scholarly journals Empagliflozin inhibits proximal tubule NHE3 activity, preserves GFR and restores euvolemia in nondiabetic rats with induced heart failure

2020 ◽  
Author(s):  
Flávio A. Borges-Júnior ◽  
Danúbia Silva dos Santos ◽  
Acaris Benetti ◽  
Renato O. Crajoinas ◽  
Ednei L. Antonio ◽  
...  
Keyword(s):  
Heart Failure ◽  
Proximal Tubule ◽  
Extracellular Volume ◽  
Sglt2 Inhibitor ◽  
Sglt2 Inhibitors ◽  
Sodium Reabsorption ◽  
Sham Operation ◽  
Lung Weight ◽  
Mortality And Morbidity ◽  
Cardiovascular Outcome Trials

ABSTRACTBackgroundSodium-glucose cotransporter type 2 (SGLT2) inhibitors reduce the risk of heart failure (HF) mortality and morbidity, regardless of the presence or absence of diabetes, but the mechanisms underlying this benefit remain unclear. We tested the hypothesis that the SGLT2 inhibitor empagliflozin inhibits proximal tubule (PT) Na+/H+ exchanger isoform 3 (NHE3) activity and improves renal salt and water handling in nondiabetic rats with HF.Methods and ResultsMale Wistar rats were subjected to myocardial infarction or sham operation. After four weeks, rats that developed HF and sham rats were treated with empagliflozin (EMPA) or untreated for an additional four weeks. EMPA-treated HF rats displayed lower levels of serum brain natriuretic peptide (BNP) and lower right ventricle and lung weight to tibia length than untreated HF rats. Upon saline challenge, the diuretic and natriuretic responses of EMPA-treated HF rats were similar to those of sham rats and were higher than those of untreated HF rats. Additionally, EMPA treatment normalized the glomerular filtration rate and proteinuria in HF rats. PT NHE3 activity was higher in HF rats than in sham rats, whereas treatment with EMPA markedly reduced NHE3 activity. Unexpectedly, SGLT2 function and protein and mRNA abundance were upregulated in the PT of HF rats.ConclusionCollectively, our data show that the prevention of HF progression by empagliflozin is associated with inhibition of PT NHE3 activity and restoration of euvolemia. Moreover, we propose that the dysregulation of PT SGLT2 may be involved in the pathophysiology of nondiabetic HF.SIGNIFICANCE STATEMENTSGLT2 inhibitors represent a class of drugs that were originally developed for improving glycemic control. Cardiovascular outcome trials that were designed to evaluate cardiovascular safety yielded unexpected and unprecedented evidence of the cardiorenal benefits of SGLT2 inhibitor. Many hypotheses have been proposed to explain the mechanisms underlying these effects. Our study demonstrates that SGLT2 inhibition restores extracellular volume homeostasis in nondiabetic heart failure (HF) rats by preserving GFR and inhibiting proximal tubule NHE3-mediated sodium reabsorption. The attenuation of kidney dysfunction may constitute an essential mechanism by which SGLT2 inhibitors attenuate HF development and progression either in the presence or absence of diabetes.

scholarly journals Empagliflozin Inhibits Proximal Tubule NHE3 Activity, Preserves GFR, and Restores Euvolemia in Nondiabetic Rats with Induced Heart Failure

2021 ◽  
pp. ASN.2020071029
Author(s):  
Flávio A. Borges-Júnior ◽  
Danúbia Silva dos Santos ◽  
Acaris Benetti ◽  
Juliano Z. Polidoro ◽  
Aline C.T. Wisnivesky ◽  
...  
Keyword(s):  
Heart Failure ◽  
Proximal Tubule ◽  
Sglt2 Inhibitor ◽  
Sham Operation ◽  
Lung Weight ◽  
Mortality And Morbidity ◽  
Water Handling ◽  
Male Wistar Rats ◽  
Gfr Decline

