https://orcid.org/0000-0002-1278-6245
Abstract
For decades, heart failure with preserved ejection fraction (HFpEF) proved an elusive entity to treat. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to reduce the composite of heart failure hospitalization or cardiovascular death in patients with HFpEF in the landmark DELIVER and EMPEROR-Preserved trials. While improvements in blood sugar, blood pressure, and attenuation of kidney disease progression all may play some role, preclinical and translational research have identified additional mechanisms of these agents. The SGLT2 inhibitors have intriguingly been shown to induce a nutrient-deprivation and hypoxic-like transcriptional paradigm, with increased ketosis, erythropoietin, and autophagic flux in addition to altering iron homeostasis, which may contribute to improved cardiac energetics and function. These agents also reduce epicardial adipose tissue and alter adipokine signalling, which may play a role in the reductions in inflammation and oxidative stress observed with SGLT2 inhibition. Emerging evidence also indicates that these drugs impact cardiomyocyte ionic homeostasis although whether this is through indirect mechanisms or via direct, off-target effects on other ion channels has yet to be clearly characterized. Finally, SGLT2 inhibitors have been shown to reduce myofilament stiffness as well as extracellular matrix remodelling/fibrosis in the heart, improving diastolic function. The SGLT2 inhibitors have established themselves as robust, disease-modifying therapies and as recent trial results are incorporated into clinical guidelines, will likely become foundational in the therapy of HFpEF.
Pathophysiology of heart failure with preserved ejection fraction (HFpEF) and mechanisms of sodium-glucose cotransporter 2 (SGLT2) inhibitors. cGMP, cyclic guanosine monophosphate; NO, nitric oxide; PKG, protein kinase G; sGC, soluble guanylate cyclase.
Heart failure is associated with an impaired quality of life, frequent hospitalizations, and increased mortality.1 Disease-modifying therapies for heart failure have traditionally consisted of neurohormonal modulators, which inhibit the renin–angiotensin–aldosterone (RAAS) or adrenergic systems.2,3 In patients with heart failure and a reduced ejection fraction (HFrEF), these therapies have proved unambiguously beneficial, resulting in striking reductions in mortality.3 The benefit of such therapies in patients who have heart failure and a preserved ejection fraction (HFpEF) has been less robust.3,4 Prognosis in these patients has remained poor and effective; disease-modifying therapies have remained elusive.3,4 Over the past decade, sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown clinical benefit in patients with heart failure across the entire spectrum of ejection fraction, and among patients with worsening heart failure and acute heart failure.5–10 Several landmark trials, DELIVER, EMPEROR-Preserved, and SOLOIST-WHF, showed significant reductions in the composite of heart failure hospitalization/cardiovascular death with these agents in patients with HFpEF.6,8,9 In this state-of-the-art review, we will summarize the recent results of SGLT2 inhibitors, discuss mechanisms of these agents in HFpEF, as well as future directions.
Mechanisms of heart failure with preserved ejection fraction
The mechanisms and pathophysiology underlying HFpEF have been reviewed in detail previously and will only be briefly summarized here.4,11–13 HFpEF traditionally described patients with an ejection fraction greater than 40%, although heart failure with mildly reduced (∼40%–49%) and improved ejection have recently been characterized as clinically distinct phenotypes.14 Some patients with an ejection fraction >40% have clinical signs and symptoms of heart failure secondary to another disorder such as infiltrative cardiomyopathies (including hemochromatosis or amyloidosis) or other cardiac conditions such as valvular heart disease, hypertrophic cardiomyopathy, or pericardial disease.15 In patients with such conditions, the mechanisms described below may not be applicable.
