1. bookVolume 1 (2021): Issue 3 (December 2021)
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Renoprotective mechanisms of SGLT2 inhibitor in diabetic kidney disease

Published Online: 10 Jun 2022
Volume & Issue: Volume 1 (2021) - Issue 3 (December 2021)
Page range: 97 - 108
Received: 28 Nov 2020
Accepted: 26 Apr 2022
Journal Details
License
Format
Journal
eISSN
2719-3500
First Published
30 Jun 2021
Publication timeframe
4 times per year
Languages
English
Abstract

Diabetic kidney disease (DKD), as the primary cause of end-stage renal disease (ESRD), is becoming a growing public health challenge worldwide. Early intervention in conditions involving high glucose levels will prevent the progression of DKD. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) comprise a new class of medications used to reduce hyperglycemia in patients with diabetes by inhibiting renal reabsorption of filtered glucose. Interestingly, SGLT2i is not only capable of controlling the blood glucose level but also has other benefits in terms of blood pressure control, body weight decrease, and albuminuria reduction. It is assumed that various events, such as energy metabolism disorder, insulin resistance, glomerular hyperfiltration, oxidative stress, inflammation, and fibrosis, attributable to the pathogenesis of DKD, can be improved by SGLT2i. Clinical trials have demonstrated that SGLT2i can exert renoprotective effects and reduce the morbidity and mortality due to ESRD. In this review, we focus on the most recent findings from clinical trials and the underlying mechanisms by which SGLT2 inhibitors afford renal protection.

Keywords

Introduction

Diabetes is a primary risk factor for kidney injury, and 40% of patients with diabetes develop diabetic kidney disease (DKD) [1, 2]. In developed countries, diabetes accounts for almost 50% of end-stage renal disease (ESRD) [3]. Diabetic patients with mild or moderate chronic kidney disease (CKD) have a doubled risk of all-cause mortality. Studies have identified various risk factors associated with DKD, including genetic defects, socioeconomic problems, uncontrolled glycemic levels, obesity, smoking, age, oxidative stress, inflammation, and hyperfiltration [3]. Classic pathogenesis of DKD includes mixed metabolic alterations inducing endothelial damage, which leads to podocyte dysfunction and glomerular capillary rarefaction. On the other hand, the development of DKD is regarded as a hemodynamic abnormality, which provides an alternative explanation for the therapeutic benefits of drugs such as renin–angiotensin system inhibitor (RASi) [4]. However, traditional antihyperglycemic drugs are insufficient to control metabolic disorders, and RASi increases the risk of acute kidney injury in patients with DKD. SGLT2i, as a new antidiabetic drug, reduces plasma glucose levels by augmenting glucosuria. Beyond glycemic control, SGLT2i exerts renoprotective effects by maintaining metabolic homeostasis, preventing hemodynamic dysfunctions, and inhibiting inflammation and oxidative stress [3, 4]. The empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes (EMPAREG OUTCOME) trial has demonstrated that empagliflozin can significantly attenuate DKD progression by reducing the incidence of doubling of serum creatinine and reducing the need for renal replacement therapy [5]. In this review, we focus on the mechanisms of renoprotection by SGLT2i, especially its effects on metabolism and hemodynamics.

Clinical Trials of SGLT2 Inhibitors

As burgeoning antidiabetic agents, the efficiency of SGLT2i in glycemic control is measured by the level of hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and postprandial glucose (PPG). A phase III, double-blind, placebo-controlled clinical trial treated patients with 2.5 mg, 5 mg, or 10 mg dapagliflozin once daily, and HbA1c decreased by 0.58%, 0.77%, and 0.89%, respectively [6]. It is worth noting that in a population with higher HbA1c (10.1%–12.0%), the degree of reduction in HbA1c was higher (2.88% and 2.66%, respectively, with 5 mg and 10 mg dapagliflozin). Another similar study examined the efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus (T2DM). Intervention with 100 mg/d or 300 mg/d canagliflozin for 26 weeks resulted in a significant decline of HbA1c from baseline by 0.77% and 1.03%, respectively. Simultaneously, canagliflozin intervention using 100 mg and 300 mg reduced FPG and 2-h PPG [7]. A meta-analysis evaluated the effect of dapagliflozin in relation with other hypoglycemic agents, including dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones (TZDs), sulfonylureas, and glucagon-like peptide-1 (GLP-1) analogs, in reducing HbA1c [8]. The mean change in HbA1c was similar among these different agents. The impact of dapagliflozin on HbA1c was −0.08%, −0.02%, and 0 relative to DPP-4 inhibitors, TZDs, and sulfonylureas, respectively. There are few clinical trials of SGLT2i on patients with T1DM. A total of 1402 patients with T1DM were enrolled to receive dual SGLT1/2 inhibitor (sotagliflozin, 400 mg/d) or placebo while maintaining insulin therapy [9]. The primary outcome was HbA1c <7.0% without hypoglycemia or diabetic ketoacidosis. After 24-week intervention, the proportion of patients achieving the primary outcome was 28.6% in the sotagliflozin population compared with 15.2% in the placebo population. The changes in glycated hemoglobin (HbA1c), weight, systolic blood pressure, and mean daily bolus insulin dose from baseline were higher in the sotagliflozin group. Another 52-week, double-blind, phase III trial revealed consistent results: placebo-adjusted HbA1c changes from baseline (7.8%) decreased 0.37% and 0.35% with sotagliflozin 200 mg and 400 mg, respectively [10]. The efficacy and safety of other SGLT2is, namely, dapagliflozin and empagliflozin, were also investigated [11,12,13].

