Minireviews Open Access
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Cardiol. Sep 26, 2021; 13(9): 464-471
Published online Sep 26, 2021. doi: 10.4330/wjc.v13.i9.464
Sodium glucose cotransporter 2 inhibitors: New horizon of the heart failure pharmacotherapy
Ryo Naito, Takatoshi Kasai
Ryo Naito, Department of Cardiovascular Biology and Medicine, Cardiovascular Respiratory Sleep Medicine, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
Takatoshi Kasai, Department of Cardiovascular Biology and Medicine, Cardiovascular Respiratory Sleep Medicine, Juntendo University Graduate School of Medicine, Sleep and Sleep Disordered Breathing Center, Juntendo University Hospital, Tokyo 113-8421, Japan
ORCID number: Ryo Naito (0000-0003-3348-2125); Takatoshi Kasai (0000-0001-5747-7668).
Author contributions: Naito R wrote the manuscript; Kasai T revised the manuscript; all authors have read and approved the final manuscript.
Conflict-of-interest statement: Authors have no conflict-of-interest relating to this work.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Takatoshi Kasai, MD, PhD, Associate Professor, Department of Cardiovascular Biology and Medicine, Cardiovascular Respiratory Sleep Medicine, Juntendo University Graduate School of Medicine, Sleep and Sleep Disordered Breathing Center, Juntendo University Hospital, 2-1-1 Hongo Bunkyo-ku, Tokyo 113-8421, Japan. kasai-t@mx6.nisiq.net
Received: March 21, 2021
Peer-review started: March 21, 2021
First decision: May 6, 2021
Revised: May 11, 2021
Accepted: July 23, 2021
Article in press: July 23, 2021
Published online: September 26, 2021

Abstract

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have gained momentum as the latest class of antidiabetic agents for improving glycemic control. Large-scale clinical trials have reported that SGLT2 inhibitors reduced cardiovascular outcomes, especially hospitalization for heart failure in patients with type 2 diabetes mellitus who have high risks of cardiovascular disease. Accumulating evidence has indicated that beneficial effects can be observed regardless of the presence or absence of type 2 diabetes mellitus. Accordingly, the Food and Drug Administration approved these agents specifically for treating patients with heart failure and a reduced ejection fraction. It has been concluded that canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin can be recommended for preventing hospitalization associated with heart failure in patients with type 2 diabetes and established cardiovascular disease or those at high cardiovascular risk. In the present review, we explore the available evidence on SGLT2 inhibitors in terms of the cardioprotective effects, potential mechanisms, and ongoing clinical trials that may further clarify the cardiovascular effects of the agents.

Key Words: Sodium glucose cotransporter 2 inhibitors, Heart failure, Clinical trials, Potential mechanisms, Diuretics

Core Tip: Sodium glucose cotransporter 2 inhibitors are newly approved by the Food and Drug Administration as treatment choice for heart failure based on evidence from several large-scale clinical trials demonstrating reduction in cardiovascular outcomes, especially hospitalization for heart failure or cardiovascular death. The background of the approval and potential mechanisms are discussed in this review. As well, summary of available evidence from clinical trials and ongoing trials examining beneficial effects of the agents are written.



