpEF, which may further contribute to exercise limitation. Reduced aortic distensibility has been shown in some patients with HFpEF and is linked with impaired exercise capacity. Combined ventricular–arterial stiffening aggravates this and results in higher blood pressure changes for any variation in afterload or preload, which further impairs diastolic dysfunction, LV remodelling and fibrosis. This ventricular–aortic uncoupling has been shown to be associated with dyspnoea and fatigue.5 Moreover, impaired nitric oxide signalling, oxidative stress and inflammation have been shown to potentially contribute to coronary microvascular dysfunction, which may lead to myocardial injury at rest and further reduction of cardiac reserves.5, 6 There is an important bi-directional relationship between kidney and heart dysfunction. Venous congestion in HFpEF can lead to activation of the renin–angiotensin–aldosterone system, which promotes oxidative stress, and systemic inflammation coupled with release of proinflammatory adipocytokines that augment renal retention of sodium and water.5 Increased retention of sodium and water perpetuates a state of volume overload, which causes an increase in cardiac filling pressures. Moreover, albuminuria has been hypothesized to be linked with abnormal cardiac mechanics and is an important risk factor for HFpEF.6 While the role of the kidney in HFpEF seems certain, the specific mechanism remains elusive. Obesity is a distinct and common HFpEF phenotype associated with insulin resistance. Obese HFpEF patients have increased cardiac filling pressures, impaired myocardial energetics and concentric LV hypertrophy, which leads to diastolic dysfunction.7 Epicardial adipose tissue deposition in the surrounding myocardium and vessels due to altered adiponectin and leptin regulation is widely implicated in ventricular dysfunction and coronary artery calcification associated with HFpEF.3 Increased epicardial fat further triggers release of proinflammatory cytokines, cell-signalling molecules and enzymes such as aldosterone, neprilysin and leptin, which causes cardiac remodelling. In addition, visceral adiposity is associated with a systemic inflammatory state, which results in cytokine mediated damage of myocardium, endothelium and renal parenchyma.6 Moreover, abnormal energy metabolism in cardiomyocytes may also stem from an increase in xanthine oxidase activity, which is reflected as an increase in uric acid in the body.8 In addition, impaired oxidation of ketone bodies, which can provide additional source of energy for the cardiomyocytes, coupled with decreased lipolysis of the epicardial adipose tissue deposited in surrounding myocardium, may further promote cardiometabolic-induced inflammation and the development of HFpEF.9 Accumulated evidence from prior trials serves as the key factor for optimism regarding the potential therapeutic effects of SGLT2 inhibitors. SGLT2 inhibitors simultaneously target multiple pathways (Figure 1) and produce favourable effects on multiple organ systems thought to be involved in HFpEF. SGLT2 inhibitors can interfere with the primary pathophysiological mechanisms driving the underlying aetiology of HFpEF, such as systemic inflammation, oxidative stress, and neurohormonal activation, reduction of which can attenuate adverse cardiovascular events in this cohort.3 The mechanistic pathways of SGLT2 inhibitors have been shown to reduce cardiac hypertrophy and inflammation.3 It is postulated that SGLT2 inhibitors may reduce the epicardial adipose tissue surrounding the myocardium, which might ultimately lead to improved distensibility. The direct pleiotropic effects of SGLT2 inhibitors have also shown to reduce excessive diastolic tension and decrease LV mass, which improves cardiac preload.10 SGLT2 inhibitors are also hypothesized to improve microcirculatory dysfunction, thereby reducing vascular stiffness and systemic blood pressure.10 An improvement in endothelial function often occurs in conjunction with kidney benefits observed with SGLT2 inhibitors. SGLT2 inhibitors promote natriuresis, which may lead to a decrease in plasma and interstitial volume, while increasing red blood cell mass and haematocrit. Elevation of haematocrit observed with SGLT2 inhibitors may lead to reverse renal remodelling and alleviate oxidative stress.11 In addition, SGLT2 inhibitors may ameliorate symptoms of HFpEF in part due to their interference with metabolic pathways. SGLT2 inhibitors induce ketogenic metabolism, which results in utilization of energy-efficient ketones over less efficient fatty acid and glucose oxidation to generate myocardial energy, thereby improving efficiency and function of both myocardium and the kidneys.3 Following SGLT2 inhibitor therapy, an increased glucagon-to-insulin ratio is hypothesized to lead to increased lipid mobilization, which is primarily responsible for weight loss. In addition, these novel therapeutics may potentially lower serum uric acid concentrations by increasing renal urate excretion, and have been shown to have a positive impact on peri-nephric fat.12 Current clinical evidence of SGLT2 inhibitors in HFpEF, albeit limited, is encouraging. A recent meta-analysis of SGLT2 inhibitor trials in HFpEF suggested reduction in composite of heart failure (HF) hospitalization and cardiovascular mortality.13 Moreover, analysis of contemporary clinical trials show similar results in patients with baseline HFpEF (Table 1).14-19 Furthermore, the optimism regarding favourable effects of SGLT2 inhibitors in HFpEF in the upcoming EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction; NCT03057951) trial also stems from the results of a prior large trial which demonstrated clinical benefit with the same intervention.18 In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), empagliflozin significantly reduced the risk of HF hospitalization by 35% and HF mortality or hospitalization by 39% in patients with or without baseline HF.20, 21 The HF cohort comprised of 10% of the overall trial population, however, the lack of detailed characterization of type of HF in these patients precludes strong inference to be drawn whether the HF benefits were observed in