Except for glycemic control, SGLT2i also displays renal and cardiovascular protective effects. In the canagliflozin and renal events in diabetes and nephropathy clinical evaluation (CREDENCE trial), 4401 patients with diabetes with estimated glomerular filtration rate (eGFR) of 30–90 mL/min/1.73m2 and albuminuria first received RAS blockade; then, randomized patients took either 100 mg canagliflozin or a placebo daily [14]. Canagliflozin treatment significantly decreased the relative risk of the primary outcome, a composite of ESRD, including dialysis, kidney transplantation, and low eGFR (<15 mL/min/1.73m2). Another canagliflozin trial with a similar protocol displayed a benefit for the progression of renal composite events (40% reduction in eGFR, renal replacement therapy, or death from renal causes) [15]. Notably, more participants in the canagliflozin group showed regression of albuminuria than in the placebo group (293.4 vs. 187.5 participants with regression per 1000 patient-years [pt-y]). Moreover, nondiabetic patients can also benefit from SGLT2i. The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) clinical trial recruited 4304 patients with an eGFR of 5–75 mL/min/1.73m2 and a urinary albumin-to-creatinine ratio of 200–5000, receiving 10 mg/d dapagliflozin or placebo, to explore the renal protective effects in CKD [16]. The occurrence rate of primary events (>50% decline in eGFR, ESKD, and death from renal or cardiovascular causes) was 9.2% in the dapagliflozin group and 14.5% in the placebo group. The efficacy of dapagliflozin was similar in patients with or without diabetes.

The EMPA-REG OUTCOME trial explored the cardiovascular protective efficiency of empagliflozin [17]. In this study, 7020 patients with T2DM at high cardiovascular risk received empagliflozin (10 mg/d or 25 mg/d) or a placebo for a median of 3.1 years. The occurrence of 3-point major adverse cardiovascular events (3P-MACE; death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) in the empagliflozin group (10.5%) was lower than in the placebo group (12.1%). As for the secondary outcomes, empagliflozin induced a 38% decline in death from cardiovascular causes, a 35% decline in hospitalization for heart failure, and a 32% decline in death from any cause. Recently, the dapagliflozin effect on cardiovascular events–thrombolysis in myocardial infarction 58 (DECLARE-TIMI 58) trial with dapagliflozin were published. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Although there was no significant difference in the incidence of MACE between the dapagliflozin and placebo groups, the rate of cardiovascular death or hospitalization was lower [18]. Similarly, 10,142 participants with T2DM and high cardiovascular risk participated in the canagliflozin cardiovascular assessment study (CANVAS) Program (Canagliflozin Cardiovascular Assessment Study) [15]. The CANVAS Program showed a 14% reduction of 3P-MACE in patients treated with canagliflozin. Patients with heart failure may also benefit from SGLT2i. The empagliflozin outcome trial in patients with chronic heart failure and a reduced ejection fraction (EMPEROR) - reduced clinical trials included 3730 heart failure patients with or without diabetes. The mean follow-up was 16 months, and the dose of empagliflozin was 10 mg/d vs. placebo. Cardiovascular death or hospitalization rate was lower in participants treated with empagliflozin (19.4%) than in those on placebo (24.7%) [19]. The efficacy of dapagliflozin was consistent in patients with or without diabetes. The main outcomes of SGLT2i from clinical trials are shown in Table 1.

