Sodium-glucose cotransporter-2 inhibitors beyond glycemic control: Their role in acute kidney injury recovery

Abstract

With notable Reno protective advantages beyond glycemic management, sodium-glucose cotransporter-2 (SGLT2) inhibitors have become a mainstay treatment for type 2 diabetes mellitus and chronic kidney disease (CKD). Although SGLT2 inhibitors' involvement in the course of CKD has been well investigated, new research indicates that they may also have protective benefits in acute kidney injury (AKI), a condition for which there are few pharmacological treatments. The possible ways that SGLT2 inhibitors aid in AKI recovery are examined in this mini-review. These include mitochondrial protection, oxidative stress attenuation, anti-inflammatory effects, intraglomerular pressure decrease, and modulation of tubuloglomerular feedback. Although there is a lack of solid clinical trial data, preclinical models and observational studies suggest that SGLT2 inhibitors may lessen ischemia-reperfusion injury and contrast-induced nephropathy. This review addresses the possibility of incorporating SGLT2 inhibitors into AKI care regimens, critically evaluates the available data, and highlights important research gaps. Robust clinical trials are required to determine the safety, effectiveness, and ideal treatment window of SGLT2 inhibitors in this context, given the burden of AKI-related morbidity and mortality.

Key Words: Sodium-glucose cotransporter-2 inhibitors; Acute kidney injury; Renal protection; Ischemia-reperfusion; Oxidative stress; Tubuloglomerular feedback

Core Tip: Sodium-glucose cotransporter-2 (SGLT2) inhibitors, traditionally used for glycemic control in type 2 diabetes, show emerging promise in acute kidney injury (AKI) recovery through mechanisms such as oxidative stress reduction, anti-inflammatory effects, improved mitochondrial function, and hemodynamic modulation. Although encouraging data from preclinical and observational studies exist, robust randomized controlled trials are lacking. This mini-review synthesizes current evidence, evaluates its quality, summarizes ongoing clinical trials, and highlights priority areas for future research to guide the safe and effective integration of SGLT2 inhibitors into AKI management.

INTRODUCTION

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, are the United States Food and Drug Administration (FDA)-licensed drugs for controlling type 2 diabetes mellitus. These include canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. They lower blood glucose levels by suppressing glucose and sodium reabsorption in the proximal tubule. Beyond glycemic control, SGLT2 inhibitors offer major benefits in patients with chronic kidney disease (CKD) and cardiovascular disease. They help reduce kidney damage, slow disease progression, and improve heart failure outcomes. Further effects include improved glomerular hemodynamics, diminished inflammation, and better fluid balance, making them important in managing complications in high-risk diabetic patients[1].

Acute kidney injury (AKI) impacts approximately 13%-18% of hospitalized patients worldwide, with even more rates seen in intensive care units and following cardiac surgery. Its frequency is increasing, notably among the elderly and individuals with severe conditions such as hypertension and diabetes. AKI is correlated with more mortality, progression to CKD, and notable healthcare expenses. Early detection and regulation are crucial to reduce AKI-related morbidity and improving outcomes, especially in resource-limited settings[2]. In AKI, pharmacological treatments are crucial for avoiding further renal damage, managing underlying causes, and optimizing fluid and electrolyte balance. Proper medication management can alleviate nephrotoxic effects, reduce complications, and support renal recovery. Timely pharmacotherapy ensures appropriate drug dosages, especially for renally eliminated drugs, reducing the risk of toxicity and improving patient outcomes[3].

Emerging evidence suggests SGLT2 inhibitors may help AKI beyond glycemic control. A recent meta-analysis in heart failure patients reveals potential renal benefits, but findings remain uncertain[4]. There is a clear need for large-scale randomized controlled trials (RCTs) to confirm efficacy and elucidate underlying mechanisms in AKI management.

PATHOPHYSIOLOGY OF ACUTE KIDNEY INJURY

The Kidney Disease: Improving Global Outcomes (KDIGO) consensus states AKI as a clinical syndrome marked by a rapid decline in kidney function, typically indicated by a rise in serum creatinine and/or a reduction in urine output. AKI is divided into three stages: Stage 1 with serum creatinine elevation of ≥ 0.3 mg/dL or 1.5-1.9 times baseline, Stage 2 with 2.0-2.9 times baseline, and Stage 3 with ≥ 3.0 times baseline or renal replacement therapy[5].

