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Current Vascular Pharmacology, 2017, 15, 96-102

REVIEW ARTICLE
ISSN: 1570-1611 Volume 15, Number 2
eISSN: 1875-6212

Current Vascular
Pharmacology
The journal for current and in-depth reviews on Vascular Pharmacology

Renoprotective Effects of SGLT2 Inhibitors: Beyond Glucose Impact

Factor:
2.374

Reabsorption Inhibition
BENTHAM
SCIENCE

V. Tsimihodimos, T.D. Filippatos, S. Filippas-Ntekouan and M. Elisaf *

Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece

ARTICLE HISTORY
Received: July 24, 2016
Revised: September 13, 2016
Accepted: September 13, 2016
DOI:
10.2174/15701611146661610071634
26
Current Vascular Pharmacology
Abstract: Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that
inhibit glucose and sodium reabsorption at proximal tubules. These drugs may exhibit renoprotective
properties, since they prevent the deterioration of the glomerular filtration rate and reduce the degree of
albuminuria in patients with diabetes-associated kidney disease. In this review we consider the patho-
physiologic mechanisms that have been recently implicated in the renoprotective properties of SGLT2
inhibitors. The beneficial effects of SGLT2 inhibitors on the conventional risk factors for kidney disease
(such as blood pressure, hyperglycaemia, body weight and serum uric acid levels) may explain, at least in
part, the observed renal-protecting properties of these compounds. However, it has been hypothesized that
the most important mechanisms for this phenomenon include the reduction in the intraglomerular pres-
sure, the changes in the local and systemic degree of activation of the renin-aldosterone-angiotensin sys-
tem and a shift in renal fuel consumption towards more efficient energy substrates such as ketone bodies.
The beneficial effects of SGLT2 inhibitors on various aspects of renal function make them an attractive
choice in patients with (and possibly without) diabetes-associated renal impairment.

Keywords: Sodium-glucose co-transporter 2 inhibitors, kidney, renoprotection, hyperfiltration, ketones, blood pressure.

INTRODUCTION
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are
a new class of oral drugs for the treatment of type 2 diabetes
mellitus (T2DM) that target renal SGLT2, which is responsi-
ble for approximately 90% of active renal glucose reabsorp-
tion in the S1 segment of the early proximal tubule [1].
SGLT2 inhibitors inhibit glucose reabsorption in the proxi-
mal renal tubules resulting in an insulin independent de-
crease of serum glucose concentration. Recent evidence sug-
gests that these drugs exhibit renoprotective properties since
they prevent the deterioration of the glomerular filtration rate
(GFR) and reduce the degree of albuminuria in patients with
diabetes-associated kidney disease. This short narrative re-
view considers the evidence regarding the mechanisms of
SGLT2 inhibitors-induced protection of kidney function.
METHODS
The PubMed database was searched for clinical studies
and narrative reviews published up to July of 2016 focusing
on the renal effects of SGLT2 inhibitors. Search terms in-
cluded: sodium-glucose co-transporter 2 inhibitors, diabetes,
kidney, nephropathy, albuminuria, glomerular filtration rate.
*Address correspondence to this author at the Department of Internal Medi-
cine, School of Medicine, University of Ioannina, 45 110 Ioannina, Greece;
Tel: +302651007509; Fax: +302651007016;
E-mails: melisaf54@gmail.com; egepi@cc.uoi.gr
The reference lists of retrieved articles were scanned for ad-
ditional relevant publications.
EFFECTS OF SGLT2 INHIBITORS ON GFR AND
ALBUMINURIA
Randomized clinical trials have shown that SGLT2 in-
hibitors initiation can induce a small, transient and reversible
reduction in GFR associated with a small increase in serum
creatinine levels, but these values usually return to baseline
levels, stabilize and remain stable over the 1-2 years of fol-
low up [2-9]. In this context, in the recently published Em-
pagliflozin Cardiovascular Outcome Event Trial in Type 2
Diabetes Mellitus Patients (EMPA-REG OUTCOME) study
[10] a short-term decrease in estimated GFR (eGFR) was
found in patients treated with empagliflozin (weekly de-
creases by 0.62±0.04 and 0.82±0.04 ml/min with the 10 and
25 mg/day doses, respectively vs 0.01±0.04 ml/min increase
in the placebo group, at week 4 vs baseline, p<0.001 for both
comparisons with placebo). Interestingly, drug cessation was
followed by an increase in eGFR (estimated weekly in-
creases of 0.48±0.04 ml/min and 0.55±0.04 ml/min for the
doses of 10 and 25 mg/day, respectively, vs 0.04±0.04
ml/min decrease in the placebo group, p<0.001 for both
comparisons with placebo [10]. This acute, mild, transient
and reversible decrease in eGFR could be due to the drug-
induced natriuresis and osmotic diuresis-associated hypo-
volaemia and reduction in blood pressure (BP) but also to
alterations in renal haemodynamics (see below) [10-12].

