Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the <scp>DELIVER</scp> trial

Solomon, Scott D.; Boer, Rudolf A. de; DeMets, David L.; Hernandez, Adrian F.; Inzucchi, Silvio E.; Kosiborod, Mikhail; Lam, Carolyn S.P.; Martínez, Felipe A.; Shah, Sanjiv J.; Lindholm, Daniel; Wilderäng, Ulrica; Öhrn, Fredrik; Claggett, Brian; Langkilde, Anna Maria; Petersson, Magnus; McMurray, John J.V.

doi:10.1002/ejhf.2249

Cited by 340 publications

(415 citation statements)

References 35 publications

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“… 7 , 8 , 9 , 15 Further studies evaluating remodelling in patients with heart failure with a preserved ejection fraction (HFpEF) would be of interest, particularly in the context of the ongoing clinical studies in these patients. 16 , 17 …”

Section: Discussionmentioning

confidence: 99%

SGLT2 inhibitors and cardiac remodelling: a systematic review and meta‐analysis of randomized cardiac magnetic resonance imaging trials

et al. 2021

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Aims Recent large randomized controlled trials (RCTs) have demonstrated efficacy of sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) in both preventing and treating heart failure (HF). SGLT2i‐induced reversal of left ventricular remodelling has been proposed as a mechanism contributing to this effect. Methods and results We performed a systematic review and meta‐analysis of RCTs to compare SGLT2i versus placebo (treatment duration >3 months) on cardiac remodelling parameters as measured by cardiac magnetic resonance imaging (cMRI) in patients with HF and/or diabetes. The PubMed and ClinicalTrials.gov databases were searched until 15 June 2021. Our primary outcome was change in absolute left ventricular mass (LVM) from baseline to study endpoint. Secondary outcomes included changes in LVM indexed to body surface area, left ventricular end‐systolic volume (LVESV), left ventricular end‐diastolic volume (LVEDV), and left ventricular ejection fraction (LVEF) from baseline to study endpoint. The Cochrane Collaboration's tool was used to assess risk of bias. Five studies representing 408 patients were included. SGLT2i was associated with greater LVM regression compared to placebo (MD, −5.76 g; 95% CI, −10.87 g to −0.64 g, I2 = 73%; overall effect, P < 0.03; four RCTs). Statistical subgroup differences were not observed in our sensitivity analysis focusing on HF with reduced ejection fraction (P = 0.37) and were observed in our sensitivity analysis focusing on diabetes (P < 0.001). SGLT2i was not associated with statistical changes in LV mass indexed to body surface area (I2 = 75%; P = 0.16; five RCTs), LVESV (I2 = 87%; P = 0.07; five RCTs), LVEDV (I2 = 81%; P = 0.20; five RCTs), nor LVEF (I2 = 85%; P = 0.19; five RCTs) versus placebo. Sixty per cent of RCTs had low risk of bias. Conclusions Sodium‐glucose cotransporter‐2 inhibitors treatment was associated with a reduction in left ventricular mass as assessed by cMRI.

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Section: Discussionmentioning

confidence: 99%

SGLT2 inhibitors and cardiac remodelling: a systematic review and meta‐analysis of randomized cardiac magnetic resonance imaging trials

et al. 2021

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“…Press release about the EMPEROR-Preserved study, which has been recently completed on HFpEF patients, stated that the study met its primary endpoint showing that empagliflozin has reduced mortality and hospitalization in the treated cohort [NCT03057951]. Moreover, optimistic results are expected from the DELIVER trial, which investigates the benefit of dapagliflozin in HFpEF patients (128), all showing that SGLTi inhibition can exert cardio-beneficial effects in HFpEF. In addition, in T2DM patients dapagliflozin could reduce the EAT volume and the occurrence cardiovascular events (94).…”

Section: Sodium-glucose Cotransporter 2 Inhibitorsmentioning

confidence: 99%

Epicardial Fat Expansion in Diabetic and Obese Patients With Heart Failure and Preserved Ejection Fraction—A Specific HFpEF Phenotype

Elsanhoury

Nelki

Kelle

et al. 2021

Front. Cardiovasc. Med.