Main outcomes of SGLT2i from clinical trials

Drug/trial name Population Sample size Dose Duration Primary end points Secondary end points Reference
Dapagliflozin Patients with T2DM 485 Dapagliflozin 2.5 mg/d, 5 mg/d, or 10 mg/d vs.placebo 24 weeks Decreased HbA1c: 0.58%, 0.77%, and 0.89% with 2.5 mg, 5 mg, and 10 mg dapagliflozin Ferrannini et al. [6]
Canagliflozin Patients with T2DM 584 Canagliflozin 100 mg/d or 300 mg/d vs. placebo 26 weeks Change from baseline in HbA1c: −0.77% and −1.03% in canagliflozin 100 mg/d and 300 mg/d, respectively Decreased FPG, 2-h PPG, body weight, and systolic BP, and increased HDL-C compared with placebo Stenlöf et al. [7]
Sotagliflozin Patients with T1DM 1402 400 mg/d vs. placebo 24 weeks HbA1c <7.0%: 28.6% vs. 15.2% Change from baseline in HbA1c (–0.46%), weight (–2.98 kg), systolic BP (–3.5 mm Hg), and mean daily bolus dose of insulin (−2.8 units/d) Stenlöf et al. [9]
Sotagliflozin Patients with T1DM 782 Sotagliflozin 200 mg/d or 400 mg/d vs. placebo 52 weeks Changes in HbA1c from baseline: −0.37% for 200 mg and −0.35% for 400 mg The proportion of patients with HbA1c <7.0%: 25.67% for 200 mg and 20.35% for 400 mg Danne et al. [10]
Empagliflozin Patients with T1DM 1707 Empagliflozin 2.5 mg/d, 10 mg/d, or 25 mg/d vs. placebo 26 weeks Changes in HbA1c: −0.28% for 2.5 mg, −0.54% for 10 mg, −0.53% for 25 mg Weight reduction: 1.8/3.0/3.4 kg; increased glucose time-in-range: 1.0/2.9/3.1 h/d; lowered total daily insulin dose: 6.4/13.3/12.7%; decreased systolic BP: 2.1/3.9/3.7 mm Hg for 2.5 mg, 10 mg, or 25 mg/d, respectively Rosenstock et al. [11]
Dapagliflozin Patients with T1DM 813 Dapagliflozin 5 mg, 10 mg vs. placebo 24 weeks Decreased HbA1c: 0.37% for 5 mg, 0.42% for 10 mg vs. placebo Total daily insulin dose (−10.78% and −11.08%), and body weight (−3.21% and −3.74%) Mathieu et al. [12]
Dapagliflozin Patients with T1DM 833 Dapagliflozin 5 mg/d and 10 mg/d vs. placebo 52 weeks Reductions in HbA1c: 0.33% and 0.36% for 5 mg and 10 mg vs. placebo Body weight −2.95% and −4.54% for 5 mg and 10 mg, respectively, vs. placebo Dandona et al. [13]
Canagliflozin Patients with T2DM 4401 Canagliflozin 100 mg/d vs. placebo 2.62 years A composite of end-stage kidney disease (dialysis, transplantation, or a sustained eGFR of <15 mL/min/1.73m2): 43.2 vs. 61.2 per 1000 pt-y A lower risk of 3P-MACE (HR: 0.80; 95% CI: 0.67–0.95; P= 0.01) and hospitalization for heart failure (HR: 0.61; 95% CI: 0.47–0.80; P < 0.001) Perkovic et al. [14]
Canagliflozin Patients with T2DM and high cardiovascular risk 10,142 Canagliflozin 100 mg/d or 300 mg/d vs. placebo 13.5 years 3P-MACE (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke): 26.9 vs. 31.5 per 1000 pt-y Renal composite (40% reduction in the eGFR, renal-replacement therapy, and death from renal causes): HR: 0.60 (95% CI: 0.47–0.77); the progression of albuminuria: HR: 0.73 (95% CI: 0.67–0.79) Neak et al. [15]
Dapagliflozin Patients with eGFR of 25–75 mL/min/1.73m2 and urinary albumin-to-creatinine ratio of 200–5000 4304 Dapagliflozin 10 mg/d vs. placebo 2.4 years Composite events (>50% decline in the ESKD, or death from renal or cardiovascular causes): 9.2% vs. 14.5% Renal composite (>50% decline in ESKD or death from renal causes): HR 0.56 (95% CI, 0.45–0.68; P < 0.001); cardiovascular composite (death from cardiovascular causes or hospitalization for heart failure): HR: 0.71 (95% CI: 0.55–0.92; P= 0.009) Heerspink et al. [16]
Empagliflozin Patients with T2DM at high cardiovascular risk 7020 Empagliflozin 10 mg/d or 25 mg/d vs. placebo 3.1 years 3P-MACE (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke): 10.5% vs. 12.1% Rates of death from cardiovascular causes: 3.7% vs. 5.9%; hospitalization for heart failure: 2.7% and 4.1% (35% relative risk reduction); and death from any causes: 5.7% and 8.3% (32% relative risk reduction) Zinman et al. [17]
Dapagliflozin Patients with T2DM and atherosclerotic cardiovascular disease or risk factors for atherosclerotic cardiovascular disease 17,160 Dapagliflozin 10 mg/d 4.2 years MACE:(rate of cardiovascular death or hospitalization for heart failure): 4.9% vs. 5.8% Renal composite (≥40% decrease in eGFR to <60 mL/min/1.73m2, new ESRD, or death from renal or cardiovascular causes): 4.3% vs. 5.6%; death from any cause: 6.2% vs. 6.6% Wiviott et al. [18]
Empagliflozin Patients with class II, III, or IV heart failure and an ejection fraction ≤ 40% 3730 Empagliflozin10 mg/d vs. placebo 16 months Composite events (cardiovascular death or hospitalization for worsening heart failure):19.4% vs. 24.7% Total number of hospitalizations for heart failure: HR: 0.70 (95% CI: 0.58–0.85; P < 0.001); decline of eGFR: 0.55 mL/min/1.73m2/y vs. 2.28 mL/min/1.73m2/y, P < 0.001 Packer et al. [19]

BP, blood pressure; CI, confidence interval; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; ESRD, end-stage renal disease; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c (glycated hemoglobin); HDL-C, high-density lipoprotein–cholesterol; HR, hazard ratio; 3P-MACE, three-point major adverse cardiovascular events; PPG, postprandial glucose; pt-y, patient-years; SGLT2i, sodium-glucose cotransporter 2 inhibitor; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.

Renal SGLT2 in Glucose Metabolism

The kidney contributes to glucose hemostasis via gluconeogenesis, energy consumption, and reabsorption of renal glucose. SGLT2, as a high-capacity and low-affinity sodium-glucose cotransporter, is expressed on the luminal side of the proximal tubular S1/S2 segments. Under normal conditions, SGLT2 reabsorbs almost 90% of urinary glucose [20, 21]. SGLT1, as a low-capacity and high-affinity cotransporter, is located on the luminal side of the proximal tubular S3 segment and reabsorbs the residual urinary glucose [20, 21]. By utilizing the sodium electrochemical potential gradients maintained by sodium- and potassium-activated adenosine 5′-triphosphatase (Na+/K+-ATPase), SGLTs transport glucose from the tubular lumen into the epithelial cells [22,23,24]. The basolateral glucose transporters GLUT2 and GLUT1 facilitate glucose reabsorption into the blood [22, 23]. Blood glucose levels increase in parallel with glucose filtration before exceeding the maximal resorptive capacity, known as the renal glucose threshold [25].

