The SGLT2 inhibitor empagliflozin improves cardiac energy status via mitochondrial ATP production in diabetic mice

Choi, Jung-Mi; Matoba, Naoki; Setoyama, Daiki; Watanabe, Daisuke; Ohnishi, Yozo; Yasui, Ryuto; Kitai, Yuichirou; Oomachi, Aki; Kotobuki, Yutaro; Nishiya, Yoichi; Pieper, Michael; Imamura, Hiromi; Yanagita, Motoko; Yamamoto, Masamichi

doi:10.1038/s42003-023-04663-y

Cited by 21 publications

(6 citation statements)

References 27 publications

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“…A recent study in db/db mice showed that EMPA treatment leads to significantly increased cytosolic and mitochondrial adenosine triphosphate (ATP) levels as well as improved maintenance of ATP both during ischaemia/reperfusion (I/R) in isolated hearts and during hypoxia in isolated cardiomyocytes. 13 This study suggests EMPA has a direct metabolic effect on energetics when the heart is stressed either by I/R, hypoxia, HF or diabetes.…”

Section: Introductionmentioning

confidence: 73%

Empagliflozin improves cardiac energetics during ischaemia/reperfusion by directly increasing cardiac ketone utilization

Chase,

Eykyn,

Shattock

et al. 2023

Cardiovascular Research

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AIM Empagliflozin (EMPA), a potent inhibitor of the renal sodium-glucose cotransporter 2 (SGLT2) and an effective treatment for type-2 diabetes, has been shown to have cardioprotective effects, independent of improved glycaemic control. Several non-canonical mechanisms have been proposed to explain these cardiac effects, including increasing circulating ketone supply to the heart. This study aims to test whether EMPA directly alters cardiac ketone metabolism independent of supply. METHODS AND RESULTS The direct effects of EMPA on cardiac function and metabolomics were investigated in Langendorff rat heart perfused in buffer containing 5 mM glucose, 4 mM β-hydroxybutyrate (βHb) and 0.4 mM intralipid, subject to low flow ischaemia/reperfusion. Cardiac energetics were monitored in situ using 31P NMR spectroscopy. Steady-state 13C-labelling was performed by switching 12C substrates for 13C1 glucose or 13C4 βHb, and 13C incorporation into metabolites determined using 2D 1H-13C HSQC NMR spectroscopy. EMPA treatment improved left ventricular developed pressure during ischaemia and reperfusion compared to vehicle-treated hearts. In EMPA-treated hearts, total ATP and PCr levels, and Gibbs free energy for ATP hydrolysis were significantly higher during ischaemia and reperfusion. EMPA treatment did not alter the incorporation of 13C from glucose into glycolytic products lactate or alanine neither during ischaemia nor reperfusion. In ischaemia, EMPA led to a decrease in 13C1 glucose incorporation and a concurrent increase in 13C4 βHb incorporation into TCA intermediates succinate, citrate, and glutamate. During reperfusion, the concentration of metabolites originating from 13C1 glucose was similar to vehicle but those originating from 13C4 βHb remained elevated in EMPA treated hearts. CONCLUSIONS Our findings indicate that EMPA causes a switch in metabolism away from glucose oxidation towards increased ketone utilisation in the rat heart, thereby improving function and energetics both during ischaemia and recovery during reperfusion. This preference of ketone utilisation over glucose was observed under conditions of constant supply of substrate, suggesting that EMPA acts directly by modulating cardiac substrate preference, independent of substrate availability. The mechanisms underlying our findings are currently unknown, warranting further study. TRANSLATIONAL PERSPECTIVE Heart failure remains a huge clinical burden. Clinical trials of SGLT2 inhibitors in patients with diabetes and heart failure have reported significant cardio-protection from EMPA treatment that appears independent of improved glycaemic control. The direct cardiac effect of EMPA in modulating ketone metabolism observed in this study raises the potential for EMPA to be used as a therapy for heart failure in both diabetic and non-diabetic patients alike.

