Reconceptualization of the Molecular Mechanism by Which Sodium-Glucose Cotransporter 2 Inhibitors Reduce the Risk of Heart Failure Events
2019; Lippincott Williams & Wilkins; Volume: 140; Issue: 6 Linguagem: Inglês
10.1161/circulationaha.119.040909
ISSN1524-4539
Autores Tópico(s)Potassium and Related Disorders
ResumoHomeCirculationVol. 140, No. 6Reconceptualization of the Molecular Mechanism by Which Sodium-Glucose Cotransporter 2 Inhibitors Reduce the Risk of Heart Failure Events Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBReconceptualization of the Molecular Mechanism by Which Sodium-Glucose Cotransporter 2 Inhibitors Reduce the Risk of Heart Failure Events Milton Packer, MD Milton PackerMilton Packer Milton Packer, MD, Baylor Heart and Vascular Institute, 621 N Hall St, Dallas, TX 75226. Email E-mail Address: [email protected] Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX. Imperial College, London, UK. Originally published5 Aug 2019https://doi.org/10.1161/CIRCULATIONAHA.119.040909Circulation. 2019;140:443–445Two sodium-glucose cotransporter 2 (SGLT2) inhibitors (ie, empagliflozin and canagliflozin) are currently approved by the Food and Drug Administration to reduce cardiovascular death or major adverse thromboembolic events in patients with type 2 diabetes mellitus. Yet, the current labeling for this class of drugs is misleading. The Food and Drug Administration indication reflects certain design features of the major cardiovascular outcome safety trials with these drugs, but it does not accurately describe the most important efficacy findings of these studies. In none of the 3 major cardiovascular trials did SGLT2 inhibitors reduce the risk of myocardial infarction and stroke.1 Instead, the primary benefit of SGLT2 inhibitors was a 25% to 35% decrease in the risk of heart failure hospitalizations, which was seen consistently across the trials. The additional benefit of empagliflozin to decrease the risk of cardiovascular death is primarily driven by an effect on pump failure deaths and sudden deaths: the 2 most common modes of death in patients with heart failure.1How can inhibition of glucose transport in the proximal renal tubule lead to such a striking decrease in the risk of heart failure events? The effect of these drugs to block glucose reabsorption is accompanied by a lowering of hemoglobin A1c, body weight, and blood pressure. However, the magnitude of these effects is modest, and these changes are not well correlated with the observed decrease in the risk of heart failure deaths or hospitalizations. Furthermore, most drugs that lower blood glucose, body weight, and blood pressure do not have beneficial effects on, and they often adversely influence, the course of heart failure.Inhibition of SGLT2 in the proximal renal tubule causes a meaningful natriuresis, and the resulting decrease in plasma volume could conceivably lead to a decrease in cardiac dimensions and pressures, resulting in favorable effects on ventricular remodeling. However, it is difficult to ascribe the benefits of these drugs primarily to an increase in urinary sodium excretion, because the reduction in heart failure events was seen in patients already receiving diuretics. Intensification of diuretic therapy has not led to a dramatic decrease in cardiovascular mortality or sudden death in patients with heart failure. Similarly, the increase in hemoglobin (that is typically seen with SGLT2 inhibitors) does not lead to clinical benefits in patients with heart failure.Important insights into the potential mechanism of benefit of SGLT2 inhibitors in heart failure have recently been provided by a post hoc analysis of the DECLARE-TIMI 58 trial (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58), which evaluated patients with type 2 diabetes mellitus who were enriched for atherosclerotic cardiovascular disease.2 The investigators retrospectively collected information on ejection fraction measured before randomization to determine which phenotype of heart failure (ie, heart failure with a reduced ejection fraction [HFrEF] or heart failure with a preserved ejection fraction [HFpEF]) was more likely to experience a reduction in heart failure events with dapagliflozin. The investigators found that, although heart failure hospitalizations were reduced in patients with HFrEF and HFpEF, the magnitude of benefit was greater in patients with HFrEF (P<0.05), and cardiovascular death was reduced only in patients with HFrEF, by 45%. The most striking benefit was observed in patients with the lowest baseline left ventricular ejection fraction (ie, <30%), in whom SGLT2 inhibition was reported to decrease the risk of cardiovascular death by ≈60%. These point estimates must be interpreted very cautiously because these post hoc analyses are based on retrospectively collected, incomplete, and sparse data. However, similar results have been reported in a retrospective analysis of heart failure phenotypes in the CANVAS clinical trial (Canagliflozin Cardiovascular Assessment Study) program with the SGLT2 inhibitor, canagliflozin.3Yet, even if these estimates represent exaggerated reflections of the true effect of SGLT2 inhibitors on the risk of serious heart failure events, the magnitude of the potential benefit of these drugs in patients with HFrEF is remarkable. The effect size rivals or exceeds that with currently available neurohormonal antagonists, which are believed to exert their favorable effects in HFrEF as a result of their action to interfere with the direct adverse biological effects of norepinephrine, angiotensin II, and aldosterone, or to enhance the adaptive effects of natriuretic peptides, on cardiomyocyte function and survival. It is important to note that a natriuretic effect of SGLT2 inhibitors would not be expected to differentially influence the course of HFrEF and HFpEF.How can SGLT2 inhibition exert such striking cardioprotective effects in heart failure? There is no detectable expression