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Dapagliflozin for Heart Failure with Preserved Ejection Fraction: Will the DELIVER Study Deliver?

Drug therapies for people with heart failure and preserved ejection fraction (HFpEF) are often limited to diuretics to improve symptoms as no therapies demonstrate a mortality benefit in this cohort. People with diabetes have a high risk of developing HFpEF and vice versa, suggesting shared pathophysiological mechanisms exist, which in turn engenders the potential for shared treatments. Dapagliflozin is a sodium–glucose co-transporter 2 (SGLT2) inhibitor which has demonstrated significantly improved cardiovascular and hospitalisation for heart failure (HHF) outcomes in previous cardiovascular outcome trials (CVOTs). These CVOTs include the DECLARE-TIMI and DAPA-HF studies which observed significant benefits for people with heart failure and specifically those with heart failure and reduced ejection fraction (HFrEF), respectively. The ongoing DELIVER study is evaluating the use of dapagliflozin specifically in people with HFpEF, which may have enormous implications for treatment and considerable economic consequences. This will complement previous and other ongoing CVOTs evaluating dapagliflozin use. In this review we discuss the use of SGLT2 inhibitors in HFrEF and HFpEF with a focus on the DELIVER study and its potential health and economic implications.


INTRODUCTION
Heart failure is an increasingly recognised diagnosis in people with diabetes and its prevalence is increasing, with an estimated 26 million people diagnosed worldwide and an estimated global economic burden of over US$108 billion [1,2]. Whilst the economic impact of heart failure is substantial, the personal impact including recurrent hospitalisation and poorer quality of life outcomes compared with most chronic diseases is significant [1]. Moreover, the projected 5-year mortality associated with heart failure is high at around 75% [3]. People with heart failure can be broadly classified as those with reduced left ventricular ejection fraction (HFrEF) and those with preserved left ventricular ejection fraction (HFpEF) based on a left ventricular ejection fraction (LVEF) \ 40% or [ 40%, respectively.
Whilst approximately 50% of people with heart failure have HFpEF, its relative prevalence is increasing and it is anticipated that HFpEF prevalence will soon exceed that of HFrEF [1,4]. Crucially, whilst treatment with angiotensin converting enzyme (ACE) inhibitors, beta blockers or mineralocorticoid receptor antagonists, amongst others, reduces mortality in people with HFrEF, there is no known therapy which reduces mortality in people with HFpEF [5][6][7].
There is a strong association between heart failure and diabetes, and people with diabetes have a 2-5-fold greater lifetime risk of developing heart failure, whilst around 45% of people with heart failure have underlying diabetes [8,9]. Indeed, heart failure is the most common first manifestation of cardiovascular disease in people with diabetes. The association with diabetes is greater with HFpEF than HFrEF, possibly a result of shared pathophysiological mechanisms including increased inflammation, aberrant angiogenesis and remodelling, impaired cardiac metabolism, altered insulin signalling and advanced glycated end-product deposition within the myocardium [10,11]. Therefore, treatments which reduce or reverse these changes have a massive potential for impact in people with type 2 diabetes (T2D) and may improve cardiovascular outcomes in this highrisk population. Indeed, treatments which improve cardiovascular outcomes in people with T2D are highly sought and of topical interest with the undertaking of cardiovascular outcome trials (CVOTs) for all T2D drug therapies. Given that heart failure typically occurs in the elderly, the use of medications such as sodium-glucose co-transporter 2 (SGLT2) inhibitors to improve outcomes in this population is attractive. However, there is limited experience seen in clinical trials and real-world data to evaluate this approach. Here, we discuss the use of SGLT2 inhibitors for heart failure with a focus on dapagliflozin and the ongoing DELIVER trial evaluating dapagliflozin in people with HFpEF. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