Glucosuria occurs when the filtrated glucose exceeds the renal glucose threshold, as the SGLTs are overloaded. Normally, the threshold is approximately 180 mg/dL [24, 26]. Under hyperglycemic conditions, it may increase to 200–240 mg/dL, due to increased SGLT2 expression [25, 27]. In genetic mouse models of DM, renal SGLT2 protein levels increase in response to hyperglycemia [28, 29]. In proximal tubular epithelial cells isolated from the urine of patients with diabetes, SGLT2 protein levels and glucose uptake were significantly increased [30]. Wang et al. [31] found increased expression of the SGLT2 gene and protein in renal biopsies from patients with diabetes. Thus, inhibition of SGLT2 may act as an effective alternative therapy for patients with diabetes.

Renal Protective Effects of SGLT2i
Metabolic mechanisms

Studies have demonstrated that SGLT2i exerts its renal protective effects through metabolic pathways, including glucose metabolism, fatty acid oxidation, and ketogenesis (Figure 1). High plasma glucose-induced glycolysis accelerates reactive oxygen species (ROS) production, resulting in activation of the polyol pathway, hexosamine pathway, lipid synthesis, and advanced glycation end product (AGE) formation [32]. These harmful factors activate transforming growth factor-β1 (TGF-β1), nuclear factor kappa-B (NF-κB), and interleukin-8 (IL-8), leading to augmented renal inflammation, fibrosis, and impaired tubular integrity [32]. Dapagliflozin reversed the high glucose-induced injury in vitro [32]. Dapagliflozin treatment at a dose of 0.1 mg/kg or 1.0 mg/kg significantly attenuated the progression of DKD [33]. In addition, high glucose stimulates ROS production via the protein kinase C (PKC)-NAD(P)H oxidase pathway in diabetic kidneys, which is blocked by canagliflozin treatment [34]. Hyperglycemia induced theexpression of the high-mobility group box 1 (HMGB1), an activator of the receptor for advanced glycation end product (RAGE). HMGB1 activates NF-κB by binding to toll-like receptors, including TLR4. Thus, hyperglycemia-induced HMGB1 plays a critical role in inflammation and immune response. Inhibition of HMGB1 may be a potential method to relieve renal injury in DKD. Dapagliflozin reversed hyperglycemia-induced kidney injury by inhibiting the HMGB1/NF-κB pathway [35]. Moreover, pretreatment with canagliflozin prevents DKD development by ameliorating insulin resistance and islet damage [36]. In a clinical trial in patients with T2DM, empagliflozin treatment induced glycosuria after fasting and meal ingestion, resulting in augmented β-cell glucose sensitivity and decreased tissue glucose disposal [2].

Figure 1

The role of SGLT2 inhibitor in regulating plasma glucose, lipid metabolism, and ketogenesis. SGLT2 inhibitor increases fatty acid oxidation and ketogenesis and decreases plasma glucose levels, glucotoxicity, lipid accumulation, and renal stress. SGLT2, sodium-glucose cotransporter 2.

The kidney is a high-oxygen-consuming organ since it needs adequate adenosine triphosphate (ATP) to meet the energy needs for absorption of metabolites and various ions. Glucose and fatty acid are the main energy substrates that provide ATP. But the two energy substrates produce ATP at different rates. Glucose oxidation, including glycolysis and aerobic oxidation, produces 36 ATP molecules, whereas β-oxidation of fatty acid provides 106–129 ATP molecules, almost fourfold more than glucose. Thus, the kidney prefers fatty oxidation, and indeed 60% of renal energy is derived from fatty oxidation [37]. However, oil red O staining in diabetic db/db mice demonstrated accumulation of neutral lipids in glomeruli and tubular cells [31]. Consistently, lipid deposits were observed in kidney biopsies of patients with T2DM [38]. These results suggest impaired renal lipid metabolism. In high-fat diet (HFD)-fed mice, lipid content increased in the kidney with a concomitant increase in SGLT2 expression [39]. In vitro, sterol regulatory element-binding protein 1 (SREBP-1) expression is augmented under high-glucose culture conditions [38]. In patients with T2DM, SREBP-1 expression increases in parallel with urinary N-acetyl-β-D-glucosidase (NAG), tumor necrosis factor-α (TNF-α), and albumin–creatinine ratio (ACR) [38]. SGLT2i JNJ 39933673 attenuates neutral lipid deposition by inhibiting key molecules and enzymes in lipid synthesis, including carbohydrate response element binding protein-1 (ChREBP-1), SREBP-1, pyruvate kinase L, stearoyl-coenzyme A desaturase 1 (SCD-1), and diacylglycerol acyltransferase 1 (DGAT1) [31]. Impairment of fatty acid β-oxidation increases serum free fatty acid, which aggravates tubulointerstitial inflammation and fibrosis [40]. Empagliflozin downregulates the peroxisome proliferator-activated receptor γ (PPARγ)–CD36 pathway to reverse the lipotoxicity of free fatty acids in the kidney [40]. Moreover, SGLT2i augments ketogenic effects. Furthermore, β-hydroxybutyrate (β-HB) increased in dapagliflozin-treated mice [41]. Dapagliflozin relieved DNA damage and cellular senescence through β-HB-induced activation of nuclear factor erythroid 2-related factor 2 (NRF2) [41]. Due to increased urinary glucose excretion by SGLT2i, there is substantial energy and glucose loss, which facilitates the whole-body energy utilization conversion from glucose to fatty acid. It may partly explain the weight-loss effect of SGLT2i [42]. It is hypothesized that SGLT2i facilitates lipolysis and ketogenesis by inducing a fasting-like transcriptional paradigm [43, 44]. In nondiabetic obese mice, canagliflozin mimics a fasting-like transcriptional paradigm through activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR) [43, 45]. In addition, SGLT2i regulates glucose levels, lipid metabolism, and ketogenesis through the sirtuin-1/peroxisome proliferator-activated receptor-gamma coactivator-1α/fibroblast growth factor-21 (SIRT1/PGC-1α/FGF21) pathway, which prevents DKD by enhancing autophagy and inhibiting inflammation [44].

