Sodium-glucose co-transporter 2 inhibitors in the failing heart : a growing potential

REVIEW ARTICLE Sodium-Glucose Co-transporter 2 Inhibitors in the Failing Heart: a Growing Potential Dulce Brito 1,2 &Paulo Bettencourt 3,4 &Davide Carvalho 4,5,6 &Jorge Ferreira 7 &Ricardo Fontes-Carvalho 8,9 & Fátima Franco 10 &Brenda Moura 4,11,12 &José Carlos Silva-Cardoso 4,12,13 &Rachel Tavares de Melo 14 & Cândida Fonseca 15,16 #The Author(s) 2020 Abstract Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a new drug class designed to treat patients with type 2 diabetes (T2D). However, cardiovascular outcome trials showed that SGLT2i also offer protection against heart failure (HF)–related events and cardiovascular mortality. These benefits appear to be independent of glycaemic control and have recently been demonstrated in the HF population with reduced ejection fraction (HFrEF), with or without T2D. This comprehensive, evidence-based review focuses on the published studies concerning HF outcomes with SGLT2i, discussing issues that may underlie the different results, along with the impact of these new drugs in clinical practice. The potential translational mechanisms behind SGLT2i cardio-renal benefits and the information that ongoing studies may add to the already existing body of evidence are also reviewed. Finally, we focus on practical management issues regarding SGLT2i use in association with other T2D and HFrEF common pharmacological therapies. Safety considerations are also highlighted. Considering the paradigm shift in T2D management, from a focus on glycaemic control to a broader approach on cardiovascular protection and event reduction, including the potential for wide SGLT2i implementation in HF patients, with or without T2D, we are facing a promising time for major changes in the global management of cardiovascular disease. Keywords SGLT2i .Diabetes .Heart failure .Cardiovascular risk .Cardiovascular outcomes trials Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10557-020-06973-3) contains supplementary material, which is available to authorized users. *Dulce Brito [email protected] 1 Department of Cardiology, Centro Hospitalar Universitário Lisboa Norte, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal 2 CCUL, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal 3 Department of Internal Medicine, Hospital CUF Porto, Porto, Portugal 4 Faculdade de Medicina, Universidade do Porto, Porto, Portugal 5 Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar, Universitário de São João, Porto, Portugal 6 Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal 7 Department of Cardiology, Hospital de Santa Cruz, Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal 8 Department of Cardiology, Centro Hospitalar Vila Nova de Gaia/Espinho, Espinho, Portugal 9 Department of Surgery and Physiology, Cardiovascular Investigation Unit, Faculdade de Medicina, Universidade do Porto, Porto, Portugal 10 Department of Cardiology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal 11 Department of Cardiology, Hospital das Forças Armadas-Pólo do Porto, Porto, Portugal 12 CINTESIS-Cardiocare, Center for Health Technology and Services Research, Porto, Portugal 13 Department of Cardiology, Centro Hospitalar Universitário de São João, Porto, Portugal 14 Medical Department, Boehringer Ingelheim, Lisboa, Portugal 15 Heart Failure Clinic, Hospital São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal 16 NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal Cardiovascular Drugs and Therapy https://doi.org/10.1007/s10557-020-06973-3 Diabetes and Heart Failure Type 2 diabetes (T2D) and heart failure (HF) are common and often coexisting conditions, with a harmful relationship. HF affects at least 26 million people worldwide, but projections regarding rising prevalence for the next decades are alarming, namely due to an ageing population and to the expected increase in HF with preserved ejection fraction (HFpEF) [1–5]. Currently, despite advances in HF treatment, mortality can reach 50% at five years, exceeding that observed in most common malignant neoplasms [6,7]. Hospitalizations contribute to the high morbidity in HF and account for most of its costs, which are likely to rise dramatically [3,4,8]. The prevalence of T2D has nearly doubled since 1980 and is expected to affect nearly 580 million individuals worldwide in 10 years, and 700 million by 2045 [9,10]. T2D is a major risk factor for the development of cardiovascular disease (CVD), its main cause of morbidity and mortality [11,12]. The relationship between T2D and HF has been well established since the Framingham study, which reported a 2and 5-fold higher