INTRODUCTION

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as the latest class of antidiabetic agents for improving glycemic control. Interestingly, the EMPA-REG OUTCOME trial, which evaluated empagliflozin in patients with type 2 diabetes and cardiovascular disease, demonstrated a greater-than-expected reduction in cardiovascular death, hospitalization for heart failure, and all-cause death[1,2]. Subsequent cardiovascular outcome trials assessing other SGLT2 inhibitors reported similar results; for instance, the Canagliflozin Cardiovascular Assessment Study (CANVAS), involving 10142 type 2 diabetic patients with high cardiovascular risk, demonstrated that canagliflozin decreased the risk of the primary outcome of a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 14%[3-5]. In the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, dapagliflozin lowered the rate of cardiovascular death or heart failure hospitalization by 17% in patients with type 2 diabetes who had or were at risk for cardiovascular disease. Those trials are summarized in Table 1. A recent meta-analysis including these clinical trials reported that SGLT2 inhibitors reduced the risk of cardiovascular death or heart failure hospitalization by 23% (HR, 0.77; 95%CI, 0.71–0.84; P < 0.0001), with a similar benefit in patients with and without a history of heart failure[6]. The magnitude of benefit associated with SGLT2 inhibitors varied with baseline renal function, with greater reductions in hospitalization for heart failure (P for interaction = 0.0073) observed in patients with more severe renal dysfunction at baseline. Additionally, sotagliflozin, a dual inhibitor of SGLT1 and SGLT2, has reduced the risk of cardiovascular death or heart failure events in patients with type 2 diabetes and chronic kidney disease[7] or type 2 diabetes complicated with heart failure[8] (Table 2). Despite these positive findings, the benefit of SGLT2 inhibitors on heart failure events was not primarily investigated in these studies, where study participants were patients with diabetes; accordingly, background medical therapy for heart failure might not be optimized. When investigating new heart failure pharmacotherapies, it is crucial to consider whether the therapies provide any additional benefits to established therapies. Therefore, it is uncertain whether these benefits can be generalized.

Table 1 Landmark clinical trials of sodium-glucose cotransporter 2 inhibitors.
Ref.
Population (n)
Age, yr (mean)
Intervention
Follow-up period (median)
Patients with a history of HF
Patients with a history of CVD
Main results
EMPA-REG[1]T2DM (7028)63.1Empagliflozin3.1 yr10.1%100%CV death or HF (HR, 0.66; 95%CI, 0.55–0.79)
HF (HR, 0.65; 95%CI, 0.50–0.85)
CV death (HR, 0.62; 95%CI, 0.49–0.77)
CANVAS[3]T2DM (9734)63.3Canagliflozin2.4 yr14.4%65.6%CV death or HF (HR, 0.78; 95%CI, 0.67–0.91)
HF (HR, 0.67; 95%CI, 0.52–0.87)
CV death (HR, 0.87 95%CI, 0.72–1.06)
DECLARE-TIMI 58[4]T2DM (17160)63.9Dapagliflozin4.2 yr10.0%40.6%CV death or HF (HR, 0.83; 95%CI, 0.73–0.95)
HF (HR, 0.73; 95%CI, 0.61–0.88)
CV death (HR, 0.98; 95%CI, 0.82–1.17)
VERTIS-CV[5]T2DM (8246)64.4Ertugliflozin3.5 yr (mean)23.7%71.4%1CV death or HF (HR, 0.88; 95%CI, 0.75–1.03)
HF (HR, 0.70; 95%CI, 0.54–0.90)
CV death (HR, 0.92; 95%CI, 0.77–1.11)
Table 2 Summary of clinical trials of sotagliflozin.
Ref.
Population (n)
Age, yr (median)
Follow-up period (median)
Patients with a history of HF
Patients with a history of CAD
Main results
SCORED[7]T2DM and CKD (10584)6316 mo31.0%22.4%CV death or HF (HR, 0.74; 95%CI, 0.63–0.88)
CV death (HR, 0.90; 95%CI, 0.73–1.12)
SOLOIST-WHF[8]T2DM and HF (1222)709.2 mo100%58.3%CV death or HF (HR, 0.67; 95%CI, 0.52–0.85)
CV death (HR, 0.84; 95%CI, 0.58–1.22)
CARDIOPROTECTIVE EFFECTS IN PATIENTS WITH HEART FAILURE WITH REDUCED EJECTION FRACTION, REGARDLESS OF DIABETIC STATUS

