The Serendipitous Story of SGLT2 Inhibitors in Heart Failure
2019; Lippincott Williams & Wilkins; Volume: 139; Issue: 22 Linguagem: Inglês
10.1161/circulationaha.119.040514
ISSN1524-4539
AutoresSubodh Verma, John J.V. McMurray,
Tópico(s)Heart Failure Treatment and Management
ResumoHomeCirculationVol. 139, No. 22The Serendipitous Story of SGLT2 Inhibitors in Heart Failure Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBThe Serendipitous Story of SGLT2 Inhibitors in Heart FailureNew Insights From DECLARE-TIMI 58 Subodh Verma, MD, PhD and John J.V. McMurray, MB ChB (Hons), MD Subodh VermaSubodh Verma Subodh Verma, MD, PhD, FRCSC, Division of Cardiac Surgery, St Michael's Hospital, University of Toronto, 8th Floor, Bond Wing, 30 Bond St, Toronto, Ontario, Canada M5B 1W8. Email E-mail Address: [email protected] Division of Cardiac Surgery, St Michael's Hospital, University of Toronto, Canada (S.V.). and John J.V. McMurrayJohn J.V. McMurray British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom (J.J.V.M.). Originally published18 Mar 2019https://doi.org/10.1161/CIRCULATIONAHA.119.040514Circulation. 2019;139:2537–2541This article is a commentary on the followingDapagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Previous Myocardial InfarctionEffect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes MellitusOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 18, 2019: Ahead of Print Articles, see p 2516 and 2528Diabetes mellitus intersects with cardiovascular disease at every level. Although there has been much focus on understanding atherosclerotic complications, less well appreciated is the relationship between diabetes mellitus and heart failure. In addition to being a key and independent risk factor for the development of heart failure,1 diabetes mellitus is also one of the most important adverse prognostic factors in those with established heart failure with either reduced or preserved ejection fraction (EF).1,2 Diabetes mellitus is associated with a high prevalence of unrecognized left ventricular diastolic and systolic dysfunction, and it accelerates the development of overt heart failure compared with similar patients without diabetes mellitus.3 In addition to cardiac predictors such as left ventricular dysfunction, hypertrophy, and coronary artery disease, features of diabetes mellitus associated with the development of heart failure include poor glycemic control, longer duration of diabetes mellitus, insulin treatment, and the presence of microvascular complications, such as retinopathy or nephropathy.2,4 Finally, data from randomized trials and registries remind us that heart failure is numerically nearly as common as ischemic complications in patients with type 2 diabetes mellitus and remains one of the leading causes of hospitalizations in this population.1,2 Although conventional risk factor control can reduce ischemic complications, heart failure risk remains a recalcitrant problem in diabetes mellitus for which intensive glycemic control has had little benefit.The serendipitous story of sodium-glucose transporter 2 (SGLT2) inhibitors and heart failure stems from the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients),5 which unexpectedly demonstrated a profound 35% relative risk reduction in hospitalization for heart failure in patients with type 2 diabetes mellitus and established atherosclerotic vascular disease (ASCVD) who were treated with empagliflozin. Two additional SGLT2 inhibitors, canagliflozin and dapagliflozin, have been studied in large cardiovascular outcome trials (the CANVAS [Canagliflozin Cardiovascular Assessment Study] Program6 and DECLARE-TIMI 58 [Dapagliflozin Effect on Cardiovascular Events: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Effect of Dapagliflozin 10 mg Once Daily on the Incidence of Cardiovascular Death, Myocardial Infarction or Ischemic Stroke in Patients With Type 2 Diabetes],7 respectively). Both confirmed the benefit of SGLT2 inhibitors on hospitalization for heart failure (HHF), the composite of HHF or cardiovascular death (HHF/CV death), and renal composite