The etiology of AKI in critically ill patients is multifactorial, commonly involving hypervolemia, sepsis, medications, and hemodynamic imbalance, with sepsis being the leading reason. AKI is classified as prerenal, postrenal, or intrarenal on the basis of the location of underlying physiological impairment. Prerenal AKI caused from less blood flow to the kidneys, frequently resulted by volume depletion, decreased cardiac output, or vasoconstriction. This form is typically transient if promptly identified and treated. Postrenal AKI arises by urinary tract obstruction, causing intratubular pressure, reducing glomerular filtration rate (GFR), and disturbing nephron function. Obstruction can occur anywhere along the tract. Ultrasound signs like hydronephrosis or post-void residual > 100 mL suggest this type. Intrarenal AKI results from frequent direct kidney injuries, due to ischemia or nephron-toxins, causing reduced GFR, tubular damage, and oliguria, especially in vulnerable patients[6].

Tubular injury and necrosis are central to AKI, especially in acute tubular necrosis, which is often stimulated by ischemia or nephron-toxins. Ischemia decreases kidney perfusion, causing cell damage and tubular death, while nephrotoxic agents directly damage tubular epithelial cells. Inflammatory responses and oxidative stress further worsen injury, as damaged cells release reactive oxygen species, causing mitochondrial dysfunction, and inflammation, and increased intra-glomerular pressure—ultimately impairing kidney function. This also contributes to endothelial damage, micro-vascular injury, and reduced renal blood flow. Early biomarkers like neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) help in early detection, with NGAL rising quickly post-injury and KIM-1 indicating proximal tubule damage[7].

SGLT2 INHIBITORS: MECHANISM OF ACTION

Glucose freely filters from the plasma through the glomerulus and is then completely reabsorbed in the proximal tubule. By the time the filtrate reaches the end of the proximal tubule, no glucose remains in the tubular fluid. Most of the filtered glucose is reabsorbed in the S1 and S2 segments by the SGLT2 transporter. Glucose enters the tubular cells from the lumen via SGLT transporters located on the luminal membrane, a process driven by the sodium electrochemical gradient. Once inside the epithelial cells, glucose exits into the bloodstream through GLUT2 transporters on the basolateral membrane. The sodium gradient essential for this process is maintained by the Na⁺/K⁺ pump, also located on the basolateral membrane. Overall, this mechanism results in the reabsorption of both glucose and sodium from the filtrate produced by the glomerulus[8].

SGLT2 inhibitors are medications used to lower blood glucose levels. They work by promoting the excretion of excess glucose in the urine (a glucosuric effect) along sodium ions, achieved by blocking the reabsorption of glucose and sodium from the kidney filtrate, thereby producing a natriuretic effect. A primary mechanism involves tubule-glomerular feedback, where SGLT2 inhibitors increase the delivery of sodium to downstream segments of the nephron. This rise in sodium is detected by macula densa cells, which signal through adenosine to constrict the afferent arterioles. This constriction lowers intraglomerular pressure, helping to protect the glomeruli. Additionally, SGLT2 inhibitors enhance oxygenation and metabolic function in the renal tubules, while reducing inflammation and fibrosis within the kidneys[9]. Figure 1 proposed renoprotective mechanisms of SGLT2 inhibitors in AKI recovery.

Figure 1 Reno-protective mechanism of sodium-glucose cotransporter-2 inhibitors in acute kidney injury recovery current clinical evidence on sodium-glucose cotransporter-2 inhibitors in acute kidney injury. ROS: Reactive oxygen species; AMPK: Adenosine monophosphate-activated protein kinase; SIRT1: Silent information regulator sirtuin 1; IL-5: Interleukin-5; IL-18: Interleukin-18; HsCRP: High sensitivity C-reactive protein; TNF-α: Tumour necrosis factor alpha; SGLT2: Sodium-glucose cotransport protein 2.

POTENTIAL ROLE OF SGLT2 INHIBITORS IN AKI RECOVERY

Hemodynamic shifts that are brought by SGLT2 inhibitors use contribute to the kidney-protective benefits including:

Reduced workload on proximal tubular cells and prevention of abnormal increases in glycolysis help lower the risk of AKI. SGLT2 inhibitors also decrease intraglomerular pressure through the activation of tubuloglomerular feedback, along with reductions in blood pressure and tissue sodium levels. Furthermore, they activate nutrient-sensing pathways similar to those triggered by fasting, which promote ketone production, enhance autophagy, and restore mitochondrial carbon metabolism without generating harmful reactive oxygen species[10].

