Drugs

https://doi.org/10.1007/s40265-021-01573-3

REVIEW ARTICLE

A Role for SGLT‑2 Inhibitors in Treating Non‑diabetic Chronic Kidney

Disease
Lucia Del Vecchio1   · Angelo Beretta2 · Carlo Jovane1 · Silvia Peiti1,3 · Simonetta Genovesi3,4

Accepted: 12 July 2021

© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2021

Abstract
In recent years, inhibitors of the sodium-glucose co-transporter 2 (SGLT2 inhibitors) have been shown to have significant
protective effects on the kidney and the cardiovascular system in patients with diabetes. This effect is also manifested in
chronic kidney disease (CKD) patients and is minimally due to improved glycaemic control. Starting from these positive
findings, SGLT2 inhibitors have also been tested in patients with non-diabetic CKD or heart failure with reduced ejection
fraction. Recently, the DAPA-CKD trial showed a significantly lower risk of CKD progression or death from renal or cardio-
vascular causes in a mixed population of patients with diabetic and non-diabetic CKD receiving dapagliflozin in comparison
with placebo. In patients with heart failure and reduced ejection fraction, two trials (EMPEROR-Reduced and DAPA-HF)
also found a significantly lower risk of reaching the secondary renal endpoint in those treated with an SGLT2 inhibitor in
comparison with placebo. This also applied to patients with CKD. Apart from their direct mechanism of action, SGLT2
inhibitors have additional effects that could be of particular interest for patients with non-diabetic CKD. Among these, SGLT2
inhibitors reduce blood pressure and serum acid uric levels and can increase hemoglobin levels. Some safety issues should
be further explored in the CKD population. SGLT2 inhibitors can minimally increase potassium levels, but this has not been
shown by the CREDENCE trial. They also increase magnesium and phosphate reabsorption. These effects could become
more significant in patients with advanced CKD and will need monitoring when these agents are used more extensively in
the CKD population. Conversely, they do not seem to increase the risk of acute kidney injury.

1 Introduction CKD is often a smouldering and insidious disease that

Chronic kidney disease (CKD) affects 697.5 million people
globally [1]. According to data from the National Health and
Nutrition Examination Survey (NHANES), the age-adjusted
prevalence of CKD ranges between 13 and 14% of the US
adult population, with minimal variation over the years [2].
As one would expect, CKD prevalence increases with age
and is slightly more common in women than men. African
Americans and low-income and low-education people are
the most affected groups. Among these patients, 2.5 million
people need renal replacement therapy (RRT) worldwide [3].
* Lucia Del Vecchio
lucia.delvecchio@asst-lariana.it
1
Department of Nephrology and Dialysis, Sant’Anna
Hospital, ASST Lariana, Como, Italy
2
Internal Medicine Unit, Valduce Hospital, 22100 Como, Italy
3
School of Medicine and Surgery, Nephrology Clinic,
University of Milano, Bicocca, 20100 Milan, Italy
4
Istituto Auxologico Italiano, IRCCS, 20100 Milan, Italy
remains asymptomatic in the majority of cases until it
is advanced; for this reason, it frequently remains unde-
tected and overlooked. Consequently, late referral and
inadequate diagnosis and treatment are missed opportu-
nities for proper management of CKD and for delaying its
progression towards kidney failure. Indeed, people with
CKD have a much higher risk of death rather than kidney
failure since they pay a severe toll in terms of increased
cardiovascular (CV) disease [4]. Moreover, in comparison
to the general population of similar age, CKD patients
progressively experience a decrease in their wellbeing and
quality of life.
Despite different aetiologies, it is believed that CKD has
common mechanisms that perpetuate and self-sustain the
initial damage [5]. Indeed, microvasculature dysfunction
and glomerular hyperfiltration activate disruptive pathways
inside the kidney, promoting mesangial activation, glomeru-
losclerosis, podocyte dysfunction, inflammation, hypoxia,
fibrosis, and tubular damage.
Given these shared mechanisms of progression despite
different underlying diseases, several nephroprotective