A meta-analysis incorporating data from EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58 revealed that the decrease in the composite of cardiovascular death or heart failure hospitalization did not statistically differ among patients with (HR, 0.71; 95%CI, 0.61–0.84) or without (HR, 0.79; 95%CI, 0.71–0.88) history of heart failure at baseline (P for interaction = 0.51). However, the cardioprotective effects of SGLT2 inhibitors in patients with heart failure, regardless of the presence or absence of diabetes, are uncertain. The question was answered by the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial, wherein 4744 patients with heart failure with reduced left ventricular ejection fraction (LVEF) were randomly assigned to receive either dapagliflozin or placebo, in addition to standard therapy for heart failure. Among the participants, 41.8% had diabetes mellitus. During a median follow-up of 18 months, the incidence of cardiovascular death or worsening heart failure was significantly lower in the dapagliflozin group than in the placebo (16.3% vs 21.2%; HR, 0.74; 95%CI, 0.65–0.85; P < 0.001). Subgroup analysis indicated that the benefit was observed regardless of diabetic status. The empagliflozin outcome trial in patients with chronic heart failure with reduced LVEF (EMPEROR-Reduced) followed the results, examining the potential benefit of empagliflozin in 3730 patients with heart failure and reduced LVEF[9]. As observed in DAPA-HF, 50.2% of the study participants did not present with diabetes mellitus. The two trials are summarized in Table 3. The study participants in the EMPEROR-Reduced presented greater severity of heart failure than those in the DAPA-HF, with a mean LVEF of 27% vs 31% and a median N-terminal prohormone of brain natriuretic peptide (NT-proBNP) value of 1907 vs 1437. Furthermore, more than 70% of the patients enrolled in EMPEROR-Reduced had a LVEF less than 30%. As in the DAPA-HF, the emapagliflozin group had lower incidence of cardiovascular death or hospitalization for heart failure than the placebo (19.4% vs 24.7%; HR, 0.75; 95%CI, 0.65–0.86; P < 0.001) during the median follow-up of 16 months. Moreover, the benefit was observed regardless of the diabetes status. A meta-analysis that included DAPA-HF and EMPEROR-Reduced reported that SGLT2 inhibitors reduced both cardiovascular (HR, 0.86; 95%CI 0.76–0.98) and all-cause mortality (HR, 0.87; 95%CI, 0.77–0.98), without evident statistical heterogeneity between dapagliflozin and empagliflozin[10]. Similarly, SGLT2 inhibitors reduced the risk for the first hospitalization for heart failure (HR, 0.69; 95%CI, 0.62–0.78), the total number of heart failure hospitalizations or cardiovascular death (HR, 0.75; 95%CI, 0.68–0.84), and worsening renal function (HR, 0.62; 95%CI, 0.43–0.90). These findings were generally consistent in subgroup analyses (Table 4). Furthermore, both agents showed no excess risk of adverse events when compared with placebo, including renal adverse events, volume depletion, severe hypoglycemia, or bone fractures. Based on this evidence, the Heart Failure Association of the European Society of Cardiology has recently issued a position paper highlighting results of clinical trials on the role of SGLT2 inhibitors in patients with heart failure[11]. On May 5, 2020, the Food and Drug Administration approved dapagliflozin, specifically, to treat patients with heart failure and reduced ejection fraction. The position paper has concluded that canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin can be recommended to prevent hospitalization for heart failure in type 2 diabetic patients with established cardiovascular disease or high cardiovascular risk[11]. Dapagliflozin and empagliflozin are recommended to reduce the risk for heart failure hospitalization and cardiovascular death in symptomatic patients with heart failure with reduced LVEF already receiving guideline-directed medical therapy, regardless of diabetic status. The Canadian Cardiovascular Society and the Canadian Heart Failure Society have recommended that SGLT2 inhibitors are to be used in patients with mild or moderate heart failure who have an LVEF of 40% or less to improve symptoms and quality of life and to reduce the risk of hospitalization and cardiovascular death[12].

