Sodium-Glucose Cotransporter 2 Inhibitors in Diabetic Kidney Disease and beyond

The global incidence and death rates of diabetic kidney disease (DKD) are on a striking upsurge, with an increase of 21.8% and 24.6%, respectively, from 1990 to 2019 [1]. According to the CDC, around 1 in 3 patients with type one or two diabetes eventually develop chronic kidney disease (CKD), and more than one in seven people are estimated to have CKD in the USA, which accounts for 35.5 million people [2]. Patients with DKD, particularly those with unmanaged risk factors, are at high risk of progression to end-stage kidney disease (ESKD) and cardiovascular complications. Currently, diabetes prevails as the most common cause of progression to ESKD [2]. Due to the rising prevalence of diabetes mellitus (DM) and CKD, healthcare systems and families face increasing financial burden. Addressing this global challenge requires limiting the progression of DKD and preventing its severe complications.

Early screening and diagnosis of DKD play a pivotal role in limiting CKD progression. Several markers of kidney damage are helpful in the clinical diagnosis of DKD, including estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR). A reduction in eGFR and/or elevated UACR in the presence of underlying diabetes highlights DKD [3]. Generally, an eGFR <60 mL/min/1.73 m² and/or albuminuria signifies kidney damage. On the other hand, albuminuria is the most predictive factor for progression into CKD [4]. It is calculated using 24-h collections of urine or UACR, which can either be moderately elevated (≥30–300 mg/g) or severely elevated (≥300 mg/g) [3]. Overall, the diagnosis of DKD is based on the evaluation of kidney markers in the context of clinical history. This is often preferred over a kidney biopsy, which can only be considered when suspecting an alternative diagnosis [5].

CKD significantly increases the risk of cardiovascular disease and mortality [6]. In fact, patients with CKD are 5 times more likely to die from cardiovascular causes than to progress to ESKD [7]. In the case of DKD, classical interventions are focused on limiting the progression to kidney failure and mitigating the risk of cardiovascular complications [8]. This is achieved through three pillars – glycemic control, blood pressure (BP) control, and renin-angiotensin-aldosterone system (RAAS) blockade. The inhibition of RAAS effectively delays the progression of DKD and exhibits cardiovascular protection [4]. Moreover, BP control through angiotensin-converting enzyme inhibitors and aldosterone receptor blockers have proven to be efficient in slowing CKD progression among patients with proteinuria [3]. Additionally, glycemic control, with hemoglobin A1c (HbA1c) <7%, is important for DKD prevention but becomes challenging in later stages of CKD due to hypoglycemia risks and unreliable HbA1c levels [3]. Overall, once DKD is established, BP and glycemic control become less effective in delaying DKD progression and preventing cardiovascular complications [9].

The addition of newer medications, such as sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide-1 agonists, and mineralocorticoid receptor antagonists, has shown great utility in treating DKD and reducing cardiovascular risk. SGLT2is, in particular, have changed the current landscape of DKD and heart failure (HF) treatment. This review aimed to discuss the mechanisms by which SGLT2is reduce the progression of DKD and decrease cardiovascular risk, highlighting key clinical trials in the field.

The pathophysiology of DKD involves several metabolic and hemodynamic pathways that eventually lead to glomerular sclerosis and tubulointerstitial fibrosis. The prime feature of DKD is chronic hyperglycemia which activates multiple intracellular and biochemical pathways, including the polyol, hexosamine, protein kinase C (PKC), and the advanced glycation end products (AGE) pathways [10]. In a diabetic environment, excess glucose increases superoxide production by the electron-transport chain. As a result, excess superoxide inhibits glyceraldehyde-3-phosphate dehydrogenase, a critical mediator of the glycolysis pathway, which activates alternative pathways [11, 12]. These pathways are, in fact, interconnected. For instance, the oxidation of sorbitol into fructose through NAD+ in the polyol pathway results in a total increased NADH:NAD+ ratio, inhibiting glyceraldehyde-3-phosphate dehydrogenase and upregulating precursors of PKC and AGE pathways [11, 13]. These pathways inevitably lead to endothelial instability, renal hypertrophy, podocyte damage, mesangial expansion, and foot process effacement [5, 14]. Additionally, the accumulation of activated macrophages within the glomerulus accelerates kidney injury through cytokines and inflammatory markers, such as reactive oxygen species (ROS), transforming growth factor-beta (TGF-β), vascular endothelial growth factor, tumor necrosis factor (TNF), interleukin-1, and interferon-gamma [14].

