Three randomized control trials (Canagliflozin Cardiovascular Assessment Study, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients [EMPA-REG OUTCOME], and Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 [DECLARE-TIMI 58]) showed that the sodium-glucose co-transporter 2 (SGLT2) inhibitors, originally developed as glucose-lowering drugs, are associated with a lower rate of adverse renal outcomes, such as need for renal replacement therapy, doubling of serum creatinine, and loss of glomerular filtration rate (GFR) compared to those in placebo groups. Besides, canagliflozin and empagliflozin also showed a lower risk of progression to macroalbuminuria. The EMPA-REG OUTCOME trial and DECLARE-TIMI 58 trial also indicated that these SGLT2 inhibitors might have beneficial effects on the prevention of acute kidney injury. The United States Food and Drug Administration (FDA) warned of the risk of acute kidney injury for canagliflozin and dapagliflozin. We compared canagliflozin, empagliflozin, and dapagliflozin with respect to chemical structure and pharmacological properties, to explain the observed differences in preventing acute kidney injury, and put forward the hypotheses of the potential mechanisms of different effects of SGLT2 inhibitors on acute kidney injury. Given the raising clinical use of SGLT2 inhibitors, our review should stimulate further basic science and clinical studies in order to definitively understand the role of SGLT2 inhibitors in acute kidney injury. A weakness of the clinical data obtained so far is the fact that the statements concerning acute kidney injury are just based on safety data – mainly creatine measurements. However, given the mode of action of SGLT2 blockers, initiation of a therapy with a SGLT2 blocker will cause an increase of creatine because of its effects on the tubuloglomerular feedback mechanisms/glomerular hemodynamics like RAAS blocking agents do. To really understand the potential effects of SGLT2 inhibitors, we need preclinical and clinical SGLT2 inhibitor studies focusing on all aspects of acute kidney injury – not just changes in GFR biomarkers.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a novel class of glucose-lowering agent that seems to be promising drugs, because recent studies suggest long-term cardiovascular and renal benefits [1-3]. Four SGLT2 inhibitors (Empagliflozin, Canagliflozin, Dapagliflozin, Ertugliflozin) have been approved by United States Food and Drug Administration (FDA) since 2013. SGLT2 inhibitors block the reabsorption of glucose in the kidney, through enhancing urinary glucose excretion, independent of glucose dependent insulin secretion, lower the blood glucose level [4]. Beyond efficacy in terms of glycemic control and glycosylated hemoglobin (HbA1c) reduction, SGLT2 inhibitors also have favorable effects on blood pressure, weight, uric acid levels, intrarenal hemodynamics, and albuminuria [1, 5].

Diabetes increased the risk for cardiovascular disease (CVD). However, there is a gap between the intensive blood sugar treatment and cardiovascular outcomes as reported in several clinical trials (Action to Control Cardiovascular Risk in Diabetes trial, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation trial, Veterans Affairs Diabetes Trial). Moreover, some of the glucose lowering drugs might have cardiovascular (CV) side effects beyond its glucose lowering potential. Consequently, the FDA strengthen the assessment of cardiovascular safety of antidiabetic drugs, rigorous specific cardiovascular outcome trials (CVOTs) were requested before any new glucose-lowering drugs are available to ensure that these drugs do not adversely affect the cardiovascular diseases since 2008 [6].

Three large randomized control trials, Canagliflozin Cardiovascular Assessment Study (CANVAS), Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLAR-TIMI 58) trial, were all primarily designed to demonstrate cardiovascular safety as new regulatory requirements for glucose-lowering drugs [1-3, 7]. Following sister trials CANVAS-Renal (CANVAS-R) was designed to assess effects on albuminuria. The integrated analysis of CANVAS and CANVAS-R as the CANVAS Program, shows the safety outcomes of Canagliflozin on cardiovascular events. The EMPA-REG OUTCOME trial shows compared with placebo that Empagliflozin treatment is associated with a significantly reduced risk of three-point major adverse CV event (3P MACE) over 3 years, reduced cardiovascular death by 38% (p < 0.001), hospitalization for heart failure by 35% (p = 0.002) in patients with type 2 diabetes mellitus (T2DM), and these benefits were independent to glycemic control [2]. Dapagliflozin was noninferior to placebo with respect to the primary safety outcome of MACE [7]. In addition, these trials demonstrated that the use of Canagliflozin, Empagliflozin or Dapagliflozin improved renal outcome and are associated with slower progression of kidney disease, also reduced the need of renal-replacement therapy in T2DM [1, 3, 7-12]. Acute kidney injury (AKI) is defined as a rapid decrease of kidney function, declined in the glomerular filtration rate (GFR), causing the elevation of serum creatinine, blood urea nitrogen (BUN), and other metabolic nitrogenous waste products, and dysregulation of extracellular volume and electrolytes. AKI is a complex and dynamic clinical syndrome, which is common in hospitalized patients. The most common etiologies among hospitalized patients are either prerenal etiologies which due to volume depletion or acute tubular necrosis (ATN) from ischemia, nephrotoxin exposure, or sepsis [13]. High frequency of renal insufficiency secondary to the patients which undergoing coronary angiography, percutaneous coronary interventions (PCI) or cardiac surgery, the mortality for this subgroup is 40–83% [14-16]. AKI is associated with an increased need for emergency renal replacement therapy and more complications, prolonged length of stay in hospital. The higher the clinical stage of AKI, the higher the morbidity and mortality, even the minimal increases in serum creatinine within 48 h following cardiac surgery resulted significantly worse outcomes and higher costs [14, 17-19]. AKI is a big challenge both to the medical institutes and society, resulting in a tremendous medical expenditure [13, 20, 21]. Prevention the development and treatment of AKI patients should be taken seriously to improve the outcome.