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Key Points  gested in CKD patients, especially in those with proteinuria.
SGLT2 inhibitors act at the proximal tubule where they
inhibit glucose and sodium reabsorption. The increased
sodium output to the macula densa induces vasoconstric-
tion of the afferent arteriole and reduces hyperfiltration.
Several other nephroprotective mechanisms have also
been identified.
Starting from the observed benefits on the kidney and
cardiovascular system in patients with diabetes, SGLT2
inhibitors have also been proposed as a possible treat-
ment for patients with non-diabetic chronic kidney dis-
ease (CKD) or with heart failure with reduced ejection
fraction.
Recent large trials have shown the efficacy of SGLT2
inhibitors on renal and cardiovascular endpoints in these
two populations.
Apart from direct benefits on the kidney and the heart,
several additional benefits could be of help in non-dia-
betic CKD, such as a decrease in blood pressure values
and of uric acid, improvement of anemia, and possibly
protection from acute kidney injury.
In people with advanced CKD, monitoring of potassium,
magnesium, and phosphate levels is warranted.
agents have been tested and introduced into clinical prac-
tice over the years.
1.1 State of the Art and Unmet Needs: RAS
Blockade, Blood Pressure Reduction, and Low
Sodium Intake
Inhibitors of the renin-angiotensin system (RAS), blood
pressure control, and reduced sodium intake are considered
the gold standard of nephroprotection.
Starting from the observation of a clear relationship
between blood pressure values and CKD progression and
that higher blood pressure values increase proteinuria, in the
last 30 years it has been widely accepted that lower blood
pressure values could slow down CKD progression, espe-
cially in proteinuric nephropathies. Indeed, proteinuria can
be worsened by the transmission of high systemic pressure to
the glomeruli. In addition to this, the treatment of hyperten-
sion can contribute to reducing the burden of cardiovascular
disease. Over the years, several studies compared different
blood pressure targets in CKD. The landmark trial is the
Modification of Diet in Renal Disease (MDRD) Study [6].
L. Del Vecchio et al.
Based on its findings, strict blood pressure control was sug-
However, the evidence supporting these recommendations
is weak and the enrolled population of the MDRD (Cau-
casian in the majority of cases with a mean age around 50
years) possibly shows little representation of the average
CKD patient at the current time. Subsequent trials did not
show any significant advantage on hard renal endpoints
associated with a more intensive blood-pressure control
[7–9]. More recently, the Systolic Blood Pressure Interven-
tion Trial (SPRINT) did not show a significant advantage on
renal outcomes (possibly because of insufficient statistical
power in this respect) and possibly a higher incidence of
acute kidney insufficiency [10], despite a clear benefit on
the risk of reaching the primary composite cardiovascular
endpoint [11].
Theoretically, any antihypertensive therapy is capa-
ble of decreasing proteinuria in hypertensive patients.
However, RAS inhibitors also have hemodynamic and
non-hemodynamic actions that confer additional nephro-
protective properties. Accordingly, they have become the
first-choice therapy of hypertension in diabetic and non-
diabetic nephropathies. Moreover, some metanalyses sup-
port their use [12, 13]. However, single trials, especially
those performed in the 1990s, have somehow been critically
reviewed, as the enrolled patient populations were not repre-
sentative of today’s CKD patients, who are old, obese, with
low proteinuria levels, and with a high burden of comorbidi-
ties in many cases. This aspect is of importance, considering
that nephroprotection with RAS inhibitors is more evident in
the presence of significant proteinuria levels [14, 15].
Other critical points have also risen over the years. For
instance, the two hallmark studies of angiotensin-II receptor
blockers (ARBs) in type 2 diabetes (T2D) gave consistent
findings, but the magnitude of nephroprotection was mod-
est and the number of patients needed to be treated to avoid
one outcome was high. Moreover, as shown in non-diabetic
nephropathies, treatment with losartan did not significantly
reduce the risk of a renal event when baseline albuminuria
was below 1.5 g/g [16].
Nearly 2 decades ago, dual blockade was proposed to
increase RAS inhibition and counterbalance the effects of
the single molecules. Several data showed a greater anti-
proteinuric effect of dual blockade in comparison to the sin-
gle agents. However, large trials did not show a significant
beneficial effect on the risk of hard endpoints but increased
the risk of hyperkalaemia and acute kidney injury (AKI)
[17–20]. Accordingly, the European Medicine Agency
(EMA) gave restrictions on dual blockade in patients with
diabetic nephropathy, discouraging the use of an angiotensin
converting enzyme (ACE) inhibitor with an ARB and strictly
contraindicating the combination of the direct renin inhibitor
aliskiren with an ACE inhibitor or an ARB [21].
SGLT-2 Inhibitors in Non-diabetic CKD
The antiproteinuric effect of RAS inhibitors can be
enhanced by reduced sodium intake [22]. Unfortunately,