Hypertension, alongside hyperglycemia, plays a major role in DKD progression; however, this does not necessarily imply that treating hypertension will mitigate CKD progression [14]. Determining an optimal BP target to slow DKD progression remains challenging. The ACCORD trial initially found that a BP target of less than 120 mm Hg did not significantly reduce the rate of major cardiovascular events [15]. Given the ACCORD trial 2 × 2 factorial design, post hoc analysis showed that only patients on intensive glycemic control did not show a difference in cardiovascular events between BP treatment strategies. On the other hand, patients under standard glycemic control had a significantly reduced incidence of cardiovascular event when intensive BP control is implemented [16]. Another recent trial enrolled over 12,000 patients with diabetes compared intensive BP control (<120 mm Hg) vs. standard treatment (<1,400 mm Hg) showed a significant decrease in major adverse cardiovascular event was observed in the intensive-treatment group [17]. Current KDIGO guidelines outline a target of systolic BP <120 mm Hg in patients with high BP and CKD based on standardized office BP measurements [8].

Further hemodynamic pathways involved in DKD are predominantly controlled by RAAS and endothelin-1. Increased levels of endothelin-1 can lead to mesangial expansion through hypertrophy and increased extracellular matrix proliferation [13]. Intrarenal RAAS is activated through increased local production of angiotensin as well as decreased delivery of sodium into the juxtaglomerular apparatus. Angiotensin II is a powerful regulator of hemodynamics and cellular growth [18, 19]. It promotes sodium reabsorption and volume expansion in both the proximal and distal segments of the nephron. In the proximal tubule, angiotensin II enhances sodium uptake by directly activating the sodium-hydrogen exchanger. It also enhances the expression of SGLT2, thus boosting proximal tubule sodium reabsorption [20]. Additionally, angiotensin II stimulates the zona glomerulosa in the adrenal cortex to release aldosterone, which subsequently increases sodium reabsorption and potassium excretion in the distal nephron. This vasoactive hormone also induces systemic vasoconstriction via G protein-coupled receptors. Within the glomeruli, angiotensin II raises resistance in both afferent and efferent arterioles, with a more pronounced effect on the efferent arteriole [18]. Moreover, as a growth factor, angiotensin II stimulates vascular smooth muscle cell, proximal tubular, and mesangial cell proliferation while also increasing collagen IV deposition [19].

The role of angiotensin II in tubuloglomerular feedback (TGF) is significant. TGF is an autoregulatory mechanism within each nephron, where specific cells of the JGA work together to maintain the glomerular filtration rate (GFR) [14]. The JGA, consists of the macula densa, situated between the ascending limb of the loop of Henle and the distal tubule, the juxtaglomerular cells of the afferent and efferent arterioles, and the mesangial cells. The macula densa detects Cl⁻ concentration. When NaCl delivery is low, the macula densa senses a low-volume state and stimulates the release of renin from the afferent arteriole, leading to vasoconstriction of the efferent arteriole (mediated by angiotensin II) and vasodilation of the afferent arteriole (due to reduced levels of adenosine, a renal vasoconstrictor) [14, 21]. Consequently, during volume depletion and decreased distal NaCl delivery, the overall effect is an increase in single-nephron GFR (snGFR). Conversely, when distal NaCl delivery is high, renin release decreases, adenosine levels rise, and snGFR is reduced. The normal physiology of the TGF is shown in Figure 1. In DKD, TGF is modified due to increased activity of SGLT2 in the proximal tubule. This results in increased reabsorption of sodium and glucose in the proximal tubule, leading to reduced Cl⁻ delivery to the macula densa and an increase in snGFR that causes hyperfiltration, as illustrated in Figure 2 [22, 23].

Hyperfiltration highlights the initial stage of DKD, followed by albuminuria and, eventually, GFR decline. Furthermore, the reduced flow of fluid to the distal nephron decreases the tubular back pressure in Bowman’s space. As a result, snGFR increases [24]. Hallow et al. [25] have shown in experimental models that both the extent of proximal tubule hyperreabsorption and distal tubular responsiveness to regulatory signals determine the degree of intraglomerular pressure and hyperfiltration in DKD.

