Associations of Empagliflozin With Left Ventricular Volumes, Mass, and Function in Patients With Heart Failure and Reduced Ejection Fraction

Omar, Massar; Jensen, Jørgen Steen; Ali, Mulham; Frederiksen, Peter H; Kistorp, Caroline; Videbæk, Lars; Poulsen, Mikael Kjær; Tuxen, Christian; Möller, Sören; Gustafsson, Finn; Køber, Lars; Schou, Morten; Møller, Jacob Eifer

doi:10.1001/jamacardio.2020.6827

Cited by 132 publications

(131 citation statements)

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“…Mechanistic clinical trials with Empagliflozin [14][15][16][17][18][19][20][21] As mentioned in the introduction, the positive clinical results of the EMPA-REG and EMPEROR-Reduced trials immediately aroused interest in establishing the intrinsic mechanisms of those clinical benefits, initiating a series of research and publications presented and analyzed below.…”

Section: Empa-reg Outcome Trialmentioning

confidence: 99%

“…In the EMPIRE-HF echocardiographic substudy, Omar et al 17 investigated the effect of empagliflozin on left atrial and left ventricular volumes and LVEF in patients with HFrEF with or without T2D. This investigator-initiated clinical substudy was a randomized, doubleblind, placebo-controlled study.…”

Section: Empire-hf Trial Echocardiographic Substudymentioning

confidence: 99%

“…In their discussion, the authors analyze the similarity of these changes with those reported in their non-diabetic animal model of heart failure 20 and correlate them with the favorable results reported in DAPA-HF 7 and EMPEROR Reduced 3 studies. Finally, they discuss the differences between EMPATROPISM and similar studies with empagliflozin [15][16][17][18][19] and dapagliflozin. [22][23] Without ruling out other hypotheses, [24][25][26][27][28] they highlight myocardial energy remodeling as the potential substrate of reported anatomical, functional, and clinical benefits.…”

Section: Empa-tropismmentioning

confidence: 99%

“…This article summarizes the results of the cardiovascular outcome trials carried out with empagliflozin, [1][2][3] and analyzes the EMPA-REG mediation sub-analysis results, 14 EMPA-HEART, 15 and EMPIRE-HF, and substudies. [16][17][18][19] Also, "EMPA-PIG" 20 and EMPA-TROPISM, 21 which outline the intrinsic myocardial mechanisms associated with clinical benefit in HFrEF in higher mammals 20 and especially in humans in-vivo. [15][16][17][18][19]21 Figure 1: Hazard ratios are illustrated with their lower and upper limits of the confidence interval for the incidence of 3-MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in cardiovascular outcome trials with empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin in a ASCVD population.…”

Section: Introductionmentioning

confidence: 99%

“…[16][17][18][19] Also, "EMPA-PIG" 20 and EMPA-TROPISM, 21 which outline the intrinsic myocardial mechanisms associated with clinical benefit in HFrEF in higher mammals 20 and especially in humans in-vivo. [15][16][17][18][19]21 Figure 1: Hazard ratios are illustrated with their lower and upper limits of the confidence interval for the incidence of 3-MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in cardiovascular outcome trials with empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin in a ASCVD population. A protective effect is observed against the 3-MACE with empagliflozin and canagliflozin, not so for dapagliflozin and ertugliflozin, which showed a noninferior or safety result.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Empagliflozin, Beyond Glucose Reduction. The Unanticipated and Welcomed Cardioprotective Results. Switching the Heart at Four Levels: Energetic, Anatomical, Functional, and Neuro-Hormonal

Enrique¹,

Castillo-Núñez

Gilberto

2021

MRAJ

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Sodium-glucose cotransporter 2 inhibitors (SGLT2i) like empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin, and sotagliflozin (both a sodium-glucose cotransporter 1 inhibitor [SGLT1i] and SGLT2i), are drugs that inhibit the action of sodium-glucose cotransporters in the proximal renal tubule and/or the intestine. Therefore, causing natriuresis, glucosuria, and reduced intestinal glucose absorption. Besides this mechanism of action, which determines glycemia reduction, there are multiple extra-glycemic mechanisms in extensive research in humans in-vivo, which, beyond in-vitro or experimental studies, is dissecting the mechanisms explaining the initially unanticipated and ultimately incredibly significant and welcomed cardiac and nephroprotective results of these drugs. This article centers on the cardioprotective effects of empagliflozin, namely, a reduction of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure, among others. These effects were demonstrated in the EMPA-REG and EMPEROR-Reduced clinical outcome trials, which will be initially summarized to later frame them in the results of the mechanistic trials EMPA-HEART, EMPIRE-HF (including sub-studies), EMPA-TROPISM, and “EMPA-PIG.” The mechanistic trials showed favorable changes in the left ventricular mass index, left ventricular end-systolic and end-diastolic volumes, extracellular and intravascular volumes, glomerular filtration rate, myocardial remodeling, among others. These were investigator-initiated studies to go beyond in-vitro and experimental evidence. The results and analysis allow us to understand myocardial energy remodeling as an intrinsic myocardial mechanism that underlies anatomical, functional, and neurohormonal myocardial remodeling. Together with other systemic actions, predominantly renal (not discussed in this article), contribute significantly to this drug's clinical benefit.