Hemodynamic hypothesis

Tubular glomerular feedback is sensitive to luminal Na+ and Cl concentrations. Changes in Na+ and Cl concentrations in the macula densa alter the chemical pathways and the production of adenosine. Adenosine binds to the adenosine A1 receptor, leading to afferent arteriolar vasoconstriction. Under the hyperglycemic condition, owing to the increase in filtration of glucose and SGLT2 expression, the reabsorption of sodium increases and sodium delivery to the macula densa decreases. Excessive reabsorption of glucose decreases sodium delivery to the macula densa, resulting in decreased production of adenosine. Decreased adenosine production accelerates afferent arteriolar vasodilation. Accordingly, more blood enters the glomeruli, leading to excessive intraglomerular hypertension and hyperfiltration. In the early stage of diabetes, higher eGFR increment is associated with DKD development [46]. Therefore, an intervention targeting initial sodium reabsorption and TGF should be more effective (Figure 2). The milestone study by Cherney et al. [47]. demonstrates that SGLT2i inhibited glomerular hypertension and hyperfiltration in patients with diabetes. Using the multiphoton in vivo image technique, Kidokoro et al. [48] found that empagliflozin increased adenosine and restored TGF in mice with T1DM. The Ins2+/Akita/empagliflozin group exhibited more renoprotective effects and higher urine adenosine excretion than the Ins2+/Akita group in rodent diabetic models. A1 adenosine receptor antagonism inhibits afferent arteriole constriction and blocks the renoprotective effects of empagliflozin. Thus, SGLT2i restores TGF, constricting the afferent arteriole and dilating the efferent arteriole through adenosine. Moreover, in metformin-treated patients with T2DM, van Bommel et al [49] proposed that additional dapagliflozin treatment reduced hyperfiltration by stimulating postglomerular vasodilation. The conventional drug for DKD, RASi, prevents hyperfiltration and DKD development via both afferent and efferent arteriolar vasodilation [50]. Although the efferent arteriole dilates more than the afferent arteriole, RASi still augments glomerular hypertension. Compared with RASi, SGLT2i constricts the afferent arteriole and dilates the efferent arteriole at the same time, conferring a better renoprotective effect than RASi. In addition, hyperglycemia induced the expression of podocyte-derived vascular endothelial growth factor A (VEGF-A). VEGF-A upregulates caveolin-1 and plasmalemmal vesicle associated protein-1 (PV-1) in endothelial cells, resulting in an increase of permeability in endothelial cells via the formation of numerous caveolae and diaphragmed fenestrae [51]. Empagliflozin attenuates endothelial cell architecture and decreased proteinuria via the VEGF-A/caveolin-1/PV-1 pathway [51].

Figure 2

SGLT2 inhibitors decrease eGFR levels and glomerular hyperfiltration. SGLT2 inhibitors inhibit natriuresis and glucose reabsorption, restoring impaired tubular glomerular feedback to stimulate afferent vasoconstriction and efferent arteriole dilation. eGFR, estimated glomerular filtration rate; MD, macula densa; PBow, hydrostatic pressure in Bowman space; SGLT2, sodium-glucose cotransporter 2.

Hypertension is a risk factor for diabetic complications and accelerates the progression of DKD [52, 53]. The renoprotective effects of SGLT2i may be partially attributed to reduction of the systemic blood pressure. At a dose of 10 mg/d, dapagliflozin treatment results in a 3.3 mm Hg decline in the baseline systolic blood pressure in patients with T2DM [54]. By analyzing 22,528 patients from 43 randomized control trials, Mazidi et al. [55] found that SGLT2i treatment significantly attenuated the systolic blood pressure levels, and the possible mechanisms include the following: (1) diuretic and natriuretic effects; (2) attenuation of arterial stiffness; (3) inhibition of sympathetic nervous system; and (4) inhibition of RAS. In ischemia/reperfusion injury (IRI) mice, luseogliflozin treatment attenuates renal endothelial rarefaction by stimulating VEGF expression [56]. Similarly, phase III clinical trials have proven that empagliflozin treatment decreases systolic blood pressure levels and reduces arterial stiffness index [57]; dapagliflozin attenuates systemic endothelial dysfunction, in addition to reducing aortic stiffness and renal resistive index [58]. Interestingly, van Bommel et al. [49] demonstrated that dapagliflozin treatment reduced blood pressure levels independent of changes in heart rate, suggesting that SGLT2i reduces blood pressure levels by affecting the sympathetic nervous system. In neurogenic hypertensive Schlager mice, hydroxydopamine treatment reduces systolic blood pressure levels and inhibits the expression of tyrosine hydroxylase and SGLT2 [59]. Dapagliflozin-treated hypertensive mice exhibit reduced blood pressure levels and antisympathetic effects, such as decline in tyrosine hydroxylase and norepinephrine production [59]. Urinary angiotensin II and angiotensinogen and the expression of angiotensin II receptor type 1 (AT1R) decreased in diabetic mice treated with dapagliflozin for 12 weeks [60].

