Empagliflozin Ameliorates Adverse Left Ventricular Remodeling in Nondiabetic Heart Failure by Enhancing Myocardial Energetics

Santos‐Gallego, Carlos G.; Requena-Ibáñez, Juan Antonio; Antonio, Rodolfo San; Ishikawa, Kiyotake; Watanabe, Shin; Picatoste, Belén; Flores, Eduardo; García‐Ropero, Álvaro; Sanz, Javier; Hajjar, Roger J.; Fuster, Valentín; Badimón, Juan J.

doi:10.1016/j.jacc.2019.01.056

Cited by 456 publications

(437 citation statements)

References 37 publications

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“…42 This was driven by enhanced myocardial utilization of ketone bodies, FFA, and BCAAs, in which the latter was due to increased BCKDH activity, resulting in lower circulating levels of BCAAs, which further supports our observations. 42 To this end, there were reports which suggested the adverse impact of prolonged ketone bodies oxidation in the failing heart including mitochondrial protein hyperacetylation, mitochondrial dysfunction, and metabolic perturbations, which require further in-depth research. 12,15,43 Albuminuria and eGFR are common risk factors of ASCVD and HF, probably due to the interlinking nature of these biological pathways such as systemic inflammation, left ventricular hypertrophy, vascular calcification, and fluid retention.…”

Section: Discussionsupporting

confidence: 88%

“…1,15 In this context, one of the hypotheses underlying the cardioprotective effects of sodium-glucose cotransporter-2 inhibitors is a switch in the energy substrate utilization in the failing heart from glucose toward ketone bodies, FFAs, and BCAAs. 7,11,42 In a non-diabetic animal model with HF due to myocardial infarction, 2 months of empagliflozin treatment was associated with decreased left ventricular hypertrophy and dilatation with improved ejection fraction. 42 This was driven by enhanced myocardial utilization of ketone bodies, FFA, and BCAAs, in which the latter was due to increased BCKDH activity, resulting in lower circulating levels of BCAAs, which further supports our observations.…”

Section: Discussionmentioning

confidence: 99%

“…7,11,42 In a non-diabetic animal model with HF due to myocardial infarction, 2 months of empagliflozin treatment was associated with decreased left ventricular hypertrophy and dilatation with improved ejection fraction. 42 This was driven by enhanced myocardial utilization of ketone bodies, FFA, and BCAAs, in which the latter was due to increased BCKDH activity, resulting in lower circulating levels of BCAAs, which further supports our observations. 42 To this end, there were reports which suggested the adverse impact of prolonged ketone bodies oxidation in the failing heart including mitochondrial protein hyperacetylation, mitochondrial dysfunction, and metabolic perturbations, which require further in-depth research.…”

Section: Discussionmentioning

confidence: 99%

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Circulating branched‐chain amino acids and incident heart failure in type 2 diabetes: The Hong Kong Diabetes Register

Lim

Lau

Fung

et al. 2020

Diabetes Metabolism Res

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Aim Levels of branched‐chain amino acids (BCAAs, namely, isoleucine, leucine, and valine) are modulated by dietary intake and metabolic/genetic factors. BCAAs are associated with insulin resistance and increased risk of type 2 diabetes (T2D). Although insulin resistance predicts heart failure (HF), the relationship between BCAAs and HF in T2D remains unknown. Methods In this prospective observational study, we measured BCAAs in fasting serum samples collected at inception from 2139 T2D patients free of cardiovascular‐renal diseases. The study outcome was the first hospitalization for HF. Results During 29 103 person‐years of follow‐up, 115 primary events occurred (age: 54.8 ± 11.2 years, 48.2% men, median [interquartile range] diabetes duration: 5 years [1‐10]). Patients with incident HF had 5.6% higher serum BCAAs than those without HF (median 639.3 [561.3‐756.3] vs 605.2 [524.8‐708.7] μmol/L; P = .01). Serum BCAAs had a positive linear association with incident HF (per‐SD increase in logarithmically transformed BCAAs: hazard ratio [HR] 1.22 [95% CI 1.07‐1.39]), adjusting for age, sex, and diabetes duration. The HR remained significant after sequential adjustment of risk factors including incident coronary heart disease (1.24, 1.09‐1.41); blood pressure, low‐density lipoprotein cholesterol, and baseline use of related medications (1.31, 1.14‐1.50); HbA1c, waist circumference, triglyceride, and baseline use of related medications (1.28, 1.11‐1.48); albuminuria and estimated glomerular filtration rate (1.28, 1.11‐1.48). The competing risk of death analyses showed similar results. Conclusions Circulating levels of BCAAs are independently associated with incident HF in patients with T2D. Prospective cohort analysis and randomized trials are needed to evaluate the long‐term safety and efficacy of using different interventions to optimize BCAAs levels in these patients.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Circulating branched‐chain amino acids and incident heart failure in type 2 diabetes: The Hong Kong Diabetes Register