Table 3 Summary of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure and the EMPEROR-Reduced trials.
Ref.
Population (n)
Patients with T2DM
Intervention
Follow-up period (median)
Main results
DAPA-HF[22]HFrEF with or without T2DM (4744)42%Empagliflozin18 monthsCV death or HF (HR, 0.71; 95%CI, 0.65–0.85)
HF (HR, 0.70; 95%CI, 0.59–0.83)
CV death (HR, 0.82; 95%CI, 0.69–0.98)
EMPEROR-Reduced[9]HFrEF (3730)49.8%Empagliflozin16 monthsCV death or HF (HR, 0.75; 95%CI, 0.65–0.86)
HF (HR, 0.69; 95%CI, 0.59–0.81)
CV death (HR, 0.92; 95%CI, 0.75–1.12)
Table 4 Subgroup analyses for the primary outcomes in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure and the EMPEROR-Reduced trials.
Subgroup
HR (95%CI) of dapagliflozin compared to placebo
HR (95%CI) of empagliflozin compared to placebo
Age
≤ 65 yr0.78 (0.63–0.96)0.71 (0.57–0.89)
> 65 yr0.72 (0.60–0.85)0.78 (0.66–0.93)
Sex
Male0.73 (0.63–0.85)0.80 (0.68–0.93)
Female0.79 (0.59–1.06)0.59 (0.44–0.80)
T2DM
Yes0.75 (0.63–0.90)0.72 (0.60–0.87)
No0.73 (0.60–0.88)0.78 (0.64–0.97)
eGFR < 60 mL/min/1.73 m2
Yes0.72 (0.59–0.86)0.83 (0.69–1.00)
No0.76 (0.63–0.92)0.67 (0.55–0.83)
MECHANISMS LINKING SGLT2 INHIBITORS AND REDUCTIONS IN CARDIOVASCULAR EVENTS ARE UNKNOWN
Potential mechanisms

The mechanisms underlying the cardioprotective effects of SGLT2 inhibitors have not been comprehensively elucidated. SGLT2 is predominantly located in the proximal tubule of the kidney and reabsorbs glucose and sodium. Thus, SGLT2 inhibitors reduce not only glucose reabsorption but also sodium reabsorption. These inhibitors behave as diuretics presenting mechanisms such as natriuresis and enhanced diuresis, which can be attributed to an osmotic effect dependent on glycosuria, resulting in a decrease in blood pressure. Research has reported that the drug provides cardiovascular benefits by reducing plasma volume, blood pressure, arterial stiffness, and vascular resistance[2,13]. Blood pressure reduction and renal protection could be the main mechanisms contributing to favorable outcomes. Recently, basic research has suggested that SGLT2 inhibitors induce sympathetic nervous system inhibition[14]. Other studies have reported that SGLT2 inhibitors improved the circadian rhythm of sympathetic activity and reduced high fat diet-induced elevation of tyrosine hydroxylase and noradrenaline in animal models[15,16]. In agreement with this evidence, cardiovascular events that were reduced by SGLT2 inhibitors included sudden cardiac death and hospitalization for heart failure[3]. This evidence presents the hypothesis that the inhibition of sympathetic nervous activity could explain the cardiovascular benefits of SGLT2 inhibitors. Several other hypotheses beyond effects on glycemia, blood pressure lowering, and weight loss have been postulated, including improvement in myocardial energetic efficiency[17] and inhibition of sodium-hydrogen exchangers in the heart, which could prevent cardiomyocyte injury[18].

