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Renal Effects of Sodium-glucose-linkedTransporter 2 Inhibitors
  JOHTN
CARDIO-DIABETES
Renal Effects of Sodium-glucose-linked
Transporter 2 Inhibitors
1M Rajasekara Chakravarthi, 2Hari K Marri
1,2Consultant
1Department of Nephrology, Star Hospitals, Hyderabad, TelanganaIndia
2Department of Nephrology, Aayush Hospitals, Vijayawada, AndhraPradesh, India
Corresponding Author: M Rajasekara Chakravarthi, ConsultantDepartment of Nephrology, Star Hospitals, Hyderabad, TelanganaIndia
Phone: +919391059322
e-mail: rajasekarac@gmail.com
 
ABSTRACT
Diabetic nephropathy (DN) is the most common cause ofend-stage renal disease worldwide. Sodium-glucose-linkedtransporter 2 (SGLT2) inhibitors are a new and promising classof antidiabetic agents that target renal tubular glucose reabsorption.Their action is based on the blockage of SGLT2 sodium-glucose cotransporters that are located at the luminal membraneof tubular cells of the proximal convoluted tubule (PCT), inducingglucosuria. It has been proven that they significantly reduce glycatedhemoglobin (HbA1c), along with fasting and postprandialplasma glucose in patients with type II diabetes mellitus (T2DM).Glomerular hyperfiltration is a potential risk factor for DN. TheSGLT2 inhibitors reduce sodium reabsorption in the proximaltubule, causing, through tubuloglomerular feedback (TGF),afferent arteriole vasoconstriction and reduction in hyperfiltration.The SGLT2 inhibitors reduced glomerular hyperfiltrationin patients with T1DM, and in patients with T2DM, they causedtransient acute reductions in glomerular filtration rate (GFR),followed by a progressive recovery and stabilization of renalfunction. Interestingly, recent studies consistently demonstrateda reduction in albuminuria. Recently, it was demonstrated thatempagliflozin presents a significant cardioprotective effect.Although the SGLT2 inhibitors' efficacy is affected by renalfunction, new data have been presented that some SGLT2inhibitors, even in mild and moderate renal impairments, inducesignificant HbA1c reduction. Although these data are promising,only dedicated renal outcome trials will clarify whether SGLT2inhibitors, in addition to their glycemic and blood pressure (BP)benefits, may provide nephroprotective effects.
Keywords: Diabetic kidney disease, Hyperfiltration, Renoprotection,Sodium-glucose-linked transporter 2 inhibitors.
How to cite this article: Chakravarthi MR, Marri HK. RenalEffects of Sodium-glucose-linked Transporter 2 Inhibitors.Hypertens J 2017;3(3):154-160.
Source of support: Nil
Conflict of interest: None
 
 

INTRODUCTION

Diabetes is one of the major health problems worldwide,with a prevalence that is expected to reach more than 550 million patients by 2030.1 Also, it is one of theleading causes of renal disease resulting in a very highprevalence among dialysis patients.2 It is estimated thatapproximately one-third of patients with T2DM havesome degree of renal impairment3 and that chronickidney disease (CKD) is detectable in an important partof diabetic patients.4
 
ROLE OF THE KIDNEY IN GLUCOSE
HOMEOSTASIS


Despite wide fluctuations in the daily supply of glucoseand the body's demand for it, homeostatic mechanismsmaintain plasma glucose levels within a narrow range, withaverage levels of ∼90 to 100 mg/dL in a 24-hour period.5,6

The kidney's crucial role in maintaining glucosebalance was first described as early as 1938.17 Along withthe liver, the kidney supplies glucose during periods offasting. The renal contribution to gluconeogenesis is ∼15to 55 gm/day, or 20 to 25% of the glucose released intothe circulation after an overnight fast.7,8

The reabsorption of glucose filtered into the glomerularfiltrate is the primary mechanism by which the kidneyinfluences glucose homeostasis.8 Glucose excretion inurine is the net difference between the amount of glucosefiltered by the kidney and the amount reabsorbed. Inhealthy individuals, the kidney contributes significantlyto glucose homeostasis by reabsorbing essentially all ofthe ∼180 gm of glucose that it filters per day.9 Individualswithout diabetes thus have very little or no glucosepresent in the urine.