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Section: Introductionmentioning

confidence: 73%

Empagliflozin improves cardiac energetics during ischaemia/reperfusion by directly increasing cardiac ketone utilization

Chase,

Eykyn,

Shattock

et al. 2023

Cardiovascular Research

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“…However, hemodynamics were not acutely deteriorated after empagliflozin administration in the present study. Recently, a direct cardiac effect of empagliflozin to improve cardiac energy status is suggested despite the lack of SGLT2 expression in cardiac tissues [ 43 ]. Such an off-target effect of empagliflozin might have helped the failing heart better tolerate the increased afterload.…”

Section: Discussionmentioning

confidence: 99%

Acute effects of empagliflozin on open-loop baroreflex function and urinary glucose excretion in rats with chronic myocardial infarction

Kawada,

Li,

Nishiura

et al. 2023

J Physiol Sci

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Sodium–glucose cotransporter 2 (SGLT2) inhibitors have exerted cardioprotective effects in clinical trials, but underlying mechanisms are not fully understood. As mitigating sympathetic overactivity is of major clinical concern in the mechanisms of heart failure treatments, we examined the effects of modulation of glucose handling on baroreflex-mediated sympathetic nerve activity and arterial pressure regulations in rats with chronic myocardial infarction (n = 9). Repeated 11-min step input sequences were used for an open-loop analysis of the carotid sinus baroreflex. An SGLT2 inhibitor, empagliflozin, was intravenously administered (10 mg/kg) after the second sequence. Neither the baroreflex neural nor peripheral arc significantly changed during the last observation period (seventh and eighth sequences) compared with the baseline period although urinary glucose excretion increased from near 0 (0.0089 ± 0.0011 mg min−1 kg−1) to 1.91 ± 0.25 mg min−1 kg−1. Hence, empagliflozin does not acutely modulate the baroreflex regulations of sympathetic nerve activity and arterial pressure in this rat model of chronic myocardial infarction.

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“… 35 These changes mirror the effects of SGLT2i on myocardial energy supply, ketonemia, suppression of cardiomyocyte death pathways, and improvements in myocardial flow reserve and vasomotor responses. 35 – 39 However, the influence of SGLT2i on myocardial function and heart structure, as assessed by echocardiography, has yet to be evaluated in dialysis patients, making it an integral part of the exploratory analysis in this trial.…”

Section: Discussionmentioning

confidence: 99%

Dapagliflozin cardiovascular effects on end-stage kidney disease (DARE-ESKD-2) trial: rationale and design.

Barreto,

Martins,

Pascoa

et al. 2023

Preprint

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Purpose. Sodium glucose co-transporter 2 inhibitors (SGLT2i) remarkably reduced the incidence of hospitalization for heart failure and cardiovascular death of conservatively managed chronic kidney disease. We hypothesized that adding SGLT2i to standard treatment would yield cardiovascular benefits also in end-stage kidney disease (ESKD) individuals on dialysis. Methods. The DARE-ESKD-2 Trial (NCT05685394) is an ongoing, single-center, open-label, controlled trial aimed at assessing the cardiovascular effects of dapagliflozin in ESKD on dialysis. Eligible patients are adults on renal replacement therapy for more than 3 prior to enrollment. Exclusion criteria encompass pregnancy, liver failure, and current use of a SGLT2i. After signing an informed consent form, participants are randomized 1:1 to either dapagliflozin 10mg PO plus standard treatment or standard treatment alone for 6 months. Echocardiogram, anthropometry, blood sample collection, 6-min walk test, gait speed, and Kansas City Cardiomyopathy Questionnaire (KCCQ), are performed at baseline and at study termination. Participants are contacted monthly during treatment for outcomes disclosure. The primary endpoint of our study is the between-groups differences in posttreatment changes in plasma levels of N-terminal pro-B natriuretic peptide. Secondary endpoints include the differences between groups in the changes of echocardiography measurements, cardiopulmonary tests performance, body composition. The incidence of safety endpoints will also be diligently compared between study arms. Conclusion. The DARE-ESKD-2 trial will provide unprecedented data on the cardiovascular safety and efficacy of SGLT2i in ESKD individuals on dialysis. This study will pave the grounds for improving clinical outcomes of dialysis recipients.

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The SGLT2 inhibitor empagliflozin improves cardiac energy status via mitochondrial ATP production in diabetic mice

Cited by 21 publications

References 27 publications

Empagliflozin improves cardiac energetics during ischaemia/reperfusion by directly increasing cardiac ketone utilization

Empagliflozin improves cardiac energetics during ischaemia/reperfusion by directly increasing cardiac ketone utilization

Acute effects of empagliflozin on open-loop baroreflex function and urinary glucose excretion in rats with chronic myocardial infarction

Dapagliflozin cardiovascular effects on end-stage kidney disease (DARE-ESKD-2) trial: rationale and design.

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