Sodium-glucose cotransporter 2 inhibitors have been shown to reduce circulating inflammatory markers. Their use is linked to lower serum levels of high-sensitivity C-reactive protein, a key indicator of chronic low-grade inflammation. Additionally, SGLT2 inhibitors therapy is associated with reduced levels of several proinflammatory cytokines in the blood, including interleukin-6, interleukin-1β, interleukin-18, tumor necrosis factor α, tumor necrosis factor receptor 1, and interferon-λ. These inflammatory mediators are known contributors to the development and progression of diabetic vascular complications. SGLT2 inhibitors reduce pro-inflammatory cytokine levels and suppress NLRP3 inflammasome activity in individuals with type 2 diabetes. Several experimental studies have shown that SGLT2 inhibitors have anti-inflammatory properties, including a reduction in macrophage recruitment. Oxidative stress is one of the main drivers of macrophage changes in AKI in diabetes. SGLT2 inhibitors play a pivot role in attenuation of this stress[11].

SGLT2 inhibitors exhibit two notable effects: They stimulate ketogenesis, resembling a fasting state, and induce erythrocytosis, mimicking a response to low oxygen levels. In conditions of nutrient scarcity, cells activate key metabolic sensors such as silent information regulator sirtuin 1 (SIRT1) and adenosine monophosphate-activated protein kinase. Activation of SIRT1 helps suppress inflammasome activity and supports mitochondrial function and integrity. Additionally, SGLT2 inhibitors enhance mitochondrial biogenesis in both the heart and kidneys, contributing to improved cellular energy balance and organ function.SGLT2 inhibitors decrease intraglomerular feedback as more sodium reaches at macula densa and thus there is decrease in intraglomerular pressure in response to it[12].

Percutaneous procedures that involve the use of contrast agents are widely used for the diagnosis and treatment of cardiovascular diseases. These contrast agents can lead to nephropathy, particularly in individuals with diabetes. Due to the direct toxic effects of contrast agents, increased risk of blood clot formation, ongoing inflammation, and reduced kidney blood flow, patients undergoing percutaneous coronary intervention for acute myocardial infarction (AMI) face a heightened risk of developing contrast-induced AKI. The nephron-protective effect of SGLT2 inhibitors has been reported in patients with CKD, defined by a reduction of the GFR and albuminuria[13]. An analysis of 16 RCTs, including 25172 patients with heart failure, showed that using SGLT-2 inhibitors lowered the chance of developing AKI by 28% when compared to a placebo. This benefit came without a notable increase in the risk of low blood pressure or fluid loss. The reduction in AKI risk was particularly evident among certain groups: Patients with reduced ejection fraction, those taking empagliflozin or dapagliflozin, participants in studies lasting a year or more, and individuals aged 65 and above[14].

CURRENT CLINICAL EVIDENCE ON SGLT2 INHIBITORS IN AKI

The use of SGLT2 inhibitors in AKI has been studied due to their potential to improve the renal outcomes beyond glucose regulation. SGLT2 inhibitors like canagliflozin have been shown in preclinical studies to offer protective advantages in animal models of ischemic-reperfusion damage. These studies revealed a significant reduction in tubular injury and renal cell apoptosis, indicating that SGLT2 inhibitors play a role in preventing renal cell death during AKI. Especially, Canagliflozin was shown to reduce cisplatin-induced nephrotoxicity in animal studies by decreasing tubular cell apoptosis and promoting autophagy, a key mechanism for cellular repair mechanism[13].

Human observational studies also contributed valuable insights into the potential role of SGLT2 inhibitors in managing AKI. A large population based cohort study reported that initiation of SGLT2 inhibitors in older patients with type 2 diabetes significantly reduce 90 days risk of AKI compared to conventional glucose control therapies. This result emphasizes the Reno-protective effect and safety of SGLT2 inhibitors in clinical routine[14]. Several ongoing clinical trials are investigating the role of SGLT2 inhibitors in the recovery from AKI. The RECOVER-AKI Trial (phase II) is specifically evaluating the impact of Dapagliflozin on patients with AKI. Preliminary results suggest, Dapagliflozin has a favorable safety profile but its efficacy in improving AKI outcomes is still inconclusive[15].

Despite encouraging preclinical and observational results, there are significant gaps in current evidence. A major gap in literature is the absence of large-scale RCTs. Many existing studies relying only on small sample sizes and heterogeneous patient populations, making it challenging to generalize results of these studies. Furthermore, the rapid onset and complex pathophysiology of AKI present significant challenges for conducting comprehensive RCTs in this specific patient group. Table 1 summary of evidence and research quality evaluation for studies on SGLT2 inhibitors in AKI.