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Section: Empa-reg Outcome Trialmentioning

confidence: 99%

Section: Empire-hf Trial Echocardiographic Substudymentioning

confidence: 99%

Section: Empa-tropismmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Empagliflozin, Beyond Glucose Reduction. The Unanticipated and Welcomed Cardioprotective Results. Switching the Heart at Four Levels: Energetic, Anatomical, Functional, and Neuro-Hormonal

Enrique¹,

Castillo-Núñez

Gilberto

2021

MRAJ

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Efficacy and Safety of Dapagliflozin in Men and Women With Heart Failure With Reduced Ejection Fraction

et al. 2021

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IMPORTANCEWomen may respond differently to certain treatments for heart failure (HF) with reduced ejection fraction (HFrEF) than men.OBJECTIVE To investigate the efficacy and safety of dapagliflozin compared with placebo in men and women with HFrEF enrolled in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF).DESIGN, SETTING, AND PARTICIPANTS Prespecified subgroup analysis of a phase 3 randomized clinical trial conducted at 410 sites in 20 countries. Patients with New York Heart Association functional class II through IV with an ejection fraction of 40% or less and elevated N-terminal pro-B-type natriuretic peptide were eligible. Data were analyzed between June 2020 and January 2021.INTERVENTIONS Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy. MAIN OUTCOMES AND MEASURESThe primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death.RESULTS A total of 4744 patients were randomized in DAPA-HF, of whom 1109 were women (23.4%). Compared with placebo, dapagliflozin reduced the risk of worsening HF events or cardiovascular death to a similar extent in both men and women (hazard ratios, 0.73 [95% CI, 0.63-0.85] and 0.79 [95% CI, 0.59-1.06], respectively; P for interaction = .67). Consistent benefits were observed for the components of the primary outcome and all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement in symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score of Ն5 points; men, 59% vs 50%; women, 57% vs 54%; P for interaction = .14) and decreased the proportion with worsening symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score decrease of Ն5 points; men, 25% vs 34%; women, 27% vs 31%; P for interaction = .15), irrespective of sex. Results were consistent for the Kansas City Cardiomyopathy Questionnaire clinical summary score and overall summary score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either men or women.CONCLUSIONS AND RELEVANCE Dapagliflozin reduced the risk of worsening HF, cardiovascular death, and all-cause death and improved symptoms, physical function, and health-related quality of life similarly in men and women with heart failure and reduced ejection fraction. In addition, dapagliflozin was safe and well-tolerated irrespective of sex.

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Evolving therapeutic strategies for patients hospitalized with new or worsening heart failure across the spectrum of left ventricular ejection fraction

Ostrominski

Vaduganathan

2022

Clinical Cardiology

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Heart failure (HF) is a chronic, progressive, and increasingly prevalent syndrome characterized by stepwise declines in health status and residual lifespan. Despite significant advancements in both pharmacologic and nonpharmacologic management approaches for chronic HF, the burden of HF hospitalization—whether attributable to new‐onset (de novo) HF or worsening of established HF—remains high and contributes to excess HF‐related morbidity, mortality, and healthcare expenditures. Owing to a paucity of evidence to guide tailored interventions in this heterogeneous group, management of acute HF events remains largely subject to clinician discretion, relying principally on alleviation of clinical congestion, as‐needed correction of hemodynamic perturbations, and concomitant reversal of underlying trigger(s). Following acute stabilization, the subsequent phase of care primarily involves interventions known to improve long‐term outcomes and rehospitalization risk, including initiation and optimization of disease‐modifying pharmacotherapy, targeted use of adjunctive therapies, and attention to contributing comorbid conditions. However, even with current standards of care many patients experience recurrent HF hospitalization, or after admission incur worsening clinical trajectories. These patterns highlight a persistent unmet need for evidence‐based approaches to inform in‐hospital HF care and call for renewed focus on urgent implementation of interventions capable of ameliorating risk of worsening HF. In this review, we discuss key contemporary and emerging therapeutic strategies for patients hospitalized with de novo or worsening HF.

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Associations of Empagliflozin With Left Ventricular Volumes, Mass, and Function in Patients With Heart Failure and Reduced Ejection Fraction

Cited by 132 publications

References 10 publications

Empagliflozin, Beyond Glucose Reduction. The Unanticipated and Welcomed Cardioprotective Results. Switching the Heart at Four Levels: Energetic, Anatomical, Functional, and Neuro-Hormonal

Empagliflozin, Beyond Glucose Reduction. The Unanticipated and Welcomed Cardioprotective Results. Switching the Heart at Four Levels: Energetic, Anatomical, Functional, and Neuro-Hormonal

Efficacy and Safety of Dapagliflozin in Men and Women With Heart Failure With Reduced Ejection Fraction

Evolving therapeutic strategies for patients hospitalized with new or worsening heart failure across the spectrum of left ventricular ejection fraction

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