Serum uric acid (UA)

High serum UA level is a risk factor for DKD development, and the highest serum UA levels occur in patients with T2DM with kidney injury [61]. In a posthoc analysis of 1342 patients with T2DM and nephropathy, every 0.5 mg/dL increment in serum UA parallels 6% harmful renal outcomes during the first 6 months of losartan treatment; and 20% of losartan renoprotective effects come from regulation of serum UA [62]. In 2014, Chino et al. [63] first demonstrated that luseogliflozin application reduces serum UA levels and promotes urinary UA excretion in healthy people. In a meta-analysis involving 34,941 patients, SGLT2i treatment reduced serum UA levels at −37.73 μmol/L compared to the placebo group [64]. However, augmented urinary UA excretion correlates with urinary D-glucose levels rather than the plasma concentration of luseogliflozin [63], suggesting that luseogliflozin regulates urinary UA indirectly. In Xenopus oocytes expressing the GLUT9 isoform, 2 mmol/L and 10 mmol/L D-glucose stimulate UA efflux, and this high glucose concentration appears in proximal tubules with SGLT2 inhibition [63]. Furthermore, a urinary concentration of 100 mmol/L D-glucose in luseogliflozin-treated collecting ducts inhibits urine UA reabsorption [63]. Therefore, it is hypothesized that SGLT2i-induced glycosuria facilitates urine UA extraction by targeting the GLUT9 isoform 2 in proximal tubules and collecting ducts [63] (Figure 3). However, this hypothesis was challenged by Novikov et al. [65] in 2019, as canagliflozin decreases serum UA levels in mice bearing a proximal tubular cell-specific deletion of GLUT9. Notably, in a double-blind trial, there was no evidence of benefits from the decline of serum urate after treatment with allopurinol in terms of kidney outcomes among patients with T1DM and early-to-moderate DKD [66]. Although this result may indicate that reducing UA alone does not provide the desired effects in patients with T1DM, it does not mean that reduction of UA is not one of the mechanisms by which SGLT2i works.

Figure 3

SGLT2 inhibitors indirectly increase UA excretion. SGLT 2 inhibitor-induced glucose retention in tubular and collecting ducts improves UA excretion by stimulating GLUT9. ATPase, adenosine triphosphatase; GLUT, glucose transporter; SGLT2, sodium-glucose cotransporter 2; UA, uric acid.

Oxidative stress and inflammation

The kidney is a high oxygen consumer and is rich in mitochondria. Early diabetes is characterized by glomerular hyperfiltration and tubular hypertrophy, resulting in increased transport workload and oxygen consumption. Metabolomic analysis, coupled with bioinformatics, reveals mitochondrial dysfunction as a characteristic of DKD [67]. Guanosine triphosphatases (GTPases), including optic atrophy factor 1 (Opa1) and mitofusin 2 (Mfn2), are pivotal in mitochondrial biogenesis. GTPase expression is suppressed by high glucose stimulation in vitro. Specific small interfering RNA (siRNA) or pharmacological blockade targeting SGLT2 restores normal levels of Opa1 and Mfn2. Using transmission electron microscopy, Takagi et al. [68] found that ipragliflozin improves HFD-induced mitochondrial abnormalities by increasing Opa1 and Mfn2 levels [68]. Consistently, high glucose breaks the balance between mitochondrial fusion and fission in vitro, and empagliflozin prevents mitochondrial dysfunction via normalizing the expression of dynamin-related protein 1 (Drp1) and Mfn1 [69]. Empagliflozin-induced AMPK phosphorylation indicates the possible role of SGLT2i in mitochondrial recovery [69].

SGLT2i reduces glucose and sodium reabsorption and decreases eGFR levels, resulting in the decline of specific oxygen consumption (QO2) in renal cortical tissues. Using the mathematical model of water and solute transport, Layton et al. [70, 71] found that QO2 in the renal cortex decreases by 30% after acute SGLT2i treatment. However, SGLT2i is concerned with aggravation of hypoxia injury in the S3 segment and the medullary thick ascending limb, as SGLT2 inhibition-induced transporter workload in the kidney medulla results in a 7% increment of QO2 [71]. The mimicked hypoxia state enhances erythropoietin (EPO) production and oxygen supplementation by promoting hypoxia-inducible factor 1α (HIF1α) expression [72].

