Chronic kidney disease (CKD) is defined as decreased kidney function (GFR <60mL/min per 1.73m2), or by markers of kidney damage, or both, for at least 3 months. While many conditions can lead to CKD, hypertension, and diabetes are the main causes globally.1,2 Around 800 million individuals globally have CKD.3 The prevalence of CKD is steadily rising over time, now affecting about 10% of people worldwide. There is an increase in the prevalence of CKD which makes it a major public health issue that requires attention.4 The first-line medications for treating individuals with CKD are angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). It has been demonstrated that the use of ACEI or ARBs has a greater impact on reducing proteinuria and delaying the course of renal disease than placebo treatment. The effectiveness of ARB and ACEI is comparable.5 In recent years, several clinical trials have demonstrated the effectiveness of various medications for kidney protection. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are among these drugs.6–9

SGLT2i were initially proposed as glucose-lowering and weight-lowering drugs in patients with type 2 diabetes mellitus (DM).10,11 SGLT2i reduces the reabsorption of filtered glucose from the tubular lumen, decreases the renal threshold for glucose (RTG), and promotes urinary glucose excretion by inhibiting the activity of SGLT2 proteins that are located in the proximal convoluted tubules of the kidneys.12–14 However, recent cardio-renal trials have demonstrated that the benefits of SGLT2i go beyond managing type 2 DM. These medications are effective in preventing cardiovascular events and slowing the progression of CKD.14,15 One of these trials is the DAPA-CKD trial, which concluded that compared to a placebo, dapagliflozin significantly reduces the risk of a composite outcome in patients with CKD, regardless of DM status. This includes a persistent reduction in estimated glomerular filtration rate (eGFR) of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes.7

Aldosterone expedites the progression of chronic renal disease.16,17 Aldosterone exerts harmful effects through many mechanisms, including inflammation and fibrosis, which culminate in glomerular, tubulointerstitial, and vascular damage to the kidney.18 The recent discovery of aldosterone inhibitors such as non-steroidal mineralocorticoid receptor antagonists (MRAs) represents a significant advancement in cardio-renal disease treatment.8,9 Similar to steroidal MRAs, non-steroidal MRAs have positive effects on inflammation, remodeling, and fibrosis in the kidneys, heart, and vasculature. However, non-steroidal MRAs distribute equally between the kidneys and heart, showing better suppression of mineralocorticoid receptor (MR) co-regulator recruitment and fibrosis than steroidal MRAs.19,20 Recent trials, including FIGARO-DKD and FIDELIO-DKD, disclosed that finerenone reduced the risk of cardiovascular and major kidney events in patients with type 2 DM and CKD.9,21 Additionally, aldosterone synthase inhibitors directly reduce aldosterone synthesis, potentially increasing treatment efficacy.18,22

We designed this systematic review and meta-analysis to study the safety and efficacy of SGLT2i and aldosterone inhibitors either MRAs or aldosterone synthase inhibitors combination in CKD. Additionally, we aimed to check whether this dual therapy is superior to either agent alone.

This systematic review and meta-analysis included three randomized controlled trials assessing the effect of SGLT2i and aldosterone inhibitors combination versus SGLT2i monotherapy and aldosterone inhibitors either MRAs or aldosterone synthase inhibitors monotherapy in CKD. The mean age range of participants ranged from 61.8 to 65.8 years, majority of participants were male (69.9%) and white ethnicity (63.09%). Pooled analysis showed that the combination therapy (SGLT2i+aldosterone inhibitors) has significant improvements compared to SGLT2i alone or aldosterone inhibitors for both 30% and 50% reductions in UACR. Combination therapy showed a significant reduction of UCAR and eGFR compared to SGLT2i alone, but no significant difference when compared to aldosterone inhibitors alone. There is also a significant reduction with combination therapy compared to both SGLT2I alone and aldosterone inhibitors alone. On the other hand, the combination therapy significantly increased the risk of hyperkalemia compared to SGLT2i alone. The low heterogeneity suggests that the included studies had consistent findings. However, no significant difference in hyperkalemia incidence was observed between the combination therapy and aldosterone inhibitors. The results are associated with moderate heterogeneity that indicates some variation among the studies; this may be a result of different types of aldosterone inhibitors, such as MRAs, either steroidal or non-steroidal, and aldosterone synthase inhibitors. According to the hyperkalemia, there is no significant difference in the incidence of potassium levels >5mmol/L observed between the combination therapy and SGLT2i. However, the combination therapy was associated with a significantly lower risk of potassium levels >5mmol/L compared to MRAs, suggesting it may be a safer option in terms of severe hyperkalemia risk. Meanwhile, no significant difference between combination therapy and either SGLT2i alone or aldosterone inhibitors alone. That indicates the combination therapy appears to be well-tolerated, with no significant increase in serious or overall adverse effects compared to monotherapy with either SGLT2i or aldosterone inhibitors.