1875-6212/17 $58.00+.00 © 2017 Bentham Science Publishers

Renoprotective Effects of SGLT2 Inhibitors
Despite these acute alterations of eGFR in the EMPA-REG
OUTCOME trial, the eGFR remained stable in both treat-
ment groups during long-term empagliflozin therapy (with
annual decreases of 0.19±0.11 ml/min in both empagliflozin
dosage groups), while it was reduced in the placebo groups
(by 1.67±1.13 ml/min, p<0.001 for comparisons with both
empagliflozin dose groups). Furthermore, a decrease in the
urine albumin to creatinine ratio (UACR) was also reported
with these compounds [6-8]. Thus, a long term renoprotec-
tive effect of SGLT2 inhibitors has been demonstrated, simi-
lar to that reported with the administration of renin-
angiotensin-aldosterone system (RAAS) blockers [13].
In the EMPA-REG OUTCOME trial [10] the effect of
empagliflozin on renal outcomes was also assessed. Empa-
gliflozin administration was followed by a significant de-
crease in the risk of incident or worsening nephropathy (de-
fined as progression to macroalbuminuria; a doubling of the
serum creatinine level, accompanied by an eGFR of 45
ml/min; the initiation of renal-replacement therapy; or death
from renal disease) [hazard ratio 0.61, 95% confidence inter-
val (CI) 0.53-0.70, p<0.001 compared with placebo]. In ad-
dition, the risk for all the other prespecified renal microvas-
cular outcomes (such as a composite of incident or worsen-
ing nephropathy or death from cardiovascular causes, the
individual components of incident or worsening nephropa-
thy, and incident albuminuria in patients with a normal al-
bumin level at baseline) was also significantly reduced by
almost 40-50%. These beneficial effects were similar in pa-
tients with or without prevalent kidney disease at baseline
and were not affected by the degree of albuminuria at study
entry [10].
POTENTIAL MECHANISMS INVOLVED IN RENO-
PROTECTION BY SGLT2 INHIBITORS
The potential mechanisms of the SGLT2 inhibition-
associated renoprotection may be related to glucose lowering
but also to glucose lowering-independent mechanisms (Fig.
1). It is well known that hyperglycaemia plays a prominent
role in the development of diabetic nephropathy and the im-
provement in glycaemic control slows the progression of this
complication [14]. However, in the EMPA-REG OUT-
COMES trial, the differences in glycated haemoglobin
(HbA1C) between treatment arms were relatively small (for
example, at week 94 the adjusted mean differences between
patients receiving empagliflozin and those receiving placebo
Fig. (1). Potential mechanisms of sodium-glucose co-transporter 2 (SGLT2) inhibitors-induced renoprotection.
Current Vascular Pharmacology, 2017, Vol. 15, No. 2 97
were 0.42% (95% CI 0.48 to 0.36) with 10 mg and
0.47% (95% CI 0.54 to 0.41) with 25 mg, respectively)
and can hardly explain the observed beneficial effects of
empagliflozin on kidney function. In addition, in the same
trial, the impressive reduction in the rate of progression of
renal disease was observed in a relatively short period of
time (3 years) and was evident during the first months of
treatment, suggesting that other mechanisms beyond glucose
lowering also contribute to these effects [10]. In this context,
since the proximal tubular cells play an important role in the
pathogenesis of diabetic nephropathy [15], the reduced glu-
cose reabsorption in the proximal tubules (due to both de-
creased glucose levels and SGLT2 inhibition) could result in
a decrease in proximal tubular cells inflammation and fibro-
sis [16]. Reduced insulin levels and improved insulin sensi-
tivity may have also played a role [17, 18].
Additionally, a number of other glucose-independent
mechanisms may contribute to SGLT2 inhibitor-induced
renoprotection (Fig. 1). Thus, the substantial decrease in BP
(mainly due to drug-related natriuresis/osmotic diuresis), the
reduction in body weight and the decrease in serum uric acid
levels that has been observed with these drugs (but also other
so far undefined mechanisms) may also play a role in kidney
