Dapagliflozin and Heart Failure: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Carlos Escobar
,
Domingo Pascual-Figal
,
Luis Manzano
,
Julio Nuñez
,
Miguel Camafort

Heart failure (HF) is associated with a high morbidity and mortality burden. In light of more recent evidence, SGLT2 inhibitors are currently recommended as first-line therapy in managing patients with HF, regardless of ejection fraction, to reduce HF burden. The DAPA-HF and DELIVER trials, and particularly, the pooled analysis of both studies, have shown that dapagliflozin significantly reduces the risk of cardiovascular death, all-cause death, total HF hospitalizations, and MACE in the whole spectrum of HF, with sustained benefits over time.

  • dapagliflozin
  • heart failure

1. Introduction

Heart failure (HF) is a very common syndrome worldwide. In the general adult population, the current prevalence of HF is around 2% but increases with age, reaching 7% in those patients >45 years and 16% in those over 75 years [1][2][3]. Of note, due to the aging of the population and the better management of acute cardiovascular conditions, it is very likely that these numbers will increase in the following years [4].
Despite traditional treatments with renin-angiotensin system inhibitors and beta blockers, death rates of patients with HF have remained unacceptably high (i.e., 40% after a median follow-up of 2.5 years) [5]. Fortunately, these numbers are improving, particularly in those countries with a higher implementation of guideline-directed medical therapy [6][7]. Along this same line, a meta-analysis of three studies, EMPHASIS-HF trial (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure), PARADIGM-HF trial (Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting–Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) and DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) showed that compared with the combination of an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blockers (ARB) and a beta blocker, the combination of an angiotensin receptor-neprilysin inhibitor (ARNI), a beta blocker, eplerenone (a mineralocorticoid receptor antagonist) and dapagliflozin (a sodium-glucose cotransporter 2 inhibitor [SGLT2i]) was associated with a significant 50% risk reduction of cardiovascular death and a significant 47% risk reduction of all-cause mortality [8].
Acute HF represents the first cause of hospitalization in patients over 65 years in developed countries [3]. HF hospitalizations are an inflection point in the evolution and progression of the disease. Thus, in-hospital mortality varies between 4% and 10% and mortality within the first year after discharge reaches 25–30% of cases [9][10]. In addition, the risk of rehospitalization is high, particularly during the vulnerable period that accounts for the first months after discharge [11]. The meta-analysis of the EMPHASIS-HF, PARADIGM-HF and DAPA-HF trials showed that compared with the combination of an ACEi/ARB and a beta blocker, the quadruple therapy with ARNI, beta blocker, a mineralocorticoid receptor antagonist and dapagliflozin significantly reduced the risk of cardiovascular death or HF hospital admission by 62% and also hospital admission for HF alone by 68% [8]. Furthermore, HF has an important impact on the health system’s economic burden, making HF hospitalizations the main determinant for total costs. As a result, reducing HF hospitalization may translate into a reduction in health care costs [12][13].
There are different phenotypes of HF according to ejection fraction. Thus, around 40–50% of patients may have HF with reduced ejection fraction (HFrEF), 40% HF with preserved ejection fraction (HFpEF), and around 10% HF with mildly reduced ejection fraction (HFmrEF) [1][14][15]. Despite the substantial differences in the clinical profile, comorbidities, and cause of death according to HF phenotypes, the risk of adverse clinical outcomes, both cardiovascular death and HF (re-)hospitalization are quite similar along the whole spectrum of left ventricular ejection fraction [1][14][15].
The pathogenesis of HF is complex, as different neurohormonal systems are involved, including the overactivation of deleterious pathways, such as the renin-angiotensin and the sympathetic nervous systems, but also the inhibition of protective pathways, such as the natriuretic peptides system and the nitric oxide-soluble guanylate cyclase-cGMP system [16][17][18][19]. SGLT2i promotes glucosuria, osmotic diuresis and natriuresis, improves volume status and cardiac metabolism, sodium-hydrogen exchange in the myocardium, reduces cardiac fibrosis, prevents and reverses adverse cardiac remodeling through the reduction of apoptosis, necrosis and autophagy and the improvement of myocardial oxygen supply/demand, reduce sympathetic stimulation, modulate the levels of leptin and adiponectin, improve control of risk factors, preserve renal function and decrease inflammation and oxidative stress [20][21][22][23][24][25][26][27][28].
The objectives of HF management should include reducing the risk of cardiovascular death and HF hospitalization and improving symptoms and quality of life [29][30]. In this context, current guidelines recommend as first-line therapy the quadruple therapy with renin-angiotensin system inhibitors, preferably with ARNI, beta-blockers, mineralocorticoid receptor antagonists (either spironolactone or eplerenone), and SGLT2i for patients with HFrEF. More recently, the use of diuretics for fluid retention and SGLT2i (dapagliflozin/empagliflozin) is also indicated for patients with HFmrEF and HFpEF [29][30][31] (Figure 1).
Figure 1. Objectives of treatment of heart failure and class I ESC guidelines recommendations. ARNI: angiotensin receptor-neprilysin inhibitor; CV: cardiovascular; ESC: European Society of Cardiology; HFmrEF: HF with mildly reduced ejection fraction; HFpEF: HF with preserved ejection fraction; HFrEF: HF with reduced ejection fraction; MRA: mineralocorticoid receptor antagonists; SGLT2i: sodium-glucose cotransporter 2 inhibitor; RAASi: renin-angiotensin system inhibitor. 
Unfortunately, adherence to evidence from practitioners and to mediation from patients remains a problem in clinical practice, which probably translates into a higher risk of events [1][15][32]. Otherwise, it seems that SGLT2i may facilitate the tolerance and persistence for other evidence-based mediations [32].

