Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors as a Dual Therapeutic Target for Cardiovascular and Renal Health: A Narrative Review

Abstract

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as a groundbreaking class of oral antihyperglycemic agents for managing type 2 diabetes mellitus (T2DM), offering dual benefits in glycemic control and cardiovascular protection. These agents work by inhibiting glucose reabsorption in the kidneys, leading to glucose excretion through urine and effectively lowering blood glucose levels. Beyond their glycemic control capabilities, SGLT2 inhibitors also reduce sodium reabsorption, contributing to blood pressure reduction through natriuresis and diuresis. Remarkably, their benefits extend to renal outcomes, showing significant improvements in patients with diabetic kidney disease and chronic kidney disease, even without diabetes. The nephroprotective mechanisms of SGLT2 inhibitors are multifaceted, including the reduction of glomerular hyperfiltration, alleviation of intraglomerular pressure, and attenuation of inflammatory and fibrotic pathways in the kidneys. This comprehensive review illustrates the diverse functions of SGLT2 inhibitors, emphasizing their significant influence on the management of T2DM and their increasing importance in the treatment of renal diseases. These inhibitors have become an integral part of the current therapeutic strategies for diabetes and its associated complications.

Keywords

SGLT2 inhibitors - canagliflozin - dapagliflozin - empagliflozin - ertugliflozin - type 2 diabetes - renoprotection

Introduction

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the treatment of choice with recent advancements in oral antihyperglycemic treatment for type 2 diabetes mellitus (T2DM). These agents facilitate a reduction in plasma glucose levels by lowering the renal threshold for glucose reabsorption to a serum glucose concentration range of 40 to 120 mg/100 mL. They inhibit SGLT2 proteins, which are primarily expressed in the renal proximal convoluted tubules. Subsequently, this mechanism ([Fig. 1]) prevents the reabsorption of filtered glucose into the bloodstream from the tubular lumen, promoting glycosuria and improving glycemic control in individuals with T2DM.[1] [2]

Fig. 1 Mechanism of action of sodium-glucose cotransporter 2 (SGLT2) inhibitors.

Canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin are some SGLT2 inhibitors approved by the United States Food and Drug Administration (USFDA) in the treatment of T2DM.[3] Furthermore, on May 26, 2023, the USFDA approved the SGLT2 inhibitor sotagliflozin to reduce the risk of cardiovascular (CV) death and hospitalizations due to heart failure (HF) in individuals with T2DM, chronic kidney disease (CKD), and other CV risk factors.[4] This approval has expanded the therapeutic utility of SGLT2 inhibitors beyond glucose regulation, highlighting their significance in both CV and renal disease management.

Furthermore, it has been established that other SGLT2 inhibitors, such as canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin, lower CV mortality, HF-related hospitalizations, CKD, and other CV risk factors. The administration of canagliflozin significantly decreased the risk of major CV events and kidney failure, according to the findings of the randomized CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial, which included 4,401 patients with T2DM and CKD.[5] Similarly, the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial found that dapagliflozin administration significantly reduced the risk of major adverse CV events (MACE), HF hospitalization, and CV death.[6] Additionally, in the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction (EMPEROR-Reduced) trial, empagliflozin administration significantly improved CV and renal outcomes in patients with HF and a reduced ejection fraction.[7] Furthermore, the administration of empagliflozin slowed the rate of decline in kidney function in both CKD and non-CKD patients, according to the EMPEROR-Reduced trial.[8] Additionally, the VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes) trial found that ertugliflozin reduced the risk of CV death and first and total hospitalizations for HF (HHF) in patients with type 2 diabetes (T2D).[9]

The cardioprotective and renoprotective properties of SGLT2 inhibitors have been established by several meta-analyses. The use of SGLT2 inhibitors was linked to lower rates of MACE, HHF, CV death, and all-cause death in patients with T2DM, CKD, or HF, according to a meta-analysis of 14 clinical trials involving 97,412 study participants.[10] Furthermore, SGLT2 inhibitors decreased the risk of first HHF by 29% in HF patients, 28% in T2DM patients, 32% in CKD patients, and 28% in atherosclerotic CVD (ASCVD) patients, according to a meta-analysis of 15 clinical trials.[11] They also decreased CV death by 15% in T2DM patients, 14% in HF patients, 13% in ASCVD patients, and 11% in CKD patients. Furthermore, SGLT2 inhibitors significantly reduced the risks of MACE by 13%, all-cause death by 15%, and CV death by 14% in patients with CKD, according to a meta-analysis of 11 clinical trials.[12]

According to a meta-analysis of 12 clinical trials with 89,191 study participants, SGLT2 inhibitor use in CKD patients was linked to lower risks of acute kidney injury, HF, CV death, and CKD progression.[13] Furthermore, SGLT2 inhibitors were found to reduce all-cause death, HF readmissions, and the composite of CV death or HF readmissions when added to conventional diuretic therapy for HF, according to a meta-analysis of 9 clinical trials involving 28,424 study participants.[14] Additionally, it was shown by a meta-analysis of six clinical trials with 2,167 participants that SGLT2 inhibitors slowed the annual decline in the estimated glomerular filtration rate (eGFR) slope, decreased the composite of CV death or HHF in patients with advanced CKD, and reduced the risk of worsening kidney function, end-stage kidney disease, or kidney death by 23%.[15]

SGLT2 inhibitors have been demonstrated to lower the risks of all-cause death, CV death, HHF, MACE, myocardial infarction (MI), and stroke in patients with T2DM and CKD, according to a meta-analysis of 9 clinical trials with 29,146 study participants.[16] Furthermore, SGLT2 inhibitors decreased the risks of MACE, kidney composite outcomes, HHF, CV death, MI, stroke, and all-cause death in patients with diabetic kidney disease (DKD), according to a meta-analysis of 8 clinical trials with 26,106 study participants.[17] Additionally, SGLT2 inhibitors reduced the risks of primary CV outcomes by 30% in patients with stage 3a CKD, 23% in patients with stage 3b CKD, 29% in patients with stage 4 CKD, 29% in patients with T2DM, 28% in patients with HF with preserved ejection fraction, 21% in patients with HF with reduced ejection fraction, and 25% in patients with ASCVD, according to a meta-analysis of 11 clinical trials with 27,823 study participants.[18]

SGLT2 inhibitors reduced the composite outcome of HHF or CV death and the risks of renal outcomes, MACE, HHF, CV death, all-cause death, and MI in patients with T2D, according to a meta-analysis of 10 clinical trials with 71,553 study participants.[19] In addition, SGLT2 inhibitors reduced the risks of MACE, HHF, CV death, and kidney outcomes in patients with T2D, according to a meta-analysis of 6 clinical trials with 46,969 study participants.[20] Moreover, SGLT2 inhibitors reduced the risks of HHF, CV death, and kidney outcomes in HF patients, according to a meta-analysis of 7 clinical trials with 14,113 study participants.[21] Furthermore, SGLT2 inhibitors significantly reduced the risks of MACE, HHF, and all-cause death as well as adverse renal outcomes in patients with T2D, according to a meta-analysis of four clinical trials.[22]

SGLT2 inhibitors are approved for a broad spectrum of therapeutic indications, significantly affecting CV and renal outcomes in patients with CV disease (CVD) and T2DM. These pharmacological agents are specifically prescribed to lower the occurrence of MACE, including CV death, nonfatal MI, and nonfatal stroke in individuals with T2DM and CVD. Moreover, they significantly reduce the risk of CV hospitalization and mortality in patients with heart failure with reduced ejection fraction (HFrEF) across New York Heart Association classes II to IV. Moreover, SGLT2 inhibitors have improved CV outcomes in patients with preserved ejection fraction (HFpEF) and HF with mildly reduced ejection fraction (HFmrEF). They also play a crucial role in minimizing the risk of a decline in eGFR and hospitalizations for patients suffering from CKD.[23] In addition to their FDA-approved uses, SGLT2 inhibitors are being studied for off-label applications in the management of type 1 diabetes mellitus,[24] [25] [26] obesity,[27] [28] [29] [30] and nonalcoholic fatty liver disease.[31] [32] [33] [34] This indicates their wide application and potential in addressing a broad spectrum of metabolic, CV, and renal disorders.

SGLT2 inhibitors have shown significant improvement in renal outcomes for a diverse range of diseased conditions, including nondiabetes. The utility of SGLT2 inhibitors in enhancing the prognosis of CKD is becoming more widely acknowledged within the medical community. Regardless of diabetic status, individuals with CKD or DKD have experienced notable renal improvements following treatment with SGLT2 inhibitors. This review elaborates on various mechanisms associated with SGLT2 inhibition that collectively contribute to nephroprotection, underscoring these agents' broad therapeutic potential in managing renal dysfunction.

Materials and Methods

To illustrate the diverse functions of SGLT2 inhibitors, emphasizing their significant influence on the management of T2DM, and their increasing importance in the treatment of renal diseases, Web-based databases like as Medline/PubMed/PubMed Central, Scopus, Embase, EBSCO host, Google Scholar, Science Direct, and reference lists were searched using terms including sodium-glucose co-transporter 2 inhibitors, SGLT-2 inhibitors, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, T2D, and renoprotection. The publications related to cardioprotective and renoprotective effects of SGLT2 inhibitors written in English were included in this review. The articles published since January 2015 are included in this comprehensive review while excluding the duplicates.

Results

Numerous studies have shown that SGLT2 inhibitors can decrease both systolic (SBP) and diastolic blood pressure, with the reductions being moderate yet clinically significant. Moreover, these inhibitors have been linked to reduced intraglomerular pressure in the kidneys. SGLT2 inhibitors can slow the progression of DKD by reducing the glomerular load. In patients with impaired kidney function, this helps maintain the glomerular filtration rate (GFR).[35] The beneficial effects of SGLT2 inhibitors are illustrated in [Fig. 2].

Fig. 2 Beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors.

Impact of Glucose Management and Weight Loss on Kidney Health in DKD

Lowering blood glucose levels has a protective impact against kidney damage in people with DKD. According to several studies, high glucose levels harm renal tissue by causing oxidative stress in the kidney.[36] Additionally, obesity leads to metabolic abnormalities in the kidney that may be improved by weight loss due to SGLT2 inhibitors. A study conducted on obese type 2 diabetic mice showed that using SGLT2 inhibitors and dietary restrictions improved renal tissue metabolism and reduced oxidative stress.[37]

SGLT2 Inhibitors on Ketone Bodies and Antihypertensive Benefits in Kidney Function

Following a reduction in blood glucose levels attributable to caloric depletion mediated by SGLT2 inhibitors, there is an endogenous production of ketone bodies for energy utilization.[38] Administration of SGLT2 inhibitors in obese T2DM mouse models promotes the formation of ketone bodies, which protects against glomerular and tubular damage.[39] Effective blood pressure management is essential for patients with CKD who also suffer from hypertension, as it plays a critical role in decelerating the progression of renal dysfunction Clinical research establishes that SGLT2 inhibitors contribute to blood pressure reduction.[40] [41] The mechanisms through which SGLT2 inhibitors achieve this include weight loss and the mitigation of hypoglycemia. Furthermore, SGLT2 inhibitors may alleviate insulin resistance, a factor that potentially contributes to their antihypertensive effects. Studies suggest that hyperinsulinemia can elevate blood pressure by promoting increased sodium reabsorption in the kidneys.[42] The natriuretic effect of SGLT2 inhibitors, facilitates sodium excretion and further aids in blood pressure reduction.[43] Additionally, evidence indicates that administration of SGLT2 inhibitors is associated with decreased sympathetic nerve activity, contributing to their blood pressure-lowering properties.[44]

SGLT2 Inhibitors on Albuminuria and Glomerular Filtration Rate

Extensive clinical research has demonstrated that SGLT2 inhibitors significantly improve renal outcomes, notably by reducing albuminuria and modulating the GFR.[45] These studies highlight the critical role of diminished intraglomerular pressure in the renoprotective effects mediated by SGLT2 inhibitors. The activation of the tubuloglomerular feedback (TGF) mechanism by SGLT2 inhibitors plays a pivotal part in reducing intraglomerular pressure.[46] This reduction occurs as SGLT2 inhibitors raise the levels of solutes, like glucose and sodium ions, at the macula densa in the distal tubules, thus triggering TGF.[47]

In response to heightened solute concentrations in the tubular lumen, macula densa cells extracellularly release adenosine and adenosine triphosphate, which prompt the constriction of adjacent glomerular afferent arterioles, which leads to a reduction in intraglomerular pressure.[48] Consequently, SGLT2 inhibitors contribute to the lowering of intraglomerular pressure (and potentially GFR), ameliorate glomerular hyperfiltration, and provide renal protection. Furthermore, research indicates that SGLT2 inhibitors may influence mesangial cell contraction, which could be integral to the regulation of GFR through the TGF mechanism.[49] Meta-analytic evidence confirms the positive impact of SGLT2 inhibitors on renal function in patients with T2DM, demonstrating their efficacy in reducing the incidence or progression of albuminuria and diminishing the risk of advancing to end-stage renal disease (ESRD) when compared with placebo or other antidiabetic treatments.[50]

Influence of SGLT2 Inhibitors on Renal Congestion through Osmotic Diuresis

SGLT2 inhibitors facilitate glucose excretion through the urine by utilizing glucose's function as an osmolyte, resulting in osmotic diuresis. This mechanism is expected to decrease the amount of water in the renal interstitium, as water moves from the renal interstitium into the urine, reducing renal congestion.[51] In a mouse model of renal fibrosis caused by ischemia-reperfusion, the use of an SGLT2 inhibitor effectively reduced renal congestion by increasing the expression of tubular vascular endothelial growth factor A.[52] This suggests that SGLT2 inhibitors have the potential to improve blood flow in the glomeruli and surrounding blood vessels. In addition, SGLT2 inhibitors have been found to cause a reduction in glucose concentrations in the renal tubulointerstitium.[53] Experimental research has demonstrated that SGLT2 inhibitors can decrease oxidative stress,[35] alleviate the effects of aging,[54] and hinder the glucose-induced epithelial-mesenchymal transition in tubular cells located in the proximal tubular S1 and S2 segments.[55] These findings highlight the potential diverse advantages of SGLT2 inhibitors in promoting renal health.

Synergistic Effects of SGLT2 Inhibitors and Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on Renal Protection

For individuals with T2DM and albuminuria, angiotensin-converting enzyme inhibitors (ACEIs)and angiotensin receptor blockers (ARBs) are recommended as the initial treatment to manage high blood pressure.[56] Current clinical guidelines recommend using renin-angiotensin system inhibition, either through ACEIs or through ARBs, as the standard treatment for patients with DKD who have albuminuria and glomerular abnormalities.[57] This treatment approach has been demonstrated to decrease the risk of progressing to ESRD in individuals with albuminuria and T2DM.

According to the American Association of Clinical Endocrinology (AACE) Clinical Practice Guideline, individuals with T2D and CKD who have an eGFR above 20 mL/min/1.73 m² should consider using SGLT2 inhibitors.[58] This approach aims to decelerate the progression of CKD and mitigate the risk of CVD. SGLT2 inhibitors work by increasing the delivery of salt to the macula densa, which then triggers the autoregulatory vasoconstriction of afferent glomerular arterioles. This helps to counteract the vascular imbalance and glomerular hypertension caused by local angiotensin II (Ang II) in patients with T2DM.[59] Experimental models have demonstrated elevated levels of SGLT2 expression in hypertension rats as compared with their normotensive counterparts. Furthermore, the treatment with ramipril or losartan led to a decrease in protein and messenger ribonucleic acid levels. This indicates that activating SGLT2 through the Ang II type 1 receptor, mediated by Ang II, may increase sodium absorption and contribute to or maintenance of hypertension.[60]

Although SGLT2 inhibitors or ACEI/ARBs can independently reduce blood pressure and albuminuria in patients with DKD, their effectiveness as standalone treatments is generally inadequate. Theoretical synergies between ACEIs/ARBs and SGLT2 inhibitors suggest a combined strategy because of their complimentary effects on the kidneys. Studies conducted on animals using T2D models have demonstrated that the combination of ACEI/ARB therapy and SGLT2 inhibitors produces additive nephroprotective advantages that are greater than those obtained with either medication class alone. These benefits include decreased blood pressure, proteinuria, glomerular injury, and renal fibrosis.[61] During a phase III clinical trial that focused on patients with DKD, the combination of ACEIs/ARBs with dapagliflozin led to a reduction in albuminuria and SBP when compared with a placebo. The results indicate that dapagliflozin's capacity to reduce albuminuria is mainly unrelated to its blood sugar-lowering effects and instead operates through many pathways.[62]

Extensive analysis has provided compelling evidence supporting the utilization of SGLT2 inhibitors in conjunction with ACEIs and/or ARBs. This combination has shown significant improvements in albuminuria and hemoglobin A1c. As a result, the use of SGLT2 inhibitors is recommended as a standard practice for patients with T2DM.[63] Ultimately, when aiming to reduce ASCVD, HF, and kidney failure events in patients with T2DM, the combined treatment of gliflozins with ACEI/ARB is more effective than using ACEI/ARB alone. This emphasizes the suggestion for using a combination of therapies, particularly in patients with T2DM who also have HF or CKD to improve protection for the heart and kidneys ([Fig. 3]).

Fig. 3 Probable mechanisms of sodium-glucose cotransporter 2 (SGLT2) inhibitors associated with cardiorenal protection.

Synergistic Effects of SGLT2 Inhibitors and ACEIs/ARBs on Cardiac Protection

Emerging evidence suggests that SGLT2 inhibitors have a beneficial effect on the heart, especially when combined with ACEI and ARB. This has led to an alteration in how patients with newly diagnosed T2DM and essential hypertension are managed. This specific group, particularly those with a notable susceptibility to ASCVD and HF, could significantly improve from an early treatment strategy that highlights the combined advantages of SGLT2 inhibitors. The reason for this recommendation is based on strong clinical evidence that shows the combined glycemic and CV advantages of SGLT2 inhibitors. These inhibitors not only enhance glycemic control but also significantly decrease the risk of CV issues and the development of HF in comparison to conventional first-line medications like metformin. This strategy is an inclusive approach to patient care, focusing on both managing blood sugar levels and reducing the risk of CV problems right from the beginning of treatment.[64] This comprehensive understanding emphasizes the significance of personalizing diabetes therapy to maximize CV results, thereby recommending the preference for SGLT2 inhibitors as a primary treatment choice in specific patient groups.

Comprehensive Evaluation of SGLT2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists in T2DM Management

The management of T2DM has evolved from a glucocentric approach to cardiometabolic, emphasizing the selection of anti-hyperglycemic medicines with CV and renal advantages.[65] As a result, selecting anti-hyperglycemic medications with established advantages for the heart and kidneys is increasingly essential for the treatment of T2D.[66] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and SGLT2 inhibitors show reduced hypoglycemia risk, enhancing renal and CV outcomes in T2DM patients.[67]

Recent advances have categorized “diabetes/disease-modifying drugs” (DMDs) as glucose-lowering medications with CV and kidney benefits. The most common DMDs include SGLT2 inhibitors and GLP-1RAs, which promote weight loss, reduced blood pressure (GLP-1RAs through weight loss and SGLT2 inhibitors via renal effects), and improvements in renal and CV health.[68]

The AACE guidelines recommend prescribing SGLT2 inhibitors/GLP-1R analogs for T2DM patients at high risk for ASCVD, HF, and/or CKD, regardless of glycemic targets, to reduce kidney failure, CV mortality, and all-cause mortality.[58] Since the risk of kidney failure, CV mortality, and all-cause mortality is decreased by both SGLT2 inhibitors and GLP-1R analogs, they are preferred for cardioprotection.[69] They are recommended as first-line treatments for T2DM patients with ASCVD or CKD. Both drug classes have reduced HF hospitalizations and composite CV endpoints, but SGLT2 inhibitors significantly reduce HF death and hospitalization, giving them an exemption in the most recent HF management guidelines.[70] GLP-1RAs reduce stroke risk in T2DM patients with ASCVD according to stroke prevention recommendations.

The risk of death or HHF has been significantly reduced by SGLT2 inhibitors, even though both classes seem to have similar effects on composite CV endpoints.[71] Consequently, SGLT2 inhibitors have been identified as one of the key components of the suggested treatment and included in the most recent guidelines for the diagnosis and management of acute and chronic HF.[72] As a result, they have been included in the guidelines for stroke prevention recommended by some associations, including the American Stroke Association.[73] When patients have an elevated risk of HF (based on the TIMI-Hadassah risk score)[74] or an elevated risk of chronic renal disease (eGFR ≤ 90 mL/min/1.73 m² and/or urine albumin to creatinine ratio ≥ 30 mg/g), the combination of SGLT2 inhibitors with metformin is recommended.[68]

According to recent meta-analysis results, when SGLT2 inhibitor was compared with a placebo or oral hypoglycemic medications, they found no obvious therapeutic benefits in lowering the incidence of acute coronary syndrome, peripheral arterial occlusive disease, or ischemic stroke. These data appeared to challenge accepted beliefs about the CV effects of SGLT2 inhibitors.[75]

The combination of GLP-1RA with metformin is recommended for those who have had ASCVD or are at high risk for it.[68] [76] Among T2DM Asian patients with dyslipidemia or hypertension but no known ASCVD, prolonged use and greater cumulative dose of GLP-1RA usage were linked to a lower risk of hospitalization for ischemic stroke.[77]

According to one meta-analysis, taking SGLT2 inhibitors did not lower the risk of stroke in patients with T2DM. The same study also revealed that SGLT2 inhibitor therapy may be more appropriate for certain T2DM patients with high-risk factors for stroke than certain oral glucose-lowering agents, such as dipeptidyl peptidase-4 inhibitors.[78]

According to a very recent cohort study, poor glycemic management in the first 3 years following diagnosis is linked to an increased risk of CVD in patients with newly diagnosed T2D who were free of CVD at baseline. But after introducing the first 2 years of treatment with SGLT2 inhibitors, this connection disappears, indicating that these medications lessen the occurrence of the legacy effect. Therefore, if a patient is diagnosed with T2D and is unable to achieve adequate glycemic control, early treatment with these medications may have a lasting positive effect.[79]

Conclusion

This review emphasizes the prioritized use of SGLT2 inhibitors over GLP-1RAs for patients with T2DM, who are at higher risk of developing CKD and HF. However, there is an ongoing study about the impact of these medications on ASCVD. Early administration of SGLT2 inhibitors has been found to reduce the long-term impact of T2DM, indicating that there is an important time frame within the first 2 years of diagnosis for improving overall outcomes. SGLT2 inhibitors are recommended as the initial treatment for patients with T2DM and albuminuria, as well as for those recently diagnosed with T2DM and essential hypertension, particularly if they are at high risk for ASCVD, HF, or CKD. This recommendation is based on the ability of SGLT2 inhibitors to protect the heart and kidneys, including their antihypertensive effects and their ability to work in combination with ACEIs/ARBs. GLP-1RAs are a suitable substitute when SGLT2 inhibitors cannot be used, especially for patients who have numerous risk factors for ASCVD or a higher likelihood of having a stroke. This therapeutic selection strategy aims to utilize the distinct advantages of these drug groups to hinder the advancement of renal and CV problems in individuals with T2DM.

Further clarification of the cellular and molecular processes underlying the cardioprotective and renoprotective effects of SGLT2 inhibitors may be the primary goal of future studies. Patients with CKD, hypertension, and HF may benefit from longer term research on the safety and effectiveness of SGLT2 inhibitors. The efficacy of SGLT2 inhibitors could be established in nondiabetic individuals with CKD, hypertension, HF, and other CV conditions. Comparative research on the effectiveness of SGLT2 inhibitors and other medications for CKD or HF may determine their place in treatment plans. The synergistic effects of SGLT2 inhibitors with other well-established medications on cardioprotection and renoprotection could be investigated further in patients with heart and kidney diseases.

Conflict of Interest

None declared.

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Publication History

Article published online:
03 March 2025