Differences between SGLT2 inhibitors and loop diuretics

Loop diuretics that act in the ascending limb of the Henle loop alleviate symptoms related to heart failure by promoting urinary sodium excretion. Despite their clinical usefulness, diuretics have failed to demonstrate prognostic effects, partly due to counter-regulatory responses through activation of the renin-angiotensin system, neurohormonal activation, and development of diuretic resistance[19]. SGLT2 inhibitors lower plasma glucose by blocking glucose reabsorption in the proximal tubule, resulting in glucose excretion into the urine. The diuretic effect of SGLT2 inhibitors was initially assumed to originate from mild osmotic diuresis owing to glycosuria. Griffin et al[20] recently conducted a double-blind, placebo-controlled, crossover study involving treatment with either empagliflozin of 10 mg or matched placebo for 2 wk, followed by a 2-wk washout period and crossover at 2 wk with the alternative treatment in diabetic patients with heart failure[20]. They reported that the natriuretic effect was synergistic with loop diuretics, resulting in a reduced blood and plasma volume, which did not activate the sympathetic nervous system or renin-angiotensin system. Renal dysfunction did not affect the natriuretic effect.

OPTIMAL TIME FOR ADMINISTERING THE AGENT

The EMPA-RESPONSE-AHF study is a multicenter pilot study that included 80 patients with acute heart failure receiving standard diuretic therapy, randomized to receive either empagliflozin of 10 mg or matched placebo daily for 30 d[21]. Empagliflozin did not demonstrate reduction in the primary outcomes of the visual analog scale of dyspnea, diuretic response, change in NT-proBNP, or length of hospital stay. A secondary composite outcome of in-hospital exacerbation of heart failure, re-hospitalization for heart failure, or death within 60 d reportedly occurred less frequently in the empagliflozin group (10% vs 13%, P = 0.014). The occurrence of adverse events related to renal function, blood pressure, and heart rate was comparable between the groups. Future trials investigating the benefits of SGLT2 inhibitors in patients with acute heart failure are warranted.

Another clinical question remains whether the effects of SGLT2 inhibitors are affected by the left ventricular ejection fraction. Heart failure treatments in patients with HFrEF have long been established, while evidence is scarce in patients with heart failure with preserved ejection fraction (HFpEF). Similarly, available evidence has revealed that the beneficial effects of SGLT2 inhibitors have been observed in HFrEF but not necessarily in HFpEF. Ongoing studies may provide some data on this issue. The ongoing heart failure outcome trials for SGLT2 inhibitors are summarized in Table 5.

Table 5 Summary of ongoing heart failure outcome trials of sodium-glucose cotransporter 2 inhibitors.

PRESERVED-HF
DELIVER
DAPA ACT HF-TIMI 68
EMPEROR-Preserved
EMPULSE
NCT number0303023503619213043636970305795104157751
PopulationHFpEF with or without T2DMHFpEF with or without T2DMAcute heart failure with reduced ejection fractionHFpEF with or without T2DMAcute Heart Failure
Sample size320470024005750500
InterventionDapagliflozin/placeboDapagliflozin/placeboDapagliflozin/placeboEmpagliflozin/placeboEmpagliflozin/placebo
Primary endpointChange from baseline in NT-proBNPTime-to-first occurrence of CV death, HF hospitalization, or urgent HF visitCV death or worsening HFTime-to-first event of HF hospitalizationDeath, number of HF events
StatusEstimated completion; February 2021Estimated completion; June 2021Estimated completion; October 2022Estimated completion; April 2021Estimated completion; June 2021
CONCLUSION

Accumulated evidence from large-scale randomized placebo-controlled trials has demonstrated the consistent effect of SGLT2 inhibitors on the clinical course of heart failure, mainly driven by a substantial decrease in hospitalization for heart failure. These benefits were attained regardless of the presence or absence of diabetes, with agents administered once daily and requiring no up-titration; additionally, no serious adverse effects were observed. This evidence supports the role of SGLT2 inhibitors as a new standard of care for HFrEF. Further studies are needed to clarify the optimal time for administering these agents, proper candidates who most benefit from these agents, and mechanisms explaining the cardioprotective effects of SGLT2 inhibitors.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Cardiac and cardiovascular systems