Sodium-glucose cotransporters (SGLTs) are a family of proteins with six different isoforms [26]. SGLT2s, found on the apical membrane of the S1 and S2 segments of the proximal tubule, are responsible for the reabsorption of 90% of filtered glucose. Meanwhile, SGLT1 is mainly expressed in the intestines and to a lesser extent in the S3 segment of the proximal tubule (shown in Fig. 2) [24]. An average of 180 g of glucose per day are freely filtered by intact kidneys and reabsorbed by SGLT2/1 [26]. Increased serum glucose levels lead to higher reabsorption until the SGLTs are fully saturated. The renal expression of SGLT2 has been shown to increase in the presence of DM through hypertrophy and hyperplasia of proximal tubules, with insulin contributing via PKC and protein kinase A activation [27]. Insulin also increases ROS production in a dose-dependent manner, which is a proposed mechanism of SGLT2 upregulation in renal tubular cells [28]. In regards to T1DM, suggested mechanisms of SGLT2 upregulation include increased angiotensin II, IL-6, TNF-α, and hepatocyte nuclear factor (HNF)-1α [23, 24, 29]. The inhibition of SGLT2 has shown multiple benefits, particularly in patients with T2DM.

As discussed earlier, SGLT2is promote glucosuria by inhibiting SGLT2 in the proximal tubules. This effect occurs even with insulin deficiency because glucose absorption by the kidneys is insulin-independent [4]. As a result, the complications of chronic hyperglycemia are mitigated, and Hb1Ac is modestly decreased [30]. Additionally, SGLT2 inhibition increases distal delivery of NaCl to the macula densa and restores TGF. This results in increased afferent arteriolar resistance and efferent arteriole dilation, reducing glomerular hyperfiltration and intraglomerular pressure, which are major contributing factors in the pathogenesis of DKD (shown in Fig. 1).

Multiple clinical trials have shown that SGLT2 inhibition increases urinary volume. Boorsma et al. [31] did not find an increase in fractional excretion of sodium when empagliflozin was added to patients with acute HF, which suggests osmotic diuresis due to glucose excretion is taking place. In a study evaluating a similar population, the addition of dapagliflozin increased 24-h measured natriuresis (mmol of Na per mg of IV furosemide) compared to standard of care [32]. SGLT2 inhibition is accompanied by the downregulation of Na⁺/H⁺ exchanger (NHE)-3 [33, 34]. This synergistic effect reduces the reabsorption of sodium in exchange for hydrogen ions (shown in Fig. 2), which plays a contributing role in restoring TGF and amplifies the natriuretic effect of SGLT2is [30, 35].

The role SGLT2is plays on NHE3 transporters enhances the excretion of sodium and reduces the reabsorption of bicarbonate, which is evident by increased urine bicarbonate and sodium in clinical trials. This can lead to hypovolemia and acidosis if not counterbalanced by compensatory mechanisms [36]. Vasopressin plays a major role in countering mild osmotic diuresis that occurs due to SGLT2 inhibition [37]. To compensate for sodium excretion, sodium reabsorption is enhanced through SGLT1, Na-K-2Cl, and NaCl cotransporters in the more distal portions of the nephron [30, 38, 39]. Moreover, SGLT2 inhibition leads to the overexpression of carbonic anhydrase, which is responsible for sodium and bicarbonate reabsorption in the proximal tubule and collecting duct. Empagliflozin can lead to an increase in luminal α-ketoglutarate, stimulating distal NaCl reabsorption and ammonium excretion [40]. Ultimately, the combination of these compensatory mechanisms eliminates the risk of hypovolemia and acidosis.