There are a variety of pathophysiological processes, which contribute to the syndrome of HFpEF (Figure 1); there is likely heterogeneity in the degree to which specific mechanisms contribute to disease in individual patients. Diastolic dysfunction is a hallmark of HFpEF; the landmark invasive study of Zile et al.16 showed impaired active relaxation and increased passive stiffness in patients with HFpEF. Adverse remodelling and dysfunction are not just seen in the left ventricle but also in the atria and vasculature.4,11,12,17,18 This may be accompanied by other processes, which contribute to the progression of HFpEF including neurohormonal activation, chronotropic incompetence, atrial arrythmias, and renal dysfunction.4,11–13,18,19
Risk factors and pathophysiological mechanisms of heart failure with preserved ejection fraction. DM, diabetes mellitus; HFpEF, heart failure with preserved ejection fraction; MI, myocardial infarction; OSA, obstructive sleep apnea; RAAS, renin–angiotensin–aldosterone system
Cellular and molecular mechanisms underlying HFpEF have been thoroughly reviewed in the past.11,13,20–22 Adverse changes to cardiomyocyte structure, function, and energetics in addition to changes in the extracellular matrix contribute to diastolic dysfunction in HFpEF.23 One key mediator of intrinsic cardiomyocyte stiffness in HFpEF is the giant elastic, cytoskeletal protein titin; dysregulation of the NO-sGC-cGMP-PKG pathway contributes to titin hypophosphorylation and isoform switching between the compliant N2BA and stiff N2B states.13,22 Increased collagen-dependent stiffness secondary to inflammatory and fibrotic processes also contribute to diastolic dysfunction in HFpEF.13,22 Finally, alterations in cardiomyocyte energetics and ionic homeostasis are other key mechanisms that may also contribute to HFpEF.13,24
Sodium-glucose cotransporter 2 inhibitors in HFpEF: a serendipitous discovery
The SGLT2 inhibitors were originally investigated in patients with type 2 diabetes mellitus. These agents were found to improve key outcomes including cardiovascular death, and unexpectedly reduced hospitalizations for heart failure as well.25,26 Subgroup analyses of patients with heart failure, including HFpEF specifically, suggested that these agents may improve outcomes in these settings.27,28 Clinical evaluation of these agents proceeded to patients with HFrEF as well as those with chronic kidney disease (CKD). The SGLT2 inhibitors proved beneficial in HFrEF, reducing the composite of heart failure hospitalization/cardiovascular death in the EMPEROR-Reduced and DAPA-HF trials.5,7 These agents also slowed the rate of kidney function deterioration as well as improved heart failure outcomes in patients with CKD.29–31 In the SOLOIST-WHF and EMPULSE trials, which included patients across the spectrum of ejection fraction, SGLT2 inhibitors improved outcomes in patients with worsening heart failure or acute heart failure, respectively.9,10 Finally, the landmark EMPEROR-Preserved and DELIVER trials both demonstrated significant reductions in their primary outcomes (cardiovascular death or hospitalization [+/− urgent visit] for heart failure) with SGLT2 inhibitors in HFpEF in addition to modest improvements in symptom burden measured by the Kansas City Cardiomyopathy Questionnaire score.6,8 These results appear to be consistent across the spectrum of mildly reduced or preserved ejection fraction (41%–49%, 50%–60%, and >60%) as well as in a variety of sub-groups based on sex, race, and presence of comorbidities such as diabetes mellitus or atrial fibrillation.6,8,32
While a five-trial meta-analysis of patients with heart failure across the entire ejection fraction spectrum did show a reduction in all-cause mortality with SGLT2 inhibitors, in a two-trial meta-analysis of only patients with HFpEF (EMPEROR-Preserved and DELIVER), no significant reduction in all-cause mortality and only a statistically borderline effect on cardiovascular death was observed.32 The magnitude of effect and absolute reduction in heart failure event rates with SGLT2 inhibitors was lower than that seen in trials of RAAS inhibitors or beta-blockers in HFrEF patients, many of which were stopped early due to clear evidence of benefit with treatment.33–35 The clinical benefits with SGLT2 inhibitors in heart failure were notably, however, observed in trials in which the vast majority of patients were already being treated with both an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor–neprilysin inhibitor (∼80%–95%) and a beta-blocker (∼80%–95%) with a significant proportion of patients treated with a mineralocorticoid receptor antagonist (∼35%–70%) as well.32 Heart failure hospitalization/cardiovascular death or a similar composite has been the primary outcome of many large trials evaluating other classes of heart failure therapies in HFpEF (including CHARM-Preserved, TOPCAT, and PARAGON-HF).36–38 Hospitalization due to heart failure was, however, only one cause for hospital admission in patients with HFpEF, a population of patients often with many comorbidities and risk factors for other cardiac and non-cardiac events.39
In summary, over the past decade, SGLT2 inhibitors have emerged unexpectedly as a therapy for heart failure. These drugs were subsequently prospectively evaluated in over 12 000 patients with HFpEF in two landmark Phase III trials where they proved efficacious. As these trial results are incorporated into clinical guidelines around the world, SGLT2 inhibitors are likely to become important mainstays of therapy in HFpEF.