compliance with a low-salt diet is often suboptimal in eve-
ryday clinical practice.
Finally, RAS inhibitors are often under-prescribed or dis-
continued in everyday clinical practice [23] because of the
fear or occurrence of AKI and/or hyperkalaemia, especially
in old and frail patients.
2 The Physiology of Sodium and Glucose
Transport and Mechanism of Action
of SGLT2 Inhibitors
Glucose homeostasis is highly regulated, and the kidney
plays a crucial role in these processes. Glucose reabsorp-
tion from the proximal tubule is one of these tasks. The
glomerulus filters ~ 162 g of glucose/day, and normally less
than 1% is finally excreted in the urine.
In 1960 at the Symposium on Membrane Transport and
Metabolism in Prague, Dr B. Crane first proposed “the
Na+/Glucose transport hypothesis”, according to which the
energy for active glucose transport is provided by the sodium
gradient across the cell membrane.
This reabsorptive capacity depends on the presence of
two different classes of glucose transporters: the SLC5
solute carriers, also called N ­ a+-glucose co-transporters
(SGLTs), and the SLC2A transporters (also called GLUTs).
GLUTs are expressed on the basolateral membrane in the
renal proximal tubule and they cause glucose to go back
to the interstitial space by facilitated diffusion [24]. The
glucose gradient across the membrane is the driving force,
whereas for SGLTs the transmembrane sodium gradient is
the driving force for glucose uptake [25, 26].
In humans at least six different SGLT isoforms have been
identified: SGLT1 and SGLT2 are mainly expressed in intes-
tinal and renal cells [25, 27].
SGLT1 is a high-affinity transporter for glucose (Michae-
lis-Menten constant [Km] = 0.4 mmol/L) and galactose [28,
29]. Two sodium ions are transported through the SGLT1
for each glucose molecule. SGLT2 Km values for glucose
and sodium are 2 and 25 mmol/L, respectively. SGLT2 is a
low-affinity and high-capacity glucose transporter. It is pre-
dominantly expressed in the kidneys of rodents and humans
[30, 31].
In the small intestine, SGLT1 is responsible for the
absorption of glucose [31–33], which enters into the epi-
thelial cells. Thereafter it flows into the circulation through
GLUT2 [34].
In the kidney, SGLT2 and SGLT1 are responsible for glu-
cose entry into the tubular cells across the apical membrane
of the proximal convoluted tubule. Glucose then reaches the
blood circulation through the action of GLUT2 and GLUT1
[35].
SGLT2 is mainly distributed in the upper part of the
proximal tubule (S1 and S2 segments), whereas SGLT1
is distributed in the lower part, the S3 segment in humans
[36–38]. In euglycemia, SGLT2 is mainly responsible for the
reabsorption of filtered glucose: it accounts for more than
80% of the glucose reabsorption; SGLT1 takes the remain-
ing glucose [39, 40]. When more glucose is delivered into
the distal proximal tubule, due to SGLT2 inhibition, SGLT1
can compensate for the reabsorption of glucose. Euglycemic
humans treated with SGLT2 inhibitors (SGLT2is) maintain
fractional glucose reabsorption of 40–50% [40, 41]. In the
presence of sustained hyperglycemia, the glucose flow to the
distal proximal tubule is increased, and SLGT1 also medi-
ates glucose reabsorption.
In this condition, SGLT2 activity leads to a decrease in
NaCl delivery to the macula densa, sensed by the juxta-glo-
merular apparatus as a reduction in the effective circulating
volume. This event induces a vasodilation of the afferent
glomerular arteriole with consequent hyperfiltration and
intra-glomerular hypertension, a phenomenon called tubulo-
glomerular feedback [42]. SGLT2is reverse this process and
increase NaCl delivery to the macula densa, inducing vaso-
constriction of the afferent arteriole via the paracrine release
of adenosine [43]. This phenomenon has been described in a
series of experimental models of diabetes mellitus [44–46]
and also in young adults with type 1 diabetes (T1D) [47].
However, vasoconstriction of the afferent arteriole seems not
to be the only mechanism through which SGLT2is exert their
nephroprotective effect. Recently, an experimental study
showed by direct measurement that the tubule-glomerular
feedback response to SGLT2 blockade involves both preglo-
merular vasoconstriction and post-glomerular vasorelaxa-
tion [48]. Moreover, in studies performed on animals with
experimental diabetes, the suppression of SGLT2 activity
reduces the production of glomerular markers of inflam-
mation and fibrosis and suppresses oxidative stress in the
diabetic mouse kidney [49, 50]. It has also been suggested
that in T2D patients, the nephroprotective mechanism of
SGLT2is is not so much due to the rebalancing of tubulo-
glomerular feedback, but to the establishment of post-glo-
merular vasodilation [51]. The evidence that SGLT2is exert
a nephroprotective effect even in non-diabetic CKD con-
firms that the mechanisms by which these drugs protect renal
function go beyond vasoconstriction of the afferent arteriole,
described in the presence of glomerular hyperfiltration, but
absent in advanced diabetic nephropathy or in non-diabetic
forms of CKD. Of note, improvement of cardiac function by
SGLT2is may also have a favorable effect on the kidneys.
Moreover, the potential nephroprotective effect of SGLT2is
can be also related to their effects on multiple risk factors

