Chronic kidney disease (CKD) poses a significant global health challenge by contributing to elevated morbidity, mortality, and healthcare costs. Cardiovascular (CV) disease remains the leading cause of death among CKD patients, while conventional therapies have shown limited efficacy in slowing renal function decline or reducing CV events in this group. Over the past decade, sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as a novel therapeutic class that was initially introduced for glycemic control in patients with type 2 diabetes mellitus (T2DM). Beyond their glucose-lowering effects, these agents have demonstrated remarkable benefits in reducing hospitalizations for heart failure (HF) and decelerating renal disease progression. Large randomized controlled trials (RCTs) have firmly established the role of SGLT2 inhibitors in patients at high CV risk. Nevertheless, the generalizability of these findings to individuals with moderate to advanced CKD remains uncertain because many landmark studies excluded patients with severely impaired kidney function. More recent dedicated trials involving CKD populations have addressed this gap, establishing SGLT2 inhibitors as a cornerstone in kidney disease management. This review examines the clinical evidence supporting SGLT2 inhibitors in both general and CKD-specific populations, offering practical insights for their application in nephrology.

SGLT2 inhibitors are orally administered agents that are primarily absorbed in the gastrointestinal tract. They undergo minimal hepatic metabolism and are largely excreted unchanged via the kidneys. Their pharmacodynamic effects are dose-dependent and correlate with renal glucose filtration [1–3]. The primary mechanism involves the inhibition of SGLT2 in the proximal convoluted tubules of the nephron. By blocking this transporter, the drugs reduce the reabsorption of filtered glucose, thereby promoting glucosuria and mild natriuresis [1–3]. Although the glucose-lowering effect diminishes as kidney function declines, SGLT2 inhibitors maintain renal and CV protective mechanisms independent of glycemic control. These benefits include improved tubuloglomerular feedback, reduced intraglomerular pressure, modulation of inflammatory and fibrotic pathways, and enhanced myocardial metabolism [1–3].

Several large-scale RCTs have demonstrated the efficacy of SGLT2 inhibitors in improving CV and renal outcomes across various patient populations. The EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial enrolled 7,020 patients with T2DM and established CV disease, reporting a 14% relative risk reduction in major adverse CV events (MACE) and a 35% decrease in HF hospitalizations [1]. Similarly, the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program—pooling data from two trials and involving over 10,000 participants—demonstrated a significant reduction in CV events along with a slower progression of albuminuria [2]. The DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) trial, which included more than 17,000 patients, confirmed the benefit of dapagliflozin in reducing HF hospitalizations, although its effect on MACE was more modest [3]. In the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, dapagliflozin 10 mg significantly reduced MACE—including worsening HF, CV death, and all-cause mortality—in patients with symptomatic HF and reduced left ventricular ejection fraction compared to placebo [4]. These trials primarily excluded individuals with advanced CKD, thereby prompting the need for dedicated renal studies.

The CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial was the first dedicated study of renal outcomes, enrolling 4,401 patients with T2DM and CKD [5]. In this trial, canagliflozin reduced the composite outcome of end-stage renal disease (ESRD), a doubling of serum creatinine, or death from renal or CV causes by 30%. The DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial was noteworthy for including patients with and without diabetes [6]; dapagliflozin produced a 39% reduction in the composite outcome of sustained estimated glomerular filtration rate (eGFR) decline (≥50%), ESRD, or CV/renal death. EMPA-KIDNEY (Study of Heart and Kidney Protection with Empagliflozin) further expanded the study population to include patients with nondiabetic CKD, demonstrating a 28% reduction in the primary outcome of kidney disease progression or CV death [7]. Table 1 summarizes the inclusion and exclusion criteria, primary outcomes, and key findings of the major RCTs involving SGLT2 inhibitors [1–7].

Meta-analyses have confirmed these results. A comprehensive analysis by Neuen et al. [8], which evaluated over 90,000 patients across multiple RCTs, concluded that SGLT2 inhibitors consistently reduce kidney disease progression and HF risk irrespective of baseline eGFR or diabetes status. Zelniker et al. [9] emphasized the robust benefits regarding HF outcomes, particularly among patients with reduced ejection fraction. Real-world studies, such as CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors) and EMPRISE (Empagliflozin Comparative Effectiveness and Safety), have supported the generalizability of these trial findings [10,11]. The CVD-REAL study, which included over 300,000 patients from several countries, demonstrated reductions in HF hospitalizations and all-cause mortality compared with other glucose-lowering agents [10]. The EMPRISE study, focusing on empagliflozin, showed a reduction in both hospitalizations for HF and the decline in kidney function under routine clinical practice [11].

SGLT2 inhibitors are generally well tolerated; however, clinicians should remain aware of potential adverse effects. The most frequently reported side effects are genital mycotic infections, particularly in women, resulting from increased glycosuria. Volume depletion may also occur, especially in older patients or those on diuretics, warranting regular monitoring of volume status [12]. Euglycemic diabetic ketoacidosis, though rare, can be serious and requires vigilance regarding precipitating factors such as prolonged fasting, acute illness, or surgical stress [12]. In these scenarios, SGLT2 inhibitors should be temporarily discontinued. Urinary tract infections and increased frequency of urination are generally mild but should nonetheless be monitored. Renal-related adverse events are uncommon, and current evidence indicates that when used appropriately, these agents do not increase the risk of acute kidney injury [12].

Multiple international guidelines have endorsed the use of SGLT2 inhibitors in CKD. The 2020 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend initiating an SGLT2 inhibitor in patients with T2DM and CKD when eGFR is ≥30 mL/min/1.73 m² and albuminuria is present, continuing therapy until dialysis initiation [13]. The American Diabetes Association supports the use of SGLT2 inhibitors for both renal and CV protection in patients with T2DM and high-risk features [14]. Additionally, European Society of Cardiology guidelines emphasize the role of these agents in managing HF and reducing CKD risk [15]. In clinical practice, SGLT2 inhibitors should be integrated into a multidisciplinary treatment strategy that includes renin-angiotensin system blockade, lifestyle interventions, and CV risk management.

Several research avenues remain open. Ongoing studies are evaluating the effects of SGLT2 inhibitors in patients with nonalbuminuric CKD, primary glomerular diseases, and autosomal dominant polycystic kidney disease [20]. Trials combining SGLT2 inhibitors with other kidney-protective agents, such as nonsteroidal mineralocorticoid receptor antagonists or GLP-1 receptor agonists, may offer synergistic benefits. Additionally, biomarker studies may help identify patient populations that are most likely to benefit [19,20].

SGLT2 inhibitors have emerged as a foundational therapy for CKD patients by providing robust protection against kidney function decline, HF hospitalizations, and CV death. Their benefits extend beyond glycemic control, as evidenced even in patients without diabetes. Recent evidence supports their safe and effective use in patients with reduced eGFR—even down to 20 mL/min/1.73 m². Real-world data and guideline recommendations are now aligned with clinical trial evidence, reinforcing the value of these agents in routine nephrology practice. As new indications and therapeutic strategies emerge, SGLT2 inhibitors are likely to remain central to the management of CKD.