BackgroundSGLT2 inhibitors reduce the risk of heart failure (HF) mortality and morbidity, regardless of the presence or absence of diabetes, but the mechanisms underlying this benefit remain unclear. Experiments with nondiabetic HF rats tested the hypothesis that the SGLT2 inhibitor empagliflozin (EMPA) inhibits proximal tubule (PT) NHE3 activity and improves renal salt and water handling.MethodsMale Wistar rats were subjected to myocardial infarction or sham operation. After 4 weeks, rats that developed HF and sham rats were treated with EMPA or untreated for an additional 4 weeks. Immunoblotting and quantitative RT-PCR evaluated SGLT2 and NHE3 expression. Stationary in vivo microperfusion measured PT NHE3 activity.ResultsEMPA-treated HF rats displayed lower serum B-type natriuretic peptide levels and lower right ventricle and lung weight to tibia length than untreated HF rats. Upon saline challenge, the diuretic and natriuretic responses of EMPA-treated HF rats were similar to those of sham rats and were higher than those of untreated HF rats. Additionally, EMPA treatment prevented GFR decline and renal atrophy in HF rats. PT NHE3 activity was higher in HF rats than in sham rats, whereas treatment with EMPA markedly reduced NHE3 activity. Unexpectedly, SGLT2 protein and mRNA abundance were upregulated in the PT of HF rats.ConclusionsPrevention of HF progression by EMPA is associated with reduced PT NHE3 activity, restoration of euvolemia, and preservation of renal mass. Moreover, dysregulation of PT SGLT2 may be involved in the pathophysiology of nondiabetic HF.

scholarly journals Increased NHE3 abundance and transport activity in renal proximal tubule of rats with heart failure

2012 ◽  
Vol 302 (1) ◽  
pp. R166-R174 ◽  
Author(s):  
Bruna H. Inoue ◽  
Leonardo dos Santos ◽  
Thaissa D. Pessoa ◽  
Ednei L. Antonio ◽  
Bruna P. M. Pacheco ◽  
...  
Keyword(s):  
Heart Failure ◽  
Proximal Tubule ◽  
Volume Expansion ◽  
Extracellular Volume ◽  
Left Ventricular ◽  
Male Rats ◽  
Sodium Reabsorption ◽  
Mrna Levels ◽  
Transport Activity ◽  
Extracellular Volume Expansion

Heart failure (HF) is associated with a reduced effective circulating volume that drives sodium and water retention and extracellular volume expansion. We therefore hypothesized that Na+/H+ exchanger isoform 3 (NHE3), the major apical transcellular pathway for sodium reabsorption in the proximal tubule, is upregulated in an experimental model of HF. HF was induced in male rats by left ventricle radiofrequency ablation. Sham-operated rats (sham) were used as controls. At 6 wk after surgery, HF rats exhibited cardiac dysfunction with a dramatic increase in left ventricular end-diastolic pressure. By means of stationary in vivo microperfusion and pH-dependent sodium uptake, we demonstrated that NHE3 transport activity was significantly higher in the proximal tubule of HF compared with sham rats. Increased NHE3 activity was paralleled by increased renal cortical NHE3 expression at both protein and mRNA levels. In addition, the baseline PKA-dependent NHE3 phosphorylation at serine 552 was reduced in renal cortical membranes of rats with HF. Collectively, these results suggest that NHE3 is upregulated in the proximal tubule of HF rats by transcriptional, translational, and posttranslational mechanisms. Enhanced NHE3-mediated sodium reabsorption in the proximal tubule may contribute to extracellular volume expansion and edema, the hallmark feature of HF. Moreover, our study emphasizes the importance of undertaking a cardiorenal approach to contain progression of cardiac disease.

scholarly journals Is There a Diabetes–Kidney–Heart Continuum? Perspectives From the Results of the Cardiovascular and Renal Outcome Clinical Trials With SGLT2 Inhibitors

2021 ◽  
Vol 8 ◽  
Author(s):  
Liwen Bao ◽  
Xiufang Gao ◽  
Kun Xie ◽  
Yong Li
Keyword(s):  
Heart Failure ◽  
Sglt2 Inhibitors ◽  
Renal Outcome ◽  
Protective Effects ◽  
Renal Protection ◽  
Mortality And Morbidity ◽  
Cardiovascular Outcome Trials ◽  
Sodium Glucose Cotransporter ◽  
Risk Of Mortality ◽  
Substantial Risk

