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• W4295420683 abstract "HomeCirculationVol. 146, No. 11SGLT2 Inhibitors in Heart Failure: Targeted Metabolomics and Energetic Metabolism Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBSGLT2 Inhibitors in Heart Failure: Targeted Metabolomics and Energetic Metabolism Carlos G. Santos-Gallego, MD, Manuel Mayr, MD, PhD and Juan Badimon, PhD Carlos G. Santos-GallegoCarlos G. Santos-Gallego https://orcid.org/0000-0003-1408-8958 AtheroThrombosis Research Unit, Mount Sinai Hospital, New York (C.G.S.-G., J.B.). Search for more papers by this author , Manuel MayrManuel Mayr Correspondence to: Juan Badimon, PhD, AtheroThrombosis Research Unit, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, 1428 Madison Ave, Atran Bldg, 6th Floor, Room 6.20, New York, NY 10029. Email E-mail Address: [email protected] https://orcid.org/0000-0002-0597-829X British Heart Foundation Centre, King’s College London, UK (M.M.). Search for more papers by this author and Juan BadimonJuan Badimon https://orcid.org/0000-0002-6780-8771 AtheroThrombosis Research Unit, Mount Sinai Hospital, New York (C.G.S.-G., J.B.). Search for more papers by this author Originally published12 Sep 2022https://doi.org/10.1161/CIRCULATIONAHA.122.060805Circulation. 2022;146:819–821This article is a commentary on the followingMetabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HFSodium-glucose cotransporter-2 (SGLT2) inhibitors exert outstanding benefits on heart failure (HF) both with reduced ejection fraction (HFrEF) and with preserved ejection fraction. However, the mechanisms of benefit of SGLT2 inhibitors on HF are not completely understood. In this issue of Circulation, Selvaraj et al1 shed more light on the effect of SGLT2 inhibitors on myocardial energetic and fuel metabolism by leveraging targeted metabolomics in blood samples of the DEFINE-HF trial (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction).Article, see p 808After the serendipitous findings of improved HF outcomes with SGLT2 inhibitors, different mechanisms were postulated, but none of them seemed to explain all the benefits. Improved diabetic or blood pressure control seems unlikely given that it would also have reduced ischemic events (which remained similar in both arms), the benefits would have taken years (instead of event rate curves separating in only weeks), and tight glycemic control has previously failed to improve HF outcomes. Diuretic effects of SGLT2 inhibitors seem unlikely because the natriuretic effects of SGLT2 inhibitors disappear after 4 days of treatment,2 and loop diuretics (which exert more potent diuretic and natriuretic effects than SGLT2 inhibitors) do not improve outcomes in chronic HF. Inhibition of the sodium/hydrogen exchanger, although initially suggested, has not been confirmed.3 Therefore, the mechanisms responsible for the benefits of the SGLT2 inhibitors remain undefined.Abnormalities in cardiac energy metabolism contribute to HF.4 The main fuel for healthy heart is free fatty acids (FFAs) because the FFA oxidative metabolism generates the highest energy yield (complete oxidation of 1 molecule of the FFA palmitate generates 129 ATP molecules; energy liberated, 298 kcal/mol).4 The healthy myocardium possesses metabolic flexibility, which allows metabolization of different substrates4,5 (eg, glucose, ketone bodies [KBs], lactate), depending on workload and substrate availability. During the pathological condition of HF, the failing heart activates a fetal genotype, and myocardial substrate oxidation switches from fat to carbohydrate utilization, which produces less energy (complete oxidation of 1 molecule of glucose generates 38 molecules of ATP; energy liberated, 224 kcal/mol).4,5 This energy deficit aggravates HF (HF begets HF) and is magnified because glucose is partially metabolized through anaerobic glycolysis,4,5 which generates only 2 ATP molecules per glucose molecule.Three issues have to be mentioned concerning KB metabolism. First, KB oxidation generates more energy than glucose oxidation (244 kcal/mol versus 224 kcal/mol, respectively).4 Second, the myocardial uptake (and thus cardiac consumption) of KBs is directly proportional to KB plasma levels.4,5 Third, SGLT2 inhibitors reduce the insulin/glucagon ratio, thus favoring lipolysis and ketogenesis. The working hypothesis is that SGLT2 inhibitors increase plasma levels of KBs and FFAs and create a switch in myocardial fuel metabolism that “forces” the heart to selectively consume FFAs and KBs as major energetic substrates instead of the