of renal impairment such as high blood glucose (for T2D),
high blood pressure, high serum uric acid, and body weight.
3 SGLT2 Inhibitors in Type 2
Diabetes: Mechanism of Actions
on the Cardiovascular System
and Available Evidence
SGLT2is were developed to lower blood glucose levels in
T2D patients. Several trials designed to evaluate SGLT2i
cardiovascular (CV) safety demonstrated that they had addi-
tional benefits for the CV system [52–55]. This finding was
confirmed by several analyses, albeit with a certain degree
of heterogeneity between the different molecules in the class.
The trials completed to date in T2D patients have predom-
inantly focused on atherosclerotic CV disease (ASCVD)-
related outcomes. In this respect, a rather modest effect was
found in risk reduction for MACE (major adverse cardiovas-
cular events: myocardial infarction, stroke, or CV death). In
particular, the Empagliflozin Cardiovascular Outcome Event
Trial in Type 2 Diabetes Mellitus Patients-Removing Excess
Glucose (EMPA–REG OUTCOME) demonstrated a 14%
relative risk reduction in three-point MACE in association
with empagliflozin use (P = 0.04 for superiority) [51]. This
difference was largely driven by significantly lower rates
of CV death in the empagliflozin group. The CANagliflo-
zin cardioVascular Assessment Study (CANVAS) Program
included data of 10,142 T2D patients at high risk for CV
events from two trials (CANVAS and CANVAS-R). In the
canagliflozin group the rate of triple MACE was signifi-
cantly lower than in the placebo group (hazard ratio (HR):
0.86; 95% confidence interval (CI) 0.75–0.97; P = 0.02 for
superiority) with regard to both primary and secondary
prevention [53]. Conversely, in the Dapagliflozin Effect on
Cardiovascular Events—Thrombolysis in Myocardial Infarc-
tion 58 (DECLARE-TIMI 58) study, dapagliflozin failed
to demonstrate significant benefit in terms of a reduction
of MACE. As opposed to the trials reported above, in this
study, the majority of the patients (10,186 out of 17,160) had
no ASCVD [56]. Accordingly, a meta-analysis including the
data from the EMPA-REG OUTCOME, CANVAS Program,
and DECLARE-TIMI 58 trials, showed an 11% reduction
in MACE associated with the use of SGLT2is (HR: 0.89;
95% CI 0.83–0.96, P = 0.0014) only in patients with previ-
ous ACVD (HR: 0.86; 95% CI 0.80–0.93) [57]. A reduction
in CV death risk was only found in empagliflozin-treated
patients, with moderate heterogeneity across the trials and
no interaction of outcome for those with or without ASCVD.
Similarly, only empagliflozin was able to reduce the risk of
all-cause mortality [52, 58].
Heterogeneity between the effect of different drugs
was also found in the reduction of the risk of myocardial
L. Del Vecchio et al.
infarction (MI). Empagliflozin [52] and canagliflozin [53]
did not significantly reduce MI risk when given to T2D
patients (HR: 0.87; 95% CI 0.70–1.09; P = 0.23 and HR:
0.85; 95% CI 0.69–1.05; P > 0.05, respectively). Data from
metanalyses are conflicting [59, 60], with only some show-
ing a benefit in this respect [61, 62].
This heterogeneity across the class for selected outcomes,
specifically for MACE and CV death, requires further explo-
ration; it remains to be explained whether this heterogene-
ity is due to differences in characteristics of patients and in
their risk profiles or differences in enrolment, definition of
outcomes, or among the drugs themselves.
Notably, the main CV benefit of SGLT2is is a reduction
in hospitalization risk for heart failure, with only moder-
ate heterogeneity between drugs in the class, with no dif-
ferences in baseline ASCVD, previous history of heart
failure, or baseline estimated (e) GFR of treated patients.
In the EMPA-REG OUTCOME, CANVAS Program, and
DECLARE-TIMI 58 trials, the three SGLT2is significantly
reduced the risk of hospitalization for heart failure in T2D
patients [52, 53] with consistency of effectiveness across
the trials, and similarly in those with or without prevalent
ASCVD. This was confirmed by the metanalysis of Zelniker
et al. [57], which demonstrated a 23% reduction in the risk of
CV death or hospitalization for heart failure (HR: 0.77; 95%
CI 0.71–0.84, P < 0.0001) in patients with and without CV
disease and in patients with and without previous heart fail-
ure. Other meta-analyses that excluded the CANVAS pro-
gram and EMPA–REG OUTCOME trials did not show any
decrease in hospitalization for heart failure [60, 61, 63, 64].
Recently, data from the SCORED study were published
[65]. This was a large, double-blind, placebo-controlled trial
that tested the efficacy of sotagliflozin in more than 10,000
T2D patients with CKD (eGFR of 25–60 mL/min/1.73 m ­ 2)
and risks for CV disease. Unfortunately, the trial ended
early because of lack of funding, thus reducing its statistical
power. In any case, the drug was found to be significantly
effective in reducing the risk of reaching the primary com-
posite endpoint of deaths from CV causes, hospitalizations
for heart failure, and urgent visits for heart failure in compar-
ison to placebo (HR: 0.74; 95% CI 0.63–0.88; P < 0.001).
It remains unclear exactly how SGLT2is exert these
effects in people with heart failure, but several mechanisms
have been proposed for the CV effects of SGLT2is.
These drugs reduce cardiac preload and lung and sys-
temic congestion by increasing both natriuresis and gly-
cosuria and causing osmotic diuresis; this reduces cardiac
preload and lung and systemic congestion. During the acute
phase, increased natriuresis and polyuria possibly activate
the RAS. However, after nearly 3 months of treatment, com-
pensatory mechanisms take place that reduce the magnitude