risk of HF in men and women with T2D, respectively, compared with individuals without T2D [13]. More recently, the Reykjavik study described a 12% prevalence of HF in the T2D population vs. 3% in individuals without T2D [14]. T2D is associated with cardiac structural changes including increased interstitial fibrosis, left ventricular hypertrophy, endothelial dysfunction, microangiopathic processes and inflammation, factors that confer a higher risk for developing HF with or without a reduced ejection fraction (rEF) [15]. T2D adversely affects outcomes amongst patients with HF, has a substantial influence on the costs of managing HF patients, extends hospital stay and worsens prognosis [4,16]. On the other hand, HF increases the risk of fatal and non-fatal cardiovascular (CV) events in T2D patients [17]. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a new class of drugs designed to treat patients with T2D, but have also been shown to be protective against HF-related events and CV mortality. Herein, we present a comprehensive, evidence-based overview concerning the use of SGLT2i in patients with or without T2D at risk for CV events, focusing on HF outcomes. Additionally, we perform a critical analysis of the SGLT2i cardiovascular outcome trials (CVOTs) and discuss the SGLT2i possible translational mechanisms behind the clinical outcomes, with an overview of the ongoing SGLT2i functional capacity, mechanistic and HF outcomes trials. Finally, we present a summary of practical considerations regarding the co-administration of SGLT2i and common therapies used in T2D and HFrEF, as well as management of safety issues, based on expert opinion and current recommendations. Improving Prognosis: the Clinical Research Arena SGLT2i Cardiovascular Outcome Trials in T2D Patients Due to concerns for possible adverse CVoutcomes with antidiabetic agents, both the Food and Drug Administration (FDA) and the European Medicines Agency require that all new glucose-lowering drugs demonstrate CV safety in T2D patients. This is now tested in CVOTs that analyse drug safety in terms of MACE (major adverse cardiovascular events), which include CV death, non-fatal myocardial infarction (MI) and non-fatal stroke (3-point MACE). Surprisingly, HF outcomes, which can be precipitated by some antidiabetic drugs [18], are not included as a mandatory component of composite endpoints [19]. A paradigm shift in T2D management emerged when CVOTs with SGLT2i [20–22] demonstrated that these drugs are not only safe in terms of 3-point MACE but may also be beneficial in HF-related and renal events, regardless of the presence of atherosclerotic CVD (ASCVD) or HF at baseline. The EMPA-REG OUTCOME Trial The EMPA-REG OUTCOME trial analysed the outcomes of the SGLT2i empagliflozin vs. placebo in patients with T2D and established CVD at baseline, and demonstrated the superiority of empagliflozin in reducing the risk of 3-point MACE, with significant reductions in CV death, all-cause death and in hospitalization for HF (HHF). Observed benefits were related to a decrease in incident HF events rather than to prevention of ischemic CV events [20]. These unexpected results led empagliflozin to become the first glucose-lowering drug approved for CV death protection in T2D patients. Post hoc analyses of the EMPA-REG OUTCOME trial revealed that besides the higher incident rates of HHF, CV death and all-cause mortality in patients with HF at baseline compared with patients without HF, the risk reductions of these outcomes with empagliflozin were consistent in both subgroups (hazard ratio (HR): 0.67, 95% confidence interval (CI) 0.47–0.97 in patients with HF burden (defined as HF at baseline, HHF or incident HF without hospitalization during the trial); HR 0.63, 95% CI 0.48–0.84 in patients without HF burden) [23]. The observed benefit with empagliflozin extends to the two causes of cardiac death in HF: sudden death and pump failure [24]. The CANVAS Program and the DECLARE-TIMI 58 Trial The CANVAS program [21], which included the CANVAS and CANVAS-R (renal) studies, assessed the CV safety and efficacy of canagliflozin in patients with T2DM and established CVD or at least two risk factors for CVD. The Cardiovasc Drugs Ther Table 1 Summary of cardiovascular outcome trials with SGLT2i in patients with type 2 diabetes EMPA-REG outcome [20] Empagliflozin vs. placebo CANVAS [21] Canagliflozin vs. placebo DECLARE-TIMI 58 [22] Dapagliflozin vs. placebo VERTIS CV[26] Ertugliflozin vs. placebo Study design and sample main features 7028 patients with T2D, 99.4% with established CVD 57% > 10 yr T2D and 25.1% 5–10 yr T2D Median follow-up 3.1 yr 9734 patients with T2D, 65.6% with