Heart failure is associated with a substantial risk of mortality and morbidity. Findings from recent cardiovascular outcome trials have shown promise for sodium-glucose cotransporter-2 (SGLT2) inhibitors in preventing heart failure in patients with type 2 diabetes mellitus (T2DM). Notably, the benefits of SGLT2 inhibitors were consistent despite the presence of risk factors like atherosclerosis. Increasing evidence suggests that SGLT2 inhibitors may confer their cardioprotective effects through multiple mechanisms, ranging from improving cardiac and vascular performance to metabolism. The reduction of heart failure risk by SGLT2 inhibitors may also be attributed to the preservation of renal function. Indeed, renal insufficiency is a frequent comorbidity of patients with heart failure and T2DM; hence, the natriuretic and kidney protective effects offered by SGLT2 inhibitors may contribute to limiting adverse cardiac outcomes. In this article, we discuss the latest findings from the cardiovascular and renal outcome trials, paying special attention to the interlink between heart and kidney function, and how effective treatment of heart failure—irrespective of T2DM diagnosis—may require agents that offer both cardiac and renal protection.

scholarly journals Cardioprotection conferred by sodium-glucose cotransporter 2 inhibitors: a renal proximal tubule perspective

2020 ◽  
Vol 318 (2) ◽  
pp. C328-C336 ◽  
Author(s):  
Danúbia Silva dos Santos ◽  
Juliano Z. Polidoro ◽  
Flávio A. Borges-Júnior ◽  
Adriana C. C. Girardi
Keyword(s):  
Proximal Tubule ◽  
Molecular Mechanisms ◽  
Extracellular Volume ◽  
Renal Proximal Tubule ◽  
Sglt2 Inhibitors ◽  
Tubular Dysfunction ◽  
Cardiovascular Outcome Trials ◽  
Sodium Glucose Cotransporter ◽  
Multiple Processes ◽  
Proximal Tubular

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, also known as gliflozins, improve glycemia by suppressing glucose reuptake in the renal proximal tubule. Currently, SGLT2 inhibitors are primarily indicated as antidiabetic agents; however, their benefits extend far beyond glucose control. Cardiovascular outcome trials indicated that all studied SGLT2 inhibitors remarkably and consistently reduce cardiovascular mortality and hospitalization for heart failure (HF) in type 2 diabetes (T2D) patients. Nevertheless, the mechanisms underlying the unprecedented cardiovascular benefits of gliflozins remain elusive. Multiple processes that directly or indirectly improve myocardial performance may be involved, including the amelioration of proximal tubular dysfunction. Therefore, this paper provides a perspective on the potential cellular and molecular mechanisms of the proximal tubule that may, at least in part, mediate the cardioprotection conferred by SGLT2 inhibitors. Specifically, we focus on the effects of SGLT2 on extracellular volume homeostasis, including its plausible functional and physical association with the apical Na+/H+ exchanger isoform 3 as well as its complex and its possible bidirectional interactions with the intrarenal angiotensin system and renal sympathetic nervous system. We also discuss evidence supporting a potential benefit of gliflozins in reducing cardiovascular risk, attributable to their effect on proximal tubule handling of uric acid and albumin as well as in erythropoietin production. Unraveling the mechanisms behind the beneficial actions of SGLT2 inhibitors may not only contribute to a better understanding of the pathophysiology of cardiovascular diseases but also enable repurposing of gliflozins to improve the routine management of HF patients with or without T2D.

SGLT2 inhibitors: A revolution in therapeutics of a major Non-Communicable Disease

2021 ◽  
pp. 1-3
Author(s):  
Muhammad Sami Khan
Keyword(s):  
Heart Failure ◽  
Health Care ◽  
Health Care Providers ◽  
Communicable Disease ◽  
Health Care Expenditure ◽  
Health Care Expenditures ◽  
Sglt2 Inhibitors ◽  
Care Providers ◽  
Cardiovascular Outcome Trials ◽  
Non Communicable Disease