The safety analysis of the EMPA-REG OUTCOME trial indicated that acute renal failure (ARF) and AKI events were numerically lower in patients on Empagliflozin treatment than those taking placebo, even in the patient subgroup with estimated glomerular filtration rate (eGFR) levels < 60 mL/min/1.73 m2 at baseline – a high risk group for AKI (Table 1) [3]. The DECLARE–TIMI 58 trail showed that fewer patients in the Dapagliflozin group reported AKI than in the placebo group (1.5 vs. 2.0%; hazard ratio 0.69; 95% CI, 0.55 to 0.87; p = 0.002) [7].

Table 1.

AKI and AFR events in EMPA-REG OUTCOME

AKI and AFR events in EMPA-REG OUTCOME
AKI and AFR events in EMPA-REG OUTCOME

On the other hand, FDA received reports of 101 confirmable cases of AKI that have sufficient detail to confirm the diagnosis and demonstrate a temporal relationship with Canagliflozin (73 patients) or Dapagliflozin (28 patients) from March 2013 to October 2015, then strengthened the warning in June 2016 [22]. A meta-analysis of SGLT2 inhibitor therapy focus on renal safety involved in more than 30,000 patients showed that a total of 511 events of acute renal impairment/failure were reported in 53 trials, revealed that Canagliflozin (OR, 1.82; 95% CI, 0.28 to 11.77) and Dapagliflozin (OR, 1.64; 95% CI, 1.26 to 2.13) had a tendency to increase the adverse renal events as compared with control group, while only Empagliflozin in those three compounds was significantly associated with lower risk of acute renal impairment/failure events than placebo (OR, 0.72; 95% CI, 0.59 to 0.87) [23].

Thus, there are obviously striking differences with respect to their effects on the prevention of acute renal failure. The pharmacokinetic and pharmacodynamic properties of the different SGLT2 inhibitors are summarized in Table 2. This link with AKI was strongest with Canagliflozin, and opposite findings were reported with Empagliflozin, while conflicting reports of Dapagliflozin. However, the potential reason for this observation is unclear, the purpose of this review is to compare the similarities and differences of these three different SGLT2 inhibitors with respect of the chemical structure, pharmacological, to explain the observed differences in preventing acute kidney failure, and put forward the hypotheses of the potential mechanism of different effects of SGLT2 inhibitors on AKI.

Table 2.

Comparison of canagliflozin, empagliflozin, and dapagliflozin

Comparison of canagliflozin, empagliflozin, and dapagliflozin
Comparison of canagliflozin, empagliflozin, and dapagliflozin

Canagliflozin, Empagliflozin and Dapagliflozin are all aryl C-glycosides SGLT2 inhibitors. Based on the attachment of the sugar ring and the aromatic ring, SGLT2 inhibitors are classified into the aryl O-glycosides, aryl C-glycosides, aryl N-glycosides, aryl S-glycosides, and non-glycosides. Phlorizin is earliest discovered SGLT2 inhibitor, belonging to aryl O-glycosides, which was extracted from the root bark of apple tree by French chemists in 1,835. Administration of phlorizin in diabetic rats resulted in glycosuria, which normalized both the fasting and fed plasma glucose levels and completely reversed insulin resistance. Due to its poor selectivity of SGLT1 and SGLT2, causing the severe adverse reactions such as diarrhea, and it is susceptible to hydrolysis by β-glucosidase enzymes, the oral bioavailability is extremely low. aryl O-glycosides eventually replaced by aryl C-glycosides (Table 2).