outcomes. Importantly, these latter studies included people with type 2 diabetes mellitus with and without established ASCVD.By contrast to the clear benefit on HHF, none of the 3 trials showed a convincing effect of SGLT2 inhibition on atherothrombotic events. A recent meta-analysis of the 3 trials confirmed the robust effect of SGLT2 inhibitors in reducing HHF/CV death by 23%, with similar benefits across primary and secondary prevention patients and in those with and without a history of heart failure.8 Worse initial renal function was associated with a higher HHF/CV death event rate, and SGLT2 inhibition appeared to offer greater risk reduction in heart failure in the setting of reduced estimated glomerular filtration rate.8 The traditional atherosclerotic composite outcome of major adverse cardiovascular events (MACE) was reduced, but only modestly, by 11%, with this benefit only clearly apparent in patients with ASCVD.8 The recent CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) in patients with type 2 diabetes mellitus and albuminuric chronic kidney disease provided further evidence that SGLT2 inhibitors can reduce atherothrombotic events. In CREDENCE, the MACE hazard ratio was 0.80 (0.67–0.95) for canagliflozin compared with placebo (with significant reductions in cardiovascular death, heart failure hospitalization and renal end points too).9Two analyses from the DECLARE-TIMI 58 trial are published in this issue of Circulationand extend our understanding of dapagliflozin in individuals with and without a prior myocardial infarction (MI),10 and according to heart failure status and baseline EF.11 Among the 17 160 patients with type 2 diabetes mellitus randomized to receive dapagliflozin or placebo in DECLARE-TIMI 58, 6974 had known ASCVD, of whom 3584 had a history of MI, with a median duration from their last event of 5.4 years.10 As observed in the other trials, patients with a prior MI were at ≈2-fold higher risk for both MACE and HHF/CV death.12 Dapagliflozin significantly reduced MACE by 16% (hazard ratio [HR], 0.84; 95% CI, 0.72–0.99; P=0.039) in those with a history of prior MI but not among those with no prior MI but with established ASCVD (HR, 0.98; 95% CI, 0.0.81–1.19; P=0.85). The effect in patients with prior MI translated into an absolute risk reduction of 2.6% and a number needed to treat of 38 over a 4-year period (Figure). These benefits were driven by reductions in recurrent MI, with numeric trends toward fewer coronary heart disease deaths (HR, 0.84), all-cause mortality (HR, 0.83), and the composite of coronary heart disease death, nonfatal recurrent MI, or sudden death (HR, 0.81). The MACE benefits appeared greater in those who had had a recent MI (<2 years ago), with statistical evidence supporting the observation that this benefit seemed to be time-dependent. Given that the number of patients in this subgroup was small, this finding should be considered hypothesis-generating. In patients without a history of a prior MI, or in those with ASCVD but without a prior MI, there were no MACE benefits observed. In contrast, the benefit on HHF/CV death was observed across all subgroups (and was largest in absolute terms in patients with prior MI). Overall, these findings are consistent with the suggestion from the meta-analysis that SGLT2 inhibitors can reduce coronary events in patients at high risk of such outcomes.Download figureDownload PowerPointFigure. Schematic representation of the effects of dapagliflozin vs placebo in the DECLARE-TIMI 58 study based on clinical history and heart function.A, Schematic representation of the effects of dapagliflozin vs placebo in the DECLARE-TIMI 58 study as a function of a history of prior myocardial infarction (MI), those without MI but with atherosclerotic cardiovascular disease (ASCVD), and those with multiple risk factors only. There was a significant reduction in major adverse cardiovascular events (MACE) in patients with a history of prior MI (but not in the other 2 groups), with a number needed to treat (NNT) of 38 in this cohort. There appeared to be a greater benefit in those patients with