SGLT2 INHIBITORS IMPROVE CARDIOVASCULAR AND RENAL OUTCOMES IN CVOTS
Several SGLT2 inhibitors have been introduced for people with T2D, including canagliflozin, dapagliflozin, empagliflozin and ertugliflozin amongst others. These drugs inhibit the SGLT2 protein in the proximal convoluted tubule of the nephron to induce a glucose-mediated osmotic diuresis and natriuresis. As a result, these drugs are associated with important improvements in glycaemic control, blood pressure, body weight and lipids [12]. Additionally, CVOTs investigating the safety of these drugs have observed improved cardiovascular and heart failure outcomes associated with their use.
A recent meta-analysis of CVOTs reported a reduced rate of 3-point major adverse cardiac events (MACE) (hazard ratio (HR) 0.88, confidence interval (CI) 0.82-0.94), cardiovascular death (HR 0.83, CI 0.75-0.92) and all-cause mortality (HR 0.85, CI 0.79-0.92) associated with SGLT2 inhibitor use versus placebo [13]. Indeed, CVOTs have consistently observed important cardiovascular and/or heart failure benefits associated with SGLT2 inhibitor use [14][15][16][17][18][19][20]. However, studies have previously included variable participant groups with differing cardiovascular risk and utilise various definitions of HFpEF and HFrEF including LVEF and N-terminal pro B-type natriuretic peptide (NT-pro BNP) amongst other variables. This is crucial to consider when distinguishing between drugs in this class for people with heart failure. Trial participant characteristics and heart failure endpoints from ongoing and completed CVOTs reporting on heart failure outcomes are presented in Table 1.
There has also been a great deal of interest in renal outcomes associated with SGLT2 inhibitors given their renal mechanism of action and the association of chronic kidney disease (CKD) in people with diabetes and cardiovascular disease. Diagnosis of CKD in people with heart failure is common, a result of chronic fluid overload and potential acute kidney injury associated with many treatments for heart failure causing the so-called cardio-renal syndrome [21]. Indeed, CVOTs investigating SGLT2 inhibitor use have reported that these drugs are associated with a delay in the decline in glomerular filtration rate (GFR) and a reduced frequency of progression to macroalbuminuria typically seen in people with enduring diabetes [22]. Given their nephroprotective impact, their use in heart failure is more appealing given the relatively high risk of developing cardio-renal syndrome and CKD.
The cardiovascular and renal benefits observed in these studies cannot be fully explained by improvements in risk factors such as glycaemic control, blood pressure or lipids [14], implying that other mechanisms must explain the cardiovascular benefits seen in HFrEF and possibly HFpEF. The most likely explanation is tubuloglomerular feedback. Here, SGLT2 inhibition results in the increased delivery of sodium (and glucose) to the macula densa, resulting in afferent arteriolar vasoconstriction to reduce the hyperfiltration which frequently characterises the earlier stages of diabetic nephropathy, thereby improving the CKD outcomes discussed above. This may explain how SGLT2 inhibitor-mediated diuresis improves heart failure outcomes also, whilst loop and thiazide diuretics do not improve cardiovascular outcomes. Indeed, loop and thiazide diuretics block sodium entry to the macula densa via the Na-Cl pump and thereby attenuate tubuloglomerular feedback [23,24].
In addition to tubuloglomerular feedback, SGLT2 inhibitor use produces a greater fluid shift from the interstitial space resulting in improved congestion whilst not significantly affecting organ perfusion. Other authors speculate that SGLT2 inhibition results in a state of 'fasting mimicry' through enhancing glycosuria which can induce enzymes within the myocardium which have anti-inflammatory and antioxidant effects. Moreover, the augmented glycosuria results in an energy shift to enhanced ketone metabolism and inhibited cardiac sodium-hydrogen exchange. These effects improve myocardial energy metabolism which appears to reduce myocardial inflammation and fibrosis [25]. Whilst there are many possible mechanisms, the exact role of SGLT2 inhibition in ameliorating cardiovascular and heart failure outcomes is unclear. Figure 1 is a schematic summarising the most appealing of these mechanisms. Nevertheless, the relative influence of these mechanisms is debated as many are unsubstantiated in humans or argued to be an indirect effect of improved glycaemic control. Further investigation in this area is warranted to corroborate these potential mechanisms.

DAPAGLIFLOZIN FOR HEART FAILURE AND CHRONIC KIDNEY DISEASE
The cardiovascular safety of dapagliflozin was first evaluated in the DECLARE-TIMI trial, in 17,160 people with T2D with pre-existing or high risk of developing cardiovascular disease over a median 4.2 years. Here, 10.0% of Moreover, participants receiving dapagliflozin had a 29% lower mean urinary albumin-to-creatinine ratio (ACR) than those using placebo [27,28]. Therefore, whilst dapagliflozin reduced the frequency of adverse heart failure and renal outcomes in this high-risk participant cohort, more specific evaluation in different cohorts was required to validate these findings further.
The subsequent DAPA-HF study investigated the use of dapagliflozin in 4744 people with HFrEF over a median 18.2 months and did not include participants with HFpEF. The study found a significant relative risk reduction compared with placebo for cardiovascular death (HR 0.82, CI 0.69-0.98) and HHF (HR 0.70, CI 0.59-0.83), with a similar impact in people with or without T2D [18]. Additionally, dapagliflozin use was associated with reduced frequency of developing the renal composite outcome (HR 0.71, CI 0.44-1.16) and renal adverse events (6.5% vs 7.2%) versus placebo. Whilst these results supported the recent Food and Drug Administration (FDA) approval for dapagliflozin use in people with HFrEF [29], as it did not include sufficient participants with HFpEF its efficacy in this patient group remains unknown and its use in this group is not approved.
The DAPA-CKD study is an ongoing trial to investigate the impact of dapagliflozin on GFR, changes in urinary ACR, cardiovascular death or HHF in around 4300 participants with CKD (baseline GFR 25-75 mL/min/1.73 m 2 ) [30]. Whilst the baseline characteristics of the number of participants with underlying heart failure are currently unavailable, secondary outcome measures of the study include time to cardiovascular death and HHF. The trial was due to complete in June 2020, and we await the results of this trial with great interest.
The impact of dapagliflozin and SGLT2 inhibitors generally in people with HFpEF remains unknown and given the lack of outcome-changing therapies for people with HFpEF the potential impact in this patient group is enormous. The ongoing EMPEROR trials will further establish the impact of empagliflozin in people with HFrEF or HFpEF [31,32], whilst the DELIVER trial will focus entirely on the cardiovascular and heart failure outcomes associated with dapagliflozin in participants with HFpEF [33].