Glucose absorbed into blood is filtered by glomerulus and reabsorbed from proximal tubules. SGLT1 and SGLT2 are related transporters that carry glucose across apical membranes of polarized epithelial cells against concentration gradients, driven by Na+ gradients [24]. SGLT2 is a high-capacity, low-affinity transporter, distributed in the S1 segment of proximal renal tubules, responsible for about 90% reabsorption of filtered glucose from the tubular lumen [4]. However, SGLT2 is the only one of SGLT family, the roles of the other SGLT family members are less well understood. Selectivity of SGLT2 inhibitors is thought to be important with regard of their efficiency and side effects. SGLT1 is also found in other organs, such as the intestine, heart, liver and lung. SGLT3 is expressed in cholinergic neurons of the small intestine and in neuromuscular junctions of skeletal muscle, may be involved in the regulation of muscle activity [25]. SGLT4, 5 and 6, are expressed in the kidney and potentially play a role in renal monosaccharide and/or sodium reabsorption [26]. Although these three compounds are all selective inhibitors of SGLT2, they could also inhibit other SGLTs. There are remarkable differences with respect to their selectivity of other SGLT. Selectivity for SGLT2 over SGLT1 of Empagliflozin, Dapagliflozin, Canagliflozin was above 2,500-fold, above 1,200-fold, above 250-fold, respectively. Canagliflozin exhibited the lowest selectivity for SGLT2 over SGLT4 and SGLT2 over SGLT4 among these three compounds (see also Table 2). Furthermore, all apart from Canagliflozin showed > 600-fold selectivity over SGLT6 [26].

The pharmacokinetics of Canagliflozin in healthy subjects and T2DM patients are similar. After oral administration of 100 or 300 mg in healthy volunteers, it was quickly absorbed and the median peak time (Tmax) was reached within 1–2h. The mean absolute oral bioavailability is approximately 65%. Plasma peak concentration (Cmax) and area under the curve (AUC) increased from 50 to 300 mg in a dose-dependent manner. The apparent terminal half-lives (t1/2) following once daily 100 and 300 mg doses were 10.6 ± 2.13 h and 13.1 ± 3.28 h, respectively. Steady-state was reached after 4 to 5 days of once-daily dosing with Canagliflozin 100 up to 300 mg. The tissue distribution was extensive, apparent distribution of a single intravenous infusion in healthy subjects was 83.5 L. Canagliflozin is 99% protein bound, which was independent of blood drug concentration. Canagliflozin was metabolized via O-glucuronidation by uridine diphosphate-glucuronosyl transferase (UGT) 1A9 and UGT2B4 to inactive O-glucuronide metabolites. After administration of a single oral [14C] Canagliflozin dose to healthy subjects, 41.5% was prototype drugs, 7% was a hydroxylated metabolite, and O-glucuronide metabolite accounted for 3.2%. Approximately 33% was excreted in urine, 30.5% as O-glucuronide metabolites, prototype drugs < 1.0%. Renal clearance rate for intravenous administration of healthy volunteers is approximately 192 mL/min [27].

The pharmacokinetics of Empagliflozin were not significantly different in healthy subjects and T2DM patients. Empagliflozin was well and rapidly absorbed after oral administration. Tmax was 1.5 h post-dosing. Plasma concentrations subsequently decreased in two phases, a fast distribution phase and a relatively slow terminal phase. Mean plasma steady-state AUC were 1,870 and 4,740 nmol/h, Cmax were 259 and 687 nmol/L following once daily 10 mg and 25 mg of Empagliflozin, respectively. Empagliflozin exposure increased proportional to the increment in Empagliflozin dose. The effect of the diet on the pharmacokinetics of Empagliflozin was not considered clinically relevant. The apparent steady-state volume of distribution was estimated at 73.8 L. Following oral administration of a solution of [14C]-Empagliflozin to healthy volunteers, distribution in red blood cells was approximately 37 and 86% bound to plasma proteins. No significant metabolites were found in human plasma, with 3 glucuronide conjugates (2-, 3-, and 6-glucuronide) is the most prominent metabolite. Systemic exposure to each metabolite was less than 10% of the total drug administered. Data obtained in vitro suggests that the primary route is the glucuronidation of uridine-5-diphosphate by UDP-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8 and UGT1A9. The terminal elimination half-life (t1/2) was 12.4 h, and apparent clearance after oral administration was 10.6 L/h. Following oral administration of a solution of [14C]-Empagliflozin to healthy volunteers, approximately 96% of drug radioactivity was excreted in feces (41%) or urine (54%). Most drug radioactivity in feces was parent drug and approximately half of the drug in urine radioactivity was prototype drug [28].