Pakistan is facing an exorbitant burden of Non-communicable diseases among which Cardiovascular diseases are the most prominent which has not only caused mortality but also posed a big threat on weakened economy and health care system of the country. Amidst of this growing crisis, Sodium glucose co-transporter 2 (SGLT2) inhibitors emerge as a ray of hope by reducing simultaneously the complication and health care expenditure associated with the management of this major mortality-bringing Non-communicable disease. SGLT2 inhibitors, including Dapagliflozin and Empagliflozin, are evidence-based standardized novel anti-diabetic agents tested in cardiovascular outcome trials namely DAPA-HF and EMPEROR-Reduced, when added to standard care in heart failure patients with reduced ejection fraction, provides breakthrough heart failure outcomes and also addresses massive health care expenditures. This novel finding provides an impetus to promote its beneficial effects among health care providers and early implementation. Continuous....

scholarly journals How should we monitor the cardiovascular benefit of sodium–glucose cotransporter 2 inhibition?

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Atsushi Tanaka ◽  
Koichi Node
Keyword(s):  
Sglt2 Inhibitor ◽  
Cardiovascular Outcomes ◽  
Sglt2 Inhibitors ◽  
Inhibitor Therapy ◽  
Cardiovascular Outcome ◽  
Cardiovascular Outcome Trials ◽  
Amino Terminal ◽  
Sodium Glucose Cotransporter ◽  
Diabetes Status ◽  
Cardiovascular Benefit

AbstractSodium–glucose cotransporter 2 (SGLT2) inhibitors are increasingly prescribed for the treatment of patients with type 2 diabetes to reduce the risk of cardiovascular events, including heart failure (HF). The mechanisms by which SGLT2 inhibitors reduce such risk are likely to be independent of diabetes status and improvement of glycemic control. In this commentary, based on recent mediation analyses of cardiovascular outcome trials with SGLT2 inhibitors, we discuss the prognostic role of a well-known HF-related biomarker, amino-terminal pro-B-type natriuretic peptide (NT-proBNP), in patients receiving SGLT2 inhibitors. Interestingly, the NT-proBNP concentration had a relatively small impact on the SGLT2 inhibitor-associated benefit on HF events, suggesting a limited value in measuring NT-proBNP concentrations to monitor effects on cardiovascular outcomes after initiation of SGLT2 inhibitor therapy. Instead, clinical factors, such as body weight and volume status, were prognostic for cardiovascular outcomes. As shown in some biomarker studies, short-term SGLT2 inhibitor treatment significantly improved volume and HF-related health status, despite the absence of a significant change in NT-proBNP concentration. Given the early and continuous risk reduction in HF events seen in the cardiovascular outcome trials with SGLT2 inhibitors, changes in these fundamental clinical parameters after initiation of SGLT2 inhibitor therapy, independent of NT-proBNP, could be more prognostic and could represent key determinants to identify responders or non-responders to SGLT2 inhibitors for cardiovascular outcomes. Thus, this commentary highlights the clinical importance of establishing how clinicians should monitor patients initiating SGLT2 inhibitor therapy to predict the expected cardiovascular benefit. Further detailed investigations and discussion to better understand this ‘‘black box’’ are urgently warranted.

scholarly journals Positive effect of dapagliflozin on left ventricular longitudinal function for type 2 diabetic mellitus patients with chronic heart failure

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Tanaka ◽  
F Soga ◽  
K Tatsumi ◽  
Y Mochizuki ◽  
H Sano ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Diastolic Function ◽  
Myocardial Function ◽  
Sglt2 Inhibitor ◽  
Left Ventricular ◽  
Sglt2 Inhibitors ◽  
Prospective Multicenter Study ◽  
Lv Diastolic Function