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Graphical AbstractEpicardial adipose tissue (EAT)-related heart failure with preserved ejection fraction (HFpEF). Obesity and type 2 diabetes mellitus (T2DM) are common triggers of HFpEF, frequently associated with EAT expansion. EAT plays metabolic and mechanical roles in HFpEF development via para/vasocrine factors and pericardial restrain, respectively. Life-style modifications including healthy diet and regular exercise can quash the EAT expansion. Statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and fat-modulating antidiabetics including metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists can target EAT. FFA, free fatty acids; AGEs, advanced glycation end-products; NO, nitric oxide; ROS, reactive oxygen species; Ang-II, angiotensin II; TGF-β, Transforming growth factor beta; MCP-1, monocyte chemoattractant protein 1; IL-6, interleukin 6; TNF-α, tumor necrosis factor alpha. Figure created via Servier Medical Art and BioRender tools.

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“…20 A trial of dapagliflozin in patients with heart failure and a preserved ejection fraction (DELIVER) is expected to complete in 2022. 21 The licences of dapagliflozin and empagliflozin have been updated to allow prescribing in patients with heart failure in addition to use in patients with diabetes.…”

Section: Discussionmentioning

confidence: 99%

Series: Cardiovascular outcome trials for diabetes drugs Canagliflozin and the CANVAS Program, dapagliflozin and DECLARE-TIMI 58, ertugliflozin and VERTIS CV

Fisher

2021

Br J Diabetes

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EMPA-REG OUTCOME was a landmark trial with the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin, which demonstrated significant reductions in major adverse cardiovascular events (MACE, a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) driven by reductions in cardiovascular deaths and accompanied by an early reduction in hospitalisation for heart failure. This was followed by cardiovascular outcome trials with canagliflozin, dapagliflozin and ertugliflozin. The CANVAS Program was an integrated analysis of the CANVAS and CANVAS-R trials with canagliflozin. It demonstrated a significant reduction in MACE, but not in any of the components, and there was an unexpected increase in amputations and fractures with canagliflozin. The DECLARE-TIMI 58 trial with dapagliflozin had two co-primary endpoints. A composite endpoint of cardiovascular death or hospitalisation for heart failure was significantly reduced, but there was no significant difference in MACE comparing dapagliflozin with placebo. Analysis of patients with a prior myocardial infarction, however, demonstrated significant reductions in MACE. The VERTIS CV trial with ertugliflozin was disappointing as there was no difference in MACE comparing ertugliflozin and placebo. In all four trials a reduction in hospitalisation for heart failure was observed in patients with type 2 diabetes, regardless of whether they had existing atherosclerotic cardiovascular disease or increased cardiovascular risk. Pre-specified renal outcomes were reduced with empagliflozin, canagliflozin and dapagliflozin, and these drugs are now commonly used in the management of people with type 2 diabetes. It is hard to envisage an ongoing role for ertugliflozin in routine clinical management as the evidence for its cardiovascular benefit is not convincing.

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Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial

Cited by 340 publications

References 35 publications

SGLT2 inhibitors and cardiac remodelling: a systematic review and meta‐analysis of randomized cardiac magnetic resonance imaging trials

SGLT2 inhibitors and cardiac remodelling: a systematic review and meta‐analysis of randomized cardiac magnetic resonance imaging trials

Epicardial Fat Expansion in Diabetic and Obese Patients With Heart Failure and Preserved Ejection Fraction—A Specific HFpEF Phenotype

Series: Cardiovascular outcome trials for diabetes drugs Canagliflozin and the CANVAS Program, dapagliflozin and DECLARE-TIMI 58, ertugliflozin and VERTIS CV

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