Dapagliflozin was rapidly and well absorbed after single-doses oral administration, and Cmax were usually attained within 2 h post-dose. The absolute oral bioavailability of Dapagliflozin is 78%. Mean steady-state Cmax and AUC values following once daily 10 mg doses of Dapagliflozin were 158 ng/mL and 628 ng h/mL, respectively. Dapagliflozin is extensively bound to proteins in plasma (91%). The mean steady-state volume of distribution of Dapagliflozin was 118 L. O-glucuronidation is the major metabolic elimination pathway for Dapagliflozin. Dapagliflozin 3-O-glucuronide is an inactive metabolite, which formation is mediated by UGT1A9. CYP-mediated metabolism of Dapagliflozin was a minor clearance pathway in humans. The mean total systemic clearance of Dapagliflozin administered intravenously was 207 ml/min. The apparent terminal half-life (t1/2) was 12.9 h for 10 mg dose to healthy subjects. Following administration of an oral 50 mg [14C]-Dapagliflozin dose, 75% of the administered radioactive dose was excreted in urine and 21% in feces [29].

The proximal tubule occupies the maximum amount of oxygen consumption in the kidney, because the reabsorption of electrolytes and organic solutes in the proximal tubule requires a lot of energy [30]. The proximal tubular SGLT2 enzyme was activated by high blood level in T2DM patients, result in increasing oxygen demand easily. Tubulointerstitial hypoxia might be a consequence, if the work load is too high. Administration of SGLT2 inhibitors could abolish this effect. A previous animal study showed that SGLT inhibition with phlorizin in diabetic rats improved renal cortical oxygen tension, which might help to improve tubular cell integrity and tubular albumin reabsorption [31].

Elevated HIF1 expression may play a major role in the protection of IR-injured renal tubule cells. The hypoxia-inducible factors (HIFs) comprise a family of oxygen-sensitive basic helix-loop-helix proteins that control the cellular transcriptional response to hypoxia [32]. Under hypoxic conditions, HIF1 mediates the synthesis of erythropoietin (EPO) by inhibiting the degradation of HIF1, increasing the production of EPO in plasma, which predominantly expressed in kidney. EPO has multiple protective effect, act as anti-oxidant, anti-apoptotic and anti-inflammatory. A number of studies using models of renal and non-renal ischemic injury pointed to a potential protective role for HIFs in these diseases [32]. A recent study showed that Dapagliflozin pretreatment induces HIF1 and reduces the Bax/Bcl2 ratio in ischemic renal tissue and cultured ischemic tubular cells, improves renal function and reduces apoptotic cell death in ischemia-reperfusion (IR) injured kidneys in mice [33]. There was no similar experiment for Empagliflozin and Canagliflozin, so far. We put forward a hypothesis that whether Empagliflozin could improve renal function through elevated HIF1 expression in AKI.

A recent study showed that Canagliflozin substantial activates AMP-activated protein kinase (AMPK), but not to any significant extent with Dapagliflozin, Empagliflozin, in human and mouse cells at concentrations corresponding to the peak plasma concentrations achieved after therapeutic doses in humans. The mechanism involving inhibition of respiratory chain Complex I, which could inhibit oxygen uptake, increase the energy-consuming burden, deteriorating the function and integrity of tubular cell [34]. This study also indicated that Canagliflozin had additional off-target effects on glucose transport compared to Dapagliflozin [34]. It is reasonable that these differences may account for their differences in AKI protection, although the mechanism is unknown (Fig. 1).

Fig. 1.

Hypotheses of different SGLT2 inhibitors in acute kidney injury (AKI). AKI is often caused by ischemia of the kidney, exposure to nephrotoxic agents such as contrast media and certain antibiotics as well as volume depletion. SGLT2 inhibitors are likely to interfere with pathways leading to AKI. Clinical data suggest that different types of SGLT2 inhibitors may have opposite effects on AKI. This cartoon summarizes the so far known pathways explain the clinical observations. a Canagliflozin seems to activate AMPK by inhibiting respiratory chain Complex I, increases the energy-consuming burden, deteriorates the function and integrity of tubular cell [34]. b SGLT2 inhibitors might improve renal cortical oxygen tension, which helps to improve tubular cell integrity and tubular albumin reabsorption [31]. Elevated HIF1 expression could be another mechanism to improve renal function of Dapagliflozin [32, 33]. Several studies have showed that Empagliflozin could improve cardiac function. According to the theory of heart-kidney interactions, the kidney function may be improved by the regulation of the neurohumoral systems [35, 36].

Fig. 1.