of this effect. A steady state is reached in which the body
has a slightly lower sodium content and blood volume [66,
SGLT-2 Inhibitors in Non-diabetic CKD
67]. This likely occurs as a consequence of increased food
and fluid intake as well as increased free-water reabsorp-
tion, which is mediated by vasopressin [68]. As opposed
to traditional diuretics, which markedly stimulate the RAS
and sympathetic system as a compensatory mechanism of
arterial underfilling, during the chronic phase SGLT2is do
not increase but rather suppress these systems [66]. This
is important, since the activation of these two systems
increases systemic vascular resistance and stimulates sodium
and water retention, contributing to diuretic resistance.
SGLT2is also decrease cardiac afterload by lowering arterial
pressure by 3–5 mmHg, without increasing the heart rate.
They may also decrease arterial stiffness [56, 69] and the
sympathetic nervous system hyperactivity related to heart
failure [70]. Norepinephrine upregulates the expression of
SGLT2, enhancing sodium and glucose reabsorption by the
proximal tubule; conversely SGLT2is have the opposite
effect [71].
3.1 SGLT2 Inhibitors in Type 2 Diabetes: Renal
Effects
SGLT2is showed significant benefits on renal outcomes in
T2D patients in terms of decrease in progression of albumi-
nuria, doubling of serum creatinine, and need for RRT, with
no interaction of outcome through the presence of ASCVD,
baseline albuminuria, or history of heart failure [57, 72].
In the EMPAREG-OUTCOME trial, empagliflozin pre-
vented the eGFR decline usually observed in T2D patients
and also reduced by 38% the relative risk of progression
to macroalbuminuria [73]. These benefits were observed in
patients with or without CKD [74]. Furthermore, the patients
treated with empagliflozin had a significantly lower risk of
either doubling the serum creatinine from baseline or the
need for RRT compared to placebo [74].
Similarly, data from the CANVAS program showed that
canagliflozin significantly reduced the risk of progression
to macroalbuminuria [53] and that of reaching the compos-
ite renal outcome, including the requirement for RRT (HR:
0.60; 95% CI 0.47–0.77).
Likely as a consequence of a hemodynamic effect, an
initial decline in eGFR occurred in the first 3 months of
treatment with an SGLT2i, and stabilized thereafter [75].
Starting from the favorable effects on kidney function
and reduced progression to macroalbuminuria shown by the
secondary analysis of the large trials mentioned above, the
CREDENCE trial was designed to primarily test the efficacy
of canagliflozin on renal outcomes in more than 4000 T2D
patients and albuminuric CKD [54]. The trial was stopped
earlier than planned due to excessive benefit since the rela-
tive risk of the primary composite renal and CV endpoint
and the renal endpoint alone was significantly lower in the
canagliflozin group than in the placebo group. Canagliflozin
efficacy was confirmed across different eGFR and albumi-
nuria values [54].
4 Experimental Evidence of Possible Use
of SGLT2 Inhibitors in Non‑diabetic
Chronic Kidney Disease (CKD)
Familiar renal glycosuria (FRG) is a well-known example of
renal glycosuria in the absence of diabetes. This genetic con-
dition is characterized by SLC5A2 gene mutation, respon-
sible for encoding the SGLT2 carrier protein. As a result,
affected subjects have “natural” inhibition of SGLT2 with
glycosuria exceeding 100 g/day. Except for glycosuria, these
patients are healthy without any other associated diseases
[76]. This suggests that SGLT2 inhibition is not harmful in
euglycemic conditions but does not necessarily indicate any
benefit. Experimental models mimicking FRG have been lit-
tle used till now. Nespoux et al. [77] studied a mouse model
of acute kidney injury (AKI) induced by bilateral ischemia-
reperfusion (IR) with or without SGLT2 gene deletion. In
both genotypes, IR equally reduced renal mRNA expression
of the ­Na+–K+–2Cl-co-transporter, suggesting comparable
thick ascending limb dysfunction, and similarly increased
renal mRNA expression of markers of injury, inflammation,
oxidative stress, and fibrosis.
After promising results were obtained in a hyperglycae-
mic setting in non-diabetic animal models, further inves-
tigations have evaluated the potential role of pharmaco-
logical SGLT2 inhibition in euglicemic non-diabetic CKD
(Table 1).
In several animal models and in vitro studies, SGLT2is
showed significant protective effects on mechanisms leading
to inflammation and renal fibrosis. This is possibly due to
direct anti-inflammatory and anti-fibrotic effects of SGLT2is
on tubular cells.
Priklbauer et al. [78] were the first to elucidate how empa-
gliflozin attenuated the expression of basal endothelin 1,
which is involved in the early inflammatory pathogenesis of
CKD, in two independent human proximal tubular cell lines
under normoglycemic conditions. Moreover, empagliflozin
inhibited the expression of interleukin 1β and the TGF-
β1-mediated expression of thrombospondin-1, tenascin-C,
and platelet-derived growth factor-beta. Interestingly, the
observed effects of empagliflozin were specific on tubular
cells, as endothelin-1 expression was not affected by cana-
gliflozin in vascular endothelial cells.
In non-diabetic rats with Ang-II-dependent hyperten-
sion, empagliflozin exerted an antifibrotic effect with
reduction of inflammatory infiltrates, regardless of blood
glucose and blood pressure values [79]. Jaikumkao et al.
[80] examined the effects of SGLT2 inhibition in a predia-
betic obese rat model and found that dapagliflozin was able
 L. Del Vecchio et al.