established CVD Mean T2D duration 13.5 yr Median follow-up 2.4 yr 17,160 patients with T2D, 40.5% with established CVD Median T2D duration 11 yr Median follow-up of 4.2 yr 8246 patients with T2D, 100% with established ASCVD Mean T2D duration 12.9 years Primary endpoint: 3P-MACE (CV death, MI or stroke) 37.4 vs. 43.9 per 1000 pt-yrs HR 0.86 (95% CI, 0.74–0.99; p< 0.001 for noninferiority and p= 0.04 for superiority) 26.9 vs. 31.5 per 1000 pt-yrs HR 0.86 (95% CI, 0.75–0.97; p< 0.001 for noninferiority and p= 0.02 for superiority) 22.6 vs. 24.2 per 1000 pt-yrs HR 0.93 (95% CI, 0.84–1.03; p= 0.17 for superiority) Estimated completion December 2019 CV death or HHF 19.7 vs. 30.1 per 1000 pt-yrs HR 0.66 (95% CI, 0.55–0.79; p< 0.001) 16.3 vs.20.8 per 1000 pt-yrs HR 0.78 (95% CI, 0.67–0.91; p=NA) 12.2 vs. 14.7 per 1000 pt-yrs HR 0.83 (95% CI, 0.73–0.95; p= 0.005) CV death 12.4 vs. 20.2 per 1000 pt-yrs HR 0.62 (95% CI, 0.49–0.77; p< 0.001) 11.6 vs. 12.8 per 1000 pt-yrs HR 0.87 (95% CI, 0.72–1.06; p=ns) 7.0 vs.7.1 per 1000 pt-yrs HR 0.98 (95% CI, 0.82–1.17; p=ns) HHF 9.4 vs. 14.5 per 1000 pt-yrs HR 0.65 (95% CI, 0.50–0.85; p= 0.002) 5.5 vs. 8.7 per 1000 pt-yrs HR 0.67 (95% CI, 0.52–0.87; p=NA) 6.2 vs. 8.5 per 1000 pt-yrs HR 0.73 (95% CI, 0.61–0.88; p=NA) Death by any cause 19.4 vs. 28.6 per 1000 pt-yrs HR 0.68 (95% CI, 0.57–0.82; p< 0.001) 17.3 vs. 19.5 per 1000 pt-yrs HR 0.87 (95% CI, 0.74–1.01; p=ns) 15.1 vs. 16.4 per 1000 pt-yrs HR 0.93 (95% CI, 0.82–1.04; p=ns) Safety data Higher incidence of genital infection (6.4% vs. 1.8%; < 0.001) Higher incidence of amputation (6.3 vs. 3.4 per 1000 pt-yrs; HR 1.97; 95% CI, 1.41–2.75) Higher incidence bone fracture (15.4 vs. 11.9 per 1000 pt-yrs; HR 1.26; 95% CI, 1.04–1.52) Higher incidence of diabetic ketoacidosis (0.3% vs. 0.1%; HR 2.18; 95% CI, 1.10–4.30; p= 0.02) Higher incidence genital infection (0.9% vs. 0.1%; HR 8.36; 95% CI, 4.19–16.68; p< 0.001) Abbreviations:3P-MACE, 3-point major adverse cardiovascular events; ASCVD, atherosclerotic cardiovascular disease;CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; HHF, hospitalization for heart failure; HR, hazard ratio; MI, myocardial infarction; NA, not available; ns, not significant; pt-yrs, patient-years; T2D, type 2 diabetes mellitus; yr,years Cardiovasc Drugs Ther DECLARE-TIMI 58 trial [25] compared dapagliflozin vs. placebo in patients with T2DM with either established ASCVD or multiple risk factors for ASCVD. These trials showed that both SGLT2i also reduced the composite endpoint of CV death and HHF in T2D patients, with similar results observed with dapagliflozin for patients with and without HF at baseline [22]. The results for both trials were driven by a reduction in HHF, with no significant reduction in CV death alone. Table 1presents a summary of the CVOTs with SGLT2i. These CVOTs have different designs and inclusion criteria, and therefore are difficult to compare; additionally, the definition of CV risk is variable across studies, and there is no information regarding baseline LV ejection fraction (LVEF). Meta-analyses A question that remains unresolved is whether the effects are consistent across the SGLT2i class, or whether pharmacologic differences between the drugs may translate into differences in clinical efficacy and safety outcomes. Two meta-analyses on SGLT2i CVOTs have been recently published, aiming to better estimate the class effect of these drugs on CV outcomes [27,28]. The most recent metaanalysis showed a consistent class effect of SGLT2i in reducing HHF in patients with or without baseline CVD, as well as a consistent effect on preventing the progression of renal disease [27]. Overall, SGLT2i reduced the risk of MI by 11% and the risk of CV death by 16%, although significant heterogeneity in CV death was observed between trials. Similarly, all-cause mortality was reduced by 15%, again with significant heterogeneity. When only patients with ASCVD were compared within trials (excluding patients with multiple CV risk factors in the CANVAS and DECLARE-TIMI 58 trials), empagliflozin was the only that showed significant reductions on CV death and all-cause mortality. Similarly, an increased risk in amputations and fractures was only noted with canagliflozin [27]. It is possible that either pharmacologic differences within the class, or differences in the baseline risk within the study populations, may be responsible for the observed heterogeneity in mortality outcomes. The consistently higher event rates in the placebo group in EMPA-REG (compared with the placebo arms in CANVAS and DECLARE-TIMI 58) reflect a higher risk population in the former (also when comparing the ASCVD groups only), which