type 2 diabetes mellitus who had had a recent MI (<2 years ago). The heart failure and renal benefits were observed across all groups. B, Schematic representation of the effects of dapagliflozin vs placebo in the DECLARE-TIMI 58 study based on baseline ejection fraction (EF) and history of heart failure (HF). In patients who had an EF <45% with or without a known history of HF (defined as the HFrEF group), there appeared to be reductions in cardiovascular (CV) and all-cause mortality. Both groups derived consistent benefits on reduction in HF hospitalizations (HHF). CVD indicates cardiovascular disease; and HFrEF, heart failure with reduced ejection fraction.In the second analysis, Kato et al11 address another important and previously unanswered question about the heart failure phenotype in patients included in the SGLT2 inhibitor trials and whether baseline EF modifies the effect of therapy. Data on baseline heart failure status were available for all 17 160 participants in DECLARE-TIMI 58, and EF data were collected in ≈5000 patients. The authors defined heart failure and a reduced ejection fraction (HFrEF) as the presence of a reduced EF (<45%), whether the patient had a history of heart failure or not. In total, 671 patients (3.9%) met this definition, although only 408 had a history of heart failure. The median EF of the patients with heart failure was 38%, and most were in either New York Heart Association functional class I or II (patients in New York Heart Association functional class IV were not eligible). A further 1316 patients (7.7% of the total) had a history of heart failure without a reduced EF (808 with a documented EF ≥45% and 508 without a documented EF) and were classified as heart failure without known reduced EF. The remaining 15 173 patients had no history of heart failure and no documented reduced EF. The rate of HHF/CV death in patients assigned to placebo in each of these 3 patient groups was 27.1%, 14.8%, and 3.9%, respectively (and was highest in the patients with HFrEF with a history of heart failure).Dapagliflozin led to a greater reduction in HHF/CV death in patients with HFrEF than in patients without HFrEF (HR, 0.62 versus 0.88; Pinteraction=0.046). Among the patients without HFrEF, there was no heterogeneity of treatment effect between patients with heart failure without known reduced EF and those with no history of heart failure. The larger treatment effect in patients with HFrEF seemed to be driven by a greater reduction in cardiovascular death (HR, 0.55 for HFrEF versus 1.08 in those without HFrEF). The number needed to treat over 4 years in patients with HFrEF was 11, 19, and 16 for HHF/CV death, cardiovascular death, and all-cause mortality, respectively (Figure). Conversely, when heart failure hospitalization alone was examined, the benefit of dapagliflozin was more consistent across all patient groups. These findings must be treated with caution given that they reflect subgroup analyses, and because there are many data on EF missing. However, several of the observations are notable. First, the prevalence of reduced EF was perhaps higher than might be expected. Of the 1724 patients with a history of heart failure, 408 (24%) had HFrEF, 808 had heart failure with preserved EF (45%), and 508 had heart failure with unknown EF (29%); a further 263 patients without a history of heart failure had a documented reduced EF. Often the focus in diabetes mellitus has been on heart failure with preserved EF, which, although more common, is not the sole heart failure phenotype and carries considerably less risk of adverse outcomes than HFrEF. More surprising, perhaps, is the suggestion that it is patients with HFrEF who benefit most from SGLT2 inhibitors, through reduction in cardiovascular death. This preliminary observation is intriguing but is based on small numbers (<100 cardiovascular deaths in each heart failure subgroup) and is thus purely hypothesis-generating. Fortunately, however, the hypothesis that SGLT2 inhibitors might reduce HHF/CV death is being tested prospectively in heart failure with reduced and preserved EF.Several