Reabsorption occurs in the PCT and is carried out bytwo isoforms of SGLT.20 The SGLT2 is located in the S1and S2 segments of the PCT and has a high capacity butlow affinity for glucose transport. In healthy individuals,it reabsorbs ∼90% of filtered glucose (Fig. 1).20 The SGLT1governs glucose transport in the S3 segment and is a lowcapacity,high-affinity glucose transporter (GLUT) thatreabsorbs the remaining 10% of the filtered glucose.10 Theactive transport of glucose is linked to downhill sodiumtransport, which is maintained by active extrusion ofsodium across the basolateral surface into the intracellularfluid (Fig. 2).10 Facilitated GLUTs carry glucose acrossthe basolateral membrane by facilitated diffusion.10

Glucose reabsorption in the PCT increases with risingplasma glucose levels until the transport maximum for glucose (Tmax) is reached. The Tmax is usually consideredto occur at a GFR of 260 to 350 mg/min/1.73 m2.The renal glucose threshold (RTG) is the plasma glucoseconcentration above which the SGLT capacity becomessaturated and urinary glucose excretion (UGE) occurs. Itis estimated to occur at a plasma glucose concentration of∼200 mg/dL (Fig. 3).5,6

 
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Renal Effects of Sodium-glucose-linked Transporter 2 Inhibitors

Renal Effects of Sodium-glucose-linkedTransporter 2 Inhibitors
Fig. 1: Renal glucose handling. In healthy individuals, the vastmajority of the glucose filtered by the kidney is reabsorbed by SGLT2in the S1 and S2 segments of the PCT, and the remaining glucoseis reabsorbed by SGLT1 in the S3 segment10

Renal Hemodynamic Effect of Sodium-Glucose
Cotransporter 2 Inhibition in Patients with T1DM


Hyperfiltration is an early renal hemodynamic abnormalityin experimental models of diabetes and is thought toreflect increased intraglomerular pressure.11-13 In humans the prevalence of renal hyperfiltration in subjects withT1DM has been reported to be as high as 60%, and thiscondition is accompanied by a significantly increasedrisk for development of DN in many studies.14-16 Thepathogenesis of hyperfiltration, however, is complex andinvolves changes in both neurohormonal/vascular factors(the vascular hypothesis) as well as TGF mechanisms (thetubular hypothesis).
 
Renal Effects of Sodium-glucose-linkedTransporter 2 Inhibitors
Fig. 2: The SGLT2 mediates glucose reabsorption in the kidney.The SGLT2 catalyzes the active transport of glucose (against aconcentration gradient) across the luminal membrane by couplingit with the downhill transport of Na+. The inward Na+ gradientacross the luminal epithelium is maintained by active extrusionof Na+ across the basolateral surface into the intracellular fluid.Glucose diffuses out of the cell down a concentration gradient viathe basolateral facilitative transporter GLUT210

The tubular hypothesis is based on an increase inproximal tubular glucose delivery attributable to chronichyperglycemia in DM. This leads to a maladaptiveincrease in glucose reabsorption along with sodiumvia the sodium-glucose cotransporter 2 (SGLT2) in the proximal tubule. As a result, distal sodium chloridedelivery to the macular densa is decreased.11


Renal Effects of Sodium-glucose-linkedTransporter 2 Inhibitors

Figs 3A to C: Postulated TGF mechanisms in normal physiology, early stages of DN, and after sodium-glucose cotransporter (SGLT2)inhibition. (A) Under physiological conditions, TGF signaling maintains stable GFR by modulation of preglomerular arteriole tone. Incases of conditional increases in GFR, the macula densa within the juxtaglomerular apparatus senses an increase in distal tubularsodium delivery and adjusts GFR via TGF accordingly. (B) Under chronic hyperglycemic conditions (DM), increased proximal SGLT2-mediated reabsorption of sodium (Na+) and glucose impairs this feedback mechanism. Thus, despite increased GFR, the macula densais exposed to lowered sodium concentrations. This impairment of TGF signaling likely leads to inadequate arteriole tone and increasedrenal perfusion. (C) The SGLT2 inhibition with empagliflozin treatment blocks proximal tubule glucose and sodium reabsorption, whichleads to increased sodium delivery to the macula densa. This condition restores TGF via appropriate modulation of arteriolar tone (e.g.,afferent vasoconstriction), which, in turn, reduces renal plasma flow and hyperfiltration