might account for the differences observed between trials. The estimated glomerular filtration rate (eGFR) cut-off for EMPA-REG was less restrictive, thus allowing for patients with more severe renal dysfunction to be included in the trial. The percentage of patients with eGFR < 60 mL/min was 25.9% in EMPA-REG compared with 20.1% in CANVAS and 7.4% in DECLARE-TIMI 58. Nonetheless, in a subanalysis conducted to determine the impact of eGFR on CV death in EMPA-REG, a consistent effect on CV mortality was observed, independent of baseline eGFR [20,29,30]. Furthermore, the recent CREDENCE trial tested canagliflozin vs. placebo in 4200 T2D patients with nephropathy, an eGFR of 30 to < 90 mL/min and albuminuria [31]. Over 50% of the population had established CVD, and 14.8% had HF at baseline. During a median follow-up of 2.62 years, canagliflozin did not significantly reduce CV death alone, despite a nominally non-significant pvalue (HR 0.78, 95% CI 0.61–1.00, p= 0.05), or all-cause death ((HR 0.83, 95% CI 0.68–1.02, p= not available (NA)), but showed a pronounced reduction in HHF (HR 0.61, 95% CI 0.47–0.80, p<0.001). In aggregate, these findings suggest that in patients with greater renal dysfunction, SGLT2i confer even higher reductions in HHF, as also suggested by the meta-analysis results [27]. However, the degree of renal dysfunction or presence of established CVD does not appear to fully explain the observed heterogeneity in terms of mortality amongst the three published SGLT2i CVOTs. Based on this heterogeneity, the 2019 European Society of Cardiology (ESC) Guidelines [32] on diabetes, pre-diabetes and CVD, developed in collaboration with the European Association for the Study of Diabetes (EASD), has given empagliflozin a class IB recommendation to reduce the risk of death in patients with T2D and CVD. In addition, empagliflozin, dapagliflozin and canagliflozin are recommended in patients with T2D and CVD or at very high/high CV risk, to reduce CVevents, as first-line antidiabetic therapy in naive patients, not previously treated with metformin [32]. This recommendation is criticized, namely by the convincing beneficial effects (HbA1c 6.5–7.5%) (glycated haemoglobin) of early combination therapy [33]. A CVOT with the SGLT2i ertugliflozin [26] is currently underway, with results expected in the near future (Table 1). SGLT2i Effects on HF Outcomes in T2D Patients Additional subanalyses of the three abovementioned CVOTs [20–22] have been published, revealing further data concerning SGLT2i effects on HF outcomes in patients with T2D. An analysis of the CANVAS program showed that canagliflozin reduced the overall risk of HF events in patients with T2D and high CVrisk, with no clear difference in effects on HFrEF vs. HFpEF events [34]. A recent analysis of the DECLARE-TIMI 58 trial investigated the efficacy of dapagliflozin in T2D patients considering baseline HF status [25]. In patients with T2D and baseline HFrEF, dapagliflozin reduced HHF, CV death and all-cause mortality, whereas in patients with T2D without baseline HFrEF, the only reduction observed was in HHF [25]. Cardiovasc Drugs Ther SGLT2i HF-Dedicated Outcomes Trials in Patients with or without T2D More recently, the DAPA-HF trial results were published [35]. The trial included 4744 HFrEF patients with our without T2D followed over a median of 18.2 months. It was demonstrated that dapagliflozin 10 mg daily significantly reduced the primary composite endpoint of worsening HF (including HHF or urgent HF visits) and CV death in a population highly treated with background disease-modifying HF therapies (HR 0.74, 95% CI 0.65–0.85, p= 0.001), either in patients with (HR 0.75, 95% CI 0.63–0.90, p= NA) or without diabetes (HR 0.73, 95% CI 0.60–0.88, p=NA) [36]. The number of patients needed to treat (NNT) with dapagliflozin to prevent one primary event during the trial duration was 21 (95% CI 15–38). Importantly, in a post hoc analysis including patients on concomitant sacubitril/valsartan therapy at baseline (nearly 10% of the trial population), the HR for the primary outcome was consistent amongst patients onor off-sacubitril/valsartan. Despite the low percentage of patients treated with sacubitril/ valsartan at baseline, it appears that the benefits of SGLT2i therapy are additive to those afforded by neurohormonal modulating agents. Moreover, possible heterogeneity was observed according to New York Heart Association (NYHA) functional class, showing greater treatment benefit in class II patients, compared with class III or IV [35]. Regarding safety, the occurrence of adverse events (AEs) was low and similar between dapagliflozin and placebo, except for