mechanisms have been suggested to mediate the cardiorenal benefits of SGLT2 inhibitors.13 Briefly, these include improvement in filling conditions, changes in left ventricular wall stress (through a reduction in preload and afterload), and improved myocardial energetics.13,14 In a recent randomized study, empagliflozin was demonstrated to promote a reduction in left ventricular mass index as assessed by cardiac magnetic resonance imaging over a 6-month period in patients with type 2 diabetes mellitus and coronary disease (EMPA-HEART Cardiolink-6 Trial; ClinicalTrials.gov identifier: NCT0299897015). These data suggest that SGLT2 inhibitors may promote reverse cardiac remodeling and reduce left ventricular wall stress, which provides translational clues to the heart failure benefit noted in clinical trials.What are the key lessons from these 2 analyses? In general, physicians should be aware that diabetes mellitus adversely affects the pump (heart failure), pipes (atherosclerosis), and filter (renal disease), and that these effects can occur independently.16 In patients with diabetes mellitus who have had a prior MI, the use of an SGLT2 inhibitor should be strongly considered as part of routine secondary prevention. In these individuals, SGLT2 inhibitors will reduce ischemic, heart failure, and renal events, benefits that appear to be mediated largely via glucose-independent mechanisms. The absolute risk reductions for MACE in post-MI patients are similar and additive to what is observed with antiplatelet therapies and intensive low-density lipoprotein cholesterol lowering in recent trials. Whether patients with a recent acute coronary syndrome can also be treated safely and effectively with an SGLT2 inhibitor has not been studied, and a definitive recommendation cannot be given. This may be a useful area for further investigation.For patients with diabetes mellitus and without a history of a prior MI or ASCVD but with multiple risk factors, SGLT2 inhibitors have still been shown to reduce incident heart failure and worsening renal function. In these individuals at much lower risk of atherothrombotic events, SGLT2 inhibitors have not been clearly shown to reduce MACE.As for patients with heart failure, especially heart failure with preserved EF, we suggest waiting for the results of the dedicated studies with SGLT2 inhibitors that are ongoing in people with heart failure (and chronic kidney disease). Combining SGLT2 inhibitors with other diuretic agents and other drugs that reduce blood pressure may not be straightforward, and the initial small decrease in estimated glomerular filtration rate with SGLT2 inhibition could potentially be problematic in patients who often have markedly impaired renal function and who are receiving renin-angiotensin-aldosterone–blocking agents. The ongoing trials will also answer the 2 remaining questions about the potential use of these drugs in patients with heart failure: can they be used in patients without diabetes mellitus, and can they be used in patients hospitalized with acute decompensation?AcknowledgmentsThe authors thank H. Teoh (St Michael's Hospital, Toronto, Ontario, Canada) for editorial assistance.DisclosuresDr Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery and has received research grants or speaking honoraria from Amgen, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Servier, and Valeant. He is a member of the scientific excellence committee of the EMPEROR-Preserved and EMPEROR-Reduced trials; a member of the scientific committee of the DETERMINE-A and DETERMINE-B trials; a member of the global expert panel of the SELECT study; and a national lead investigator of the Dapa-HF, DELIVER, DETERMINE-A, DETERMINE-B, EMPEROR-Preserved, EMPEROR-Reduced, SELECT and SOLOIST studies. Dr McMurray's employer, the University of Glasgow, paid for his participation in clinical trial committees by AbbVie, AstraZeneca, Amgen, Bayer, Bristol-Myers Squibb, DalCor, GlaxoSmithKline, Merck, Novartis, Resverlogix, Stealth, and Theracos. In addition, his travel and accommodation costs for attendance at meetings related to some of the clinical trials have been funded by these sponsors. Dr McMurray's employer has also paid for his attendance at advisory boards organized by Novartis and Sanofi-Aventis.