2. Dapagliflozin: Beyond Heart Failure Protection

Dapagliflozin is rapidly absorbed after oral administration (Cmax of 2 h), has an absolute oral bioavailability of 78%, and can be taken with or without food. Dapagliflozin is approximately 91% protein bound. Of note, the CYP-mediated metabolism of dapagliflozin is minor, which leads to a low risk of drug-drug interactions. The mean plasma terminal half-life is around 13 h and is mainly eliminated through urinary excretion (75% in urine and 21% in feces). The dose of dapagliflozin (10 mg once daily) is not required to be adjusted according to renal or hepatic function, age, gender, race, or body weight [33][34][35].
The benefits of dapagliflozin have been proven not only in patients with HF but also in patients with type 2 diabetes and chronic kidney disease, providing a wide spectrum of cardiovascular protection. The DECLARE–TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) trial included 17,160 patients with type 2 diabetes who had (40.6%) or were at risk (59.4%) for atherosclerotic cardiovascular disease. After a median follow-up of 4.2 years, compared to placebo, treatment with dapagliflozin was non-inferior with respect to MACE, a composite of cardiovascular death, myocardial infarction, or ischemic stroke (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.84–1.03), but was superior when considering those patients with prior myocardial infarction (HR 0.84; 95% CI 0.72–0.99) [36][37]. Remarkably, dapagliflozin significantly reduced the risk of cardiovascular death or hospitalization for HF (HR 0.83; 95% CI 0.73–0.95), largely due to a reduction in HF hospitalizations (HR 0.73; 95% CI 0.61–0.88) and the renal composite of ≥40% decrease in estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, new end-stage renal disease, or death from renal or cardiovascular causes (HR 0.76; 95% CI 0.67–0.87) [36].
The DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial included 4304 individuals with an eGFR of 25 to 75 mL/min/1.73 m2 and a urinary albumin-to-creatinine ratio of 200 to 5000 mg/g. After a median follow-up of 2.4 years (the trial was prematurely stopped because of the overwhelming efficacy of dapagliflozin), compared to placebo (on top of renin-angiotensin system inhibition), dapagliflozin significantly reduced the risk of the primary outcome composed of a sustained decline in the eGFR ≥ 50%, end-stage kidney disease, or death from renal or cardiovascular causes by 39% (HR 0.61; 95% CI 0.51–0.72), the risk of death from cardiovascular causes or HF hospitalization by 29% (HR 0.71; 95% CI 0.55–0.92) and all-cause death by 31% (HR 0.69; 95% CI 0.53–0.88) [38]. Dapagliflozin also decreased the risk of major adverse kidney and cardiovascular events and mortality for any cause regardless of the presence of type 2 diabetes [39]. The benefits of dapagliflozin were maintained even in those patients with stage 4 chronic kidney disease [40]. Moreover, dapagliflozin reduced the risk of kidney failure and cardiovascular death or HF hospitalization and improved survival in patients with chronic kidney disease, regardless of the baseline presence of prior HF [41].