significantly more severe renal adverse events (AEs) in the placebo group (2.7% vs. 1.6%, p=0.009)[36]. Table 2and Table 3summarize the ongoing HF-dedicated outcomes [36–38] and functional capacity clinical trials with SGLT2i, which will enhance the body of evidence for these agents in HF populations. From Clinical Trials to the Real World The SGLT2i positive impact on CV outcomes observed in CVOTs, specifically regarding HHF, was also observed in the real-world evidence (RWE) studies CVD-REAL and EMPRISE [41,42]. CVD-REAL study included 309,056 T2D patients with or without CVD at baseline, newly treated with SGLT2i or other glucose-lowering drugs, from registries within six countries. All primary analyses showed a benefit of SGLT2i over other glucose-lowering drugs: HHF (HR 0.61, 95% CI 0.51–0.73, p< 0.001); all-cause mortality (HR 0.49, 95% CI 0.41–0.57, p< 0.001), and HHF or death by any cause composite outcome (HR 0.54, 95% CI 0.48–0.60, p<0.001)[42]. The ongoing EMPRISE study aims to assess empagliflozin’s effectiveness, safety, and healthcare utilization in routine care in the USA, including data from 232,000 T2D patients newly initiated on empagliflozin or sitagliptin. After five months follow-up of the nearly 32,000 matched patients, empagliflozin decreased the risk of HHF by 50% (HR 0.50, 95% CI 0.28–0.91, p= NA), with consistent results in patients with or without baseline CVD [41]. The available data on SGLT2i, both from CVOTs and from RWE, has undoubtedly shifted the paradigm of T2D management in clinical practice from a focus on glycaemic control to a broader approach on CV event reduction, and also as a potential new class of drugs for HF treatment even in people without T2D. Given the impressive cardioprotective effects of SGLT2i, the results of the DAPA-HF trial were enthusiastically received. Results of other ongoing trials with SGLT2i in high-risk diabetic and non-diabetic cardiovascular populations are keenly awaited and should shed more light into possible differences in clinical outcomes and prognosis, most importantly in mortality and on potential beneficial effect on MI, which remains an active topic of investigation [27,43]. Potential Mechanisms Behind the Cardio-renal Benefits Observed with SGLT2i Although impressive results have been achieved with SGLT2i, there is a lack of knowledge of the mechanisms associated with the observed benefits. SGLT2i inhibit glucose and sodium reabsorption in the kidneys, thus resulting in glycosuria. Their effects consequently include reductions in HbA1c, blood glucose levels and blood pressure (BP), but also reductions in body weight and adiposity, all mechanisms that may contribute to reducing cardiovascular risk and HF [27,44]. The reduction in systolic and diastolic BP is reported to be about 3–7and2mmHg, respectively, and seems to be independent of disease status or treatment with antihypertensive drugs [45]. Also, a reduction in body weight is consistently observed in individuals taking SGLT2i, but the magnitude of weight loss is modest (1 to 3 kg) both in T2D and in obese patients without diabetes, due to counter-regulatory mechanisms striving to maintain body weight. It is unknown whether such effects can translate into reduced cardiovascular disease events, including HF [45]. However, the evidence indicates that the cardioprotective benefits behind SLGT2i go beyond roles in glycemia, BP control, and weight loss. Firstly, the glucose and BPlowering effects of SGLT2i compared with placebo are not sufficient to explain the outcomes observed in randomized clinical trials (RCT). Secondly, if the beneficial effects of SGLT2i were due exclusively to glycaemic or BP control, these effects should impact all CV outcomes. Although SGLT2i have a significant effect on the prevention of HF events, they are neutral in preventing atherothrombotic events such as stroke, with only a possible modest effect on MI. A Cardiovasc Drugs Ther Table 2 Summary of published or ongoing dedicated heart failure outcome trials of SGLT2i EMPEROR-Preserved [37] EMPEROR-Reduced DELIVER DAPA-HF [36,38] Hamad Medical Corporation (ISS) NCT number 03057951 03057977 03619213 03036124 03794518 Active substance/comparator Empagliflozin/placebo Dapagliflozin/placebo Dapagliflozin/placebo Pioglitazone + dapagliflozin/placebo Population HFpEF HFrEF HFpEF with or without T2D HFrEF with or without T2D HFpEF with T2D With or without T2D Sample size 5750 3600 4700 4744 648 Key inclusion criteria –Chronic HF –Elevated NT-proBNP –eGFR ≥20 mL/min/1.73 m 2 –BP ≥100 mmHg –Symptomatic HFpEF –Elevated NT-proBNP –eGFR ≥25 mL/min/1.73 m 2 –Ambulatory and hospitalized patients –HFpEF (LVEF > 40%) –Symptomatic