SGLT2is effect on RAAS is limited [41, 42]. This may be due to the opposing effects of these medications on the RAAS pathway: increased Cl⁻ delivery to the macula densa leads to RAAS inactivation, while the natriuretic effect and loss of circulating volume trigger RAAS activation. RAAS and SGLT2 inhibition have additive effects in decreasing intraglomerular pressure [33]. Unlike drugs working on RAAS, SGLT2is do not increase the risk of hyperkalemia and do not require potassium monitoring [8]. Moreover, natriuresis can lead to a modest decrease in body weight and systolic and diastolic BP [43, 44]. A prespecified analysis of the DAPA-CKD trial showed a mean difference between systolic and diastolic BP of 3.5 and 2.2 mm Hg, respectively, in the dapagliflozin group compared to placebo [45]. The EMPA-KIDNEY showed 2.6 mm Hg lower systolic BP and 0.5 mm Hg lower diastolic BP using empagliflozin when compared to placebo [46]. This mild decline may be in part due to the compensatory mechanisms discussed earlier that prevent hypovolemia. Unlike glucosuria, the BP-lowering effect is not affected by declining kidney function [47]. Additionally, the natriuretic effect of SGLT2is does not lead to reflexive activation of the sympathetic nervous system, which differs from the mechanism of other diuretics [48].

It is reasonable to predict an initial decline in eGFR in patients started on SGLT2is due to the glomerular hemodynamics already described. In fact, shortly after starting these drugs, clinical trials have shown a modest dip in eGFR ranging from 3 to 6 mL/min/1.73 m² [10, 45, 49, 50]. Notably, this decline is reversible, and a long-term attenuation of eGFR decline is seen in patients with DKD when compared to placebo. This phenomenon can explain how mitigation of initial hyperfiltration, even at the cost of reduced eGFR, leads to longstanding nephroprotection [51].

In the presence of hyperfiltration and increased intraglomerular pressure, microalbuminuria, followed by overt proteinuria, play an important role in CKD progression. Albuminuria in DKD is also a key cardiovascular risk factor. A reduction in albuminuria is observed in the presence of SGLT2is even after adjustment for eGFR, HbA1c, and systolic BP [52]. This suggests the presence of separate mechanisms by which SGLT2is can attenuate albuminuria in DKD. Further studies are needed to explore the mechanisms by which SGLT2is decrease CKD progression and reduce cardiovascular risk despite normal albuminuria and across different types of kidney disease [53].

The hyperglycemic environment surrounding cortical tubules permits ROS generation, hypoxia, and tubular damage. Alleviating hyperglycemia attenuates the need for ATP required to activate ATP-dependent Na⁺/K⁺ pumps. As a result, reduced proximal tubule transporter workload alleviates the need for oxygen. Additionally, the continued loss of glucose induces a state of starvation which is highlighted by ketogenesis and lipolysis [54]. Compared to free fatty acids, ketone bodies, in particular, have the unique ability to generate more ATP using an equal amount of oxygen [54]. SGLT2is facilitate this shift toward ketogenesis and fatty acid oxidation, optimizing energy production and contributing to improved renal oxygenation [30]. Ketogenesis can play a role in upregulating adenosine monophosphate-activated protein kinase, further reducing inflammatory cytokines and oxidative stress markers [55]. Ketone bodies can upregulate transcription factors that promote autophagia, thereby helping clear damaged proteins and organelles [56]. As a result, SGLT2is can prevent fibrosis by promoting autophagia and reducing inflammation. Moreover, this mechanism is thought to improve myocardial function and mitigate cardiac remodeling through ATP production [55].

Furthermore, with increased metabolic stress, peritubular fibroblasts are more likely to differentiate into myofibroblasts, producing fibrotic tissue [57]. As a result, a decrease in erythropoietin production in the setting of CKD is evident. Heerspink et al. showed that the use of SGLT2is not only increased hematocrit by 2–4% compared to placebo but also increased hemoglobin, erythropoietin, and reticulocyte count [58].

Increased delivery of glucose into the renal corticomedullary junction is expected, which is followed by a compensatory increase in the expression of SGLT1 in the S3 segment of the proximal convoluted tubule [30]. Thus, medullary hypoxia ensues. Gullaksen et al. [59] showed a decrease in medullary oxygenation following 32 weeks of empagliflozin administration. The transition of tubular absorption to the medullary segment may play a role in inducing erythropoiesis through reduced oxygenation, mediating nephroprotection [60]. In addition, a reduction in plasma volume with SGLTis can contribute to increased hemoglobin levels. This is primarily due to the hemoconcentration effect.