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This distal tubular condition is sensed as a loweffective circulating volume stimulus at the level of thejuxtaglomerular apparatus, causing an afferent renalvasodilatory response. The consequence of this alteredTGF results in supranormal GFR values into the hyperfiltrationrange. Targeting TGF in renal hyperfiltrationhas shown promising results in experimental animalmodels by using phlorizin, a nonspecific inhibitor ofthe renal tubular GLUTs SGLT1 and SGLT2.17,18 Theclinical relevance of these findings, however, could notbe conclusively studied in humans, because of the poortolerability of phlorizin resulting from its low selectivityfor SGLT2, SGLT1 inhibition-related gastrointestinalside effects, and very limited oral bioavailability.18Subsequent studies with selective SGLT2 inhibitors inanimals have also shown similar significant effects onrenal hyperfiltration.19

First SGLT2 Inhibitors

The first SGLT2 inhibitor, known as phlorizin, was isolatedfrom the bark of the apple tree in 1835 and was usedfirstly as an antipyretic. The glucosuric effect of phlorizinwas discovered only 50 years later and its mechanism ofaction was found to be localized at the PCT in the 1970s.20

Animal studies on phlorizin demonstrated normalizationof both fasting and postprandial plasma glucoseconcentrations in diabetic rats, improvement in peripheralinsulin sensitivity, improvement in insulin secretion, anddecline of elevated plasma glucagon levels in diabeticdogs. Due to poor oral bioavailability (15%), low SGLT2selectivity, and gastrointestinal side effects from SGLT1inhibition, phlorizin failed to progress to use in humans.Nevertheless, its beneficial effects on diabetic patientstriggered research on other agents that inhibit SGLT2transporters.20

Efficacy of SGLT2 Inhibitors on Glycemic Control

In human studies, it has also been reported that canagliflozinlowers the RTG in diabetic patients from 240 mg/dL(in normal individuals this value is 180 mg/dL) toapproximately 80 to 90 mg/dL. Additionally, a significantHbA1c reduction has been exhibited in diabetic patientstreated with dapagliflozin, canagliflozin, empagliflozin,and tofogliflozin. Furthermore, treatment with ipragliflozinfor 12 weeks induced a dose-dependent decreasein HbA1c from -0.49 to -0.81%. Administration of dapagliflozinproduces glucosuria-related urinary calorie loss(200-300 calories/day).21 In addition, inhibition of renalglucose reabsorption from empagliflozin ranged from13.1 to 49.6% with single doses from 1 to 100 mg and the amount of glucose excreted in the urine within the first24 hours after empagliflozin administration ranged from19.6 gm for a 1 mg dose to 74.3 gm for a 100 mg dose. TheUGE in ipragliflozin-treated patients was dose-dependentand reached approximately a maximum of 59 gm glucose.Dapagliflozin significantly decreases both fasting plasmaglucose (FPG) and postprandial glucose levels.20

 
Additional Beneficial Effects of SGLT2 Inhibitors

Body weight exhibited significant reduction with dapagliflozin,canagliflozin, and tofogliflozin. With ipragliflozin,body weight decreased up to 1.7 kg in 12 weeks. Also, inpatients treated with dapagliflozin and tofogliflozin, asignificant waist circumference reduction was observed.It has been suggested that body weight decrease may beattributed to visceral fat tissue lipolysis and enhancedlipid metabolism.22

Mean systolic and diastolic BP were found to be lowerin patients treated with dapagliflozin, possibly because ofosmotic diuresis and volume reduction, or canagliflozin.23

The SGLT2 inhibitors also demonstrated beneficialeffects on the lipidemic profile of T2DM patients. Highdensitylipoprotein cholesterol significantly increasedwith canagliflozin and triglycerides presented a smallreduction, although only one trial reached significance.The ß-cell function and homeostatic model assessment2B improved in patients treated with canagliflozin. It wasshown that SGLT2 inhibitors evoked beneficial effect onß-cell mass and retarded the loss of ß-cells in T2DM, possiblyby lowering glucose toxicity (Table 1).20

MAIN ADVERSE EFFECTS

According to the existing clinical studies, the mostcommon side effects of SGLT2 inhibitors are the increasedincidence of genital infections (GIs) and urinary tractinfections (UTIs) that could be attributed to the glucosuriceffect of these agents.