protection [16, 19-23]. In fact, increased serum uric acid
levels have been associated with the progression of chronic
kidney disease [24]. It should be mentioned that the effects
of SGLT2 inhibitors on BP may extend beyond the relatively
small decreases in BP that have been reported with these
compounds. Indeed, it has been hypothesized that SGLT2
inhibitors acting as diuretics can convert salt-sensitive hyper-
tension to non-sensitive one and also normalize BP patterns
from non-dipper to dipper; these effects may contribute to
the renoprotective properties of these drugs [25].
However, the reduction of renal hyperfiltration is consid-
ered the most important mechanism of SGLT2-inhibitors
associated renoprotection (Fig. 2) [16, 20]. Thus, the drug-
associated decreased reabsorption of Na+-glucose in the
proximal tubules along with a potential inhibition of Na+-H +
anti-porter in proximal tubules results in increased sodium
delivery to the macula densa [26]. This process activates the
tubuloglomerular feedback (through adenosine production),
which, in turn, induces afferent arteriole vasoconstriction and
decreased intraglomerular pressure. This decrease in intra-
glomerular pressure is associated with the reduction of GFR
observed with the SGLT2 inhibitors in the short-term, but in
98 Current Vascular Pharmacology, 2017, Vol. 15, No. 2
Fig. (2). Sodium-glucose co-transporter 2 (SGLT2) inhibitors-associated decrease of hyperfiltration.
NHE3: antiporter Na+-H+; GFR: glomerular filtration rate; TGF: tubuloglomerular feedback.
the long-term it can reduce albuminuria and also the hyper-
filtration-associated glomerular injury, which is crucial for
the initiation and progression of diabetic renal disease [27,
28]. In fact, in patients with type 1 diabetes mellitus (T1DM)
and glomerular hyperfiltration, empagliflozin reduced the
intraglomerular pressure (by 6-8 mmHg) [12]. In another 8-
week trial, SGLT2 inhibitors reduced GFR by 19% in T1DM
patients with hyperfiltration at baseline; this reduction was
independent of the decrease in serum glucose levels [29].
Other trials in patients with chronic kidney disease also
showed that these drugs can decrease both GFR and albu-
minuria [30, 31]. Furthermore, the SGLT2 inhibitors-
associated reduction in the reabsorption of sodium in the
proximal tubules results in increased fluid delivery to the
distal tubules and promotes increased hydrostatic pressure in
Bowman space, which can further lower GFR in patients
with renal hyperfiltration [20].
SGLT2 inhibitors may also affect the RAAS axis both
systemically and locally in the kidney (Fig. 3). In fact, em-
pagliflozin administration in patients with T1DM was asso-
ciated with increased circulating levels of angiotensin II and
aldosterone [8, 29]. However, since most of diabetic patients
also receive drugs affecting the renin-angiotensin axis, such
as angiotensin converting enzyme inhibitors or angiotensin
receptor blockers (81% of the participants in the EMPA-
REG OUTCOME trial were receiving these drugs [10]), the
increased angiotensin II levels are expected to act only
through the unopposed angiotensin II receptors (AT-II recep-
tors), leading to vasodilator, antiproliferative, antihypertro-
phic, antiarrhythmic and antinflammatory effects as well as
to a reduction in the magnitude of albuminuria [32, 33]. In-
terestingly, in one experimental study the combination of
RAAS blockage with SGLT2 inhibitors was associated with
additive renoprotection [34]. Thus, the renoprotective effects
of empagliflozin may, at least in part, be attributed to the
activation of AT-II receptors. It should be mentioned that
although SGLT2 inhibitors are associated with increased
Tsimihodimos et al.
circulating levels of angiotensin II and aldosterone, the in-
creased sodium delivery to the macula densa results in de-
creased activity of the intrarenal renin-angiotensin axis lead-
ing to renoprotection (Fig. 3) [35-38].
Recently it was suggested that SGLT2 inhibitors can de-
crease oxygen consumption in the kidneys (suggesting de-