SGLT2i mitigates inflammation through multisignal pathways, thereby ameliorating kidney injury and fibrosis. SGLT2i attenuates pancreatic oxidative injury, apoptosis, inflammation, and endoplasmic reticulum stress, in addition to recovering autophagic flux [73]. Dapagliflozin inhibits NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and fibrosis factor expression in the BTBR ob/ob mice model of T2DM [74] by boosting the tricarboxylic acid (TCA) cycle metabolite itaconate [45]. In mice treated with empagliflozin, microtubule-associated protein 1 light chain 3 (LC3)-II/LC3-I and bcl2/bax ratios decreased, revealing autophagy activation and apoptosis inhibition [75]. AMPK is an energy sensor. AMPK phosphorylation suppresses energy consumption, mTOR, and NF-κB, which eventually leads to inhibitor cell hypertrophy and hyperplasia, inflammation, and fibrosis [76]. In human kidney-2 (HK-2) cells cultured with high glucose, phosphorylated AMPK (p-AMPK) and autophagic flux decreased [77]. Dapagliflozin restores autophagy and inhibits NLRP3 inflammasome, IL-1β, IL-6, and TNFα via the AMPK/mTOR pathway [77].

Conclusion

DM displays variable effects in its different stages. Glomerular hyperfiltration and increased tubular reabsorption at the onset of DM are risk factors for DKD development, resulting in higher proximal tubular transporter workload and oxygen consumption. Clinical trials among patients with diabetes have revealed the renoprotective effects of SGLT2 inhibition in lowering diabetes-associated glomerular hyperfiltration, preventing renal toxicity of glucose, and reducing albuminuria. In summary, SGLT-2is may play a protective role through multiple mechanisms. It is not clear whether there is a dominant mechanism responsible for the clinical outcomes. Meanwhile, the difference in the SGLT2i protective mechanism between patients with T1DM and those with T2DM is also unclear. Current experimental studies mainly focus on the effect of SGLT2i on T2DM rather than on T1DM. The potential role of SGLT2i in T1DM needs further investigations. Clinical trials have demonstrated that SGLT2i can inhibit the progression of proteinuria, but the specific mechanism needs to be further explored. As SGLT2i improves renal outcomes in patients with diabetes, the role of SGLT1 in DKD progression needs more investigation. SGLT2 inhibition-induced switch of sodium and glucose transport from the cortex to the medulla may increase the risk of acute kidney injury, especially in patients with low volume. Although clinical trials have demonstrated the renoprotective effects of SGLT2i in patients with CKD without diabetes, it is still not clear whether SGLT2i can be added to the treatment regimen of the population as a conventional drug.

Figure 1

The role of SGLT2 inhibitor in regulating plasma glucose, lipid metabolism, and ketogenesis. SGLT2 inhibitor increases fatty acid oxidation and ketogenesis and decreases plasma glucose levels, glucotoxicity, lipid accumulation, and renal stress. SGLT2, sodium–glucose cotransporter 2.
The role of SGLT2 inhibitor in regulating plasma glucose, lipid metabolism, and ketogenesis. SGLT2 inhibitor increases fatty acid oxidation and ketogenesis and decreases plasma glucose levels, glucotoxicity, lipid accumulation, and renal stress. SGLT2, sodium–glucose cotransporter 2.

Figure 2

SGLT2 inhibitors decrease eGFR levels and glomerular hyperfiltration. SGLT2 inhibitors inhibit natriuresis and glucose reabsorption, restoring impaired tubular glomerular feedback to stimulate afferent vasoconstriction and efferent arteriole dilation. eGFR, estimated glomerular filtration rate; MD, macula densa; PBow, hydrostatic pressure in Bowman space; SGLT2, sodium–glucose cotransporter 2.
SGLT2 inhibitors decrease eGFR levels and glomerular hyperfiltration. SGLT2 inhibitors inhibit natriuresis and glucose reabsorption, restoring impaired tubular glomerular feedback to stimulate afferent vasoconstriction and efferent arteriole dilation. eGFR, estimated glomerular filtration rate; MD, macula densa; PBow, hydrostatic pressure in Bowman space; SGLT2, sodium–glucose cotransporter 2.

Figure 3

SGLT2 inhibitors indirectly increase UA excretion. SGLT 2 inhibitor-induced glucose retention in tubular and collecting ducts improves UA excretion by stimulating GLUT9. ATPase, adenosine triphosphatase; GLUT, glucose transporter; SGLT2, sodium–glucose cotransporter 2; UA, uric acid.
SGLT2 inhibitors indirectly increase UA excretion. SGLT 2 inhibitor-induced glucose retention in tubular and collecting ducts improves UA excretion by stimulating GLUT9. ATPase, adenosine triphosphatase; GLUT, glucose transporter; SGLT2, sodium–glucose cotransporter 2; UA, uric acid.