of SGLT2 in cardiomyocytes. SGLT2 inhibitors increase fasting levels of ketone bodies and, thus, may enhance the use of this efficient metabolic fuel in the failing heart; however, recent work from experimental studies has not supported this hypothesis.4 Although other known and unknown pathophysiological mechanisms may be at play, it has been postulated that SGLT2 inhibitors may act within the heart to inhibit the activity of sodium-hydrogen exchanger-1 (NHE-1). SGLT2 inhibitors bind with high affinity to the extracellular Na+-binding site of NHE-1, thereby attenuating the exchanger's activity in cardiomyocytes.5Why might NHE-1 inhibition in the heart be important? The expression of NHE-1 is increased by both diabetes mellitus and by heart failure, and this increase drives an increase in intracellular calcium2; the resulting calcium overload state has been implicated in the dysfunction and loss of cardiomyocytes in experimental cardiomyopathy. Inhibition of NHE-1 with cariporide can prevent myocardial injury in patients who are undergoing coronary artery bypass graft surgery.1 It is intriguing that NHE-1 is likely to play a more important role in HFrEF than in HFpEF, because the former is characterized by cardiomyocyte loss,2 whereas the latter phenotype appears to be primarily related to a systemic inflammatory state that (when transmitted to the myocardium) results in impaired cardiac distensibility.Should we be referring to SGLT2 inhibitors as NHE antagonists? Interference with NHE-1 activity in the myocardium would be expected to have benefits in both patients with and without diabetes mellitus. Ongoing large-scale trials are evaluating the effect of empagliflozin and dapagliflozin on the risk of cardiovascular death and hospitalization for heart failure in both HFrEF and HFpEF, in patients with and without diabetes mellitus. If these trials demonstrate a reduction in the risk of cardiovascular death in nondiabetic patients with HFrEF, but not in patients with HFpEF, such a finding would reinforce the hypothesis that SGLT2 inhibitors exert a direct cardioprotective effect that is independent of their action on glucose reabsorption in the proximal renal tubule.Does a reconceptualization of the action of SGLT2 inhibitors matter? If these drugs have a dramatic effect on the clinical course of HFrEF, will physicians not prescribe them to appropriate patients? Can we not expect evidence for a meaningful reduction in the risk of cardiovascular death to motivate a change in clinical practice? Sadly, many physicians do not rely on the results of clinical trials for decision making. For many practitioners, an understanding of how a drug might work is as important as (and is often more important than) familiarity with the clinical trial data. If this cognitive bias exists, then reconceptualization of the mechanism of action of SGLT2 inhibitors will be critical to their current and future acceptance by physicians who care for patients with or are at high risk of developing heart failure. The current incomplete and misleading framework that views SGLT2 inhibitors as diuretics, antihyperglycemic agents, or metabolic fuel modulators has meaningfully hindered the uptake of these drugs to reduce the risk of serious cardiovascular events in type 2 diabetes mellitus. Given the totality of evidence,1 it is time for our conceptualization of this drug class to change.DisclosuresDr Packer has recently consulted for Abbvie, Actavis, Akcea, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead, Johnson & Johnson, NovoNordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Milton Packer, MD, Baylor Heart and Vascular Institute, 621 N Hall St, Dallas, TX 75226. Email milton.[email protected]eduReferences1. Packer M, Anker SD, Butler J, Filippatos G, Zannad F. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action.JAMA Cardiol. 2017; 2:1025–1029. doi: 10.1001/jamacardio.2017.2275CrossrefMedlineGoogle Scholar2. Kato ET, Silverman MG, Mosenzon O, Zelniker TA, Cahn A, Furtado RHM, Kuder J, Murphy SA, Bhatt DL, Leiter LA, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus.Circulation. 2019; 139:2528–2536. doi: 10.1161/CIRCULATIONAHA.119.040130LinkGoogle Scholar3. Figtree GA, Rådholm K, Barrett TD, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Matthews DR, Shaw W, Neal B. Effects of canagliflozin on heart failure outcomes associated with preserved and reduced ejection fraction in type 2 diabetes mellitus.Circulation. 2019; 139:2591–2593. doi: 10.1161/CIRCULATIONAHA.119.040057LinkGoogle Scholar4. Abdurrachim D, Teo XQ, Woo CC, Chan WX, Lalic J, Lam CSP, Lee PTH. Empagliflozin reduces myocardial ketone utilization while preserving glucose utilization in diabetic hypertensive heart disease: a hyperpolarized 13 C magnetic resonance spectroscopy study.Diabetes Obes Metab. 2019; 21:357–365. doi: 10.1111/dom.13536CrossrefMedlineGoogle Scholar5. Uthman L, Baartscheer A, Bleijlevens B, Schumacher CA, Fiolet JWT, Koeman A, Jancev M, Hollmann MW, Weber NC, Coronel R, et al. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation.Diabetologia. 2018; 61:722–726. doi: 10.1007/s00125-017-4509-7CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Actis Dato V, Benitez-Amaro A, Garcia E, Claudi L, Lhoëst M, Iborra A, Escola-Gil J, Guerra J, Samouillan V, Enrich C, Chiabrando G and Llorente-Cortés V (2022) Targeting cholesteryl ester accumulation in the heart improves cardiac insulin response, Biomedicine & Pharmacotherapy, 10.1016/j.biopha.2022.113270, 152, (113270), Online publication date: 1-Aug-2022. 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August 6, 2019Vol 140, Issue 6 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.119.040909PMID: 31381418 Originally publishedAugust 5, 2019 Keywordscanagliflozindiabetes mellitus, type 2dapagliflozinsodium-glucose transporter 2 inhibitorsheart failurePDF download Advertisement SubjectsHeart Failure
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