creased oxygen needs) and thus can reduce tissue hypoxia
(Fig. 4). Renal oxygen consumption and energy expenditure
is increased in diabetic individuals; this increase is necessary
for the increased sodium reabsorption (through the tubular
sodium-glucose reabsorption and the Na+/K+ ATPase pump
in the basolateral side), but it induces renal hypoxia and pro-
gressive renal dysfunction, contributing to the evolution of
chronic kidney disease [39, 40]. Treatment with SGLT2 in-
hibitors is associated with decreased sodium reabsorption
and less hypoxia [41]. It has been proposed that SGLT2 in-
hibitors may increase oxygen consumption in the outer me-
dullary S3 segment via an increased sodium and glucose
delivery to this segment (an effect largely depended on the
extent of GFR lowering) [42, 43]. Additionally, the increased
concentrations of ketones, which are commonly observed in
patients treated with SGLT2 inhibitors, can induce a shift in
renal fuel utilization towards this substrate [19, 41, 44, 45]. It
is well known that
-hydroxybutyric acid is a more efficient
fuel than glucose and free fatty acids, leading to the produc-
tion of more ATP and more Na+ reabsorption per molecule
of O2 consumed. Thus, SGLT2 inhibitors can increase the
production of ketones (mainly due to increased glucagon to
insulin ratio), which may be used as the preferred fuel to
enable increased sodium reabsorption in the more distal
nephrons necessary to maintain volume status. This process
is associated with a reduction in renal oxygen consumption,
and in turn less renal hypoxia and long-term renoprotection
(Fig. 4).
The decrease in BP, HbA1C, body weight, and intra-
glomerular pressure is expected to also decrease albuminuria
in diabetic individuals. In this context, clinical trials have
Renoprotective Effects of SGLT2 Inhibitors
Fig. (3). Sodium-glucose co-transporter 2 (SGLT2) inhibitors, renoprotection and renin angiotensin axis.
AT2: angiotensin II.
Fig. (4). Sodium-glucose co-transporter 2 (SGLT2) inhibitors and renoprotection: The role of renal hypoxia.
GFR: glomerular filtration rate.
shown that canagliflozin and dapagliflozin decrease albu-
minuria in diabetic patients [30, 31, 46-49]. A recently pub-
lished study which examined the effect of empagliflozin on
UACR by pooling data from patients with T2DM and micro-
or macroalbuminuria showed that empagliflozin significantly
reduced UACR in patients with either microalbuminuria or
macroalbuminuria by 32% and 41%, respectively (p<0.001
for both groups vs. placebo) [50]. Interestingly, regression
analysis confirmed that most of this decrease in albuminuria
was not explained by the decreases in HbA1C, systolic BP
and body weight. This finding suggests that the antiproteinu-
ric effects of SGLT2 inhibitors may be due to their renal
haemodynamic effects, that is the decrease in intraglomeru-
lar pressure [50]. As previously mentioned, this decrease has
already been described in patients with T1DM [29]. This
decrease in albuminuria was positively associated with the
small decreases in GFR over the first 3-4 weeks of treatment
Current Vascular Pharmacology, 2017, Vol. 15, No. 2 99
[50]. Other factors that may contribute in the observed de-
crease in albuminuria include: decreased BP and arterial
stiffness [51], decreased serum uric acid levels [52], down-
regulation of pro-inflammatory pathways [8, 53-56], mild
decrease of effective circulating fluid volume known to po-
tentiate the effects of RAAS blockers on albumin [38] and
also the reduction of natriuretic peptides known to be ele-
vated in diabetic patients and possibly affecting renal hyper-
filtration [38].
CLINICAL IMPLICATIONS OF THE EFFECTS OF
SGLT2 INHIBITORS ON RENAL FUNCTION
It is worth mentioning that the majority of diabetic pa-
tients are also treated with RAAS blockers. The additive
haemodynamic effects of SGLT2 inhibitors with these drugs
(SGLT2-mediated increase in glomerular afferent arteriole
100 Current Vascular Pharmacology, 2017, Vol. 15, No. 2
tone and RAAS blockers-mediated decrease of glomerular