energy-inefficient glucose, thus improving this energetic deficit.Our group experimentally confirmed this hypothesis of SGLT2 inhibitors improving myocardial energetics.5 In a porcine HFrEF model, we directly quantified myocardial fuel consumption by measuring transcardiac gradient by simultaneous sampling of coronary artery and coronary sinus. Empagliflozin improved myocardial utilization of FFA and KB while reducing glucose consumption, thus generating higher myocardial ATP content and improving energetics.5 Enhanced KB myocardial use was directly associated with improvement in diastolic function,6 which is the energy-consuming part of cardiac cycle. This SGLT2 inhibitor–induced metabolic switch and enhanced cardiac energetics were confirmed in a rat model of HFrEF.7 This mechanistic role of KBs has been confirmed in humans given that infusion of KBs improves cardiac function.8 However, the definitive demonstration of SGLT2 inhibitors boosting energetics in HF will eventually come from the EMPAVISION trial (A Randomised, Double-Blind, Placebo-Controlled, Mechanistic Cardiac Magnetic Resonance Study to Investigate the Effects of Empagliflozin Treatment on Cardiac Physiology and Metabolism in Patients With Heart Failure),9 which measures resting phosphocreatine-to-ATP ratio by phosphorus-31 magnetic resonance spectroscopy.It is important to note that the mechanisms of the benefits induced by KBs might not be attributed exclusively to improved energetics because ketones also exert other salutary effects. KBs mitigate sympathetic activation by antagonizing GPR4110; the lower catecholamines levels after empagliflozin treatment in our porcine model support this KB-induced sympathetic modulation.5 Epigenetic effects of ketones have also been observed; specifically, the KB β-hydroxybutyrate (but not acetoacetate) inhibits class I histone deacetylases, thus modifying the transcriptome and upregulating genes that mitigate oxidative stress.11 In addition, β-hydroxybutyrate suppresses the activation of the NLRP3 inflammasome,12 inducing anti-inflammatory activity. Therefore, the metabolic switch toward KB metabolism seems adaptive and can act as a metabolic stress defenseSelvaraj et al1 shed more light on this hypothesis of SGLT2 inhibitor–induced metabolic switch and improved energetics. DEFINE-HF is a randomized, placebo-controlled trial investigating the effect of dapagliflozin on biomarkers, symptoms, and functional status in HFrEF. Patient characteristics were typical of an HFrEF trial: mean age was 62±11 years; 25% were women; left ventricular ejection fraction was 27±8%; NT-proBNP (N-terminal pro-B-type natriuretic peptide) was elevated (median, 1131 pg/mL); systolic blood pressure was normal (124±20 mm Hg); and average estimated glomerular filtration rate was mildly diminished (68±21 mL·min−1·1.73 m−2). The present subanalysis included all participants with available baseline and follow-up samples (234 of the 263 trial participants, 90% of participants). The authors performed targeted mass spectrometry–based profiling of 63 metabolites: 45 acyl-carnitines (markers of FFA oxidation), 15 amino acids, and 3 conventional metabolites (nonesterified fatty acids, total KBs, and β-hydroxybutyrate).The authors have to be congratulated for expanding insight into the benefits of SGLT2 inhibitors. First, the authors demonstrated that dapagliflozin increased KB-related and short-/medium-chain acylcarnitine metabolite clusters. Short-/medium-chain acylcarnitines are byproducts of FFA oxidation, which suggests that SGLT2 inhibitors increase myocardial utilization of both FFAs and KBs; this metabolic shift is supported by similar results in animal HFrEF models.5,7 A previous study with targeted metabolomics had already hinted at increased FFA use.13 The importance of the present analysis1 involves its randomized, placebo-controlled trial design with a large sample size specifically in HFrEF (whereas the previous study13 involved before-after intervention, no placebo arm, individuals with type 2 diabetes, and only 25 patients).Another important issue involves the information about KBs. First, the authors confirm increased ketonemia with SGLT2 inhibitors; given that myocardial KB uptake is directly proportional to blood KB levels, this would justify the increased myocardial utilization of KBs under SGLT2 inhibitors (evaluated as increased medium-chain acylcarnitines). It is important to note that ketosis (defined by the authors as β-hydroxybutyrate levels >500 µmol/L) was rare (2.5% in the dapagliflozin versus 1% in placebo arm). Moreover, very