Mechanisms of sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction
The mechanisms underlying clinical benefit with SGLT2 inhibitors in HFpEF are complex and likely multifactorial (Graphical Abstract). Attempts to tease apart the mechanisms of these agents have involved investigations in preclinical models, mechanistic trials including evaluation of proteomics and cardiac remodelling in human patients, in addition to extrapolation from trials conducted in other populations (such as HFrEF and diabetes mellitus/cardiovascular disease). Given the remarkable consistency in benefits of SGLT2 inhibitors observed in patients with heart failure across the entire spectrum of reduced to preserved ejection fraction, there is likely significant overlap in the underlying mechanisms of SGLT2 inhibitors in patients with HFrEF and those with HFpEF.32,40 These two entities share many common risk factors (including hypertension, diabetes mellitus, and CKD), and while amelioration of these traditional risk factors may play some role in the robust effect of these medications, translational research as well as the rapid time course of clinical benefit and remodelling seen with these drugs suggest there are additional mechanisms at play.
Here, we will summarize mechanisms, which may contribute to the benefit of SGLT2 inhibitors in HFpEF with a focus on direct and indirect myocardial effects related to metabolism, energetics, autophagic flux, ionic homeostasis, inflammation, oxidative stress, and cardiac remodelling (Figure 2).
Mechanisms of SGLT2 inhibitors in heart failure with preserved ejection fraction. HFpEF, heart failure with preserved ejection fraction.
Blood pressure, blood sugar, and kidney function
The SGLT2 inhibitors improve many traditional risk factors for HFpEF including blood pressure and blood sugar.41 However, these properties alone likely do not explain the benefits of this class of drugs in HFpEF.42 The SGLT2 inhibitors have been shown to reduce systolic blood pressure by an average 4 mmHg as assessed using 24-h ambulatory monitoring.43 In the EMPEROR-Preserved trial, empagliflozin had similar benefits in patients with baseline systolic blood pressure below and above the median.8 With regard to blood sugar, other agents that lower glucose to a similar or even greater degree do not have such potent benefits in heart failure.42 Relative effects of SGLT2 inhibitors in HFpEF in EMPEROR-Preserved and DELIVER were near identical in patients with and without diabetes mellitus.6,8
The cardiorenal effects of these drugs are an important consideration given the strong association between CKD and HFpEF. In Phase III trials, SGLT2 inhibitors have been shown to reduce the rate of decline in kidney function as well as to reduce kidney failure/death in patients with CKD with or without diabetes; the underlying mechanisms here are believed to be a reduction in trans-glomerular pressure and regulation of tubule-glomerular feedback to protect kidney function.29,31,44–47 This is distinct and may be synergistic with the mechanism of RAAS inhibitors, which reduce hyperfiltration through efferent vasodilation.45,48 Cardiorenal effects play a major role in heart failure: kidney dysfunction worsens heart failure, and impaired cardiovascular function impairs kidney perfusion and function.47,49 This interplay is mediated through several important factors, many of which are key markers and therapeutic targets in heart failure including natriuretic peptides and the adrenergic and RAAS systems.49 Improvement of kidney function is likely both a contributory mechanism and beneficial by-product of these drugs in heart failure but does not solely explain their benefits in HFpEF. The SGLT2 inhibitors were equally beneficial in patients with estimated glomerular filtration rate below and above 60 mL/min/1.73 m2 in EMPEROR-Preserved and DELIVER, and have been shown to improve cardiovascular outcomes throughout the spectrum of kidney function.5,8
Natriuresis/diuresis
Natriuresis/diuresis may be an important contributor to the clinical improvement observed with SGLT2 inhibitors in patients with acute heart failure.50–52 In the EMPA-RESPONSE-AHF trial, empagliflozin significantly increased urine output and net fluids loss in patients with acutely decompensated heart failure over the first 4 days of hospital admission compared with placebo.53 In the EMPULSE trial of patients admitted to hospital for acute heart failure, empagliflozin was associated with significant weight loss by Day 15, which was sustained to Day 90 (including after adjustment for daily loop diuretic dose).54 Significant improvements compared with placebo in both clinical scores and markers (haematocrit and N-terminal pro-B-type natriuretic peptide) of congestion were also observed with empagliflozin by Day 15.54 The acute decongestion observed with SGLT2 inhibitors has led to proposed frameworks for incorporating SGLT2 inhibitors into the management of patients presenting with acutely decompensated heart failure alongside other diuretics like furosemide and acetazolamide.51