Hypotheses of different SGLT2 inhibitors in acute kidney injury (AKI). AKI is often caused by ischemia of the kidney, exposure to nephrotoxic agents such as contrast media and certain antibiotics as well as volume depletion. SGLT2 inhibitors are likely to interfere with pathways leading to AKI. Clinical data suggest that different types of SGLT2 inhibitors may have opposite effects on AKI. This cartoon summarizes the so far known pathways explain the clinical observations. a Canagliflozin seems to activate AMPK by inhibiting respiratory chain Complex I, increases the energy-consuming burden, deteriorates the function and integrity of tubular cell [34]. b SGLT2 inhibitors might improve renal cortical oxygen tension, which helps to improve tubular cell integrity and tubular albumin reabsorption [31]. Elevated HIF1 expression could be another mechanism to improve renal function of Dapagliflozin [32, 33]. Several studies have showed that Empagliflozin could improve cardiac function. According to the theory of heart-kidney interactions, the kidney function may be improved by the regulation of the neurohumoral systems [35, 36].

Close modal

Next, heart-kidney interactions are bi-directional. Ronco put forward generalized cardiorenal syndrome (CRS) in 2008, that one organ in acute or chronic dysfunction may induce acute or chronic dysfunction in the other. Heart and kidneys keep the balance of dynamic hemodynamic system. The pathogenesis of CRS includes activation of both the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS), unbalance between nitric oxide and reactive oxygen species, systemic inflammation, and the influence and interplay of various substances [35]. Clinical trials showed both Canagliflozin and Empagliflozin have benefits on major adverse cardiovascular events (MACE), apart from Dapagliflozin which did not result in a significantly lower rate of MACE. However, the potential mechanisms of favorable CV effects are still unclear. A study reported echocardiograms of patients with T2DM and established CV disease taking Empagliflozin, and showed a significant reduction in left ventricular mass index and improved diastolic function [36]. It is expected that Canagliflozin will have similar research in the future. Hypothesis generating that Empagliflozin improved cardiac function, enhanced diastolic and systolic function, therefore, the kidney function may be improved by the regulation of the neurohumoral systems.

Recently, a clinical study observed Dapagliflozin treatment compared to placebo treatment. Dapagliflozin treatment reduced urinary Kidney Injury Molecule-1 (KIM-1) excretion by 22.6% (0.3–39.8%; p = 0.05), reduced urinary IL-6 excretion by 23.5% (1.4–40.6%; p = 0.04) [37]. KIM-1 is a marker for hypoxic injury to proximal tubular cells, which would suggest that Dapagliflozin reduces proximal tubular cell injury. IL-6 is an inflammatory cytokine and has been implicated in the progression of long-term mortality in adults after cardiac surgery. As far as we know, there is no similar research on Empagliflozin and Canagliflozin. Further research is needed to explore the potential mechanism of different SGLT2-inhibitor agents differ from one another in their respective risk for AKI. In this context, it is of note that another glucose lowering drug might have beneficial effects in the setting of AKI as well, it thus might be of interest to combine SGLT2 blockade using Empagliflozin and dipeptidyl peptidase 4 (DPP4) inhibitor [38].

Currently available studies indicate that SGLT2 inhibitors have beneficial effects on diabetic nephropathy. They all could delay the progression of kidney disease, including decrease the sustained reduction in eGFR, reduce the need for renal replacement therapy and less frequency die from renal causes. Canagliflozin and Empagliflozin could also reduce the incidence of new onset macroalbuminuria. This seems to be a class effect. With regard to prevention of acute renal failure, however, only Empagliflozin seems to be promising, Dapagliflozin has been controverted, whereas in particular Canagliflozin might even have negative effects. The underlying mechanisms seems to be related to differences in off-target effects of them (for example activation of AMPK (see Fig. 1) and probably differences in selectivity towards SGLT1. Appreciate head to head comparisons of SGLT2 inhibitors in preclinical AKI models are needed to rule out in more detail underlying mechanisms. This is in particular of major clinical impact given the raising clinical use of SGLT2 inhibitors. A weakness of the clinical data obtained so far is the fact that the statements concerning acute kidney injury are just based on safety data – mainly creatine measurements. However, given the mode of action of SGLT2 blockers, initiation of a therapy with a SGLT2 blocker will cause an increase of creatine because of its effects on the tubuloglomerular feedback mechanisms/glomerular hemodynamics like RAAS blocking agents do. To really understand the potential effects of SGLT2 inhibitors, we need preclinical and clinical SGLT2 inhibitor studies focusing on all aspects of acute kidney injury – not just changes in GFR biomarkers.

The first author C.C. appreciates the financial support of the China Scholarship Council (Grant No. 201806780037).

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