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circSubodh Verma, MD, PhD, FRCSC, Division of Cardiac Surgery, St Michael's Hospital, University of Toronto, 8th Floor, Bond Wing, 30 Bond St, Toronto, Ontario, Canada M5B 1W8. Email [email protected]caReferences1. McMurray JJ, Gerstein HC, Holman RR, Pfeffer MA. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored.Lancet Diabetes Endocrinol. 2014; 2:843–851. doi: 10.1016/S2213-8587(14)70031-2CrossrefMedlineGoogle Scholar2. Seferović PM, Petrie MC, Filippatos GS, Anker SD, Rosano G, Bauersachs J, Paulus WJ, Komajda M, Cosentino F, de Boer RA, Farmakis D, Doehner W, Lambrinou E, Lopatin Y, Piepoli MF, Theodorakis MJ, Wiggers H, Lekakis J, Mebazaa A, Mamas MA, Tschöpe C, Hoes AW, Seferović JP, Logue J, McDonagh T, Riley JP, Milinković I, Polovina M, van Veldhuisen DJ, Lainscak M, Maggioni AP, Ruschitzka F, McMurray JJV. Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology.Eur J Heart Fail. 2018; 20:853–872. doi: 10.1002/ejhf.1170CrossrefMedlineGoogle Scholar3. Rørth R, Jhund PS, Mogensen UM, Kristensen SL, Petrie MC, Køber L, McMurray JJV. Risk of incident heart failure in patients with diabetes and asymptomatic left ventricular systolic dysfunction.Diabetes Care. 2018; 41:1285–1291. doi: 10.2337/dc17-2583CrossrefMedlineGoogle Scholar4. Verma S, Wanner C, Zewiener I, Ofstad AP, George JT, Fitchett D, Zinman B; EMPA-REG OUTCOME Investigators. Influence of microvascular disease on cardiovascular events in type 2 diabetes [published online March 15, 2019].J Am Coll Cardiol. doi: 10.1016/j.jacc.2019.03.002. https://www.sciencedirect.com/science/article/pii/S0735109719338070?via%3DihubGoogle Scholar5. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; for the EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373:2117–2128. doi: 10.1056/NEJMoa1504720CrossrefMedlineGoogle Scholar6. Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377:2099. doi: 10.1056/NEJMc1712572CrossrefMedlineGoogle Scholar7. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johansson PA, Langkilde AM, Sabatine MS; for the DECLARE–TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2019; 380:347–357. doi: 10.1056/NEJMoa1812389CrossrefMedlineGoogle Scholar8. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RHM, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Sabatine MS. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.Lancet. 2019; 393:31–39. doi: 10.1016/S0140-6736(18)32590-XCrossrefMedlineGoogle Scholar9. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW; CREDENCE Trial Investigators. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy [published online ahead of print April 14, 2019].N Engl J Med. doi: 10.1056/NEJMoa1811744Google Scholar10. Furtado RHM, Bonaca MP, Raz I, Zelniker TA, Mosenzon O, Cahn A, Kuder J, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Nicolau JC, Gause-Nilsson IAM, Fredriksson M, Langkilde AM, Sabatine MS, Wiviott SD. Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes mellitus and previous myocardial infarction: subanalysis from the DECLARE-TIMI 58 Trial.Circulation. 2019; 139:2516–2527. doi: 10.1161/CIRCULATIONAHA.119.039996LinkGoogle Scholar11. Kato ET, Silverman MG, Mosenzon O, Zelniker TA, Cahn A, Furtado RHM, Kuder J, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Bonaca MP, Ruff CT, Desai AS, Goto S, Johansson PA, Gause-Nilsson I, Johanson P, Langkilde AM, Raz I, Sabatine MS, Wiviott SD. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus.Circulation. 2019; 139:2528–2536. doi: 10.1161/CIRCULATIONAHA.119.040130LinkGoogle Scholar12. Verma S, Poulter NR, Bhatt DL, Bain SC, Buse JB, Leiter LA, Nauck MA, Pratley RE, Zinman B, Ørsted DD, Monk Fries T, Rasmussen S, Marso SP. Effects of liraglutide on cardiovascular outcomes in patients with type 2 diabetes mellitus with or without history of myocardial infarction or stroke.Circulation. 2018; 138:2884–2894. doi: 10.1161/CIRCULATIONAHA.118.034516LinkGoogle Scholar13. Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review.Diabetologia. 2018; 61:2108–2117. doi: 10.1007/s00125-018-4670-7CrossrefMedlineGoogle Scholar14. Verma S, Rawat S, Ho KL, Wagg CS, Zhang L, Teoh H, Dyck JE, Uddin GM, Oudit GY, Mayoux E, Lehrke M, Marx N, Lopaschuk GD. Empagliflozin increases cardiac energy production in diabetes: novel translational insights into the heart failure benefits of SGLT2 inhibitors.JACC Basic Transl Sci. 2018; 3:575–587. doi: 10.1016/j.jacbts.2018.07.006CrossrefMedlineGoogle Scholar15. Verma S, Mazer CD, Yan AT, Mason T, Slabiak A, Bello OO, Opingari E, Fitchett DH, Goldenberg RM, Goodman SG, Farkouh ME, Partridge A, Bonneau C, Bakbak E, Dhingra N, Williams AH, Lambotharan SG, Gupta N, Chowdhury C, Dai DWH, Jüni P, Teoh H, Quan A, Liuni A, Leiter LA, Bhatt DL, Zinman B, Connelly KA; for the EMPA-HEART Investigators. EMPA-HEART CardioLink-6 Trial: a randomized trial evaluating the effect of empagliflozin on left ventricular structure, function and biomarkers in people with type 2 diabetes (T2D) and coronary heart disease. Presented at: 2018 American Heart Association Annual Scientific Sessions; Chicago, IL; November 10-12, 2018. Circulation. 2018; 138:e762. Abstract 19332.Google Scholar16. Verma S, Jüni P, Mazer CD. Pump, pipes, and filter: do SGLT2 inhibitors cover it all?Lancet. 2019; 393:3–5. doi: 10.1016/S0140-6736(18)32824-1CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByConnelly K, Mazer C, Puar P, Teoh H, Wang C, Mason T, Akhavein F, Chang C, Liu M, Yang N, Chen W, Juan Y, Opingari E, Salyani Y, Barbour W, Pasricha A, Ahmed S, Kosmopoulos A, Verma R, Moroney M, Bakbak E, Krishnaraj A, Bhatt D, Butler J, Kosiborod M, Lam C, Hess D, Rizzi Coelho-Filho O, Lafreniere-Roula M, Thorpe K, Quan A, Leiter L, Yan A and Verma S (2022) Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial, Circulation, 147:4, (284-295), Online publication date: 24-Jan-2023. Janjusevic M, Fluca A, Gagno G, Pierri A, Padoan L, Sorrentino A, Beltrami A, Sinagra G and Aleksova A (2022) Old and Novel Therapeutic Approaches in the Management of Hyperglycemia, an Important Risk Factor for Atherosclerosis, International Journal of Molecular Sciences, 10.3390/ijms23042336, 23:4, (2336) Gottlieb S (2021) Heart Failure With Reduced Ejection Fraction, Journal of the American College of Cardiology, 10.1016/j.jacc.2021.09.015, 78:20, (2013-2016), Online publication date: 1-Nov-2021. Ferrari F, Martins V, Scheffel R, da Silveira A, Motta M, Moriguchi E, Santos R and Stein R (2021) The Role of Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Heart Failure, Regardless of Diabetes Status: Focus on Cardiovascular Disease, Annals of Pharmacotherapy, 10.1177/1060028020985111, 55:10, (1267-1275), Online publication date: 1-Oct-2021. Mkrtumyan A, Markova T and Mishchenko N (2021) Cardioprotective mechanisms of sodium-glucose cotransporter 2 inhibitors, Diabetes mellitus, 10.14341/DM12541, 24:3, (291-299) La Rosa S, Guglielmo C, Ocello A, Sessa C, Seminara G and Granata A (2021) Dalla medicina reattiva alla medicina di precisione, Giornale di Clinica Nefrologica e Dialisi, 10.33393/gcnd.2021.2316, 33, (112-119) Arnott C, Li J, Cannon C, Zeeuw D, Neuen B, Heerspink H, Charytan D, Agarwal A, Huffman M, Figtree G, Bakris G, Chang T, Feng K, Rosenthal N, Zinman B, Jardine M, Perkovic V, Neal B and Mahaffey K (2021) The effects of canagliflozin on heart failure and cardiovascular death by baseline participant characteristics: Analysis of the CREDENCE trial , Diabetes, Obesity and Metabolism, 10.1111/dom.14386, 23:7, (1652-1659), Online publication date: 1-Jul-2021. McDermott J, Tennyson C and Bell-McClure E (2021) Sodium–Glucose Cotransporter-2 Inhibitors for Heart Failure: The New Kid on the Block, The Journal for Nurse Practitioners, 10.1016/j.nurpra.2021.02.008, 17:6, (652-656), Online publication date: 1-Jun-2021. Dutka M, Bobiński R, Ulman-Włodarz I, Hajduga M, Bujok J, Pająk C and Ćwiertnia M (2020) Sodium glucose cotransporter 2 inhibitors: mechanisms of action in heart failure, Heart Failure Reviews, 