Abstract Background Type 2 diabetes mellitus (T2DM) has come to be considered an independent predictor of mortality, and also a contributor to the development of heart failure (HF) with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). Left ventricular (LV) longitudinal myocardial dysfunction as assessed in terms of lower global longitudinal strain (GLS), has been identified even in T2DM patients with preserved LV ejection fraction (LVEF), and should be considered the first marker of a preclinical form of DM-related cardiac dysfunction, leading to HFpEF. Sodium glucose cotransporter type 2 (SGLT2) inhibitors represent a new class of anti-hyperglycemic agents for T2DM, but the effect of SGLT2 inhibitors on LV longitudinal myocardial function in T2DM patients with HF remains uncertain. To examine this effect, as well as the association of LV longitudinal myocardial function with LV diastolic function after administration of SGLT2 inhibitor in T2DM patients with stable HF, we analyzed data from our previous prospective multicenter study, in which we investigated the effect of SGLT2 inhibitor on LV diastolic functional parameters of T2DM patients with stable HF at five institutions in Japan. Methods Our previous trial was a prospective multicenter study of 58 T2DM patients with stable HF at five institutions in Japan. Patients who had been taking at least one antidiabetic drugs other than SGLT2 inhibitors started the administration of 5 mg/day of dapagliflozin. Echocardiography was performed at baseline and 6 months after administration of dapagliflozin. LV diastolic function was defined as the ratio of mitral inflow E to mitral e' annular velocities (E/e'). LV longitudinal myocardial function was assessed as GLS based on the current guidelines. Results E/e' significantly decreased from 9.3 to 8.5 cm/s 6 months after administration of dapagliflozin (p=0.020) as previously described, while GLS showed significant improvement from 15.5±3.5% to 16.9±4.1% (p<0.01) 6 months after administration of dapagliflozin. Furthermore, improvement of GLS in HFpEF patients was more significant from 17.0±1.9% to 18.7±2.0% (p<0.001), compared to that in HFrEF patients from 11.3±3.8% to 11.8±4.6% (p=0.13). It was noteworthy that multiple regression analysis showed that the change in GLS after administration of dapagliflozin was the only independent determinant parameter for the change in E/e' after administration of dapagliflozin. Conclusion Dapagliflozin was found to be associated with improvement of LV longitudinal myocardial function, which led to further improvement of LV diastolic function of T2DM patients with stable HF. GLS-guided management may thus lead to improved management of T2DM patients with stable HF. Representative case Funding Acknowledgement Type of funding source: None

scholarly journals Effects of SGLT2 Inhibitors beyond Glycemic Control—Focus on Myocardial SGLT1

2021 ◽  
Vol 22 (18) ◽  
pp. 9852
Author(s):  
Alex Ali Sayour ◽  
Mihály Ruppert ◽  
Attila Oláh ◽  
Kálmán Benke ◽  
Bálint András Barta ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Large Scale ◽  
Sglt2 Inhibitor ◽  
Basic Research ◽  
Additional Benefit ◽  
Sglt2 Inhibitors ◽  
Preclinical Studies ◽  
Sodium Glucose Cotransporter

Selective sodium–glucose cotransporter 2 (SGLT2) inhibitors reduced the risk of hospitalization for heart failure in patients with or without type 2 diabetes (T2DM) in large-scale clinical trials. The exact mechanism of action is currently unclear. The dual SGLT1/2 inhibitor sotagliflozin not only reduced hospitalization for HF in patients with T2DM, but also lowered the risk of myocardial infarction and stroke, suggesting a possible additional benefit related to SGLT1 inhibition. In fact, several preclinical studies suggest that SGLT1 plays an important role in cardiac pathophysiological processes. In this review, our aim is to establish the clinical significance of myocardial SGLT1 inhibition through reviewing basic research studies in the context of SGLT2 inhibitor trials.

scholarly journals EMPEROR-Preserved: SGLT2 inhibitors breakthrough in the management of heart failure with preserved ejection fraction

2021 ◽  
Vol 2021 (3) ◽  
Author(s):  
Kerolos Wagdy ◽  
Sherif Nagy
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Complex Disease ◽  
Hospital Admissions ◽  
Sglt2 Inhibitor ◽  
Cardiovascular Death ◽  
Sglt2 Inhibitors ◽  
Preserved Ejection Fraction ◽  
Reduced Ejection Fraction ◽  
Sglt2 Inhibition

Background: Heart failure with preserved ejection fraction (HFpEF) is a complex disease which accounts for more than half of all HF hospital admissions with high prevalence and lack of effective evidence-based management. Sodium-glucose cotransporter 2 (SGLT2) inhibitor is a new antidiabetic drug that recently gained a new role in the management of heart failure with reduced ejection fraction but its role in HFpEF had yet to be studied.Study and results: EMPEROR-Preserved trial set out to evaluate the effects of SGLT2 inhibition with empagliflozin on major heart failure outcomes in patients with HFpEF. The patients were randomized in a 1:1 fashion into two groups; to receive either empagliflozin 10 mg per day (n = 2,997) or placebo (n = 2,991) in addition to usual therapy. Empagliflozin led to a 21% risk reduction of the composite of cardiovascular death or hospitalization for heart failure, which was mainly related to a 29% lower risk of hospitalization for heart failure rather than effect on cardiovascular death empagliflozin. The effects SGLT2 inhibitors were consistent in all patients.