efferent arteriole tone) could confer additive renoprotection
but also lead to more adverse renal effects resulting from a
significant decrease of intraglomerular pressure [9, 48]. In
fact, the Food and Drug Administration (FDA) recently
strengthened its drug label warning about the risk of acute
renal injury associated with canagliflozin and dapagliflozin
[57]. Interestingly, 101 confirmed cases of SGLT2 inhibi-
tors-associated acute renal injury were reported to the FDA.
Many patients developed acute renal injury within 1 month
of drug initiation, while the main predisposing factors were
dehydration, low BP, or administration of other drugs affect-
ing kidney function [57]. In some cases, discontinuation of
the drug resulted in an improvement in renal function. Thus,
special attention should be given to predisposing factors for
the development of acute kidney injury, such as hypovolae-
mia, chronic renal disease, low output heart failure and drugs
affecting renal function, such as diuretics, angiotensin con-
verting enzyme inhibitors, angiotensin receptor blockers and
non-steroidal anti-inflammatory drugs [57]. Renal function
should be checked before and periodically after dapagliflozin
or canagliflozin administration, and in case of renal function
deterioration, prompt interruption of therapy, careful man-
agement of the predisposing risk factors and in certain cases
correction of hypovolaemia is indicated [57, 58]. In this set-
ting it should be mentioned that dipeptidyl peptidase-4
(DPP-4) inhibitors can downregulate Na+-H+ exchanger NH3
in rat proximal tubules leading to natriuresis, increased
diuresis and decrease in BP [59, 60]. Even though data in
diabetic patients are limited, acute renal failure with a de-
crease in BP has been recently reported with linagliptin in a
case report [61]. It is possible that the combination of DPP-4
inhibitors and drugs affecting RAAS may adversely affect
renal haemodynamics leading to a deterioration of renal per-
fusion [62, 63]. In such cases the co-administration of
SGLT2 inhibitors may result in further renal hypoperfusion
and kidney injury.
It should be mentioned that in a rat model of polycystic
kidney disease, dapagliflozin administration was associated
with an increase in cyst volume and total kidney weight even
though no change in creatinine clearance was observed [64].
This finding of increased cyst volume needs further investi-
gation. However, in another experimental study in
Han:SPRD rats with polycystic kidney disease dapagliflozin
administration improved renal function and reduced albu-
minuria but had no effect on cyst growth [65].
CONCLUSION
Accumulating evidence suggests that SGLT2 inhibition
may provide renoprotection in diabetic patients with or with-
out diabetes-associated kidney disease. The most important
mechanisms for this phenomenon include the reduction in
the intraglomerular pressure, the changes in the local and
systemic degree of activation of the RAAS system, and a
shift in renal fuel consumption towards more efficient energy
substrates such as ketone bodies. Although SGLT2 inhibitors
must be used with caution in hypovolaemic states and in
individuals receiving drugs that may affect renal function,
their beneficial effects on various aspects of renal physiology
makes them an option worth considering in patients with
(and possibly without) diabetes-associated renal dysfunction.
Tsimihodimos et al.
AUTHORSHIP
ME has received speaker honoraria, consulting fees, and
research funding from AstraZeneca, Schering Plough, Merck,
Pfizer, Solvay, Abbott, Boehringer Ingelheim and Fournier,
and has participated in clinical trials with AstraZeneca, Merck,
Sanofi-Synthelabo, Solvay, Glaxo, Novartis, Pfizer and
Fournier. The authors have given talks and attended confer-
ences sponsored by various pharmaceutical companies, in-
cluding Bristol-Myers Squibb, Pfizer, Lilly, Abbott, Amgen,
AstraZeneca, Novartis, Vianex, Teva and MSD.
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
Declared none.
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