While natriuresis/diuresis may explain the effect of SGLT2 inhibitors in patients with acute heart failure and may contribute to the rapid time-course benefit observed with these agents, the available evidence suggests against diuresis as the primary driving mechanism by SGLT2 inhibitors improves outcomes in chronic heart failure. In the EMPEROR-Reduced trial, empagliflozin was not more effective in patients initially identified as having clinical evidence of volume overload (n = 1477) compared with those initially characterized as euvolemic, and decline in weight with empagliflozin was similar in patients with and without volume overload.42,55 In the DELIVER trial, which evaluated dapagliflozin, there was a similar relative reduction (but greater absolute reduction) in the primary outcome of worsening heart failure event/cardiovascular death in patients with recent heart failure hospitalization compared with those without.56 There was no relation between changes in body weight and natriuretic peptides in EMPEROR-Reduced suggesting against diuresis-induced reduction in volume overload as the underlying cause of weight loss.55 Sustained weight reduction with SGLT2 inhibitors may instead be related to loss of calories through glycosuria and reduction in visceral fat.55,57,58
Metabolism, energetics, and autophagic flux
The SGLT2 membrane protein resides in the proximal convoluted tubule and is responsible for 90% of glucose reabsorption from the filtrate under physiological conditions.59 Renal glycosuria through SGLT2 inhibition represents a net loss of calories from the body, and some have suggested that the SGLT2 protein may also function as a physiological sensor of nutrient surplus.42,60–62 Inhibition of SGLT2 is therefore proposed to induce a state of perceived starvation and hypoxia, up-regulating signals to induce a ‘fasting’ and ‘hypoxic’-like transcriptional paradigm.42,60–65 This results in adaptions such as increased erythropoietin (EPO) levels and ketogenesis.42,60–62 The majority of cardiac energy is normally generated from fatty acid oxidation; in the failing heart, fatty acid oxidation is reduced, and alternative pathways including glucose metabolism and anaerobic glycolysis are relied upon.66,67 The SGLT2 inhibitors increase serum ketone bodies, which represent additional source of energy for the failing heart.66,68 Ketone bodies have been shown to increase cardiac contractility and have important signalling roles as well, triggering cellular processes like autophagy.66,68
The downstream effects of the fasting and hypoxic-like transcriptional paradigms have been suggested to be a key aspect of SGLT2 inhibitors, which may be mediated at a cellular level through autophagic flux.60,62,63 This is a cellular degradation process mediated by lysosomes by which cells recycle organelles, proteins, and debris to generate energy, and is triggered in response to cellular stress including perceived nutritional depletion and hypoxia. Induction of autophagy can also contribute to degradation of dysfunctional mitochondria and subsequent reduction in oxidative stress.60,62,63 This cellular process is impaired in the failing myocardium, and induction of autophagy by SGLT2 inhibitors may contribute to the improvements in cardiac function observed with these drugs.69–71 Several of the most widely discussed cellular mediators thought to mediate this effect are the nutrient-deprivation sensors AMPK and sirtuins (SIRT1, SIRT3, and SIRT6) as well as hypoxia-inducible factors (HIF) and mammalian target of rapamycin (mTOR). Regulation of these mediators, which are all involved in maintaining homeostasis of energy, metabolism, and oxygen, is dysfunctional in heart failure, which contributes to the development of cardiomyopathy.65,69 Mechanistic studies demonstrate that SGLT2 inhibitors increase the activities of AMPK, sirtuins, and HIFs and decrease phosphorylation/activation of mTOR in the myocardium as well as in other tissues, which may at least partially underlie their benefit on organ function.72–80 The totality of evidence on this topic has recently been reviewed in great detail.80 The mechanisms by which SGLT2 inhibitors promote autophagy in tissues that do not express the SGLT2 protein have yet to definitively established; proposed but unproven mechanisms include nutrient-deprivation signalling secondary to caloric loss, or direct effects of these drugs on other cellular transporters/proteins such as glucose transporters or sirtuins.80 In summary, the proposed paradigm is as follows: SGLT2 inhibition enhances autophagic flux and induces a fasting/hypoxic mimicry state resulting in activation of mediators including AMPK, sirtuins, and HIF, which promote ketosis and erythropoiesis that lead to reductions in oxidative stress and inflammation as well as improved cellular function. This emerging mechanism may explain the beneficial effects of SGLT2 inhibitors on metabolism and cellular function in tissues/organs (such as the heart) that do not express the SGLT2 protein and could be a contributing factor to the reduction in oxidative stress and inflammation observed with these agents.