Main outcomes of SGLT2i from clinical trials

Drug/trial name Population Sample size Dose Duration Primary end points Secondary end points Reference
Dapagliflozin Patients with T2DM 485 Dapagliflozin 2.5 mg/d, 5 mg/d, or 10 mg/d vs.placebo 24 weeks Decreased HbA1c: 0.58%, 0.77%, and 0.89% with 2.5 mg, 5 mg, and 10 mg dapagliflozin Ferrannini et al. [6]
Canagliflozin Patients with T2DM 584 Canagliflozin 100 mg/d or 300 mg/d vs. placebo 26 weeks Change from baseline in HbA1c: −0.77% and −1.03% in canagliflozin 100 mg/d and 300 mg/d, respectively Decreased FPG, 2-h PPG, body weight, and systolic BP, and increased HDL-C compared with placebo Stenlöf et al. [7]
Sotagliflozin Patients with T1DM 1402 400 mg/d vs. placebo 24 weeks HbA1c <7.0%: 28.6% vs. 15.2% Change from baseline in HbA1c (–0.46%), weight (–2.98 kg), systolic BP (–3.5 mm Hg), and mean daily bolus dose of insulin (−2.8 units/d) Stenlöf et al. [9]
Sotagliflozin Patients with T1DM 782 Sotagliflozin 200 mg/d or 400 mg/d vs. placebo 52 weeks Changes in HbA1c from baseline: −0.37% for 200 mg and −0.35% for 400 mg The proportion of patients with HbA1c <7.0%: 25.67% for 200 mg and 20.35% for 400 mg Danne et al. [10]
Empagliflozin Patients with T1DM 1707 Empagliflozin 2.5 mg/d, 10 mg/d, or 25 mg/d vs. placebo 26 weeks Changes in HbA1c: −0.28% for 2.5 mg, −0.54% for 10 mg, −0.53% for 25 mg Weight reduction: 1.8/3.0/3.4 kg; increased glucose time-in-range: 1.0/2.9/3.1 h/d; lowered total daily insulin dose: 6.4/13.3/12.7%; decreased systolic BP: 2.1/3.9/3.7 mm Hg for 2.5 mg, 10 mg, or 25 mg/d, respectively Rosenstock et al. [11]
Dapagliflozin Patients with T1DM 813 Dapagliflozin 5 mg, 10 mg vs. placebo 24 weeks Decreased HbA1c: 0.37% for 5 mg, 0.42% for 10 mg vs. placebo Total daily insulin dose (−10.78% and −11.08%), and body weight (−3.21% and −3.74%) Mathieu et al. [12]
Dapagliflozin Patients with T1DM 833 Dapagliflozin 5 mg/d and 10 mg/d vs. placebo 52 weeks Reductions in HbA1c: 0.33% and 0.36% for 5 mg and 10 mg vs. placebo Body weight −2.95% and −4.54% for 5 mg and 10 mg, respectively, vs. placebo Dandona et al. [13]
Canagliflozin Patients with T2DM 4401 Canagliflozin 100 mg/d vs. placebo 2.62 years A composite of end-stage kidney disease (dialysis, transplantation, or a sustained eGFR of <15 mL/min/1.73m2): 43.2 vs. 61.2 per 1000 pt-y A lower risk of 3P-MACE (HR: 0.80; 95% CI: 0.67–0.95; P= 0.01) and hospitalization for heart failure (HR: 0.61; 95% CI: 0.47–0.80; P < 0.001) Perkovic et al. [14]
Canagliflozin Patients with T2DM and high cardiovascular risk 10,142 Canagliflozin 100 mg/d or 300 mg/d vs. placebo 13.5 years 3P-MACE (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke): 26.9 vs. 31.5 per 1000 pt-y Renal composite (40% reduction in the eGFR, renal-replacement therapy, and death from renal causes): HR: 0.60 (95% CI: 0.47–0.77); the progression of albuminuria: HR: 0.73 (95% CI: 0.67–0.79) Neak et al. [15]
Dapagliflozin Patients with eGFR of 25–75 mL/min/1.73m2 and urinary albumin-to-creatinine ratio of 200–5000 4304 Dapagliflozin 10 mg/d vs. placebo 2.4 years Composite events (>50% decline in the ESKD, or death from renal or cardiovascular causes): 9.2% vs. 14.5% Renal composite (>50% decline in ESKD or death from renal causes): HR 0.56 (95% CI, 0.45–0.68; P < 0.001); cardiovascular composite (death from cardiovascular causes or hospitalization for heart failure): HR: 0.71 (95% CI: 0.55–0.92; P= 0.009) Heerspink et al. [16]
Empagliflozin Patients with T2DM at high cardiovascular risk 7020 Empagliflozin 10 mg/d or 25 mg/d vs. placebo 3.1 years 3P-MACE (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke): 10.5% vs. 12.1% Rates of death from cardiovascular causes: 3.7% vs. 5.9%; hospitalization for heart failure: 2.7% and 4.1% (35% relative risk reduction); and death from any causes: 5.7% and 8.3% (32% relative risk reduction) Zinman et al. [17]
Dapagliflozin Patients with T2DM and atherosclerotic cardiovascular disease or risk factors for atherosclerotic cardiovascular disease 17,160 Dapagliflozin 10 mg/d 4.2 years MACE:(rate of cardiovascular death or hospitalization for heart failure): 4.9% vs. 5.8% Renal composite (≥40% decrease in eGFR to <60 mL/min/1.73m2, new ESRD, or death from renal or cardiovascular causes): 4.3% vs. 5.6%; death from any cause: 6.2% vs. 6.6% Wiviott et al. [18]
Empagliflozin Patients with class II, III, or IV heart failure and an ejection fraction ≤ 40% 3730 Empagliflozin10 mg/d vs. placebo 16 months Composite events (cardiovascular death or hospitalization for worsening heart failure):19.4% vs. 24.7% Total number of hospitalizations for heart failure: HR: 0.70 (95% CI: 0.58–0.85; P < 0.001); decline of eGFR: 0.55 mL/min/1.73m2/y vs. 2.28 mL/min/1.73m2/y, P < 0.001 Packer et al. [19]

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