THE DELIVER TRIAL: WHAT WILL IT ADD?
The DELIVER trial is a phase III international, multicentre, parallel-group, randomised, Fig. 1 Key potential mechanisms by which SGLT2 inhibitors may improve heart failure and cardiovascular outcomes in people with HFrEF and HFpEF [23][24][25]. SGLT2 sodium-glucose co-transporter 2 double-blind, placebo-controlled study evaluating the impact of dapagliflozin 10 mg versus placebo in participants with HFpEF [33]. The study started in August 2018 and is due to complete in June 2021, with an estimated enrolment of 6100 participants. The primary outcome measure is the time to first occurrence of either cardiovascular death, HHF or urgent heart failure visit. Secondary outcome measures include the number of HHF and cardiovascular death, changes in the total symptom score measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), the proportion of patients with worsened New York Heart Association (NYHA) class and time to the occurrence of death from any cause. Inclusion and exclusion criteria are presented in Table 2 and the study design is presented in Fig. 2.
The DELIVER study runs in parallel with two other key trials evaluating dapagliflozin: The DAPA-HF study [18] and the DAPA-CKD study [30]. The findings from the DELIVER study will complement those of the DAPA-HF study and determine whether the impact of dapagliflozin on the rate of HHF and cardiovascular death in people with HFrEF is also reproduced in people with HFpEF. As discussed earlier, this would potentially have a major impact for people with HFpEF as no current drug therapy has yet demonstrated any cardiovascular outcome benefit in this patient group. The study is well powered for superiority with a large participant number expected to enrol. This adds significantly to the previous sub-analysis of 1316 participants with HFpEF in the DECLARE-TIMI trial, which may explain the limited findings and relative lack of study power in this relatively small cohort [26]. Moreover, as participants without underlying diabetes are included, data on incident diabetes in this group will be available thereby adding to the DAPA-HF study which reported a significant 32% relative risk  [34]. Of course, should results favour dapagliflozin use the economic gains in addition to improved patient outcomes may be substantial given the increasing financial burden associated with HFpEF, discussed below. Whilst we await the completion and publication of the results of the DAPA-CKD study [30], results from previous CVOTs evaluating dapagliflozin have shown the drug is both safe and probably improves renal outcomes in highrisk participants with cardiovascular disease [17,18,27,28]. Thus, dapagliflozin would prove an attractive option for people with HFpEF who frequently develop renal complications and improve glycaemic control and incident diabetes in this population which frequently have or are at a very high risk of developing T2D.