3. Dapagliflozin and Heart Failure

Although the most important clinical trials that have assessed the role of dapagliflozin among the HF population are the DAPA-HF and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trials [42][43], many other studies have been involved in the HF clinical development of dapagliflozin. For example, the DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients with HF with Reduced Ejection Fraction) trial was an investigator-initiated, multicentre, randomized controlled trial of 263 patients with NYHA II-III HFrEF, eGFR ≥ 30 mL/min/1.73 m2, and elevated natriuretic peptides. Patients received dapagliflozin 10 mg daily or placebo for 12 weeks. Although natriuretic peptide levels were not significantly modified by dapagliflozin, there were significantly more patients experiencing clinically meaningful improvements in HF-related health status assessed by the Kansas City Cardiomyopathy Questionnaire or natriuretic peptides, regardless of type 2 diabetes status [44]. In addition, a direct effect of dapagliflozin on more effective “decongestion”, as dapagliflozin improved lung fluid volumes measured by remote dielectric sensing after 12 weeks of therapy [45]. A pooled patient-level analysis from DEFINE-HF (263 patients with symptomatic HFrEF) and PRESERVED-HF (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients with Preserved Ejection Fraction Heart Failure that included 324 patients with symptomatic HFpEF and elevated natriuretic peptides) trials showed that after 12 weeks of treatment, dapagliflozin improved symptoms and reduced physical limitations across the full range of ejection fraction [46]. The evidence, supporting the role of dapagliflozin on short-term maximal functional capacity was assessed in the DAPA-VO2 randomized clinical trial. 