Country/Territory of origin: Japan

Peer-review report’s scientific quality classification

Grade A (Excellent): 0

Grade B (Very good): B

Grade C (Good): 0

Grade D (Fair): 0

Grade E (Poor): 0

P-Reviewer: Al-Mohammad A S-Editor: Ma YJ L-Editor: A P-Editor: Wu RR

References
1.  Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373:2117-2128.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5250]  [Cited by in F6Publishing: 1906]  [Article Influence: 875.0]  [Reference Citation Analysis (0)]
2.  Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME® trial investigators. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur Heart J. 2016;37:1526-1534.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 576]  [Cited by in F6Publishing: 449]  [Article Influence: 115.2]  [Reference Citation Analysis (0)]
3.  Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377:644-657.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3094]  [Cited by in F6Publishing: 1146]  [Article Influence: 773.5]  [Reference Citation Analysis (0)]
4.  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; DECLARE–TIMI 58 Investigators. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019;380:347-357.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1899]  [Cited by in F6Publishing: 712]  [Article Influence: 949.5]  [Reference Citation Analysis (0)]
5.  Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, Charbonnel B, Frederich R, Gallo S, Cosentino F, Shih WJ, Gantz I, Terra SG, Cherney DZI, McGuire DK; VERTIS CV Investigators. Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. N Engl J Med. 2020;383:1425-1435.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 217]  [Cited by in F6Publishing: 70]  [Article Influence: 217.0]  [Reference Citation Analysis (0)]
6.  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.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1022]  [Cited by in F6Publishing: 359]  [Article Influence: 340.7]  [Reference Citation Analysis (0)]
7.  Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Inzucchi SE, Kosiborod MN, Cherney DZI, Dwyer JP, Scirica BM, Bailey CJ, Díaz R, Ray KK, Udell JA, Lopes RD, Lapuerta P, Steg PG; SCORED Investigators. Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. N Engl J Med. 2021;384:129-139.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 110]  [Cited by in F6Publishing: 27]  [Article Influence: 110.0]  [Reference Citation Analysis (0)]
8.  Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Voors AA, Metra M, Lund LH, Komajda M, Testani JM, Wilcox CS, Ponikowski P, Lopes RD, Verma S, Lapuerta P, Pitt B; SOLOIST-WHF Trial Investigators. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N Engl J Med. 2021;384:117-128.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 167]  [Cited by in F6Publishing: 52]  [Article Influence: 167.0]  [Reference Citation Analysis (0)]
9.  Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Böhm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F; EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383:1413-1424.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 593]  [Cited by in F6Publishing: 166]  [Article Influence: 593.0]  [Reference Citation Analysis (0)]
10.  Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G, Brueckmann M, Ofstad AP, Pfarr E, Jamal W, Packer M. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396:819-829.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 192]  [Cited by in F6Publishing: 63]  [Article Influence: 192.0]  [Reference Citation Analysis (0)]
11.  Butler J, Zannad F, Filippatos G, Anker SD, Packer M. Totality of evidence in trials of sodium-glucose co-transporter-2 inhibitors in the patients with heart failure with reduced ejection fraction: implications for clinical practice. Eur Heart J. 2020;41:3398-3401.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 9]  [Article Influence: 12.0]  [Reference Citation Analysis (0)]
