Effect of Empagliflozin on Hemodynamics in Patients With Heart Failure and Reduced Ejection Fraction

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

doi:10.1016/j.jacc.2020.10.005

Cited by 69 publications

(74 citation statements)

References 30 publications

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“…35 In summary, the changes in atrial volume and LV strains indicate that dapagliflozin treatment reduced cardiac preload and are in line with recent findings of reduced pulmonary capillary wedge pressure after 12 weeks of empagliflozin treatment. 36 Recently, Brown et al showed improved LV contractility, assessed by global longitudinal LV strain, after 1 year of SGLT2i treatment, suggesting that early reductions in preload may be associated with improved contractility over the long term. 37…”

Section: Heart Mass Volumes and Strainmentioning

confidence: 99%

Effects of 6 weeks of treatment with dapagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, on myocardial function and metabolism in patients with type 2 diabetes: A randomized, placebo‐controlled, exploratory study

Oldgren

Laurila

Åkerblom

et al. 2021

Diabetes Obesity Metabolism

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Aim: To explore the early effects of dapagliflozin on myocardial function and metabolism in patients with type 2 diabetes without heart failure.Materials and Methods: Patients with type 2 diabetes on metformin treatment were randomized to double-blind, 6-week placebo or dapagliflozin 10 mg daily treatment.Investigations included cardiac function and structure with myocardial resonance imaging; cardiac oxygen consumption, perfusion and efficiency with [ 11 C]-acetate positron emission tomography (PET); and cardiac and hepatic fatty acid uptake with [ 18 F]-6-thia-heptadecanoic acid PET, analysed by ANCOVA as least square means with 95% confidence intervals.Results: Evaluable patients (placebo: n = 24, dapagliflozin: n = 25; 53% males) had a mean age of 64.4 years, a body mass index of 30.2 kg/m 2 and an HbA1c of 6.7%.Body weight and HbA1c were significantly decreased by dapagliflozin versus placebo. Dapagliflozin had no effect on myocardial efficiency, but external left ventricular (LV) work (−0.095 [−0.145, −0.043] J/g/min) and LV oxygen consumption were significantly reduced (−0.30 [−0.49, −0.12] J/g/min) by dapagliflozin, although the changes were not statistically significant versus changes in the placebo group.Change in left atrial maximal volume with dapagliflozin versus placebo was −3.19 (−6.32, −0.07) mL/m 2 (p = .056). Peak global radial strain decreased with dapagliflozin versus placebo (−3.92% [−7.57%, −0.28%]; p = .035), while peak global longitudinal and circumferential strains were unchanged. Hepatic fatty acid uptake

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Section: Heart Mass Volumes and Strainmentioning

confidence: 99%

Effects of 6 weeks of treatment with dapagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, on myocardial function and metabolism in patients with type 2 diabetes: A randomized, placebo‐controlled, exploratory study

Oldgren

Laurila

Åkerblom

et al. 2021

Diabetes Obesity Metabolism

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“…The DAPA-HF trial [ 55 ] and the EMPEROR-Reduced trial [ 56 ] have shown that SGLT-2 inhibitors (dapagliflozin and empagliflozin) reduced the risk of worsening HF events in adults with reduced EF, irrespective of the presence of diabetes at baseline. The precise mechanism of SGLT-2 inhibition in achieving its effect remains uncertain, although a modest reduction in central venous pressure has been demonstrated [ 57 , 58 ]. No data are available in children, but this class of drugs appears to be helpful in adult clinical trials.…”

Section: Chronic Heart Failure Syndromementioning

confidence: 99%

Current and Future Drug and Device Therapies for Pediatric Heart Failure Patients: Potential Lessons from Adult Trials

2021

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This review discusses the potential drug and device therapies for pediatric heart failure (HF) due to reduced systolic function. It is important to realize that most drugs that are used in pediatric HF are extrapolated from adult cardiology practices or consensus guidelines based on expert opinion rather than on evidence from controlled clinical trials. It is difficult to conclude whether the drugs that are well established in adult HF trials are also beneficial for children because of tremendous heterogeneity in the mechanism of HF in children and variations in the pharmacokinetics and pharmacodynamics of drugs from birth to adolescence. The lessons learned from adult trials can guide pediatric cardiologists to design clinical trials of the newer drugs that are in the pipeline to study their efficacy and safety in children with HF. This paper’s focus is that the reader should specifically think through the pathophysiological mechanism of HF and the mode of action of drugs for the selection of appropriate pharmacotherapy. We review the drug and device trials in adults with HF to highlight the knowledge gap that exists in the pediatric HF population.

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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%

“…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%

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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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Effect of Empagliflozin on Hemodynamics in Patients With Heart Failure and Reduced Ejection Fraction

Cited by 69 publications

References 30 publications

Effects of 6 weeks of treatment with dapagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, on myocardial function and metabolism in patients with type 2 diabetes: A randomized, placebo‐controlled, exploratory study

Effects of 6 weeks of treatment with dapagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, on myocardial function and metabolism in patients with type 2 diabetes: A randomized, placebo‐controlled, exploratory study

Current and Future Drug and Device Therapies for Pediatric Heart Failure Patients: Potential Lessons from Adult Trials

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

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