Evaluation of the effects of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR‐Preserved Trial

Anker, Stefan D.; Butler, Javed; Filippatos, Gerasimos; Jamal, Waheed; Salsali, Afshin; Schnee, Janet; Kimura, Karen; Zeller, Cordula; George, Jyothis T.; Brueckmann, Martina; Zannad, Faı̈ez; Packer, Milton; Perrone, Sergio V.; Nicholls, Stephen J.; Janssens, Stefan; Bocchi, E.A.; Giannetti, Nadia; Zhang, Jiän; Mesa, Juan E.; Špinar, Jindřich; Böhm, Michael; Merkely, Béla; Chopra, Vijay; Senni, Michele; Taddi, Stefano; Chuquiure, Eduardo; Rocca, Hans Pieter Brunner La; Vinereanu, Dragoş; Sim, David; Choi, Dong‐Ju; Juanatey, José Ramón González; Squire, Iain B.; Piña, Ileana L.; Pocock, Stuart J.; Carson, Peter E.; Doehner, Wolfram; Miller, Alan B.; Haas, Markus; Pehrson, Steen; Komajda, Michel; Anand, Inder; Teerlink, John R.; Rabinstein, Alejandro A.; Steiner, Thorsten; Kamel, Hooman; Tsivgoulis, Georgios; Lewis, James D.; Freston, James W.; Kaplowitz, Neil; Mann, Johannes F.E.; Petrie, Mark C.; Bernstein, Richard A.; Cheung, Alfred K.; Green, Jennifer; Januzzi, James L.; Kaul, Sanjay; Ping, Carolyn Lam Su; Lip, Gregory Y.H.; Marx, Nikolaus; McCullough, Peter A.; Mehta, Cyrus R.; Ponikowski, Piotr; Rosenstock, Julio; Sattar, Naveed; Scirica, Benjamin M.; Tsutsui, Hiroyuki; Verma, Subodh; Wanner, Christoph; Welty, Francine K.; Parhofer, Klaus G.; Clayton, Tim; Pedersen, Terje R.; Lees, Kennedy R.; Konstam, Marvin A.; Greenberg, Barry; Palmér, Mats

doi:10.1002/ejhf.1596

Cited by 208 publications

(177 citation statements)

References 58 publications

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“…At the same time, two randomized clinical trials are evaluating the effects of SGLT2 inhibitors in patients with established heart failure with a preserved ejection fraction (HFpEF), regardless the presence of diabetes. One is the EMPEROR-Preserved trial [NCT03057951] with empagliflozin (78), and the other one is the DELIVER trial [NCT03619213] with dapagliflozin. Several preclinical studies proposed the mechanism how SGLT2 inhibitor alleviates cardiac diastolic dysfunction, a major cause of HFpEF.…”

Section: Future Directionsmentioning

confidence: 99%

SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function

Maejima

2020

Front. Cardiovasc. Med.

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Three cardiovascular outcome trials of sodium glucose cotransporter 2 (SGLT2) inhibitors, including the EMPA-REG OUTCOME trial, CANVAS Program, and DECLARE TIMI 58 trial, revealed that SGLT2 inhibitors were superior to a matching placebo in reducing cardiovascular events, including mortality and hospitalization for heart failure, in patients with type 2 diabetes. However, the detailed mechanism underlying the beneficial effects that SGLT2 inhibitors exert on cardiovascular diseases remains to be elucidated. We herein review the latest findings of the salutary mechanisms of SGLT2 inhibitors in cardiomyocytes, especially focusing on their mitochondrial function-mediated beneficial effects. The administration of SGLT2 inhibitors leads to the elevation of plasma levels of ketone bodies, which are an efficient energy source in the failing heart, by promoting oxidation of the mitochondrial coenzyme Q couple and enhancing the free energy of cytosolic ATP hydrolysis. SGLT2 inhibitors also promote sodium metabolism-mediated cardioprotective effects. These compounds could reduce the intracellular sodium overload to improve mitochondrial energetics and oxidative defense in the heart through binding with NHE and/or SMIT1. Furthermore, SGLT2 inhibitors could modulate mitochondrial dynamics by regulating the fusion and fission of mitochondria. Together with ongoing large-scale clinical trials to evaluate the efficacy of SGLT2 inhibitors in patients with heart failure, intensive investigations regarding the mechanism through which SGLT2 inhibitors promote the restoration in cases of heart failure would lead to the establishment of these drugs as potent anti-heart failure drugs.

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Section: Future Directionsmentioning

confidence: 99%

SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function

Maejima

2020

Front. Cardiovasc. Med.