THE DELIVER AND EMPEROR STUDIES: WHAT ARE THE DIFFERENCES?
As discussed briefly above, the EMPEROR studies are two distinct trials which aim to establish the effect of empagliflozin on heart failure and cardiovascular outcomes in people with HFrEF [31] and HFpEF [32], which we recently reviewed [35]. Given that these medications are from the same drug class, comparisons in trial results will naturally be made when available. The trials are broadly similar, aiming to establish the impact of an SGLT2 inhibitor in people with HFpEF in similar numbers of enrolled trial participants (5750-6100), as shown in Table 3. However, there are important differences between the trials also. For example, the DELI-VER trial will include both ambulatory and hospitalised participants stable on oral therapy for at least 24 h. In contrast, the EMPERORpreserved trial requires a greater duration of stability on oral therapy ([ 1 week). This earlier initiation and in hospitalised participants may show changes in length of hospital stay which would have significant clinical and economic implications. However, the study may not be sufficiently powered to address this outcome. Moreover, the DELIVER trial includes participants with symptomatic HF for at least 6 weeks, compared with the EMPEROR-preserved trial in which participants are symptomatic for at least 3 months. Additionally, the DELIVER trial excludes people with BMI [ 50 kg/m 2 , whilst EMPEROR-preserved excludes those with liver disease [32,33].
The primary outcome in both studies includes the time to first occurrence of cardiovascular death or HHF, though the DELIVER trial also includes urgent heart failure visits such as to the emergency department or outpatient clinic in addition to hospitalisation. This is noteworthy, because whilst hospitalisation is a major determinant for quality of life and health expenditure outcomes, the use of extra outpatient or emergency department costs is often overlooked. As secondary outcomes, both trials will report on HHF, cardiovascular and all-cause death and quality of life outcomes using the Fig. 2 The trial design and key outcome measures from the DELIVER study. Figure adapted from ClinicalTrials.gov [33]. CV cardiovascular, HHF Hospitalisation for Heart Failure, KCCQ Kansas City Cardiomyopathy Questionnaire, LVEF left ventricular ejection fraction, NYHA New York Heart Association, NT-pro BNP N-terminal pro B-type natriuretic peptide Table 3 Similarities and differences between the DELIVER and EMPEROR-preserved trials. . However, the EMPEROR-preserved trial will also report on changes in eGFR, time to chronic dialysis, renal transplant or sustained reduction of eGFR and rates of incident diabetes in those using empagliflozin whilst these secondary outcomes have not yet been pre-specified for the DELIVER trial [32,33].

COST-EFFECTIVENESS
The use of drugs which reduce HHF may have the greatest impact on healthcare expenditure for people with heart failure, as approximately 70% of the cost associated with the heart failure treatment results from hospitalisation, and around two-thirds of patients have at least one readmission within 1 year [36]. Whilst there is no published cost analysis undertaken by the DAPA-HF study group, several authors have analysed the potential cost saving associated with dapagliflozin use in people with HFrEF. An Australian study estimated the cost-effectiveness of dapagliflozin in people with HFrEF at $12,482 Australian dollars per quality-adjusted life year (QALY) versus the standard of care, with similar cost savings in people with or without T2D [37]. Furthermore, a Swedish study compared real-world healthcare costs associated with dapagliflozin use compared with people initiated on non-SGLT2 inhibitor glucose-lowering treatments. The study observed lower hospital costs of US$321 per patient over 12 months associated with dapagliflozin, mostly a result of fewer cardiovascular, heart failure and other T2D-related complications [38]. The impact of dapagliflozin or other SGLT2 inhibitors on HHF and other cardiovascular health outcomes in people with HFpEF is unknown, and therefore cost analyses are impossible. However, given that around 50% of people hospitalised for heart failure have underlying HFpEF [1,39] and the cost of HHF is the largest contributor to heart failure treatment costs, any reduction in the HHF or length of hospital stay would incur major cost savings.

CONCLUSIONS
The use of dapagliflozin in the treatment of people with HFrEF will soon be commonplace following the results of the DAPA-HF study and recent FDA approval. The DELIVER study has the potential to deliver similarly clinically meaningful outcomes with dapagliflozin use for people with HFpEF. This is reflected in the potential biological mechanisms by which SGLT2 inhibitors may affect cardiovascular outcomes and the previous subgroup analyses of CVOTs demonstrating important beneficial outcomes in people in this cohort. There is an absolute need for meaningful drug therapy in this difficult-to-treat group as no current pharmacological therapy is known to improve cardiovascular mortality. Similarly, the EMPERORpreserved trial will report on heart failure outcomes in people with HFpEF associated with empagliflozin use. However, caution needs to be taken interpreting the results of these studies because of important differences in trial design and planned study outcomes. Moreover, further clinical trial or real-world evidence to evaluate any additive impact of SGLT2 inhibitors with other drugs classes used in people with heart failure and diabetes such as ACE inhibitors or glucagon-like peptide 1 (GLP-1) analogues would be useful. Benefits seen with dapagliflozin may be associated with important personal, clinical and economic implications given the burden of HFpEF. These may include improved quality of life, less frequent hospitalisation, improved financial costs associated with the disease and less frequent development of co-morbidities including diabetes and CKD in this group.

ACKNOWLEDGEMENTS
Funding. No funding or sponsorship was received for this study or publication of this article.
Authorship. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work, and have given their approval for this version to be published.
Disclosures. David M Williams has nothing to disclose. Marc Evans received financial support for consultancy from Novartis, Merck Sharp & Dohme Corp. and Novo Nordisk and has served on the speaker's bureau for Novartis, Lilly, Boehringer lngelheim, Merck Sharp & Dohme Corp., Novo Nordisk, Janssen and Takeda. Marc Evans is also the Editor-in-Chief of Diabetes Therapy.
Compliance with Ethics Guidelines. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.
Data Availability. Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

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