HFrEF –Elevated NT-proBNP –eGFR ≥30 mL/min/1.73 m 2 –BP ≥95 mmHg –HFrEF (LVEF ≤40%) –T2D –Drug naïve or on stable dose of antidiabetic therapy for 3 months –Hospitalized for HFpEF –eGFR > 60 mL/min –HFpEF (LVEF > 50%) HFpEF (LVEF > 40%) HFrEF (LVEF ≤40%) Primary endpoint Time to first event of adjudicated CV death or adjudicated HHF Time to first occurrence of CV death, HHF or urgent HF visit Time to first occurrence of CV death, HHForurgentHFvisit Time to first HHF after starting intervention (3 years) Key secondary endpoints –Individual components of primary endpoint –Time to all-cause mortality –All-cause hospitalization –Time to first occurrence of chronic dialysis, kidney transplant or sustained reduction of eGFR –Change from baseline in KCCQ –Total number of CV death or HHF –Time to death from any cause –Proportion of patients with worsened NYHA class –Change from baseline in KCCQ –Total number of CV death or HHF –Time to death from any cause –Composite of ≥50% sustained eGFR decline, ESRD or kidney death –Change from baseline in KCCQ –Number of all-cause mortality (total mortality, incidence of acute coronary syndrome and non-fatal CVA) Results/status Estimated completion November 2020 Estimated completion July 2020 Estimated completion June 2021 Primary outcome, 16.3% in the dapagliflozin group and 21.2% in the placebo group (HR 0.74; 95% CI 0.65–0.85). Risk of the primary endpoint: HR 0.7 3, 95% CI 0.60–0.88 in patients without T2D and HR 0.75, 95% CI 0.63–0.85 in patients with T2D. Low number of AEs with no differences between groups. Estimated completion December 2021 Abbreviations:AE, adverse events; BP, blood pressure; CI, confidence interval; CV, cardiovascular; CVA, cerebrovascular accidents; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HHF, hospitalization for heart failure; HR, hazard ratio; KCCQ,Kansas City Cardiomyopathy Questionnaire; LVEF, left ventricular ejection fraction; NT-proBNP,N-terminalpro–B-type natriuretic peptide; NYHA, New York Heart Association classification; T2D,type2 diabetes mellitus Cardiovasc Drugs Ther subanalysis from DECLARE-TIMI 58 suggested a reduction in type 2 MI, possibly by ischemic and not anti-thrombotic mechanisms [27,43]. Additionally, the beneficial effects of SLGT2is are seen at similar proportions across patients with different levels of HbA1c and eGFR. Several hypotheses have thus been postulated to explain the cardio-renal outcomes observed with SLGT2i, beyond effects on glycemia, BP and weight loss (Fig. 1). The “Super Fuel”Hypothesis The healthy myocardium is metabolically “omnivorous”and able to switch between different sources of energy; it can use carbohydrates, ketones, lactate and certain amino acids as fuel, but utilizes preferentially free fatty acids (FFA) for energy production, which yield substantial amounts of energy in the form of adenosine triphosphate (ATP) molecules, albeit at the expense of higher oxygen consumption [47]. Ketone bodies may also be used by the myocardium as the most energyefficient fuel source, producing the largest number of ATP molecules at the lowest oxygen expense. In the diseased myocardium, there is an increased uptake of glucose and FFA into the cytosol, but this becomes uncoupled from their uptake and oxidation in the mitochondria, leading to an accumulation of metabolic intermediates, ultimately resulting in toxicity [48]. In patients treated with empagliflozin the induced glycosuria results in lower plasma glucose and insulin levels, with concomitant increased plasma glucagon (resembling a fasting state), leading to enhanced lipid mobilization [49,50]. The lower ratio of insulin/ glucagon at the portal vein and the increased circulation of FFA stimulate ketogenesis in the liver [51]. This hypothesis, suggested by previous authors as the “thrifty substrate”hypothesis, postulates that SGLT2i cause a mild but persistent increase in the production of ketone bodies, in particular beta-hydroxybutyrate, which becomes, along with FFA, the main substrates for ATP production in the myocardium, in detriment of glucose. Because ketone bodies are more energy-efficient than FFA, this shift greatly improves the energetic efficiency of the heart [52] and reduces cytotoxicity [48]. Although animal studies have been conducted to test this hypothesis, it still lacks confirmatory clinical data to support it. A study in a non-diabetic porcine model subjected to MI showed that empagliflozin increases myocardial consumption of ketones at the same time that it reduces glucose consumption, with increased myocardial energetics leading to reverse remodelling at anatomical, metabolic and neurohormonal levels [46].Thesameinvestigators