Recent proteomics analysis from the EMPEROR-Pooled analysis, which included 535 patients from the EMPEROR-Preserved trial, assessed differential levels of circulating proteins in patients randomized to empagliflozin compared with placebo at baseline, Week 12 and Week 52.81 This analysis showed that empagliflozin had substantial effects on circulating levels of proteins previously shown to be mediators of cardiac autophagy and apoptosis (including IGFBP1, TfRI, FST, RBP2, and Mdk) in addition to EPO and other circulating proteins related to fibrosis, oxidative stress, hypertrophy, and energetics.81
The effect of SGLT2 inhibitors on iron homeostasis and erythrocytosis has proved to be an intriguing development and has recently been reviewed in detail.82 Iron deficiency is a common comorbidity among patients with heart failure and is associated with reduced functional status and poor outcomes.83,84 Increasingly, evidence suggests that iron deficiency in patients with heart failure may be more likely to be functional (i.e. related to inflammatory-mediated increases in hepcidin, resulting in suppression of duodenal iron absorption and release from hepatocytes and the reticulocyte-endothelial system) rather than absolute in nature.82 In either case, reduced circulating and bioreactive cytosolic iron contributes to both anaemia and may impair synthesis of iron-containing proteins involved in ATP production in cardiomyocytes.82,85 In a preclinical study, iron deficiency has been directly shown to impair contractility, cellular ATP levels, and ATP-linked respiration in isolated human cardiomyocytes.85 In several placebo-controlled trials including analyses from DAPA-HF and the EMPEROR programme, SGLT2 inhibitors have been consistently shown to decrease circulating levels of both hepcidin and ferritin, while increasing levels of transferrin receptor protein 1.81,82,86–89 This combination of findings suggests SGLT2 inhibitors may alleviate functional iron deficiency, enabling increased iron mobilization and augmenting bioreactive cytosolic iron levels in erythroid precursors and cardiomyocytes.82 While further research is needed to clarify the mechanisms by which SGLT2 inhibitors alter iron homeostasis, possible contributors include the reductions in inflammatory mediators (which may impact ferritin and hepcidin levels) as well as downstream effects of nutrient-deprivation signalling (including SIRT1) induced by SGLT2 inhibition.82 The SGLT2 inhibitors have also been consistently shown to increase EPO levels, doing so in as little as 1 month of treatment initiation in the EMPA-HEART CardioLink-6 trial.90 In the DAPA-HF trial, treatment with dapagliflozin led to rises in haematocrit to the point of correction into the non-anemic range in 62.2% of patients with anaemia at baseline (compared with 41.1% in the placebo arm).86 Intriguingly, while treatment with EPO analogues has not been shown to improve outcomes in heart failure or patients with diabetes mellitus and CKD, the degree of erythrocytosis/increase in haematocrit has been strongly associated with improved heart failure outcomes in the CANVAS program as well as the VERTIS-CV and EMPA-REG OUTCOME trials.91–95 While correction of anaemia may result in improved oxygen delivery to the failing myocardium, the association between changes in haematocrit and improved outcomes could also stem from common underlying pathways (i.e. autophagy signalling pathways and increased cytosolic bioreactive iron available for iron-dependent proteins in cardiomyocytes) as opposed to representing a direct causal mechanism.