This entry is adapted from the peer-reviewed paper 10.3390/jcm12216798

References

  1. Escobar, C.; Palacios, B.; Varela, L.; Gutiérrez, M.; Duong, M.; Chen, H.; Justo, N.; Cid-Ruzafa, J.; Hernández, I.; Hunt, P.R.; et al. Prevalence, Characteristics, Management and Outcomes of Patients with Heart Failure with Preserved, Mildly Reduced, and Reduced Ejection Fraction in Spain. J. Clin. Med. 2022, 11, 5199.
  2. Lippi, G.; Sanchis-Gomarm, F. Global epidemiology and future trends of heart failure. AME. Med. J. 2020, 5, 15.
  3. Fernández-Rodríguez, J.M.; Casado, J.; Formiga, F.; González-Franco, A.; Arévalo, J.C.; Beltrán, M.; Cerqueiro González, J.M.; Llàcer, P.; Manzano, L.; Morales-Rull, J.L.; et al. Executive summary of the 2023 update on the consensus regarding basic conduct during hospital admission for patients with acute heart failure. Rev. Clin. Esp. 2023, 223, 499–509.
  4. van Riet, E.E.; Hoes, A.W.; Wagenaar, K.P.; Limburg, A.; Landman, M.A.; Rutten, F.H. Epidemiology of heart failure, the prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review. Eur. J. Heart Fail. 2016, 18, 242–252.
  5. Pocock, S.J.; Ariti, C.A.; McMurray, J.J.; Maggioni, A.; Køber, L.; Squire, I.B.; Swedberg, K.; Dobson, J.; Poppe, K.K.; Whalley, G.A.; et al. Predicting survival in heart failure, a risk score based on 39,372 patients from 30 studies. Eur. Heart J. 2013, 34, 1404–1413.
  6. Shahim, B.; Kapelios, C.J.; Savarese, G.; Lund, L.H. Global Public Health Burden of Heart Failure: An Updated Review. Card Fail Rev. 2023, 9, e11.
  7. Codina, P.; Zamora, E.; Levy, W.C.; Revuelta-López, E.; Borrellas, A.; Spitaleri, G.; Cediel, G.; Ruiz-Cueto, M.; Cañedo, E.; Santiago-Vacas, E.; et al. Mortality Risk Prediction Dynamics After Heart Failure Treatment Optimization: Repeat Risk Assessment Using Online Risk Calculators. Front. Cardiovasc. Med. 2022, 9, 836451.
  8. Vaduganathan, M.; Claggett, B.L.; Jhund, P.S.; Cunningham, J.W.; Pedro Ferreira, J.; Zannad, F.; Packer, M.; Fonarow, G.C.; McMurray, J.J.V.; Solomon, S.D. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction, a comparative analysis of three randomised controlled trials. Lancet 2020, 396, 121–128.
  9. Chioncel, O.; Mebazaa, A.; Maggioni, A.P.; Harjola, V.P.; Rosano, G.; Laroche, C.; Piepoli, M.F.; Crespo-Leiro, M.G.; Lainscak, M.; Ponikowski, P.; et al. Acute heart failure congestion and perfusion status—Impact of the clinical classification on in-hospital and long-term outcomes, insights from the ESC-EORP-HFA heart failure long-term registry. Eur. J. Heart Fail. 2019, 21, 1338–1352.
  10. Tomasoni, D.; Lombardi, C.M.; Sbolli, M.; Cotter, G.; Metra, M. Acute heart failure, more questions than answers. Prog. Cardiovasc. Dis. 2020, 63, 599–606.
  11. Minana, G.; Bosch, M.J.; Nunez, E.; Mollar, A.; Santas, E.; Valero, E.; García-Blas, S.; Pellicer, M.; Bodí, V.; Chorro, F.J.; et al. Length of stay and risk of very early readmission in acute heart failure. Eur. J. Intern. Med. 2017, 42, 61–66.
  12. Escobar, C.; Varela, L.; Palacios, B.; Capel, M.; Sicras, A.; Sicras, A.; Hormigo, A.; Alcázar, R.; Manito, N.; Botana, M. Costs and healthcare utilisation of patients with heart failure in Spain. BMC Health Serv. Res. 2020, 20, 964.
  13. Escobar, C.; Palacios, B.; Varela, L.; Gutiérrez, M.; Duong, M.; Chen, H.; Justo, N.; Cid-Ruzafa, J.; Hernández, I.; Hunt, P.R.; et al. Healthcare resource utilization and costs among patients with heart failure with preserved; mildly reduced; and reduced ejection fraction in Spain. BMC Health Serv. Res. 2022, 22, 1241.
  14. Redfield, M.M.; Borlaug, B.A. Heart Failure with Preserved Ejection Fraction, A Review. JAMA 2023, 329, 827–838.
  15. Escobar, C.; Palacios, B.; Gonzalez, V.; Gutiérrez, M.; Duong, M.; Chen, H.; Justo, N.; Cid-Ruzafa, J.; Hernández, I.; Hunt, P.R.; et al. Burden of Illness beyond Mortality and Heart Failure Hospitalizations in Patients Newly Diagnosed with Heart Failure in Spain According to Ejection Fraction. J. Clin. Med. 2023, 12, 2410.