are currently conducting a trial with empagliflozin (the EMPA-TROPISM study [53]), attempting to translate these results into the clinical arena. The Sodium-Hydrogen Exchanger Hypothesis One alluring hypothesis that has been put forward is that SLGT2i may offer cardio-renal benefits by directly binding to and inhibiting the sodium-hydrogen exchangers (NHE) in the heart and kidney [54]. The NHE1 isoform is ubiquitously distributed and is the predominant isoform expressed in the heart [55], whereas NHE3 expression is limited to epithelial cells of the gut and kidney, being responsible for most of the sodium reuptake after glomerular filtration [56,57]. In HF, the activity of NHE1 in cardiomyocytes is markedly increased, leading to higher concentrations of Na + in the cytosol, which in turn triggers an increase in intracellular Ca 2+ and ultimately lead to cardiomyocyte injury and cardiomyopathy [54]. Experimental models have shown that SLGT2i directly bind to NHE1 in cardiomyocytes, reducing cytoplasmic Na + and Ca 2+ levels [58–60]. It should be noted that the SLGT2 transporter is not expressed in the heart [61]; thus, SLGT2i cannot exert their action in cardiomyocytes via SLGT2 inhibition. It has been postulated that SLGT2i may also downregulate the activity of NH3 in the proximal tubule [62]. Animal models have shown that NH3 expression is increased in HF as a result of upregulation of mineralocorticoids, leading to fluid retention and peripheral oedema [63,64]. Mineralocorticoid antagonists such as spironolactone inhibit both NHE1 and NHE3 and ameliorate experimental models of HF [65–71]. Interestingly, in the EMPA-REG OUTCOME trial, the CV benefits with empagliflozin were attenuated in patients receiving spironolactone at baseline [29]. However, the same effect was not observed in the DAPA-HF trial, where over 70% of the population received background therapy with aldosterone antagonists [35]. The “Smart Diuretic”Hypothesis The “smart diuretic”hypothesis suggests that the favourable effects observed with SGLT2i are in part due to their more selective diuretic effects. SGLT2i have unique diuretic properties whereby they modulate the function of the proximal tubule, leading to natriuresis, glycosuria and ensuing osmotic diuresis [72]. The consequent sodium and volume reductions would result in lower preload and afterload, leading to improved cardiac loading conditions [73]. The proximal tubule action and natriuretic effect act as stimuli for tubuloglomerular feedback, resulting in afferent arteriolar vasoconstriction, thus lowering glomerular hypertension, and likely causing an antiproteinuric effect [73]. Besides volume contraction, SGLT2i have also been shown to increase haemoconcentration, possibly also associated to intrinsic renal mechanisms, such as the recovery of tubulointerstitial hypoxia and increased erythropoietin (EPO) production, mechanisms that require further clarification [74,75]. It may be hypothesized that the haemoconcentration can lead to increased Cardiovasc Drugs Ther Table 3 Summary of ongoing dedicated heart failure functional capacity trials of SGLT2i EMPERIALPreserved [39] EMPERIALReduced [39] Effects of empagliflozin on exercise capacity and LV diastolic function in patients with HFpEF and T2D PRESERVED-HF DEFINE-HF [40] DETERMINEPreserved DETERMINEReduced Treatment of diabetes in patients with systolic HF NCT number 03448406 03448419 03753087 03030235 02653482 03877224 03877237 02920918 Active substance/- comparator Empagliflozin/Placebo Empagliflozin/none (unmasked) Dapagliflozin/placebo Dapagliflozin/placebo Dapagliflozin/placebo Canagliflozin/sitagliptin Population HFpEF HFrEF HFpEF with T2D HFpEF with or without T2D HFrEF with or without T2D HFpEF HFrEF HFrEF with T2D With or without T2D With or without T2D Sample size 300 300 100 320 263 400 (estimated) 300 (estimated) 36 Key inclusion criteria –Chronic HF NYHA class II–IV –Walking distance in the 6MWT ≤350 m –Aged 45–80 years –T2D (HbA1c ≥6.5% and ≤10%) –HF NYHA class II–IV –HFpEF (LVEF > 40%) and elevated NT-proBNP –HF NYHA class II–IV –No change in diuretic management for at least 1 week prior to enrolment –BNP ≥100 pg/mL and/or NT-proBNP ≥400 pg/mL at enrolment –HFrEF (LVEF ≤40%) and elevated NT-proBNP –Aged ≥40 years –HF NYHA class II–IV –Evidence of structural heart disease –6MWT ≥100 m and ≤425 m –HFpEF (LVEF > 40%) and elevated NT-proBNP –HF NYHA class II–IV –6MWT ≥100 m and ≤425 m –HFrEF (LVEF ≤40%) and elevated NT-proBNP –T2D and HF NYHA class II–III –RER > 1.00 –HFrEF (LVEF ≤40%) –HFpEF (LVEF > 40%) and elevated NT-proBNP –HFrEF (LVEF ≤40%) and elevated NT-proBNP Aim To evaluate the effect of empagliflozin 10 