patients with HFpEF or HFrEF. Although not known for certain, it is plausible that majority of the HF patients enrolled in EMPA-REG OUTCOME trial had HFpEF. This is hypothesized as the HF hospitalization event rates observed in the placebo arm were similar to event rates observed in other HFpEF trials such as PEP-CHF (Perindopril in Elderly People with Chronic Heart Failure) (74 per 1000 patient-years), CHARM-Preserved (Candesartan in Patients with Chronic Heart Failure and Preserved Ejection Fraction) (69 per 1000 patient-years), PARAGON-HF (Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction) (50 per 1000 patient-years), TOPCAT (Spironolactone for Heart Failure with Preserved Ejection Fraction) (46 per 1000 patient-years), and I-PRESERVE (Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction) (43 per 1000 patient-years) (Figure 2A).22-26 In contrast, HFrEF trials have had higher event rates for HF hospitalization in the placebo arm. This can be substantiated by inferring event rates of HF hospitalization in trials such as EMPEROR-Reduced (155 per 1000 patient-years), DAPA-HF (98 per 1000 patient-years), CHARM-Alternative (Candesartan in Patients with Chronic Heart Failure and Reduced Systolic Function Intolerant to Angiotensin-Converting Enzyme Inhibitors) (128 per 1000 patient-years), CHARM-Added (Candesartan in Patients with Chronic Heart Failure and Reduced Systolic Function Taking Angiotensin-Converting Enzyme Inhibitors) (110 per 1000 patient-years) and PARADIGM-HF (Angiotensin-Neprilysin Inhibition vs. Enalapril in Heart Failure) (78 per 1000 patient-years).1, 2, 27-29 Similar trends can be observed for event rates of all-cause mortality, where EMPA-REG OUTCOME results (55 per 1000 patient-years) were comparable with event rates observed in other HFpEF trials (range 30 to 59 per 1000 patient-years) compared with HFrEF trials (range 91 to 115 per 1000 patient-years) (Figure 2B). These results suggest that majority of the EMPA-REG OUTCOME population with HF may have indeed been constituted of HFpEF patients, and we therefore expect largely similar benefits observed in the HF subgroup of EMPA-REG OUTCOME in EMPEROR-Preserved as well (Figure 3). In light of the current clinical evidence, it is also plausible that the potential applicability of SGLT2 inhibitors may extend to patients with heart failure with mildly reduced (or mid-range) ejection fraction (HFmrEF) as well. The 2016 Heart Failure Association (HFA) and European Society of Cardiology (ESC) guidelines define HFmrEF as LVEF 40–49% and HFpEF as LVEF >50%.30 Given that majority of the HFpEF trials, including the ongoing EMPEROR-Preserved and DELIVER (Dapagliflozin evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure; NCT03619213) trials, have enrolled patients with LVEF >40% (Table 1), the beneficial effects of SGLT2 inhibitors can potentially be observed in both HFmrEF and HFpEF.18, 19 For this reason, the EMPEROR-Preserved trial aims to conduct subgroup analysis stratified via LVEF, which may provide further insight to clinical benefits of SGLT2 inhibitors in both HFmrEF and HFpEF populations. It is important to acknowledge that different diagnostic criteria are employed to diagnose HFpEF. The American College of Cardiology/American Heart Association guidelines recommend a diagnostic approach via exclusion of severe renal, pulmonary, or hepatic disease in patients with elevated natriuretic peptide biomarkers, preserved LVEF and dyspnoea.31 In contrast, the American Society of Echocardiography and the European Association of Cardiovascular Imaging recommend using echocardiographic parameters including mitral E/A ≥2 or two of the following criteria: mitral average E/e′ >14, left atrial volume index >34 mL/m2, or tricuspid regurgitation velocity >2.8 m/s to categorize HFpEF.32 The recent HFA/ESC guidelines, however, advocate for a more comprehensive approach in diagnosing HFpEF by assessing for HF symptoms, utilizing diagnostic laboratory parameters, electrocardiograms and electrocardiography and conducting functional testing in the absence of any overt non-cardiac cause of dyspnoea.33 This further substantiates the significance of the upcoming EMPEROR-Preserved and DELIVER trials, which utilize a comprehensive diagnostic approach to evaluate HFpEF.18, 19 The results of SGLT2 inhibitors in both of these trials would therefore aid in ascertaining the magnitude of therapeutic response in patients diagnosed with HFpEF through various different parameters. Future expert consensus and guideline groups should comprehensively evaluate the most accurate diagnostic approach which may be universally applicable in diagnosing HFpEF. SGLT2 inhibitors simultaneously target multiple pathophysiological processes implicated in HFpEF, which may result in improving clinical outcomes in these patients. This is supported by early clinical data as well. The ongoing EMPEROR-Preserved and DELIVER trials will provide critical insights into the potential advantage this novel class of drugs may have for patients with HFpEF.18, 19 Open Access funding enabled and organized by Projekt DEAL. Conflict of interest: S.D.A. reports grants from Vifor; personal fees from Vifor, Bayer, Boehringer Ingelheim, Novartis, Servier, Impulse Dynamics, Cardiac Dimensions, and Thermo Fisher Scientific; and grants and personal fees from Abbott Vascular, outside the submitted work. G.F. reports receiving payment from Boehringer Ingelheim for being a trial committee member during the conduct of the study and from Medtronic, Vifor, Servier, and Novartis for being a trial committee member outside the submitted work. A.J.S.C. reports honoraria and/or lecture fees from AstraZeneca, Bayer, Menarini, Novartis, Nutricia, Servier, Vifor, Actimed, Cardiac Dimensions, CVRx, Enopace, Faraday, Gore, Impulse Dynamics, Respicardia, Stealth Peptides, V-Wave, Corvia, Arena, and ESN Cleer. J.B. reports consultancy fees from Boehringer Ingelheim during the conduct of the study; and consultancy fees from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, BerlinCures, Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave, and Vifor, outside the submitted work. All other authors have nothing to disclose.