  16. Antoine, S.; Vaidya, G.; Imam, H.; Villarreal, D. Pathophysiologic mechanisms in heart failure, role of the sympathetic nervous system. Am. J. Med. Sci. 2017, 353, 27–30.
  17. Sayer, G.; Bhat, G. The renin-angiotensin-aldosterone system and heart failure. Cardiol. Clin. 2014, 32, 21–32.
  18. Hubers, S.A.; Brown, N.J. Combined angiotensin receptor antagonism and neprilysin inhibition. Circulation 2016, 133, 1115–1124.
  19. Kansakar, S.; Guragain, A.; Verma, D.; Sharma, P.; Dhungana, B.; Bhattarai, B.; Yadav, S.; Gautam, N. Soluble guanylate cyclase stimulators in heart failure. Cureus 2021, 13, e17781.
  20. Nightingale, B. A review of the proposed mechanistic actions of sodium glucose cotransporter-2 inhibitors in the treatment of heart failure. Cardiol. Res. 2021, 12, 60–66.
  21. Severino, P.; D’Amato, A.; Prosperi, S.; Costi, B.; Angotti, D.; Birtolo, L.I.; Chimenti, C.; Lavalle, C.; Maestrini, V.; Mancone, M.; et al. Sodium-glucose cotransporter 2 inhibitors and heart failure, the best timing for the right patient. Heart Fail. Rev. 2023, 28, 709–721.
  22. Velliou, M.; Polyzogopoulou, E.; Ventoulis, I.; Parissis, J. Clinical pharmacology of SGLT-2 inhibitors in heart failure. Expert Rev. Clin. Pharmacol. 2023, 16, 149–160.
  23. Salah, H.M.; Verma, S.; Santos-Gallego, C.G.; Bhatt, A.S.; Vaduganathan, M.; Khan, M.S.; Lopes, R.D.; Al’Aref, S.J.; McGuire, D.K.; Fudim, M. Sodium-Glucose Cotransporter 2 Inhibitors and Cardiac Remodeling. J. Cardiovasc. Transl. Res. 2022, 15, 944–956.
  24. Green, J.B.; McCullough, P.A. Roles for SGLT2 Inhibitors in Cardiorenal Disease. Cardiorenal Med. 2022, 12, 81–93.
  25. Aguilar-Gallardo, J.S.; Correa, A.; Contreras, J.P. Cardio-renal benefits of sodium-glucose co-transporter 2 inhibitors in heart failure with reduced ejection fraction, mechanisms and clinical evidence. Eur. Heart J. Cardiovasc. Pharmacother. 2022, 8, 311–321.
  26. Xie, Y.; Wei, Y.; Li, D.; Pu, J.; Ding, H.; Zhang, X. Mechanisms of SGLT2 Inhibitors in Heart Failure and Their Clinical Value. J. Cardiovasc. Pharmacol. 2023, 81, 4–14.
  27. Lytvyn, Y.; Bjornstad, P.; Udell, J.A.; Lovshin, J.A.; Cherney, D.Z.I. Sodium Glucose Cotransporter-2 Inhibition in Heart Failure, Potential Mechanisms; Clinical Applications; and Summary of Clinical Trials. Circulation 2017, 136, 1643–1658.
  28. De Lorenzi, A.B.; Kaplinsky, E.; Zambrano, M.R.; Chaume, L.T.; Rosas, J.M. Emerging concepts in heart failure management and treatment, focus on SGLT2 inhibitors in heart failure with preserved ejection fraction. Drugs Context 2023, 12, 2022-7-1.
  29. McDonagh, T.; Metra, M.; Adamo, M.; Gardner, R.S.; Baumbach, A.; Böhm, M.; Burri, H.; Butler, J.; Čelutkienė, J.; Chioncel, O.; et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur. Heart J. 2021, 42, 3599–3726.
  30. McDonagh, T.; Metra, M.; Adamo, M.; Gardner, R.S.; Baumbach, A.; Böhm, M.; Burri, H.; Butler, J.; Čelutkienė, J.; Chioncel, O.; et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure, Developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. Heart J. 2023, 44, 3627–3639.
  31. Kittleson, M.M.; Panjrath, G.S.; Amancherla, K.; Davis, L.L.; Deswal, A.; Dixon, D.L.; Januzzi, J.L., Jr.; Yancy, C.W. 2023 ACC Expert Consensus Decision Pathway on Management of Heart Failure with Preserved Ejection Fraction, A Report of the American College of Cardiology Solution Set Oversight Committee. J. Am. Coll. Cardiol. 2023, 81, 1835–1878.
  32. Savarese, G.; Kishi, T.; Vardeny, O.; Adamsson Eryd, S.; Bodegård, J.; Lund, L.H.; Thuresson, M.; Bozkurt, B. Heart Failure Drug Treatment-Inertia; Titration; and Discontinuation, A Multinational Observational Study (EVOLUTION HF). JACC. Heart Fail. 2023, 11, 1–14.