high KB levels suggestive of safety issues were not observed, which reinforces the safety of SGLT2 inhibitors observed in previous clinical trials. This highlights that SGLT2 inhibitors can be administered safely in nondiabetic patients. Of note, SGLT2 inhibitors are also safe in terms of ketoacidosis in diabetes provided that patients comply with long-acting insulin administration, avoid prolonged fasting, and follow “sick-day rules.”Furthermore, the authors identify clusters of metabolites associated with worse HF status. Increases in long-chain acylcarnitine and dicarboxylacylcarnitine (suggestive of impaired utilization of KB and FFA, which are metabolized as medium-chain acylcarnitine) were associated with decreases in quality of life and increases in NT-proBNP levels. These observations emphasize that impaired myocardial energetics caused by reduced KB-FFA consumption are associated with worsening of quality of life, congestion, and adverse cardiac remodeling. It is tempting to speculate that these biomarkers might be used in the future to risk-stratify patients with HFrEF.An additional advantage of the trial is the high diversity of the participants. Although most trials enroll predominantly White subjects, >40% of the DEFINE-HF patients are minorities. This is a call to action for future trials to increase diversity in trial enrollment, which is both a coveted aim and a perfectly achievable goal (for instance, EMPATROPISM [Are the Cardiac Benefits of Empagliflozin Independent of Its Hypoglycemic Activity? (ATRU-4)] enrolled up to 70% of minorities14). Increased diversity in trials is a cornerstone due not only to social justice, but also because of scientific reasons given that we have to confirm clinically relevant results in all ethnic groups (eg, Black individuals benefit especially from hydralazine-nitrates, whereas the β-blocker bucindolol is particularly deleterious for these patients).This article also presents certain limitations. First, there is no direct demonstration of the energetic hypothesis; for instance, KBs might exercise their benefits by ameliorating oxidative stress or sympathetic activation instead of through enhanced energetics. Direct demonstration of improved myocardial energetics in human HF will be provided by the EMPAVISION trial.9 Second, changes at the plasma metabolite level may not accurately reflect tissue-level metabolism changes; however, increased transcardiac gradients of ketones and FFAs in pigs were paralleled by enhanced myocardial expression and activity of the rate-limiting enzymes of the metabolic pathways responsible for oxidation of FFAs and KBs.5 Third, the metabolomic analysis determined concentrations but not flux (ie, metabolomics provides a snapshot of a static moment but does not evaluate a dynamic process in flux). Elevations in KB-related metabolites have previously been reported in cardiovascular pathologies,15 but it remained unknown whether this was attributable to increased hepatic production or decreased consumption. Concomitant flux studies using stable isotope tracers or tissue-based metabolomics are needed to discern these 2 options. Last, KBs are also used by other organs such as the brain and skeletal muscle; it is reasonable to assume that these reported changes reflect the effect of SGLT2 inhibitors not only in the heart but also in other organs.In summary, targeted metabolomics showed that dapagliflozin increased KB- and FFA-related metabolites, thus suggesting that SGLT2 inhibitors augment myocardial consumption of both KBs and FFAs, which enhances cardiac energetics. These findings add to the growing body of literature implying that SGLT2 inhibitors act by improving energetics and suggest that specific metabolism biomarkers can risk-stratify patients with HFrEF.Article InformationSources of FundingNone.Disclosures None.FootnotesCirculation is available at www.ahajournals.org/journal/circThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 821.Correspondence to: Juan Badimon, PhD, AtheroThrombosis Research Unit, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, 1428 Madison Ave, Atran Bldg, 6th Floor, Room 6.20, New York, NY 10029. Email juan.[email protected]eduReferences1. Selvaraj S, Fu Z, Jones P, Kwee LC, Windsor SL, Ilkayeva O, Newgard CB, Margulies KB, Husain M, Inzucchi SE, et al. Metabolomic profiling of the effects of dapagliflozin in heart failure with reduced ejection fraction: DEFINE-HF.Circulation. 