SGLT2 inhibition reduces the activation of alternative metabolic pathways, leading to decreased oxidative stress. By limiting the activation of the polyol pathway, NADPH depletion is reduced, increasing the availability of the antioxidant glutathione. Additionally, the downregulation of TGF-β, TNF- α, interleukin-1, IL-6, fibronectin, and laminin occurs due to reduced activity in the hexosamine, PKC, and AGE pathways. AGE products contribute to inflammation and atherosclerosis in the kidneys, heart, and vasculature, where receptors for AGE are highly expressed. In one study, the blockade of SGLT2 reduced receptors for AGE expression levels, thereby preventing AGE-induced tubular cell apoptosis [61]. Hyperuricemia is another factor that can promote inflammation through mediators, such as TNF-α and RANTES, and fibrosis, possibly though fibroblast expansion and promotion of endothelin-1 and fibronectin [62]. SGLT2is reduce serum uric acid through increased uric acid excretion in the urine, a process linked to glycosuria and changes in uric acid transport via GLUT9 activation [63]. SGLT2 inhibition contributes to increased uricosuria by indirectly blocking URAT1-mediated uric acid reabsorption [64]. SGLT2 inhibition leads to an increased tubular Cl⁻ concentration in the late proximal tubule, which plays a significant role in URAT1 blockade [65, 66].

The anti-inflammatory and anti-oxidative stress benefits of SGLT2is extend beyond glycemic control. Empagliflozin has been shown to increase heme oxygenase-1, a nephroprotective antioxidant protein induced by hypoxia-inducible factor 1, in type 1 diabetic mice [67]. Another study demonstrated empagliflozin’s effects in reducing gene expressions of multiple inflammatory mediators in diabetic rats, including TGF-β, fibronectin, TNF-α, MCP-1, CXCL12, and RANTES. Empagliflozin also attenuated NF-kB activity, leading to reduced TLR-4 expression and suppression of the HGMB1-TLR-4 proinflammatory pathway [68]. Furthermore, urinary IL-6 and kidney injury molecule 1 excretion was shown to decrease in patients receiving dapagliflozin compared to placebo, contributing to reduced tubular injury [69].

Initial trials of SGLT2 inhibitors focused on cardiovascular outcomes. Among the first to demonstrate cardiovascular benefits and improved renal outcomes in patients with T2DM were the EMPA-REG OUTCOME [50], CANVAS [70], and DECLARE-TIMI-58 trials [71]. The EMPA-REG trial demonstrated reduced incidence or progression of nephropathy, a reduced rate of creatinine doubling, and a reduced need for renal replacement therapy in patients taking empagliflozin compared to placebo [50]. Both CANVAS and DECLARE-TIMI-58 trials showed a decreased incidence of renal events, including at least a 40% decrease in eGFR, ESKD, and death from renal causes in patients taking canagliflozin and dapagliflozin, respectively [70, 71]. In light of these results, other trials were designed to primarily study renal outcomes. Major trials involving SGLT2is are summarized in Table 1. The Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy (CREDENCE) trial was the first to study primary renal outcomes by including 4,401 patients with T2DM and albuminuric CKD, defined as an eGFR of 30–90 mL/min/1.73 m² and a UACR >300–5,000 mg/g of creatinine. Patients with an eGFR of 30 to <60 mL/min/1.73 m² represented 60% of the sample. The canagliflozin cohort showed a significant 30% risk reduction and an NNT of 22 [95% CI, 15–38] in the composite renal outcome without significant adverse events, which led to the FDA approval of canagliflozin for DKD [49].

DAPA-CKD evaluated the effect of dapagliflozin in patients with CKD, 68% of whom had T2DM. The dapagliflozin cohort included 2,152 patients with an eGFR 25–90 mL/min/1.73 m² and a UACR >200–5,000 mg/g of creatinine. The primary outcome, which included a composite of decline of eGFR by at least 50%, ESKD, or death from renal or cardiovascular causes, occurred 39% less in the dapagliflozin cohort. The NNT to prevent one primary outcome event was 19 (95% CI, 15–27) [45]. Interestingly, these results were consistent in diabetic and nondiabetic subgroups, pinpointing the potential of using SGLT2is in cases other than DKD. This consistency was again shown in EMPEROR-REDUCED, a trial that studied primary cardiac outcomes of empagliflozin in patients with HF, 48% of whom had an eGFR of <60 mL/min/1.73 m². Empagliflozin was associated with a slower eGFR decline rate in patients with HF, while also lowering the composite risk of death from cardiovascular cause or hospitalization for worsening HF by 25% [10]. Additionally, a large systematic review of SGLT2i trials found similar relative risk reductions for risk of kidney disease progression, acute kidney injury, death from cardiovascular disease, or hospitalization for HF between diabetic and nondiabetic groups. This encourages the use of SGLT2is in patients with CKD regardless of their diabetes status.