According to our results, the combination of SGLT2i and aldosterone inhibitors has a potential synergistic effect in managing albuminuria, which is a marker of kidney damage. Our results are consistent with the results of Provenzano et al., who reported the combination of dapagliflozin (SGLT2i) and eplerenone (MRA) had a greater albuminuria-lowering effect than either drug alone in patients with CKD.23,29 The combination therapy also shows promise in reducing systolic blood pressure, which could have additional cardiovascular benefits. This is consistent with the results of the same trial that also found that the combination therapy resulted in a significant reduction in SBP compared to MRA alone.29 While the combination therapy showed a significant reduction in eGFR compared to SGLT2 inhibitors alone, this difference was not observed when compared to aldosterone inhibitors alone. The clinical significance of this finding needs further investigation. These results are consistent with the results of Rossing et al. and Provenzano et al.29,30 According to hyperkalemia, the absence of a significant difference between the combination and the aldosterone inhibitors is consistent with the results of Tuttle et al. that the hyperkalemia manifested at a frequency characteristic of a chronic kidney disease cohort; however, the majority of instances did not necessitate medical intervention or the cessation of BI 690517 (a potent, highly selective aldosterone synthase inhibitor).28 However, the combination has a significantly higher risk of hyperkalemia compared to the SGLT2i. Therefore, clinicians should be cautious about hyperkalemia risk when prescribing combination therapy, particularly when comparing it to SGLT2i alone. The choice between combination therapy and aldosterone inhibitors should consider individual patient risks, as combination therapy may reduce the likelihood of severe hyperkalemia. Further studies with larger sample sizes and standardized methodologies are needed to confirm these findings and clarify the clinical significance of potassium level changes.

Experimental studies and secondary analyses from large clinical outcome trials have suggested that SGLT2i and MRAs have complementary biological mechanisms of action that may result in significant reductions in albuminuria and clinically meaningful reductions in kidney outcomes. Empagliflozin and finerenone combination therapy produced a synergistic anti-albuminuric effect and enhanced survival compared with either medication alone, according to a preclinical rat trial in a model of cardio-renal illness.32 It is of great importance to determine the fundamental biological mechanisms that govern the response of each individual to treatment. To better customize therapy, future research may shed more light on the specific biological pathways and biomarkers that predict each patient's reaction to a certain medicine.

This is the first systematic review and meta-analysis conducted to assess the safety and efficacy of SGLT2i and aldosterone inhibitors combination on patients with CKD. Our study provides promising results in the treatment of CKD and in reducing the disease progression. The included studies are low risk of bias.

The analysis is based on only three studies, with a small sample size, which limits the generalizability of the findings. There was significant heterogeneity in some of the analyses, particularly for changes in UACR and SBP, which suggests variability in the results across studies. Additionally, different types of aldosterone inhibitors, such as MRAs and aldosterone synthase inhibitors, are a major source of heterogeneity. Therefore, more head-to-head randomized controlled trials are needed to directly compare the efficacy and safety of SGLT2i and aldosterone inhibitor combinations versus each drug separately in CKD patients. We also need more RCTs that assess the effects of the combination for longer-term durations of follow-up. The metabolic acidosis was not assessed or reported in the trials included in this review, representing a notable limitation. This omission is clinically relevant, as metabolic acidosis can significantly influence potassium homeostasis by promoting extracellular potassium shifts and impairing renal potassium excretion. While the combination of SGLT2 inhibitors and MRAs was associated with a higher incidence of hyperkalemia across various MRA doses, this effect appeared to be independent of bicarbonate levels. The lack of data on acid-base status limits the ability to fully interpret the mechanisms underlying hyperkalemia in these patients. Future studies should consider evaluating metabolic acidosis and bicarbonate levels to better understand their potential contribution to electrolyte disturbances during combination therapy. While the results are promising, more research is needed to establish the long-term efficacy and safety of this combination therapy before it can be widely recommended in clinical practice.

The combination of SGLT2 inhibitors and aldosterone inhibitors may offer a promising approach for managing albuminuria and potentially slowing the progression of kidney disease in patients with CKD. Clinicians should be cautious about hyperkalemia risk when prescribing combination therapy. However, larger and longer-term studies are needed to confirm these findings and assess the impact on hard clinical outcomes such as progression to end-stage renal disease or cardiovascular events.

RS and AWH: conceptualization, validation, data curation, and original draft preparation. AKA, AH, ME, and KL: methodology. RS, LM, MA, WN, GEA, and SM: writing. RS and EIB: supervision. RS, AA, and AA: writing – reviewing and editing.

Not applicable.

Not applicable.

This research received no specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

The authors declare no competing interest.