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“…Furthermore, in patients with heart failure, dapagliflozin reduced the risk of worsening heart failure or CV death irrespective of the presence or absence of T2DM at baseline [7]. Additional trials in heart failure patients are planned to further assess the potential cardioprotective effect of SGLT2 inhibitors in this high-risk patient group [49,50], including one study specifically enrolling heart failure patients without diabetes [51]. The ongoing VERTIS CV trial, designed to assess the effect of ertugliflozin treatment on CV and renal outcomes in 8246 patients with T2DM and established CV disease [52], is due to report out in 2020 and will provide additional insight on the effect of this class to reduce CV risk.…”

Section: Summary Perspectives and Conclusionmentioning

confidence: 99%

Overview of the Clinical Pharmacology of Ertugliflozin, a Novel Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor

et al. 2020

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Ertugliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), is approved in the US, EU, and other regions for the treatment of adults with type 2 diabetes mellitus (T2DM). This review summarizes the ertugliflozin pharmacokinetic (PK) and pharmacodynamic data obtained during phase I clinical development, which supported the registration and labeling of this drug. The PK of ertugliflozin was similar in healthy subjects and patients with T2DM. Oral absorption was rapid, with time to peak plasma concentrations (T max) occurring at 1 h (fasted) and 2 h (fed) postdose. The terminal phase half-life ranged from 11 to 18 h and steady-state concentrations were achieved by 6 days after initiating once-daily dosing. Ertugliflozin exposure increased in a dose-proportional manner over the tested dose range of 0.5-300 mg. Ertugliflozin is categorized as a Biopharmaceutical Classification System Class I drug with an absolute bioavailability of ~ 100% under fasted conditions. Administration of the ertugliflozin 15 mg commercial tablet with food resulted in no meaningful effect on ertugliflozin area under the plasma concentration-time curve (AUC), but decreased peak concentrations (C max) by 29%. The effect on C max is not clinically relevant and ertugliflozin can be administered without regard to food. Mild, moderate, and severe renal impairment were associated with a ≤ 70% increase in ertugliflozin exposure relative to subjects with normal renal function, and no dose adjustment in renal impairment patients is needed based on PK results. Consistent with the mechanism of action of SGLT2 inhibitors, 24-h urinary glucose excretion decreased with worsening renal function. In subjects with moderate hepatic impairment, a decrease in AUC (13%) relative to subjects with normal hepatic function was observed and not considered clinically relevant. Concomitant administration of metformin, sitagliptin, glimepiride, or simvastatin with ertugliflozin did not have clinically meaningful effects on the PK of ertugliflozin or the coadministered medications. Coadministration of rifampin decreased ertugliflozin AUC and C max by 39% and 15%, respectively, and is not expected to affect efficacy in a clinically meaningful manner. This comprehensive evaluation supports administration to patients with T2DM without regard to prandial status and with no dose adjustments for coadministration with commonly prescribed drugs, or in patients with renal impairment or mild-to-moderate hepatic impairment based on ertugliflozin PK.

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“…30,31 Studies (DE-LIVER and EMPEROR-Preserved) are currently going on to determine whether sodium glucose cotransporter-2 inhibitors will have a positive impact on the prognosis of HFpEF patients. 32 Association between fibroblast growth factor 23 levels and clinical characteristics…”

Section: Mechanistic Insight Into the Pathogenesis Of Diseasementioning

confidence: 99%

Fibroblast growth factor 23: a biomarker of fibrosis and prognosis in heart failure with preserved ejection fraction

et al. 2020

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Aims Besides regulating calcium-phosphate metabolism, fibroblast growth factor 23 (FGF-23) has been associated with incident heart failure (HF) and left ventricular hypertrophy. However, data about FGF-23 in HF and preserved ejection fraction (HFpEF) remain limited. The aim of this study was to assess the association between FGF-23 levels, clinical and imaging characteristics, particularly diffuse myocardial fibrosis, and prognosis in HFpEF patients. Methods and results We prospectively included 143 consecutive HFpEF patients (78 ± 8 years, 61% female patients) and 31 controls of similar age and gender (75 ± 6 years, 61% female patients). All subjects underwent a complete two-dimensional echocardiography and cardiac magnetic resonance with extracellular volume (ECV) assessment by T1 mapping. FGF-23 was measured at baseline. Among the patients, differences in clinical and imaging characteristics across tertiles of FGF-23 levels were analysed with a trend test across the ordered groups. Patients were followed over time for a primary endpoint of all-cause mortality and first HF hospitalization and a secondary endpoint of all-cause mortality. Median FGF-23 was significantly higher in HFpEF patients compared with controls of similar age and gender (247 [115; 548] RU/mL vs. 61 [51; 68] RU/mL, P < 0.001). Among HFpEF patients, higher FGF-23 levels were associated with female sex, higher incidence of atrial fibrillation, lower haemoglobin, worse renal function, and higher N terminal pro brain natriuretic peptide levels (P for trend < 0.05 for all). Regarding imaging characteristics, patients with higher FGF-23 levels had greater left atrial volumes, worse right ventricular systolic function, and more fibrosis estimated by ECV (P for trend < 0.05 for all). FGF-23 was moderately correlated with ECV (r = 0.46, P < 0.001). Over a mean follow-up of 30 ± 8 months, 43 patients (31%) died and 69 patients (49%) were hospitalized for HF. A total of 87 patients (62%) reached the primary composite endpoint of all-cause mortality and/or first HF hospitalization. In multivariate Cox regression analysis for the primary endpoint, FGF-23 (HR: 3.44 [2.01; 5.90], P < 0.001) and E wave velocities (HR: 1.01 [1.00; 1.02], P = 0.034) were independent predictors of the primary composite endpoint. In multivariate Cox regression analysis for the secondary endpoint, ferritin (HR: 1.

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Evaluation of the effects of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR‐Preserved Trial

Cited by 208 publications

References 58 publications

SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function

SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function

Overview of the Clinical Pharmacology of Ertugliflozin, a Novel Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor

Fibroblast growth factor 23: a biomarker of fibrosis and prognosis in heart failure with preserved ejection fraction

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