Lim

Lau

Fung

et al. 2020

Diabetes Metabolism Res

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“…SGLT2 inhibitors increase fasting levels of ketone bodies, and thus, they have been hypothesized to enhance the utilization of this efficient metabolic fuel in the failing heart . However, the findings of experimental studies have provided inconsistent support for this hypothesis . Instead, it has been proposed that SGLT2 inhibitors may slow the course of cardiomyocyte injury and loss by inhibiting the sodium–hydrogen exchanger‐1 (NHE‐1) in the myocardium, whose overactivity may lead to increases in intracellular sodium and calcium, which can impair cardiomyocyte function and viability .…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the effect of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR‐Reduced trial

Investigators

Statistician

2019

European J of Heart Fail

171

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Drugs that inhibit the sodium-glucose co-transporter 2 (SGLT2) have been shown to reduce the risk of hospitalizations for heart failure in patients with type 2 diabetes. In populations that largely did not have heart failure at the time of enrolment, empagliflozin, canagliflozin and dapagliflozin decreased the risk of serious new-onset heart failure events by ≈30%. In addition, in the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of both pump failure and sudden deaths, the two most common modes of death among patients with heart failure. In none of the three trials could the benefits of SGLT2 inhibitors on heart failure be explained by the actions of these drugs as diuretics or anti-hyperglycaemic agents. These observations raise the possibility that SGLT2 inhibitors could reduce morbidity and mortality in patients with established heart failure, including those without diabetes. The EMPEROR-Reduced trial is enrolling ≈3600 patients with heart failure and a reduced left ventricular ejection fraction (≤ 40%), half of whom are expected not to have diabetes. Patients are being randomized to placebo or empagliflozin 10 mg daily, which is added to all appropriate treatment with inhibitors of the renin-angiotensin system and neprilysin, beta-blockers and mineralocorticoid receptor antagonists. The primary endpoint is the time-to-first event analysis of the combined risk of cardiovascular death and hospitalization for heart failure, but the trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all-cause mortality, and recurrent hospitalization events. By adjusting eligibility based on natriuretic peptide levels to the baseline ejection fraction, the trial will preferentially enrol high-risk patients. A large proportion of the participants is expected to have an ejection fraction < 30%, and the estimated annual event rate is expected to be at least 15%. The EMPEROR-Reduced trial is well-positioned to determine if the addition of empagliflozin can add meaningfully to current approaches that have established benefits in the treatment of chronic heart failure with left ventricular systolic dysfunction.

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“…Experiments in diabetic mice treated with empagliflozin demonstrated increased cardiac ATP production resulting from an increase in the rate of fatty acid oxidation [18]. In non-diabetic pig hearts subjected to left anterior artery ischaemia, those randomized to empagliflozin (vs. placebo) experienced a reduced rate of cardiac remodelling and switched myocardial fuel utilization away from glucose and towards ketone bodies [19]. These findings have been consistent between people with and without a baseline history of heart failure [15,[20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 78%

Treatment of heart failure with sodium glucose co‐transporter‐2 inhibitors in people with type 2 diabetes mellitus: current evidence and future directions

et al. 2019

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Diabetes is one the most common comorbidities among people with established heart failure. Interest in heart failure as an outcome among people with diabetes has emerged since it was shown that there was an association between increased risk of hospitalization for heart failure with use of thiazolidinediones and some dipeptidyl peptidase‐4 inhibitors. Recently, sodium‐glucose co‐transporter‐2 inhibitors were shown to lead to a reduction in the risk of cardiovascular death and hospitalization for heart failure in people with Type 2 diabetes mellitus and either cardiovascular risk factors or atherosclerotic cardiovascular disease. These findings appear to be consistent in people both with and without a baseline history of heart failure. Based on current evidence there are several clinical scenarios in which the use of sodium‐glucose co‐transporter‐2 inhibitors would be justified for people with heart failure and atherosclerotic cardiovascular disease: (1) in people with a new diagnosis of Type 2 diabetes and for whom anti‐hyperglycaemic management strategies are being considered; (2) in people with sub‐optimal glycaemic control, regardless of baseline antihyperglycaemic therapy; and (3) in people with symptomatic heart failure (or other high‐risk features such as recent hospitalization for heart failure), if glycaemic control is optimized and the individual is on a sulfonylurea or dipeptidyl peptidase‐4 inhibitor; here, it may be reasonable to consider substituting one of those therapies for a sodium‐glucose co‐transporter‐2 inhibitor. There are now a number of ongoing trials evaluating the role of sodium‐glucose co‐transporter‐2 inhibitors as therapy for people with established heart failure (with preserved or with reduced ejection fraction) and regardless of the presence of diabetes. These trials will provide the evidence for the safety and efficacy of sodium‐glucose co‐transporter‐2 inhibitors among people with established heart failure.

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Empagliflozin Ameliorates Adverse Left Ventricular Remodeling in Nondiabetic Heart Failure by Enhancing Myocardial Energetics

Cited by 456 publications

References 37 publications

Circulating branched‐chain amino acids and incident heart failure in type 2 diabetes: The Hong Kong Diabetes Register

Circulating branched‐chain amino acids and incident heart failure in type 2 diabetes: The Hong Kong Diabetes Register

Evaluation of the effect of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR‐Reduced trial

Treatment of heart failure with sodium glucose co‐transporter‐2 inhibitors in people with type 2 diabetes mellitus: current evidence and future directions

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