2022; 146:808–818. doi: 10.1161/CIRCULATIONAHA.122.060402LinkGoogle Scholar2. Mordi NA, Mordi IR, Singh JS, McCrimmon RJ, Struthers AD, Lang CC. Renal and cardiovascular effects of SGLT2 inhibition in combination with loop diuretics in Patients with type 2 diabetes and chronic heart failure: the RECEDE-CHF trial.Circulation. 2020; 142:1713–1724. doi: 10.1161/CIRCULATIONAHA.120.048739LinkGoogle Scholar3. Chung YJ, Park KC, Tokar S, Eykyn TR, Fuller W, Pavlovic D, Swietach P, Shattock MJ. Off-target effects of sodium-glucose co-transporter 2 blockers: empagliflozin does not inhibit Na+/H+ exchanger-1 or lower [Na+]i in the heart.Cardiovasc Res. 2021; 117:2794–2806. doi: 10.1093/cvr/cvaa323CrossrefMedlineGoogle Scholar4. Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis.Diabetes Care. 2016; 39:1108–1114. doi: 10.2337/dc16-0330CrossrefMedlineGoogle Scholar5. Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, Ishikawa K, Watanabe S, Picatoste B, Flores E, Garcia-Ropero A, Sanz J, Hajjar RJ, et al. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics.J Am Coll Cardiol. 2019; 73:1931–1944. doi: 10.1016/j.jacc.2019.01.056CrossrefMedlineGoogle Scholar6. Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, Garcia-Ropero A, Ishikawa K, Watanabe S, Picatoste B, Vargas-Delgado AP, Flores-Umanzor EJ, Sanz J, et al. Empagliflozin ameliorates diastolic dysfunction and left ventricular fibrosis/stiffness in nondiabetic heart failure: a multimodality study.JACC Cardiovasc Imaging. 2021; 14:393–407. doi: 10.1016/j.jcmg.2020.07.042CrossrefMedlineGoogle Scholar7. 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Design and rationale of the EMPA-VISION trial: investigating the metabolic effects of empagliflozin in patients with heart failure.ESC Heart Fail. 2021; 8:2580–2590. doi: 10.1002/ehf2.13406CrossrefMedlineGoogle Scholar10. Kimura I, Inoue D, Maeda T, Hara T, Ichimura A, Miyauchi S, Kobayashi M, Hirasawa A, Tsujimoto G. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via protein G protein-coupled receptor 41 (GPR41).Proc Natl Acad Sci U S A. 2011; 108:8030–8035. doi: 10.1073/pnas.1016088108CrossrefMedlineGoogle Scholar11. Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D’Agostino D, Planavsky N, Lupfer C, Kanneganti TD, et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease.Nat Med. 2015; 21:263–269. doi: 10.1038/nm.3804CrossrefMedlineGoogle Scholar12. Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor.Science. 2013; 339:211–214. doi: 10.1126/science.1227166CrossrefMedlineGoogle Scholar13. Kappel BA, Lehrke M, Schütt K, Artati A, Adamski J, Lebherz C, Marx N. Effect of empagliflozin on the metabolic signature of patients with type 2 diabetes mellitus and cardiovascular disease.Circulation. 2017; 136:969–972. doi: 10.1161/CIRCULATIONAHA.117.029166LinkGoogle Scholar14. Santos-Gallego CG, Vargas-Delgado AP, Requena-Ibanez JA, Garcia-Ropero A, Mancini D, Pinney S, Macaluso F, Sartori S, Roque M, Sabatel-Perez F, et al; EMPA-TROPISM (ATRU-4) Investigators. Randomized trial of empagliflozin in nondiabetic patients with heart failure and reduced ejection fraction.J Am Coll Cardiol. 2021; 77:243–255. doi: 10.1016/j.jacc.2020.11.008CrossrefMedlineGoogle Scholar15. Mayr M, Yusuf S, Weir G, Chung YL, Mayr U, Yin X, Ladroue C, Madhu B, Roberts N, De Souza A, et al. Combined metabolomic and proteomic analysis of human atrial fibrillation.J Am Coll Cardiol. 2008; 51:585–594. doi: 10.1016/j.jacc.2007.09.055CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Anan G, Hirose T, Kikuchi D, Takahashi C, Endo A, Ito H, Sato S, Nakayama S, Hashimoto H, Ishiyama K, Kimura T, Takahashi K, Sato M and Mori T (2022) Inhibition of sodium-glucose cotransporter 2 suppresses renal stone formation, Pharmacological Research, 10.1016/j.phrs.2022.106524, 186, (106524), Online publication date: 1-Dec-2022. Zhang X, Zhang Y and Hu Y (2022) Knowledge domain and emerging trends in empagliflozin for heart failure: A bibliometric and visualized analysis, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2022.1039348, 9 Tang Y and Sang H (2022) Cost-utility analysis of empagliflozin in heart failure patients with reduced and preserved ejection fraction in China, Frontiers in Pharmacology, 10.3389/fphar.2022.1030642, 13 Related articlesMetabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HFSenthil Selvaraj, et al. Circulation. 2022;146:808-818 September 13, 2022Vol 146, Issue 11 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.060805PMID: 36095062 Originally publishedSeptember 12, 2022 Keywordsmetabolomicsheart failureEditorialsmetabolismpharmacologyclinical trialPDF download Advertisement" @default.
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