Other metabolic pathways may contribute to the effects of SGLT2 inhibitors as well. The SGLT2 inhibitors attenuate insulin resistance, which is associated with poor cardiac function and future risk of HFpEF.96–100 The SGLT2 inhibitors are also associated with reductions in serum uric acid, although the degree to which this has any clinical significance is unclear.41,101 Uric acid may increase oxidative stress, inflammation, and endothelial dysfunction and is associated with a poor prognosis in heart failure.41,101
Adipose tissue
Epicardial adipose tissue (EAT) is a form of white, visceral adipose tissue around the heart with important paracrine/vasocrine signalling properties.102,103 Expansion of this tissue in patients with diabetes mellitus and/or obesity induces states of insulin resistance, oxidative stress, inflammation, and fibrosis and alters calcium homeostasis, all of which may contribute to diastolic dysfunction.102,103 Expansion of EAT has been associated with a poor prognosis and worse haemodynamic profiles in patients with HFpEF.104,105 In meta-analyses, SGLT2 inhibitors have been associated with reductions in EAT despite having no significant effects on total body mass index.57,106 The reduction in EAT may contribute to the attenuation of myocardial inflammation and fibrosis observed with SGLT2 inhibitors. In addition to reducing visceral fat, SGLT2 inhibitors also modulate adipokines levels, increasing levels of adiponectin, an insulin-sensitizing and anti-inflammatory hormone, and reducing levels of leptin, a hormone released by adipose tissue in states of nutritional excess.107 Paracrine leptin release from epicardial tissue impairs calcium homeostasis and induces cardiac fibrosis and microcirculatory dysfunction.108
Inflammation and oxidative stress
The SGLT2 inhibitors are known to decrease oxidative stress and inflammation.109,110 The SGLT2 inhibitors reduce levels of circulating pro-inflammatory factors such as C-reactive protein, tumour necrosis factor-α, and interleukin-6.111 They also reduce markers of oxidative stress and reactive oxygen species including hydrogen peroxide in the myocardium.112,113 The attenuation of oxidative stress and inflammation associated with SGLT2 inhibitors is likely multifactorial, and a number of mechanisms including decreased uric acid, reduced epicardial fat, alterations in adipokine levels and up-regulation of autophagy all may play a role.114 Another important dimension is the NLRP3 inflammasome, a multimeric cytoplasmic protein complex in macrophages, which plays an important role in the chronic inflammation of heart failure and atherosclerosis.115–117 Treatment with SGLT2 inhibitors inhibits activation of the NLRP3 inflammasome, an effect which may be in part mediated by the increased ketosis and decreased uric acid associated with these agents.91,92 Reduced NLRP3 activity results in decreased macrophage infiltration and pro-inflammatory cytokine release.115–117 This effect may not be limited to the heart, with data showing inhibition of the NLRP3 inflammasome by SGLT2 inhibitors in the kidney, liver, and vasculature.117–119 Within the vasculature, SGLT2 inhibitors have been shown to increase nitric oxide bioavailability, attenuate endothelial dysfunction, and increase circulating levels of pro-angiogenic progenitor cells.120,121 In a head-to-head comparison, treatment with empagliflozin compared with insulin or metformin was recently shown to be associated with with improvement in microRNA profiles associated with endothelial dysfunction in patients with HFpEF and diabetes mellitus.122
Ion handling/homeostasis: Na+ and Ca2+
Features of ionic imbalance in heart failure include a state of calcium overload as well as increased intracellular sodium.123,124 The SGLT2 inhibitors reduce intracellular sodium and cytosolic calcium, although the mechanism underlying these changes has not been definitively established.125–127 Sodium–hydrogen antiporters (NHE) are expressed in various sites including the heart and the kidneys.128,129 The SGLT2 protein in the kidney interacts closely with NHE-3, which is a transporter primarily responsible for sodium reabsorption from the filtrate.62 Increased NHE-3 activity increases oxidative stress and adrenergic activation, and increased sodium reabsorption by this transporter decreases distal sodium delivery to the macula densa, leading to glomerular hyperfiltration and destruction of nephrons.62 The NHE-3 is functionally intertwined with SGLT2 in the nephron, and knockout/inhibition of one impairs the activity of the other.62 This may in part explain the nephroprotective effects of SGLT2 inhibitors. The NHE-1 is expressed in cardiomyocytes and is up-regulated in the failing heart, increasing intracellular sodium and calcium.130,131 The SGLT2 inhibitors reduce intracellular sodium despite the SGLT2 protein not being expressed in the heart.62,132 It has been postulated that direct, off-target inhibition of NHE-1 by SGLT2 inhibitors could be responsible for improved cardiac remodelling and reduced fibrosis with these agents. There is conflicting evidence about whether SGLT2 inhibitors can directly inhibit the NHE-1 transporter in cardiomyocytes.62,133,134 The reduction in intracellular sodium with SGLT2 inhibitors observed could instead be a downstream effect of other signalling pathways, and there is some evidence that SGLT2 inhibitor may reduce NHE-1 mRNA expression, which may be mediated through an AMPK-dependent pathway.62,135 Another potential off-target effect of SGLT2 inhibitors is interaction with the cardiac sodium channel Nav1.5 (also known as SCN5A), which mediates late sodium current.136,137 A molecular study showed that SGLT2 inhibitors may bind to the same site on Nav1.5 as known Class 1 antiarrhythmics such as lidocaine and inhibit late sodium current; whether this interaction has any clinical significance has yet to be determined.137 These effects on ionic homeostasis could in part explain the rapid time course of benefits observed with SGLT2 inhibitors.