10.1007/s10741-020-10041-1, 26:3, (603-622), Online publication date: 1-May-2021. Randhawa V, Dhanvantari S and Connelly K (2021) How Diabetes and Heart Failure Modulate Each Other and Condition Management, Canadian Journal of Cardiology, 10.1016/j.cjca.2020.11.014, 37:4, (595-608), Online publication date: 1-Apr-2021. Vallon V and Verma S (2021) Effects of SGLT2 Inhibitors on Kidney and Cardiovascular Function, Annual Review of Physiology, 10.1146/annurev-physiol-031620-095920, 83:1, (503-528), Online publication date: 10-Feb-2021. Tuttle K, Brosius F, Cavender M, Fioretto P, Fowler K, Heerspink H, Manley T, McGuire D, Molitch M, Mottl A, Perreault L, Rosas S, Rossing P, Sola L, Vallon V, Wanner C and Perkovic V (2020) SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation, Diabetes, 10.2337/dbi20-0040, 70:1, (1-16), Online publication date: 1-Jan-2021. Ye G, Wang S and Peng D (2021) Effects of SGLT2 Inhibitor on Ischemic Events Stemming From Atherosclerotic Coronary Diseases: A Systematic Review and Meta-analysis With Trial Sequential Analysis of Randomized Controlled Trials, Journal of Cardiovascular Pharmacology, 10.1097/FJC.0000000000001018, 77:6, (787-795) Brown E, Wilding J, Alam U, Barber T, Karalliedde J and Cuthbertson D (2021) The expanding role of SGLT2 inhibitors beyond glucose-lowering to cardiorenal protection, Annals of Medicine, 10.1080/07853890.2020.1841281, 53:1, (2072-2089), Online publication date: 1-Jan-2021. Tuttle K, Brosius F, Cavender M, Fioretto P, Fowler K, Heerspink H, Manley T, McGuire D, Molitch M, Mottl A, Perreault L, Rosas S, Rossing P, Sola L, Vallon V, Wanner C and Perkovic V (2021) SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation, American Journal of Kidney Diseases, 10.1053/j.ajkd.2020.08.003, 77:1, (94-109), Online publication date: 1-Jan-2021. Grassi G, Seravalle G and Esler M (2020) Sympathomodulation in congestive heart failure: From drugs to devices, International Journal of Cardiology, 10.1016/j.ijcard.2020.07.027, 321, (118-125), Online publication date: 1-Dec-2020. Verma S, Anker S, Butler J and Bhatt D (2020) Early initiation of SGLT2 inhibitors is important, irrespective of ejection fraction: SOLOIST‐WHF in perspective, ESC Heart Failure, 10.1002/ehf2.13148, 7:6, (3261-3267), Online publication date: 1-Dec-2020. Sabouret P, Galati G, Angoulvant D, Germanova O, Castelletti S, Pathak A, Metra M and Margonato A (2020) The interplay between cardiology and diabetology: a renewed collaboration to optimize cardiovascular prevention and heart failure management, European Heart Journal - Cardiovascular Pharmacotherapy, 10.1093/ehjcvp/pvaa051, 6:6, (394-404), Online publication date: 1-Nov-2020. Verma S, Klug E, Mareev V, Kobalava Z, Connelly K, Arici M, Berwanger O, Santoso A, Mehta R, Meglis G and Kosiborod M (2020) Sodium–glucose cotransporter 2 inhibitors at the intersection of cardiovascular, renal and metabolic care: an integrated and multidisciplinary approach to patient-centered care, Current Opinion in Cardiology, 10.1097/HCO.0000000000000774, 35:5, (589-601), Online publication date: 1-Sep-2020. Koyani C, Plastira I, Sourij H, Hallström S, Schmidt A, Rainer P, Bugger H, Frank S, Malle E and von Lewinski D (2020) Empagliflozin protects heart from inflammation and energy depletion via AMPK activation, Pharmacological Research, 10.1016/j.phrs.2020.104870, 158, (104870), Online publication date: 1-Aug-2020. Tanaka A and Node K (2020) Promising roles of sodium–glucose cotransporter 2 inhibitors in heart failure prevention and treatment, Diabetology International, 10.1007/s13340-020-00445-7, 11:3, (252-260), Online publication date: 1-Jul-2020. Butler J, Handelsman Y, Bakris G and Verma S (2020) Use of sodium–glucose co‐transporter‐2 inhibitors in patients with and without type 2 diabetes: implications for incident and prevalent heart failure, European Journal of Heart Failure, 10.1002/ejhf.1708, 22:4, (604-617), Online publication date: 1-Apr-2020. Santos-Ferreira D, Gonçalves-Teixeira P and Fontes-Carvalho R (2019) SGLT-2 Inhibitors in Heart Failure and Type-2 Diabetes: Hitting Two Birds with One Stone?, Cardiology, 