EMPA-KIDNEY added substantially to the current literature by being the first to enroll patients with a UACR of less than 300 mg/g and using a lower eGFR cutoff of up to 20 mL/min. The study included 6,609 patients, 54% of whom had no diabetes, and 34.5% had an eGFR of <30 mL/min/1.73 m². Significant benefit in primary outcome, which included a composite of progression of kidney disease, was shown in patients with increased albuminuria ≥300 mg/g, whereas no improvement in the primary outcome was shown in the subgroup of patients with normal albuminuria [50]. This may be due to the early termination of the trial and the slow progression of CKD at lower levels of albuminuria. Nonetheless, EMPA-KIDNEY was the first to demonstrate significant reductions in the long-term slope of eGFR among patients with a UACR of less than 30 mg/g [46]. Current KDIGO guidelines recommend using SGLT2i as level 1A recommendation in the following scenarios: adults with diabetes and an eGFR above 20 mL/min, adults with an eGFR above 20 mL/min and a UACR above 200 mg/g regardless of diabetes status, and adults with HF and eGFR >20 mL/min. For those without diabetes and with a UACR less than 200 mg/g, along with an eGFR of 20–45 mL/min, SGLT2is are suggested as a level 2B recommendation [8].

In most trials evaluating CKD, SGLT2is were used with concomitant maximally tolerated RAAS blockade. In the most recent EMPA-KIDNEY trial, around 15% of patients did not have baseline RAAS blockade [46]. In this subgroup, the efficacy of empagliflozin in slowing CKD progression was consistent, regardless of the status of RAAS blockade. Additionally, Neuen et al. [73] demonstrated that kidney-protective effects of SGLT2 inhibition are consistent irrespective of RAAS blockade through pooled analysis in a systematic review of SGLT2 inhibitors in patients with T2DM.

SGLT2 inhibitors, initially developed to manage blood glucose levels, have shown significant outcomes in reducing cardiovascular risk, particularly among patients with T2DM and CKD. Mechanisms underlying these cardiovascular benefits are multifaceted and are summarized (shown in Fig. 3). In addition to decreasing preload and afterload and reducing arterial stiffness [74], suggested direct mechanisms involve downgrading proinflammatory processes, relieving oxidative stress, and ameliorating metabolic and mitochondrial pathways [14]. Another significant mechanism involves the inhibition of NHE-1 in myocardial cells [75], which is elevated in HF [76]. NHE-1 activates calcium-dependent pathways that lead to myocardial cell death, hypertrophy, and fibrosis [76]. The blockade of NHE-1 has been shown to mitigate oxidative stress and myocardial fibrosis, ultimately improving cardiac remodeling and function [14, 76].

Clinical trials, such as EMPA-REG OUTCOME and CANVAS, were pivotal in establishing the cardiovascular advantages of SGLT2 inhibitors. The EMPA-REG OUTCOME trial showed that empagliflozin significantly reduced the risk of cardiovascular death by 38% and hospitalization for HF by 35% in patients with T2DM at high cardiovascular risk [50]. Similarly, the CANVAS program reported that canagliflozin lowered the risk of major adverse cardiovascular events by 14% and reduced HF hospitalizations by 33% [70]. In fact, empagliflozin is FDA-approved for HF regardless of DM status to reduce the risk of cardiovascular death and hospitalization [77]. This was primarily due to the EMPEROR-Preserved and EMPEROR-Reduced clinical trials, which have established a reduced risk of cardiovascular death and hospitalization in the absence of diabetes [10, 78].