to reduce hyperfiltration, inflammation, microalbuminuria,
and tubulointerstitial fibrosis. Similar results were obtained
by Yamato et al. [81], who tested the benefits of ipragli-
flozin in a mouse model of adenine-induced CKD. They
documented that ipragliflozin improved renal function dose-
dependently and also decreased interleukin-6 and hematocrit
levels. Of note, the decrease in plasma creatinine levels was
independent of glucose plasma concentration and urinary
glucose excretion. In another study, ipragliflozin was found
to promote morphological changes in CKD mice by reducing
renal tubular dilatation and fibrosis and by restoring renal
tubular cell mitochondrial abnormalities induced by a high-
fat diet [82].
SGLT2is also seem to improve renal oxygenation, sug-
gesting the involvement of the vascular endothelial growth
factor (VEFG) pathway. Accordingly, luseogliflozin was
found to attenuate renal hypoxia, together with endothelial
rarefaction and interstitial fibrosis, by increasing the expres-
sion of VEGF [83]. Moreover, the improvement in renal oxy-
genation could also activate/suppress the hypoxia-inducible
factor (HIF) system. The activation timing of HIF could be
of importance. Indeed, if the amelioration of hypoxia occurs
at a late stage of CKD, it could be beneficial in reducing
renal damage and fibrosis through increased renal tubular
expression of VEGF and its isoforms [84].
Podocytes can also be targeted by SGLT2 inhibition.
Cassis et al. [85] demonstrated that the SGLT2 protein is
constitutively expressed in podocytes either in culture or in
a murine model of bovine serum albumin (BSA)-induced
overload proteinuria. In this experimental model of renal
disease, which is characterized by mild glomerulosclerosis,
interstitial inflammation, and interstitial fibrosis, the expres-
sion and concentration of SGLT2 on podocytes are enhanced
by albumin load in an NF-κ B-dependent manner; treatment
with dapagliflozin was capable of reducing proteinuria and
improving podocyte dysfunction and loss. Moreover, in
cultured podocytes it limited the cytoskeletal remodelling
induced by the albumin load.
SGLT2 is also expressed in mesangial cells and has a
major influence on their contractility according to glucose
concentrations [86]. This is of interest, considering that fol-
lowing different types of injury, mesangial cells upregulate