  33. Obaya, J.C.; Escobar, C.; Pallarés, V.; Egocheaga, I. Practical approach of dapagliflozin for the treatment of heart failure. Role of primary care physician. Semergen 2021, 47 (Suppl. 1), 5–10.
  34. Forxiga (Dapagliflozin). Summary of Product Characteristics. Available online: https://www.ema.europa.eu/en/documents/product-information/forxiga-epar-product-information_en.pdf (accessed on 26 August 2023).
  35. Escobar, C.; Anguita, M.; Barrios, V.; Fernández Rodríguez, J.M.; García Pinilla, J.M.; González-Costello, J.; González Franco, A.; Gómez Huelgas, R. Update on dapagliflozin for heart failure with reduced ejection fraction. Rev. Esp. Cardiol. Supl. 2021, 21(B), 1–9.
  36. Wiviott, S.D.; Raz, I.; Bonaca, M.P.; Mosenzon, O.; Kato, E.T.; Cahn, A.; Silverman, M.G.; Zelniker, T.A.; Kuder, J.F.; Murphy, S.A.; et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N. Engl. J. Med. 2019, 380, 347–357.
  37. Furtado, R.H.M.; Bonaca, M.P.; Raz, I.; Zelniker, T.A.; Mosenzon, O.; Cahn, A.; Kuder, J.; Murphy, S.A.; Bhatt, D.L.; Leiter, L.A.; et al. Dapagliflozin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus and Previous Myocardial Infarction. Circulation 2019, 139, 2516–2527.
  38. Heerspink, H.J.L.; Stefánsson, B.V.; Correa-Rotter, R.; Chertow, G.M.; Greene, T.; Hou, F.F.; Mann, J.F.E.; McMurray, J.J.V.; Lindberg, M.; Rossing, P.; et al. Dapagliflozin in Patients with Chronic Kidney Disease. N. Engl. J. Med. 2020, 383, 1436–1446.
  39. Wheeler, D.C.; Stefánsson, B.V.; Jongs, N.; Chertow, G.M.; Greene, T.; Hou, F.F.; McMurray, J.J.V.; Correa-Rotter, R.; Rossing, P.; Toto, R.D.; et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease, a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021, 9, 22–31.
  40. Chertow, G.M.; Vart, P.; Jongs, N.; Toto, R.D.; Gorriz, J.L.; Hou, F.F.; McMurray, J.J.V.; Correa-Rotter, R.; Rossing, P.; Sjöström, C.D.; et al. Effects of Dapagliflozin in Stage 4 Chronic Kidney Disease. J. Am. Soc. Nephrol. 2021, 32, 2352–2361.
  41. McMurray, J.J.V.; Wheeler, D.C.; Stefánsson, B.V.; Jongs, N.; Postmus, D.; Correa-Rotter, R.; Chertow, G.M.; Hou, F.F.; Rossing, P.; Sjöström, C.D.; et al. Effects of Dapagliflozin in Patients with Kidney Disease; with and without Heart Failure. JACC Heart Fail. 2021, 9, 807–820.
  42. McMurray, J.J.V.; Solomon, S.D.; Inzucchi, S.E.; Køber, L.; Kosiborod, M.N.; Martinez, F.A.; Ponikowski, P.; Sabatine, M.S.; Anand, I.S.; Bělohlávek, J.; et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N. Engl. J. Med. 2019, 381, 1995–2008.
  43. Solomon, S.D.; McMurray, J.J.V.; Claggett, B.; de Boer, R.A.; DeMets, D.; Hernandez, A.F.; Inzucchi, S.E.; Kosiborod, M.N.; Lam, C.S.P.; Martinez, F.; et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N. Engl. J. Med. 2022, 387, 1089–1098.
  44. Nassif, M.E.; Windsor, S.L.; Tang, F.; Khariton, Y.; Husain, M.; Inzucchi, S.E.; McGuire, D.K.; Pitt, B.; Scirica, B.M.; Austin, B.; et al. Dapagliflozin Effects on Biomarkers; Symptoms; and Functional Status in Patients with Heart Failure with Reduced Ejection Fraction, The DEFINE-HF Trial. Circulation 2019, 140, 1463–1476.
  45. Nassif, M.E.; Windsor, S.L.; Tang, F.; Husain, M.; Inzucchi, S.E.; McGuire, D.K.; Pitt, B.; Scirica, B.M.; Austin, B.; Fong, M.W.; et al. Dapagliflozin effects on lung fluid volumes in patients with heart failure and reduced ejection fraction, Results from the DEFINE-HF trial. Diabetes Obes. Metab. 2021, 23, 1426–1430.
  46. Nassif, M.E.; Windsor, S.L.; Gosch, K.; Borlaug, B.A.; Husain, M.; Inzucchi, S.E.; Kitzman, D.W.; McGuire, D.K.; Pitt, B.; Scirica, B.M.; et al. Dapagliflozin Improves Heart Failure Symptoms and Physical Limitations Across the Full Range of Ejection Fraction, Pooled Patient-Level Analysis From DEFINE-HF and PRESERVED-HF Trials. Circ. Heart Fail. 2023, 16, e009837.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback