Advances in Cardiorenal Medicine: The Year 2024 in Review

In 2024, there were a multitude of new developments in the field of cardiorenal medicine with a potential impact on the care of patients with a dual burden of heart and kidney disease. Several studies were published that addressed the knowledge gaps in the management of these patients by exploring the newer classes of medications and trying to expand their indications. In the past year, there has been a remarkable surge in studies investigating glucagon-like peptide 1 (GLP-1) receptor agonists, with more recent research highlighting their benefits across diverse patient populations. Nonsteroidal mineralocorticoid receptor agonists (MRAs) also seem to have traction and continue to show significant cardiorenal benefits. Although sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have already become a cornerstone of therapy for patients with kidney disease, heart failure (HF), and diabetes, they have remained the focus of much investigation in a variety of patient populations. In this article, we summarize some of the key work that impacted the field of cardionephrology in a meaningful way in 2024, thereby setting the stage for more fertile growth and expansion in the future.

The landmark FLOW (Evaluate Renal Function with Semaglutide Once Weekly) randomized controlled trial (RCT) assessed the efficacy and safety of subcutaneous semaglutide in patients with type 2 diabetes and chronic kidney disease (CKD) [1]. Among 1,767 patients in the semaglutide arm, there was a 24% lower risk of major kidney disease events compared to the placebo group. Semaglutide also reduced albuminuria, slowed the annual loss of kidney function, and resulted in an 18% lower risk of major cardiovascular events and a 20% reduction in death from any cause. Of note, the trial was stopped after a median follow-up of 3.4 years based on the recommendation of the data and safety monitoring committee because of the significant efficacy of the drug. This large international trial confirmed the results of several smaller studies and brought GLP-1 receptor agonists to the forefront of the management of diabetic kidney disease.

In a prespecified analysis of the FLOW trial, Pratley et al. [2] explored the effects of semaglutide on HF outcomes. They found that semaglutide was associated with significantly lower HF events or cardiovascular death. Importantly, the effects were consistent regardless of the history of HF (in each arm, 19% of the patients had concomitant HF) [2]. In another prespecified analysis, semaglutide significantly reduced the risk of cardiovascular death, myocardial infarction, and stroke regardless of the baseline CKD severity [3].

With the GLP-1 receptor agonists becoming a key component of the quadruple therapy for diabetic kidney disease along with renin-angiotensin system inhibition, MRA, and SGLT-2i, the order and priority of use of these medications would need scrutiny. A meta-analysis of 3 landmark trials of GLP-1 receptor agonists, including more than 17,000 patients, reported that only 10.2% of the participants with type 2 diabetes were receiving SGLT-2i at baseline [4]. GLP-1 receptor agonists reduced the risk of major adverse cardiovascular events by 21%, with consistent effects in those receiving or not receiving SGLT-2i. Notably, GLP-1 receptor agonists were associated with a lower hospitalization rate in patients with HF. Similarly, the impact on composite kidney outcome and estimated glomerular filtration rate (eGFR) slope did not vary according to SGLT-2i use. Therefore, the current evidence suggests that the cardiorenal benefits of GLP-1 receptor agonists in diabetes are consistent regardless of concomitant SGLT-2i use.

It is expected that GLP-1 receptor agonists remain the focus of intensive investigations in 2025. There are several ongoing studies exploring their roles in a variety of clinical settings related to cardionephrology, such as pulmonary hypertension and myocardial infarction.

MRAs have an established place in the therapy of patients with HF and reduced ejection fraction. The molecular structure of these pharmacological agents is known to modulate the balance between the cardiac anti-remodeling effects and the renal tubular effects of mineralocorticoid blockade [5]. Finerenone, a highly selective nonsteroidal MRA, binds to mineralocorticoid receptors preferentially in the heart. As such, in contrast to the steroidal MRAs (spironolactone and eplerenone), which have higher concentrations in the kidney, it has been proposed to offer significant end-organ protection with a reduced risk of electrolyte disturbances [6]. Previously, it was shown that finerenone can reduce the risk of kidney disease progression and cardiovascular events in patients with CKD and diabetes [7].

In 2024, the results of the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure (FINEARTS-HF) were released [8]. This multicenter RCT, which included 6,001 patients, explored the impact of finerenone in patients with HF and an ejection fraction of 40% or greater. Finerenone was found to significantly reduce the risk of a composite of total worsening HF events and death from cardiovascular causes, with an absolute difference of 2.8 events in 100 patient-years. Given the limited options that have shown benefit in patients with HF and preserved ejection fraction, this finding represents a remarkable advancement; it is expected that it would lead to a change in the class IIb recommendation of the current guidelines for use of MRA in this setting. In the broader context of trials of MRAs in HF, this study completes the picture; now, this class has proven efficacy in patients with HF across the entire spectrum of ejection fractions. It is noteworthy, however, that while the risk of serious adverse events was the same in both arms, increases in creatinine and potassium levels were more common with finerenone than with placebo. Therefore, patients treated with finerenone need to be monitored for kidney function and serum potassium levels.

Since sex-related differences have been observed in several aspects of HF, including its epidemiology and response to therapy, Chimura et al. [9] conducted a prespecified analysis of FINEARTS-HF to compare the impact of finerenone in men and women and found no difference regarding the primary outcome of HF events and cardiovascular death [9]. Another secondary analysis reported that finerenone reduced the primary outcome and improved symptoms across a broad age spectrum [10]. In addition, the investigators found that finerenone was safe and well tolerated in this setting, irrespective of age.

As finerenone offers cardiorenal benefits in patients with CKD and diabetes, BARACK-D (Benefits of Aldosterone Receptor Antagonism in Chronic Kidney Disease) tested the impact of adding its steroidal counterpart, low dose of spironolactone (25 mg/day), in patients with stage-3b CKD [11]. The investigators did not find any difference in death or cardiovascular outcomes between spironolactone and placebo in this RCT that included 1,434 patients with a mean age of 74.8 years. Interestingly, two-thirds of patients randomized to spironolactone stopped treatment within 6 months primarily because of prespecified safety criteria such as worsening renal function or hyperkalemia. Similarly, the Effects of Spironolactone on Kidney Function in Kidney Transplant Recipients (SPIREN) tested the impact of spironolactone on the stabilization of kidney function in kidney transplant recipients treated with calcineurin inhibitors [12]. In this RCT that included 188 patients with a baseline eGFR filtration rate of 51 mL/min, adding spironolactone to standard therapy for 3 years did not improve kidney allograft function, proteinuria, or interstitial fibrosis. As such, current evidence does not support the addition of spironolactone to the treatment of patients with CKD or kidney transplant recipients unless another explicit indication exists.

Finally, the results of the MIRACLE (Mineralocorticoid Receptor Modulator and Sodium-Glucose Cotransporter 2 Inhibitor in HF and CKD) trial were published in 2024. This was an international phase 2 RCT that tested the impact of balcinrenone and dapagliflozin on albuminuria, as a modifiable biomarker of cardiovascular risk, in patients with both HF and CKD [13]. It followed another phase 2 study that had previously reported an additive effect for an aldosterone synthase inhibitor in decreasing urinary albumin excretion, potentially introducing a promising new therapeutic pathway [14]. Balcinrenone, a selective modulator of mineralocorticoid receptor with concomitant partial antagonist activity, was used to see if it can show similar benefits. A total of 133 patients were randomized to receive three different doses of balcinrenone with dapagliflozin or placebo with dapagliflozin for 12 weeks. Unfortunately, the study was stopped early due to slow recruitment, and the authors could not detect an impact on urinary albumin excretion. As such, it remains to elucidate whether a study with a larger number of patients and adequate power would be able to show any benefits for balcinrenone in patients with chronic cardiorenal syndrome.

Although the cardiorenal benefits of SGLT-2i are indisputable, the pathophysiological basis of their effects is largely elusive. In parallel with a significant increase in the use of SGLT-2i over the last few years, a number of studies have been carried out to identify some of the mechanistic pathways of these medications. The SGLT-2 is expressed almost exclusively in the proximal tubules of the kidney and the beneficial effects of its inhibition do not seem to be driven by its antihyperglycemic effects because the outcomes are improved independent of the presence or severity of diabetes. To investigate the cardiorenal effects of SGLT-2i, Rao et al. [15] conducted a mechanistic RCT in patients with stable HF and diabetes by using endogenous lithium as a measure of regional nephron sodium handling. They found that empagliflozin substantially increased sodium delivery to the loop of Henle and distal nephron, and the magnitude of its effect on proximal tubular sodium absorption was larger than expected from inhibition of the SGLT-2 alone (suggesting involvement of sodium hydrogen exchanger 3 [NHE3]). However, natriuresis remained modest with SGLT-2i because sodium exiting proximal tubules was reabsorbed in both the loop of Henle and the distal nephron (acute compensation). Interestingly, urinary sodium excretion waned after 14 days of empagliflozin due to attenuation of sodium exiting the proximal tubule and/or the loop of Henle. Some of the effects of this class of medications may be explained by the above-mentioned changes in intrarenal solute handling (e.g., decrease in plasma volume without activation of RAS and a rise in serum magnesium level). Moreover, increase in erythropoietin and hematocrit due to reduced sodium reabsorption and oxygen tension in the loop of Henle are believed to mediate some of the cardiorenal benefits of SGLT-2i [16].

While the natriuretic effects of SGLT-2i are modest and short-lasting, their glucosuric effect does persist. Marton et al. [17] conducted a mechanistic RCT to study the potential adaptive water conservation response of the kidney to increased urinary glucose excretion. DAPA-Shuttle1 (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment) recruited 29 patients with stable HF who were randomly assigned to receive dapagliflozin or placebo for 4 weeks. The primary endpoint was a change from baseline in urine osmolyte concentration. Although dapagliflozin increased 24-h solute excretion that persisted over time, it had no effect on urine sodium, nor did it change tissue sodium content. As such, the observed early and late increase in solute excretion was almost entirely explainable by glucosuria. Interestingly, within a couple of days, there was an increase in urine solute concentration as well as serum copeptin, indicating that those patients treated with dapagliflozin were able to prevent glucose-driven water loss through increasing copeptin/vasopressin. The study convincingly showed that SGLT-2i triggered water-conservative mechanisms in the kidney, hence countering the osmotic diuresis effects of glucosuria, which led to the stabilization of the urine volume. Importantly, it showed that not only do patients with stable HF exhibit physiologically intact osmotic vasopressin release at baseline but they can also respond to the additional osmotic dehydration challenge of SGLT-2i, hence preventing excessive water loss.

Whether diuretic effects of SGLT-2i attenuate at lower levels of kidney function was the focus of a substudy of EMPA-KIDNEY (Study of Heart and Kidney Protection With Empagliflozin) [18]. Using bioimpedance spectroscopy in 660 patients with CKD (mean eGFR of 36 mL/min), the investigators found that fluid overload (excess of extracellular water) was lower in the empagliflozin arm by 240 mL, which persisted throughout the 18 months of follow-up, irrespective of level of kidney function. The effect did not vary by baseline fluid status or diuretic use, and reports of symptomatic dehydration did not increase during this time.

Finally, the Dapagliflozin in Patients With Critical Illness (DEFENDER) trial explored the impact of SGLT-2i use in critically ill patients with acute organ dysfunction [19]. In this RCT, including 507 patients admitted to the intensive care unit with at least one organ dysfunction, the investigators used dapagliflozin, 10 mg/day, for 14 days or until discharge from the intensive care unit. The addition of dapagliflozin to standard therapy was not associated with improvement in mortality, use of kidney replacement therapy, or length of stay in the intensive care unit. Therefore, although the preliminary results of SGLT-2i in specific acute settings (i.e., myocardial infarction and acute HF) have been promising, its use in critically ill patients would need more investigation. Table 1 summarizes the key studies of these classes of medications.

In clinical practice, impairment of kidney function remains a frequent barrier to the full implementation of HF standard of care. Neprilysin inhibition is the cornerstone of therapy in patients with HF and reduced ejection fraction. Whether the treatment response will be modified by kidney-related parameters (eGFR and albuminuria) was evaluated in a post hoc analysis of the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial [20]. Based on the Kidney Disease Improving Global Outcomes (KDIGO) risk stratification, the investigators found that 26% of the 1,910 patients with available kidney-related data were classified at “high” or “very high” risk. Interestingly, the cardiovascular and kidney protective benefits as well as the safety profile of sacubitril/valsartan were persistent across all KDIGO risk categories, hence supporting the initiation of this medication in patients with HF across a broad spectrum of kidney risk.

Current HF guidelines identify an eGFR of <30 mL/min as a contraindication for neprilysin inhibitors. In a post hoc analysis of PARADIGM-HF and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) trials, the investigators assessed the safety and efficacy of continuing sacubitril/valsartan in patients with deterioration of kidney function below an eGFR of 30 mL/min [21]. Out of over 13,000 patients included in both trials, 1,304 had an eGFR of <30 mL/min at least once during follow-up. Although these patients identified a higher cardiovascular and renal risk group, the incidence of the primary outcome still remained lower with sacubitril/valsartan compared with RAS inhibitors. As such, the authors concluded that continuation of the neprilysin inhibitor in patients experiencing deterioration of GFR to less than 30 mL/min is associated with persistent clinical benefits and no increment safety risk.

In 2022, the landmark multinational STRONG-HF (Safety, tolerability and efficacy of uptitration of guideline-directed medical therapies for acute heart failure) RCT showed that, compared with usual care, a high-intensity care strategy (i.e., early uptitration of guideline-directed medical therapy) improves outcomes in acute HF (i.e., HF readmission or all-cause mortality at 6 months) [22]. In order to assess whether the benefits of high-intensity care are similar across various cardiovascular risk groups, Ambrosy et al. [23] applied MAGGIC (Meta‐Analysis Global Group in Chronic) HF risk score to the patient population included in STRONG-HF and reanalyzed the data. MAGGIC provides a simple yet powerful approach to risk stratification of patients for HF-related morbidity and mortality based on 13 readily available clinical variables such as age, sex, and serum creatinine. They found that a high-intensity care strategy led to better adherence to guideline-directed medical therapy during follow-up and lower HF-related morbidity and mortality compared with usual care across a wide range of MAGGIC risk scores. These results lend further support to the notion of promptly implementing and uptitrating the standard of care therapy in patients hospitalized with acute HF.

In addition to the above-mentioned themes that were addressed in 2024, there were several important articles that tried to answer a number of clinical questions related to cardionephrology. Here is a selected summary:

Although patients with CKD are at high risk of cardiovascular disease, they have generally been underrepresented in cardiovascular RCTs, potentially creating evidence gaps to guide cardiovascular risk management in these patients. To further explore the representation of patients with CKD, Colombijn et al. [24] identified all RCTs of cardiovascular medications (e.g., cholesterol-lowering drugs, antithrombotics, and blood pressure-lowering drugs) that were conducted between 2000 and 2021. They observed that among 1,194 RCTs involving more than 2.2 million participants, 74% of the RCTs have excluded patients with CKD; interestingly, this number seems to have increased over the past years (from 66 to 79%). Only 2% of these studies reported results for patients with an eGFR of less than 30 mL/min. This systematic review highlights the fact that the representation of patients with CKD in cardiovascular RCTs is low and has not improved over the past 2 decades. The complexity of extrapolating results to patients with CKD was previously illustrated by statin use, where these medications reduced cardiovascular risk in patients with an eGFR of less than 60 mL/min but failed to show effectiveness in those with kidney failure [25].