Diastolic function and remodelling
Treatment with empagliflozin has been shown to improve diastolic function after only 3 months in a small cohort of patients with diabetes and high cardiovascular risk.138 The IDDIA trial of patients with type 2 diabetes mellitus and at least grade 1 left ventricular diastolic dysfunction showed improvements in left ventricular diastolic function, including diastolic reserve, assessed by diastolic stress echocardiography after 24 weeks of treatment with dapagliflozin compared with placebo.139 As discussed above, diastolic dysfunction in HFpEF has several components including intrinsic myofilament stiffness (related to titin regulation and NO-sGC-cGMP-PKG signalling) as well as extracellular matrix-related stiffness/myocardial fibrosis.23 It may be here where the various pathways involved in SGLT2-mediated reductions in oxidative stress and inflammation converge. In animal models, SGLT2 inhibitors increase NO bioavailability, and restore the pathologically altered phosphorylation of titin mediated through downstream cGMP-PKG signalling; this translates to improved diastolic function.140 In a mechanistic analysis of isolated human and murine myocardial tissue, SGLT2 inhibitors were shown to reduce diastolic tension and passive myofilament stiffness as well as alter phosphorylation of myofilament proteins including titin.141,142 Beyond direct cardiomyocyte effects, SGLT2 inhibitors have been shown to reduce macrophage infiltration, regulate macrophage polarization, inhibit cardiac fibroblast differentiation, and suppress fibrotic markers such as type 1 collagen, resulting in attenuated fibrosis and adverse extracellular remodelling in the heart.66,78,109,113,118,143–145 In addition to reducing myofilament stiffness and fibrosis, SGLT2 inhibitors have been shown to reduce hypertrophy measured by left ventricular mass index within only 6 months in patients with type 2 diabetes mellitus and coronary artery disease in the EMPA-HEART CardioLink-6 trial.146 A systematic review of five randomized controlled trials showed that SGLT2 inhibitors were associated with left ventricular mass regression compared with placebo, although none of the included trials were conducted in patients with HFpEF.147
Future directions
While SGLT2 inhibitors have already proved to improve outcomes in patients with HFpEF, there are several avenues of research that are ongoing (Figure 3).
Ongoing and completed trials of SGLT2 inhibitors in patients with cardiovascular or renal disease. CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; DM, diabetes mellitus; HFH, heart failure hospitalization; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction, HR, hazard ratio; nsMRA, non-steroidal mineralocorticoid receptor antagonist.