Table 1 Summary of evidence and research quality evaluation for studies on sodium-glucose cotransport protein 2 inhibitors in acute kidney injury.

No.	Trial name	Phase	Drug	Inclusion population	Primary endpoints	Expected completion date
1	Recover-AKI	II	Empagliflozin	Patients with AKI	AKI recovery and MAKE365	Late 2025
2	Defender	III	Dapagliflozin 10 mg	Patients with acute organ dysfunction in ICU	Hospital mortality, use of kidney replacement therapy, ICU stay	Completed 2023
3	Discover pilot	III	Dapagliflozin 10 mg	Patients post AKI recovery	Renal functions after 12 weeks	Expected approximately 2025
4	Prevents-AKI	III	Dapagliflozin 10 mg	Patient in ICU at risk of AKI	Incidence of new and worsening AKI	Expected approximately 2027
5	CI AKI prevention (NCT04853615)	II	Empagliflozin 25 mg	Diabetic CKD patients undergoing contrast procedures	Incidence of contrast induced AKI in diabetic kidney	Approximately 2025-2026 (unknown status)
6	DAPA-PCI-AKI	IV	Dapagliflozin 10 mg	Patients undergoing coronary angioplasty at risk of AKI	Incidence of AKI post percutaneous coronary intervention	Expected 2025
7	JAMA network open study	Cohort study	SGLT2 inhibitors	Patients with type 2 diabetes and AKD	Mortality and MAKE in T2D patients with AKD	Completed 2024

AKI: Acute kidney injury; MAKE365: Major adverse kidney events; SGLT2: Sodium-glucose cotransport protein 2; CKD: Chronic kidney disease; ICU: Intensive care unit; CPI: Percutaneous coronary intervention; JAMA: Journal of the American Medical Association; DAPA: Dapagliflozin; CI: Confidence interval.

CHALLENGES AND CONCERNS

Besides the promising preclinical and observational results, several challenges hinder the clinical application of SGLT2 inhibitors in AKI management. A major concern is increased risk of hypervolemia, SGLT2 inhibitors increase urinary excretion and induce osmotic diuresis which can result in volume depletion and hypotension. These adverse events usually occur in susceptible individuals taking SGLT2 inhibitors[16]. SGLT2 inhibitors are also prescribed for conditions beyond type 2 diabetes, which involves insulin deficiency that worsens ketonemia even though blood glucose remains normal and increased risk of euglycemic diabetic ketoacidosis[17]. There is currently no FDA or expanded access program of FDA approval for SGLT2 inhibitors use in AKI management while dapagliflozin-CKD trial reported renal protective effects of SGLT2 inhibitors only in chronic kidney patients[18]. Additionally, the lack of standardized dosing guidelines and large scale conclusive trials for use of SGLT2 inhibitors in AKI management are the regulatory barriers in their integration into clinical practice.

To optimize the clinical application of SGLT2 inhibitors (SGLT2i) in the context of AKI, several important research questions need to be addressed: (1) What is the ideal timing for initiating SGLT2i therapy in patients with ICU-acquired AKI? Should therapy be started early during AKI onset, or does a delayed initiation result in better renal recovery and clinical outcomes? (2) What are the long-term effects of SGLT2i use during episodes of AKI? How does SGLT2i administration impact the risk of progression to CKD and long-term cardiovascular outcomes? (3) Should SGLT2i dosing be adjusted according to AKI severity or residual renal function? Is there a clinical benefit in modifying the dose based on KDIGO staging (Stages 1-3) or on the extent of preserved kidney function? (4) How do individual SGLT2 inhibitors compare in terms of renoprotective effects during AKI? Among empagliflozin, dapagliflozin, and canagliflozin, which agent demonstrates superior efficacy in supporting renal recovery? and (5) What is the safety and efficacy of combining SGLT2 inhibitors with other nephroprotective therapies during AKI? Can co-administration with other agents enhance therapeutic outcomes, and what are the associated risks?

CONCLUSION

SGLT2 inhibitors have emerged as promising agents with reno-protective effects expanding beyond glycemic control. Their potential in AKI recovery lies in their ability to lower oxidative stress, modulate inflammation, and enhance mitochondrial and hemodynamic function. Preclinical and observational studies provide encouraging data on their efficacy in mitigating renal damage and promoting recovery. Nevertheless, despite these findings, the absence of robust RCTs and regulatory approvals limits their clinical application in AKI management. Future research should focus on large-scale RCTs to determine efficacy, safety, optimal dosing, and timing to fully integrate SGLT2 inhibitors into AKI treatment paradigms.