scholarly journals Use of sodium glucose cotransporter 2 inhibitors and risk of major cardiovascular events and heart failure: Scandinavian register based cohort study

BMJ ◽  
2019 ◽  
pp. l4772 ◽  
Author(s):  
Björn Pasternak ◽  
Peter Ueda ◽  
Björn Eliasson ◽  
Ann-Marie Svensson ◽  
Stefan Franzén ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiovascular Events ◽  
Sglt2 Inhibitor ◽  
Cardiovascular Death ◽  
Sglt2 Inhibitors ◽  
Major Cardiovascular Events ◽  
Hazard Ratios ◽  
History Of

Abstract Objective To investigate the cardiovascular effectiveness of sodium glucose cotransporter 2 (SGLT2) inhibitors in routine clinical practice. Design Cohort study using data from nationwide registers and an active-comparator new-user design. Setting Denmark, Norway, and Sweden, from April 2013 to December 2016. Participants 20 983 new users of SGLT2 inhibitors and 20 983 new users of dipeptidyl peptidase 4 (DPP4) inhibitors, aged 35-84, matched by age, sex, history of major cardiovascular disease, and propensity score. Main outcome measures Primary outcomes were major cardiovascular events (composite of myocardial infarction, stroke, and cardiovascular death) and heart failure (hospital admission for heart failure or death due to heart failure). Secondary outcomes were the individual components of the cardiovascular composite and any cause death. In the primary analyses, patients were defined as exposed from treatment start throughout follow-up (analogous to intention to treat); additional analyses were conducted with an as-treated exposure definition. Cox regression was used to estimate hazard ratios. Results Mean age of the study cohort was 61 years, 60% were men, and 19% had a history of major cardiovascular disease. Of the total 27 416 person years of follow-up in the SGLT2 inhibitor group, 22 627 (83%) was among patients who initiated dapagliflozin, 4521 (16%) among those who initiated empagliflozin, and 268 (1%) among those who initiated canagliflozin. During follow-up, 467 SGLT2 inhibitor users (incidence rate 17.0 events per 1000 person years) and 662 DPP4 inhibitor users (18.0) had a major cardiovascular event, whereas 130 (4.7) and 265 (7.1) had a heart failure event, respectively. Hazard ratios were 0.94 (95% confidence interval 0.84 to 1.06) for major cardiovascular events and 0.66 (0.53 to 0.81) for heart failure. Hazard ratios were consistent among subgroups of patients with and without history of major cardiovascular disease and with and without history of heart failure. Hazard ratios for secondary outcomes, comparing SGLT2 inhibitors with DPP4 inhibitors, were 0.99 (0.85 to 1.17) for myocardial infarction, 0.94 (0.77 to 1.15) for stroke, 0.84 (0.65 to 1.08) for cardiovascular death, and 0.80 (0.69 to 0.92) for any cause death. In the as-treated analyses, hazard ratios were 0.84 (0.72 to 0.98) for major cardiovascular events, 0.55 (0.42 to 0.73) for heart failure, 0.93 (0.76 to 1.14) for myocardial infarction, 0.83 (0.64 to 1.07) for stroke, 0.67 (0.49 to 0.93) for cardiovascular death, and 0.75 (0.61 to 0.91) for any cause death. Conclusions In this large Scandinavian cohort, SGLT2 inhibitor use compared with DPP4 inhibitor use was associated with reduced risk of heart failure and any cause death, but not with major cardiovascular events in the primary intention-to-treat analysis. In the additional as-treated analyses, the magnitude of the association with heart failure and any cause death became larger, and a reduced risk of major cardiovascular events that was largely driven by the cardiovascular death component was observed. These data help inform patients, practitioners, and authorities regarding the cardiovascular effectiveness of SGLT2 inhibitors in routine clinical practice.

Sign in / Sign up

Export Citation Format

Share Document