Table 1  Experimental studies of SGLT2 inhibitors in non-diabetic CKD

References Experimental model Conclusion

Wakisaka et al. [86] Rat mesangial cells Rat mesangial cells change their contractility according to
the extracellular glucose concentration via SGLT2
Zhang et al. [92] Non-diabetic subtotal nephrectomised rats No renoprotective effects
Ma et al. [93] Non-diabetic mouse model with progressive CKD due to No renoprotective effects
tubule-interstitial disease
Jaikumkao et al. [80] CKD obese rat model (high-fat diet) Dapagliflozin reduced hyperfiltration, inflammation, micro-
albuminuria and tubulointerstitial fibrosis
Cassis et al. [85] In vivo model of protein-overload proteinuria with BSA Dapagliflozin reduced the number of glomerular lesions,
with experimental CKD (nephrectomy) and in vitro improved proteinuria and podocyte dysfunction and loss
model with cultured podocyte.
Yamato et al. [81] Adenine-induced CKD in mice Ipragliflozin dose-dependently improved renal function and
decreased interleukin-6 and hematocrit levels
Zhang et at. [83] Nephrectomised mice with ischemic-reperfusion injury in Luseogliflozin attenuated renal hypoxia, endothelial rarefac-
the remaining kidney tion and interstitial fibrosis by increasing the expression of
VEGF
Mohamed et al. [88] Gentamicin-induced CKD rat model Dapagliflozin improved kidney function, oxidative stress
markers, decrease apoptosis of renal tubular cells by
modulating effects on RNA
Nespoux et al. [77] Kidney injury induced by bilateral ischemia-reperfusion in SGLT2 deletion does not have protective effect
SGLT2 gene deletion or wild-type mice
Castoldi et al. [79] Non-diabetic rats with angiotensin II-dependent hyperten- Empagliflozin had antifibrotic effect with reduction of
sion inflammatory infiltrates, regardless of blood glucose and
blood pressure values
Hasan et al. [89] Mouse model of sympathetic overactivity Canagliflozin reduced renal oxidative stress and inflamma-
tion
Onishi et al. [89] Nondiabetic mice with tubule-specific ­Na+-H+ exchanger 3 Low-dose empagliflozin causes acute small increase in urine
knockdown (NHE3-ko) and wild-type animals pH and bicarbonate excretion but reduced urine pH and
increased bicarbonate absorption in the long term in wild-
type mice but not in NHE3-ko mice