12.  O'Meara E, McDonald M, Chan M, Ducharme A, Ezekowitz JA, Giannetti N, Grzeslo A, Heckman GA, Howlett JG, Koshman SL, Lepage S, Mielniczuk LM, Moe GW, Swiggum E, Toma M, Virani SA, Zieroth S, De S, Matteau S, Parent MC, Asgar AW, Cohen G, Fine N, Davis M, Verma S, Cherney D, Abrams H, Al-Hesayen A, Cohen-Solal A, D'Astous M, Delgado DH, Desplantie O, Estrella-Holder E, Green L, Haddad H, Harkness K, Hernandez AF, Kouz S, LeBlanc MH, Lee D, Masoudi FA, McKelvie RS, Rajda M, Ross HJ, Sussex B. CCS/CHFS Heart Failure Guidelines: Clinical Trial Update on Functional Mitral Regurgitation, SGLT2 Inhibitors, ARNI in HFpEF, and Tafamidis in Amyloidosis. Can J Cardiol. 2020;36:159-169.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 28]  [Article Influence: 36.0]  [Reference Citation Analysis (0)]
13.  Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, Johansen OE. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17:1180-1193.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 246]  [Cited by in F6Publishing: 206]  [Article Influence: 41.0]  [Reference Citation Analysis (0)]
14.  Zelniker TA, Braunwald E. Cardiac and Renal Effects of Sodium-Glucose Co-Transporter 2 Inhibitors in Diabetes: JACC State-of-the-Art Review. J Am Coll Cardiol. 2018;72:1845-1855.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 103]  [Cited by in F6Publishing: 78]  [Article Influence: 34.3]  [Reference Citation Analysis (0)]
15.  Rahman A, Fujisawa Y, Nakano D, Hitomi H, Nishiyama A. Effect of a selective SGLT2 inhibitor, luseogliflozin, on circadian rhythm of sympathetic nervous function and locomotor activities in metabolic syndrome rats. Clin Exp Pharmacol Physiol. 2017;44:522-525.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 20]  [Article Influence: 6.5]  [Reference Citation Analysis (0)]
16.  Matthews VB, Elliot RH, Rudnicka C, Hricova J, Herat L, Schlaich MP. Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. J Hypertens. 2017;35:2059-2068.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 78]  [Cited by in F6Publishing: 33]  [Article Influence: 26.0]  [Reference Citation Analysis (0)]
17.  Packer M. Activation and Inhibition of Sodium-Hydrogen Exchanger Is a Mechanism That Links the Pathophysiology and Treatment of Diabetes Mellitus With That of Heart Failure. Circulation. 2017;136:1548-1559.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 101]  [Cited by in F6Publishing: 35]  [Article Influence: 25.3]  [Reference Citation Analysis (0)]
18.  Uthman L, Baartscheer A, Bleijlevens B, Schumacher CA, Fiolet JWT, Koeman A, Jancev M, Hollmann MW, Weber NC, Coronel R, Zuurbier CJ. 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.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 191]  [Cited by in F6Publishing: 159]  [Article Influence: 47.8]  [Reference Citation Analysis (0)]
19.  Hoorn EJ, Ellison DH. Diuretic Resistance. Am J Kidney Dis. 2017;69:136-142.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 45]  [Cited by in F6Publishing: 31]  [Article Influence: 9.0]  [Reference Citation Analysis (0)]
20.  Griffin M, Rao VS, Ivey-Miranda J, Fleming J, Mahoney D, Maulion C, Suda N, Siwakoti K, Ahmad T, Jacoby D, Riello R, Bellumkonda L, Cox Z, Collins S, Jeon S, Turner JM, Wilson FP, Butler J, Inzucchi SE, Testani JM. Empagliflozin in Heart Failure: Diuretic and Cardiorenal Effects. Circulation. 2020;142:1028-1039.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 68]  [Cited by in F6Publishing: 13]  [Article Influence: 68.0]  [Reference Citation Analysis (0)]
21.  Damman K, Beusekamp JC, Boorsma EM, Swart HP, Smilde TDJ, Elvan A, van Eck JWM, Heerspink HJL, Voors AA. Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF). Eur J Heart Fail. 2020;22:713-722.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 78]  [Cited by in F6Publishing: 60]  [Article Influence: 78.0]  [Reference Citation Analysis (0)]
22.  McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde AM; DAPA-HF Trial Committees and Investigators. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381:1995-2008.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1426]  [Cited by in F6Publishing: 477]  [Article Influence: 713.0]  [Reference Citation Analysis (0)]