Due to their mechanism of action, SGLT2 inhibitorshave a very low risk of hypoglycemia. The reportedhypoglycemic episodes were mild-to-moderate in severity.Other side effects that can be observed with SGLT2inhibitors are polyuria and thirst, which can be assignedto osmotic diuresis due to the glucosuric effect of SGLT2inhibitors.

Hyperketonemia and ketonuria were also observed,as a result of increased lipolysis and mobilization oflipids and free fatty acids. It was recently described thatthe potential mechanisms that may be responsible forketoacidosis in patients treated with SGLT2 inhibitorsinclude lower insulin and higher glucagon levels that leadto increased lipolysis and ketogenesis and potentiallyincreased renal tubular reabsorption of ketones.

 
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Table 1: The SGLT2 inhibitors currently in clinical development
Renal Effects of Sodium-glucose-linkedTransporter 2 Inhibitors
EMA: European Medicines Agency; FDA: Food and Drug Administration

According to the new drug application for dapagliflozin,which was submitted to the US Food and Drug Administrationin 2011, a numerical imbalance was observed inbladder and breast cancer cases between treatment groups:9 out of 5,478 patients on dapagliflozin and 1 out of 3,156patients in the control group reported bladder cancer inthe pooled dapagliflozin studies and nine patients ondapagliflozin and one in the control group reported breastcancer. A post hoc pooled analysis of dapagliflozin clinicaltrials was published recently that confirmed the numericalimbalance of bladder cancer cases. It was reported in thesame study that none of the preclinical studies indicatedthat dapagliflozin is carcinogenic.20

SODIUM-GLUCOSE- LINKED TRANSPORTER 2
INHIBITORS IN CKD


Glucose-lowering Efficacy of SGLT2 Inhibitors in
Patients with CKD


Data regarding the efficacy and safety of SGLT2 inhibitorsin patients with T2DM and CKD present a specialinterest, given that renal failure is a common complicationof T2DM, and UGE is related to GFR and blood glucoselevels. According to a dapagliflozin study on diabeticpatients with CKD, decreasing GFR restrains the abilityof dapagliflozin to inhibit tubular glucose reabsorption.20

In another study on T2DM patients with stage 3 CKD(30 ≤ GFR ≤ 60 mL/min), the administration of dapagliflozinresulted in a 50% lower UGE than in T2DMpatients with normal or mildly impaired renal function.Although the use of dapagliflozin in patients with GFRbetween 45 and 59 mL/min resulted in a modest decreasein FPG and in HbA1c, there was no significant reductionof these parameters in patients with more advanced CKD.Although dapagliflozin-treated patients with CKD did not achieve a glycemic benefit, they presented a significantweight improvement. Finally, it was demonstratedthat dapagliflozin administration lowered albumin excretionin CKD patients compared with placebo.20

 
For patients with estimated GFR (eGFR) 30 to60 mL/min/1.73 m2, empagliflozin 25 mg also significantlyreduced HbA1c compared with placebo over 24 weeks.Empagliflozin 25 mg decreased body weight and bothsystolic and diastolic BP. In this study, empagliflozin wasalso tested in patients with stages 2 and 4 CKD. Not surprisingly,empagliflozin was more efficacious in reducingHbA1c in patients with stage 2 than stage 3 CKD, while itwas ineffective in patients with stage 4 CKD. Thus, thesestudies demonstrate that in patients with eGFR of 30 to 60mL/min/1.73 m2, the efficacy of SGLT2 inhibitors in reducingHbA1c is less than in patients with preserved GFR.Moreover, in patients with eGFR, 45 mL/min/1.73 m2,SGLT2 inhibitors did not lower HbA1c, and for this reason,discontinuation is recommended when this level of renalinsufficiency is reached.24

Sodium-glucose-linked transporter 2 Inhibitors
and Renal Function in Clinical Studies


The changes in GFR during SGLT2 inhibition are similarin patients with normal renal function and in those withCKD. The time course of changes in renal function is typicallycharacterized by a rapid decline in GFR during thefirst weeks of treatment, followed by a progressive recoverythat is faster and more evident in patients with normalrenal function at baseline. Studies performed in patientswith moderate renal impairment25-27 demonstrated significantrenal effects; thus, treatment with dapagliflozin(104 weeks),21 canagliflozin (26 weeks),26 and empagliflozin(52 weeks)27 resulted in an initial decrease in eGFRwith a trend toward an increase over time (Figs 2 and 3). In patients with CKD stage 3, after 1 week of treatment,there was a reduction in eGFR21 with a progressive recoveryof GFR during the following weeks (Fig. 2). In a studywhere patients with eGFR of 30 to 50 mL/min/1.73 m2were randomized to canagliflozin or placebo for 26weeks,26 a similar eGFR course was observed

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Renal Effects of Sodium-glucose-linkedTransporter 2 Inhibitors
Fig. 4: Glomerular filtration pressure that drives albuminuria, podocyte loss, and glomerulosclerosis in diabetesImage courtesy: Anders H. Nephron protection in diabetic kidney disease. N Engl J Med.2016;375(21):2096-2098.