Currently, starting an SGLT2i is recommended in patients with eGFR >20 mL/min/1.73 m² [8]. This becomes a concern for patients with ESKD or on dialysis, which are usually excluded from major SGLT2i trials. The current KDIGO guidelines recommend not halting SGLT2i therapy even if eGFR falls below 20 unless it becomes untolerated due to side effects or kidney replacement therapy is initiated [8]. Nonetheless, recent evidence is pointing toward the safety of SGLT2is in the presence of dialysis. For instance, safety assessment of patients in the DAPA-CKD trial who continued dapagliflozin when starting dialysis did not reveal any difference in side effects when compared to placebo. Moreover, fewer deaths were observed in the dapagliflozin group compared to placebo [45]. However, further trials need to address this gap. The DAPA-HD phase 2 trial will examine cardiovascular outcomes using dapagliflozin in diabetic and nondiabetic patients undergoing hemodialysis [79]. Additionally, the EMPESKD phase 1/2 trial aims to study the feasibility of empagliflozin in diabetic and nondiabetic patients with ESKD and on dialysis. Another population of patients that are usually excluded is kidney transplant recipients [80]. Not only do many of these patients have decreased kidney function, but they are also at an increased risk of infections due to immunosuppression. SGLT2is become a concern in this specific group because of an increased risk of urogenital infections. A recent meta-analysis on the effect of SGLT2i on kidney transplant patients with diabetes included a total of 8 studies (132 patients), only one of which was a randomized clinical trial [81]. SGLT2is were effective in reducing HbA1c and body weight while preserving kidney function [81]. Further randomized clinical trials need to assess the risks and benefits of using SGLT2is in kidney transplant recipients. The RENAL LIFECYCLE trial plans to examine the effects of dapagliflozin on patients with (1) advanced CKD with an eGFR ≤25 mL/min/1.73 m², (2) patients on ongoing dialysis, or (3) kidney transplant recipients with an eGFR ≤45 mL/min/1.73 m² [82]. These developing trials will play a major role in paving the way for the use of SGLT2is in these specific populations.

Beyond DKD, SGLT2is could drastically change the landscape of other diseases. Several kidney diseases, particularly proteinuric ones, share similar pathophysiology to DKD and benefit from SGLT2 inhibition. Extending SGLT2 inhibition to nondiabetic CKD subtypes, such as maladaptive focal segmental glomerulosclerosis and obesity-induced nephropathy, can address many unmet clinical needs [83]. A recent systematic review demonstrated the benefit of SGLT2 inhibition on BP, weight, and BMI in patients mostly diagnosed with obesity and prediabetes [77]. An increasing trend of clinical trials is evaluating SGLT2is as primary prevention rather than treatment. For instance, SGLT2is have been shown to attenuate cardiac remodeling after myocardial infarctions, aiding in the prevention and progression of HF [84].

Dual SGLT2 and SGLT1 inhibition is another avenue that needs to be explored. Sotagliflozin is the first dual SGLT1/2 inhibitor approved by the FDA for HF, offering a new therapeutic avenue for patients with diabetes. This dual action helps in reducing blood glucose levels by inhibiting glucose absorption in the gut and promoting its excretion in the urine. Its cardiovascular benefits were evident in the SCORED trial, which enrolled patients with CKD and diabetes regardless of albuminuria. The trial indicated that sotagliflozin reduced the risk of composite deaths from cardiovascular causes, hospitalizations for HF, and urgent visits for HF (HR, 0.74; 95% CI, 0.63–0.88) [85]. Despite these promising results, longer trials are necessary to establish the cardiovascular benefits and safety profile of dual SGLT1/2 inhibition.

Limited research exists on the renal effects of SGLT2is in the pediatric and adolescent populations. In these populations, CKD can be due to different etiologies which require special care. Tirucherai et al. [86] established that dapagliflozin exhibited a similar pharmacokinetic and pharmacodynamic profile in patients aged 10–17 and in the adult population with T2DM. The long-term use of SGLT2i could theoretically exhibit certain drawbacks affecting optimal growth in the pediatric population [8]. Further clinical trials are needed to assess the safety profile and efficacy of SGLT2i use in the pediatric population with CKD.

The mechanisms by which SGLT2 inhibitors protect renal and cardiovascular function are diverse. Clinical trials have consistently shown that SGLT2is lower the risk of major renal and cardiovascular events in patients with T2DM and DKD, with benefits extending to nondiabetic individuals. While these findings support the widespread use of SGLT2is, ongoing research is needed to better understand cellular mechanisms and optimize their use across various patient demographics and different disease etiologies.

The authors express their gratitude to Haya Almhmoud for drawing the figure illustrations.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

Z.A.H: writing – original draft; C.E.C. and M.H: writing – review and editing; and M.G.A: supervision and writing – review and editing.