mg vs. placebo on exercise ability using the 6MWT in patients with HFrEF or HFpEF Effects of empagliflozin on exercise capacity and LV diastolic function in patients with HFpEF and T2D Effects of dapagliflozin on biomarkers, symptoms and functional status in patients with HFpEF Dapagliflozin effect on symptoms and biomarkers in patients with HF Effect of dapagliflozin on exercise capacity in patients HFpEF Effect of dapagliflozin on exercise capacity in patients with HFrEF Treatment of diabetes in patients with systolic HF Primary endpoint Change from baseline to week 12 in exercise capacity (6MWT) Change in 6MWT at 24 weeks Change from baseline in NT-proBNP at 6 and 12 weeks 6-week and 12-week NT-proBNP levels Composite of elevation in HF-specific health status by at least 5 points in the KCCQ score or ≥20% decrease in NT-proBNP levels Change from baseline to week 16 in 6MWT Change from baseline aerobic exercise capacity at 12 weeks measured by cardiopulmonary exercise test Results/status Estimated completion October 2019 Estimated completion May 2020 Estimated completion February 2021 No significant difference in average NT-proBNP with dapagliflozin vs. placebo (1133 pg/dL, 95% CI 1036–1238, vs. 1191 pg/dL, 95% CI 1089–1304, p= 0.43). Composite of elevation in HF health status and Estimated completion February 2020 Estimated completion January 2020 Estimated completion September 2018 No results available Cardiovasc Drugs Ther oxygen delivery to myocardial tissue and serve as a complementary mechanism to the “super fuel”hypothesis, further enhancing myocardial efficiency [52]. Furthermore, it has been proposed that SGLT2i have the ability to selectively reduce interstitial fluid, a property unique to this class, which may be particularly relevant for patients with congestive HF and interstitial oedema [72]. This differs from the drastic reduction in intravascular volume observed with loop diuretics, which may lead to compensatory mechanisms and neurohormonal activation, associated with deleterious effects [76]. Alternatively, a sympathoinhibitory afferent renal nerve signal is another possible mechanism to explain the absence of SGLT2i activation on the sympathetic nervous system, typically activated with diuretic therapies [77]. Other differences between SLGT2i and traditional diuretics include their uricosuric effect [78], as well as their ability to improve endothelial function and aortic stiffness [79–81]. Other Proposed Mechanisms Multiple other mechanisms have been proposed to explain the early cardio-renal benefits of SGLT2i, including hypotheses that rely on leptin, calcium-calmodulin inhibition, visceral adipose tissue loss and direct vascular (arterial rigidity and central pressure) effects. The effect of SGLT2i on the secretion of leptin (which contributes to the retention of sodium and to the cardiac and renal fibrosis present in patients with obesity-related HFpEF) may reduce Na + retention and the accumulation of visceral adipose tissue, namely epicardial fat, and thus ameliorate the effects of systemic inflammation on the vasculature and visceral organs [82,83]. The recently published EMPA-HEART CardioLink-6 trial [84] added information to the SGLT2i CVOTs, with the inclusion of imaging parameters evaluations. EMPA-HEART aimed to determine whether the CV benefits of SGLT2i could be secondary to a reduction in LV mass, an important and independent predictor of MI, HF and mortality. Individuals with T2D, coronary artery disease and a normal LV mass index (LVMi), representative of the EMPA-REG OUTCOME cohort, were included. After six months, there was a significant reduction in LVMi (measured by cardiac magnetic resonance imaging) associated with empagliflozin [84]. Importantly, the observed reduction in LVMi appeared to occur without reductions in LV volumes, thus reflecting an overall reduction in LV wall thickness, with a greater magnitude of regression observed in patients with higher LVMi at baseline. However, the mechanisms behind the reduction in wall thickness remain to be elucidated, possibly relating to changes in interstitial water content or reduced cardiomyocyte mass. Other evidence from small studies (Moura, B et al. Empagliflozin: effects on the heart and Table 3 (continued) EMPERIALPreserved [39] EMPERIALReduced [39] Effects of empagliflozin on exercise capacity and LV diastolic function in patients with HFpEF and T2D PRESERVED-HF DEFINE-HF [40] DETERMINEPreserved DETERMINEReduced Treatment of diabetes in patients with systolic HF decrease in NT-proBNP levels, the OR effect for dapagliflozin was 1.8 (95% CI, 1.03–3.06, p= 0.039). 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