10.1159/000504694, 145:5, (311-320), . Chilton R (2019) Effects of sodium‐glucose cotransporter‐2 inhibitors on the cardiovascular and renal complications of type 2 diabetes, Diabetes, Obesity and Metabolism, 10.1111/dom.13854, 22:1, (16-29), Online publication date: 1-Jan-2020. Couselo-Seijas M, Agra-Bermejo R, Fernández A, Martínez-Cereijo J, Sierra J, Soto-Pérez M, Rozados-Luis A, González-Juanatey J and Eiras S (2020) High released lactate by epicardial fat from coronary artery disease patients is reduced by dapagliflozin treatment, Atherosclerosis, 10.1016/j.atherosclerosis.2019.11.016, 292, (60-69), Online publication date: 1-Jan-2020. Turan B (2020) Role of Sodium-Glucose Co-transporters on Cardiac Function in Metabolic Syndrome Mammalians Biochemistry of Cardiovascular Dysfunction in Obesity, 10.1007/978-3-030-47336-5_7, (125-144), . Mellville M (2019) The role of the heart failure nurse and use of sodium glucose cotransporter-2 inhibitors, Journal of Prescribing Practice, 10.12968/jprp.2019.1.12.602, 1:12, (602-609), Online publication date: 2-Dec-2019. Norhammar A, Bodegard J, Nyström T, Thuresson M, Rikner K, Nathanson D and Eriksson J (2019) Dapagliflozin vs non‐SGLT‐2i treatment is associated with lower healthcare costs in type 2 diabetes patients similar to participants in the DECLARE‐TIMI 58 trial: A nationwide observational study, Diabetes, Obesity and Metabolism, 10.1111/dom.13852, 21:12, (2651-2659), Online publication date: 1-Dec-2019. Verma S (2019) Potential Mechanisms of Sodium-Glucose Co-Transporter 2 Inhibitor-Related Cardiovascular Benefits, The American Journal of Cardiology, 10.1016/j.amjcard.2019.10.028, 124, (S36-S44), Online publication date: 1-Dec-2019. Angoulvant D and Cohen A (2019) Contrôle glycémique des patients diabétiques : la fin de l'inertie thérapeutique pour les cardiologues?, Archives of Cardiovascular Diseases Supplements, 10.1016/S1878-6480(19)30958-9, 11, (S1-S2), Online publication date: 1-Dec-2019. Verma S, Mazer C, Yan A, Mason T, Garg V, Teoh H, Zuo F, Quan A, Farkouh M, Fitchett D, Goodman S, Goldenberg R, Al-Omran M, Gilbert R, Bhatt D, Leiter L, Jüni P, Zinman B and Connelly K (2019) Effect of Empagliflozin on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease, Circulation, 140:21, (1693-1702), Online publication date: 19-Nov-2019. Wakisaka , Kamouchi and Kitazono (2019) Lessons from the Trials for the Desirable Effects of Sodium Glucose Co-Transporter 2 Inhibitors on Diabetic Cardiovascular Events and Renal Dysfunction, International Journal of Molecular Sciences, 10.3390/ijms20225668, 20:22, (5668) Melville M (2019) The role of the heart failure nurse and use of sodium glucose cotransporter-2 inhibitors, British Journal of Cardiac Nursing, 10.12968/bjca.2019.0055, 14:11, (1-12), Online publication date: 2-Nov-2019. Vaduganathan M and Butler J (2019) SGLT-2 inhibitors in heart failure: a new therapeutic avenue, Nature Medicine, 10.1038/s41591-019-0647-4, 25:11, (1653-1654), Online publication date: 1-Nov-2019. Verma S (2019) Potential Mechanisms of Sodium-Glucose Co-Transporter 2 Inhibitor-Related Cardiovascular Benefits, The American Journal of Medicine, 10.1016/j.amjmed.2019.08.007, 132:10, (S39-S48), Online publication date: 1-Oct-2019. Garg V, Verma S and Connelly K (2019) Mechanistic insights regarding the role of SGLT2 inhibitors and GLP1 agonist drugs on cardiovascular disease in diabetes, Progress in Cardiovascular Diseases, 10.1016/j.pcad.2019.07.005, 62:4, (349-357), Online publication date: 1-Jul-2019. Related articlesDapagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Previous Myocardial InfarctionRemo H.M. Furtado, et al. Circulation. 2019;139:2516-2527Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes MellitusEri T. Kato, et al. Circulation. 2019;139:2528-2536 May 28, 2019Vol 139, Issue 22 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.119.040514PMID: 30882236 Originally publishedMarch 18, 2019 KeywordsSGLT2 inhibitorsheart failureEditorialsdiabetes mellitusPDF download Advertisement SubjectsHeart Failure
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