The DAPA ACT HF-TIMI 68 trial is evaluating the effects of in-hospital initiation of dapagliflozin on cardiovascular death or worsening heart in patients hospitalized for acute heart failure, irrespective of ejection fraction.148 This trial will help inform the most appropriate time point for initiation of these agents in patients with HFpEF. Atrial fibrillation is known to be associated with HFpEF: each condition independently increases the risk factor for the other.15 The relative benefit of SGLT2 inhibitors in patients with HFpEF is similar in those with and without atrial fibrillation; however, given that patients with atrial fibrillation suffer from a higher rate of adverse heart failure events at baseline, the absolute benefit may likely be greater.149 The SGLT2 inhibitors have also been shown to reduce the rate of atrial fibrillation events in analyses of adverse event reporting from randomized controlled trials.149 DAPA-AF and EMPA-AF are two ongoing randomized trials, which will quantify the effects of SGLT2 inhibitors on atrial fibrillation burden.150,151 Finally, there are also ongoing trials (DAPA-MI and EMPACT-MI) evaluating the effects of SGLT2 inhibitors following myocardial infarction.152,153
Two other classes of medications, which have emerged over the past decade and have also shown benefit in patients with diabetes and/or kidney disease, are glucagon-like peptide-1 receptor agonists and non-steroidal mineralocorticoid receptor antagonists.154,155 Evaluation of potential synergy of these classes of agents with SGLT2 inhibitors is an area of interest. Two trials, MIRACLE and CONFIDENCE, will evaluate the effects of the combination of SGLT2 inhibitors with non-steroidal mineralocorticoid receptor antagonists in patients with cardiorenal disease.156,157
Finally, SGLT1 inhibition, through molecules such as the SGLT1/2 inhibitor sotagliflozin, has been hypothesized to also have possible supplementary benefits in heart failure as well.158 The SGLT1 is expressed in the small intestine where it contributes to glucose absorption, as well as in other sites including the kidney.158 Decreases in SGLT1-mediated glucose absorption increase serum glucagon-like peptide-1 levels, and SGLT1 inhibition may also inhibit hypertrophy and fibrosis within the myocardium.158,159 The SGLT1/2 inhibitor sotagliflozin reduced myocardial infarction and stroke in the SCORED trial, a finding that has not been seen with traditional SGLT2 inhibitors, and which has been postulated to be mediated in part through increased endogenous incretin levels.31 There are no direct data comparing dual SGLT1/2 inhibitors with SGLT2 inhibitors, but this may prove to be an area of interest in the future.
Conclusion
In summary, HFpEF has proved an elusive entity to treat. With the results of DELIVER, SOLOIST-WHF, and EMPEROR-Preserved, SGLT2 inhibitors have solidified themselves as robust therapies to improve outcomes in patients with HFpEF. The underlying mechanism of these agents cannot be wholly ascribed to improvements in traditional risk factors such as blood pressure, blood sugar, volume status, and renal function. Rather, the rapid time course of improvement as well as experimental evidence suggests that a combination of mechanisms for SGLT2 inhibitors in HFpEF including induction of autophagy improved ionic homeostasis and reduced inflammation and oxidative stress, which contribute to reduced adverse remodelling and diastolic dysfunction. As recent trial results are incorporated into clinical guidelines, SGLT2 inhibitors will become foundational in the therapy of HFpEF.
Acknowledgements
The authors would like to thank Sana Khan for assistance with preparation of the figures.
Declarations
Disclosure of Interest
A.P. has no disclosures.
D.L.B. discloses the following relationships—advisory board: AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Stasys; board of directors: AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, TobeSoft; chair: Inaugural Chair, American Heart Association Quality Oversight Committee; consultant: Broadview Ventures; data monitoring committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); honoraria: American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org; chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (editor in chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor; associate editor), K2P (co-chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (course director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (chief medical editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (chair), VA CART Research and Publications Committee (chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (editor, Braunwald’s Heart Disease); site co-investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; trustee: American College of Cardiology; Unfunded Research: FlowCo, Takeda.
A.P. has no disclosures.
N.M. has received support for clinical trial leadership from Boehringer Ingelheim, Novo Nordisk, served as a consultant to Boehringer Ingelheim, Merck, Novo Nordisk, AstraZeneca, BMS, received grant support from Boehringer Ingelheim, Merck, Novo Nordisk, and served as a speaker for Boehringer Ingelheim, Merck, Novo Nordisk, Lilly, BMS, and AstraZeneca. He declines all personal compensation from pharma or device companies.
F.C. has served as a speaker and advisory board members for AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Merck Sharp & Dohme, Novo Nordisk, and Pfizer; and has received research grants from the City Pharmacy, Abu Dhabi, UAE, King Gustav V and Queen Victoria Foundation, the Swedish Heart & Lung Foundation, and the Swedish Research Council.
A.P. has received research grant support from the Gilead Sciences Research Scholar Program and Applied Therapeutics; honoraria outside the present study as an advisor/consultant for Tricog Health Inc and Lilly, USA, Rivus, and Roche Diagnostics, and nonfinancial support from Pfizer and Merck.
S.V. holds a Tier 1 Canada Research Chair in Cardiovascular Surgery, and has received research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group. He is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization.
Data Availability
All data described were obtained from published sources that are cited within the manuscript.
Funding
All authors declare no funding for this contribution.