In 2022, the multicenter STOP-ACEi trial, which included 403 patients, showed that discontinuation of RASi does not change the rate of decline in kidney function or development of end-stage kidney disease in patients with advanced CKD [26]. Since angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) possess important different biological properties the investigators set out to report the effect of withdrawing ARB or ACEI separately in STOP-ACEi participants in a post hoc analysis [27]. They found that while discontinuation of both classes did not lead to a clinically relevant difference in eGFR at 3 years, more patients who discontinued ACEI, but not ARB, progressed to end-stage kidney disease. It is important to note that the observed difference may be related to the small sample size, but in general, the results lend support to the findings of the original study, implying that in patients with advanced and progressive CKD, discontinuation of either of these two classes does not have any kidney-related benefit and does not increase the dialysis-free time.

While several studies have previously tried hypertonic saline in patients admitted with acute HF with promising results, its use has not been studied in ambulatory patients who present with worsening HF as a means to avoid hospitalization. The Efficacy and Safety of Hypertonic Saline Therapy in Ambulatory Patients with Heart Failure (SALT-HF) trial was a multicenter RCT that evaluated the feasibility, safety, and efficacy of adding hypertonic saline to intravenous furosemide in ambulatory patients with worsening HF and fluid overload [28]. In this study, which included 167 patients, the patients were randomized to receive furosemide alone or furosemide with 10–15 mL of 20% sodium chloride. Interestingly, hypertonic saline did not result in an increased diuresis or natriuresis within 3 h of administration, and patients did not experience a significant decrease in weight compared to the furosemide-alone group. No difference was observed at 7 and 30 days, nor in safety measures such as worsening kidney function. The relatively small sample size and the methodology (e.g., measurement of urine sodium and diuresis only 3 h after one single administration) may have affected the results of this study.

Congestion is the primary reason for admission of patients with HF and is the driver of outcomes. A variety of strategies have been tested to efficiently address fluid overload in these patients (e.g., stepped pharmacologic therapy and extracorporeal ultrafiltration). The Peritoneal Ultrafiltration in Cardiorenal Syndrome (PURE) (NCT03994874) is a phase II multicenter unblinded RCT designed to evaluate the safety and efficacy of using an investigational solution, the PolyCore [29]. The study population consists of patients with HF who present with refractory congestion for 3 months despite appropriate therapy. They will be treated with peritoneal ultrafiltration using PolyCore, a glucose-free hypertonic solution that includes polydextrin 4%, for 6 months (a single 2-L dwell nightly exchange for 8–14 h, 4–7 nights a week). The control arm will continue to receive guideline-directed medical therapy. The primary endpoint of the study is a composite of mortality and hospitalization for cardiovascular causes. The plan is to enroll a total of 84 patients to allow an 80% power in this trial, which is scheduled to be completed in early 2026.

In 2024, significant advancements were made in the field of cardiorenal medicine, highlighting its promising future. Efforts were made to expand HF and cardiorenal therapies and redefine their boundaries by exploring new medications and testing the existing therapies with broadened indications. In 2025, patients with CKD, HF, and diabetes will have an increasing number of options as it relates to efficacious medical management with a proven salutary impact on the outcomes. From a practical standpoint, the results of these studies have helped patients with background therapies to know which medications are likely to be beneficial if added to their current regimen. Moreover, guidelines are evolving to not only include these new data and expand the previous indications of these agents but also to explore whether the order in which they are used is of clinical relevance to the patients. Notably, several high-impact clinical trials that were published in 2024 foster evidence-based, multidisciplinary care for this high-risk patient population. In light of the rapidly evolving field, innovative clinical care models would be needed to facilitate the implementation of these therapies and address the complexities inherent to these clinical settings. The development of an advanced cardiorenal unit and the creation of a coalition of clinicians and researchers in the field (e.g., the International Cardiometabolic Working Group) are among these efforts suggested by experts in the past year [30, 31].

None of the authors has any relevant conflict of interest.

No funding has been received for preparation of this article.

A.K. has crafted the initial draft. C.R. has provided critical revisions and additions.