Finally, in CKD stage 3, patients treatment withempagliflozin 25 mg had reduced eGFR by 4 mL/minat 12 weeks, with a slight recovery at 52 weeks. Interestingly,after drug discontinuation, GFR returned to thebaseline values, suggesting that the decrease in GFRduring treatment is hemodynamic and not consequentof renal injury.27

In addition to the effects on GFR, SGLT2 inhibitorsalso influence albuminuria. Progression of albuminuriaoccurred less frequently among participants assignedto canagliflozin than among those assigned to placebo(89.4 vs 128.7 participants with an event per 1,000 patientyears),corresponding to a hazard ratio of 0.73 [95% confidenceinterval (CI), 0.67-0.79] (Figs 3 and 4); the effectswere greater in CANVAS-R (hazard ratio, 0.64; 95% CI,0.57-0.73) than in CANVAS (hazard ratio, 0.80; 95%CI, 0.72-0.90) (p = 0.02 for homogeneity). Regression of albuminuria also occurred more frequently among thoseassigned to canagliflozin than among those assigned toplacebo (293.4 vs 187.5 participants with regression per1,000 patient-years; hazard ratio, 1.70; 95% CI, 1.51-1.91).The composite outcome of sustained 40% reduction ineGFR, the need for renal replacement therapy, or deathfrom renal causes occurred less frequently among participantsin the canagliflozin group than among those in theplacebo group (5.5 vs 9.0 participants with the outcomeper 1,000 patient-years, corresponding to a hazard ratioof 0.60; 95% CI, 0.47-0.77) (Figs 3 and 4); no significantdifference in this outcome was seen between CANVASand CANVAS-R.28

 
The EMPA-REG OUTCOME trial analyzes the secondaryrenal outcomes. Compared with those receivingplacebo, patients receiving empagliflozin experienced a39% reduction in the risk of new or worsening nephropathy(defined as a UACR 300 mg/gm, doubling of serumcreatinine with an eGFR of 45 mL/min/1.73 m2 or less,initiation of renal replacement therapy, or death due torenal disease). When the composite outcome of doublingof serum creatinine, initiation of renal replacementtherapy, or death due to renal disease was considered, the relative risk reduction in the empagliflozin groupwas even more pronounced (46%). These data providea strong support for a nephroprotective effect of SGLT2inhibitors.

 
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Renal Effects of Sodium-glucose-linked Transporter 2 Inhibitors

CONCLUSION

It is the first time in diabetes history that the kidneys havebeen used as a therapeutic target. The SGLT2 inhibitors,this new class of antidiabetic agents, via glucosuria induction,significantly decrease HbA1c and FPG levels. Giventhat these agents do not interfere with insulin secretionand action, ß-cell progressive failure does not attenuatetheir efficacy. Nevertheless, as the glucosuric effectdepends on renal function, the efficacy of these agentsdecreases along with the stages of renal impairment. TheSGLT2 inhibition also provides a significant beneficialeffect on body weight and BP reduction due to calorieloss and osmotic diuresis from glucosuria.

Being a new kid on the block, large randomized controlledtrials (RCTs) are necessary to investigate the longtermeffects of SGLT2 inhibitors on renoprotection andcardiovascular safety in diabetic kidney disease patients.

The current RCT evidence showed that SGLT2inhibitors increase the risk of GIs, and the effects maydiffer among SGLT2 inhibitors and trials with differentfollow-up. The impact of SGLT2 inhibitors on the riskof UTIs remains uncertain; the upcoming major trialsmay provide important insights on this issue. Whentheir results are available, an updated meta-analysis iswarranted.

Since even more agents of this new class are completingtheir clinical programs and reaching marketauthorization, our antidiabetic armamentarium is nowequipped with more promising and effective weaponsin the fight against diabetes.

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