BSA bovine serum albumin, CKD chronic kidney disease, SGLT2 sodium-glucose co-transporter-2
SGLT-2 Inhibitors in Non-diabetic CKD
the expression of α-smooth muscle actin, change their con-
tractile abilities, and increase the production of matrix pro-
teins, chemokines, and cytokines [87]. The contractility of
mesangial cells could also regulate glomerular blood flow
and filtration. It is unknown whether SGLT2 inhibition could
influence mesangial cells in euglycemic conditions.
Amongst pleiotropic effects, SGLT2 inhibition also
exerts modulating effects on RNA. In a gentamicin-induced
nephrotoxicity rat model, dapagliflozin showed early pro-
tection against drug-induced renal injury [88]. This was
mediated by a modulating effect on a specific class of non-
coding RNA called microRNAs (miRNA 21 and 181a)
known to play a major role in regulation of gene expres-
sion and signalling pathways. Accordingly, dapagliflozin
improved kidney function and oxidative stress markers,
decreased apoptosis of renal tubular cells, and increased
miR-21, but decreased the expression of miR-181, with a
restoration of the renal architecture after 14 days of treat-
ment following injury.
Sympathetic nerve activation is among the factors impli-
cated in CKD progression. Interestingly, canagliflozin
reduced renal oxidative stress and inflammation in a mouse
model mimicking overactivity of the sympathetic nervous
system [89].
In non-diabetic mice, recent experimental data also
showed a possible contributory role of the N ­ a + –H +
exchanger 3 (NHE3) in the natriuretic effect of SGLT2is,
leading to an acute small increase in urine pH and bicar-
bonate excretion but to reduced urine pH and increased
bicarbonate absorption in the long term [90]. It is possible
that these changes may reflect a modestly increased acid
load following metabolic modifications following treatment
with empagliflozin. Whether increased H ­ + urinary excre-
tion could be an additional nephroprotective mechanism
or possibly be negative needs further clarification [91].
Indeed, the mild worsening of metabolic acidosis could
somehow enhance the progression of CKD; however, the
functional inhibition of NHE3 by chronic empagliflo-
zin is probably counterbalanced by other mechanisms of
renal bicarbonate reabsorption. Conversely, the increase
in bicarbonate reabsorption may reduce tubule-interstitial
inflammation.
Apart from these positive findings, other studies failed to
provide evidence of reno-protective effects in non-diabetic
CKD. In non-diabetic, subtotal nephrectomised rats, Zhang
et al. [92] found that dapagliflozin did not significantly affect
the development of hypertension and did not modify the
heavy proteinuria and the declining GFR. Similarly, Ma
et al. [93] documented that SGLT2 inhibition did not attenu-
ate the extent of glomerulosclerosis and tubulointerstitial
fibrosis in a mouse model of CKD with tubulointerstitial
injury.
5 Clinical Trials with SGLT2 Inhibitors
in Non‑diabetic CKD
The experience accumulated so far in patients with dia-
betic CKD has shown that the nephroprotective properties
of SGLT2is are minimal due to improved glycemic con-
trol and that, among other effects, SGLT2is decrease the
intraglomerular pressure and consequently hyperfiltration.
Therefore, the idea has taken root that these agents can also
be nephroprotective in non-diabetic CKD. Similarly, many
of the mechanisms leading to reduced cardiovascular risk
and hospitalization for heart failure could also apply to the
non-diabetic CKD population.
Bearing these considerations in mind, the Dapagliflozin
and Prevention of Adverse Outcomes in Chronic Kidney
Disease (DAPA-CKD) trial was designed [94].
This was a large, randomized, double-blind, parallel-
group, placebo-controlled trial aimed at testing the efficacy
of the SGLT2i dapagliflozin on kidney and cardiovascular
events in CKD patients with and without T2D [95]. Between
February 2017 and July 2018 (for most countries), 4304
subjects with a urinary albumin/creatinine ratio (UACR) ≥
200 mg/g and an eGFR between 25 and 75 mL/min/1.73
­m2 were randomized to dapagliflozin 10 mg once daily or
placebo. Of these, 2906 (67.5%) had a diagnosis of diabetes
at baseline; the others were non-diabetics; the mean eGFR
was 43.1 mL/min/1.73 ­m2 and the median urinary albumin
to creatinine ratio (UACR) was 949.3 mg/g. The study par-
ticipants were of mixed races, but predominantly Caucasians
(53.2%), followed by Asians (34.1%), and only 4.4% were
African Americans; more than half of them had a history of
cardiovascular disease, heart failure, myocardial infarction,
or stroke. All participants were given a maximum tolerated
dose of an ACEi or ARB (except 2% who had documented
intolerance).
The trial was stopped early because of clear efficacy
after a median follow-up of 2.4 years (interquartile range,
2.0–2.7). The primary composite outcome of eGFR decrease
of at least 50%, end-stage kidney disease, or death from
renal or cardiovascular causes occurred in a significantly
lower number of subjects in the dapagliflozin than the pla-
cebo group (197 (9.2%) and 312 (14.5%), respectively; HR
0.61; 95% CI 0.51–0.72; P < 0.001). To prevent one primary
endpoint, 19 subjects (95% CI 15–27) needed to be treated
(NNT) during the trial. This NNT is not dissimilar to that
calculated in the IDNT and RENAAL trials for ARBs in
diabetic nephropathy in comparison to placebo (16 and 29,
respectively) [96]; however, in DAPA-CKD it is obtained
in addition to RAS blockade and not in comparison to sup-
portive therapy alone.
In DAPA-CKD, the effect of dapagliflozin on the primary
endpoint was consistent for both diabetic and non-diabetic

patients, as testified by the same NNT (19 in both cases, as
in the whole population). It was also similar across severi-
ties of CKD and proteinuria levels. Moreover, the patients
randomized to dapagliflozin had a significantly lower risk of
reaching the secondary renal endpoint (eGFR decrease of at
least 50%, ESKD, or death from renal causes). As expected,
the patients receiving the drug experienced a significant
drop in GFR in the first 2 weeks of treatment; thereafter,
the annual GFR decline was steeper in the placebo than in
the dapagliflozin group (− 3.59 ± 0.11 mL/min/1.73 ­m2
and –1.67 ± 0.11 mL/min/1.73 m ­ 2, respectively). These
trends are a further confirmation of the favorable actions
of SGLT2is on intraglomerular pressure when given in
conjunction with RAS blockers. Unfortunately, no informa-
tion has yet been published on proteinuria changes during
follow-up.
Among pre-specified analyses, DAPA-CKD investigated
possible differences in study outcomes between diabetic and
non-diabetic CKD [97]. The latter subpopulation included
1794 patients: 695 (38.7%) had chronic glomerulonephritis,
687 (38.3%) had ischemic/hypertensive nephropathy, 412
(23%) had other or unknown causes of nephropathy. Note
that in this study the recognised cause of nephropathy in dia-
betic patients was not always the presence of diabetes mel-
litus [98]. The separate analysis of the effect of dapagliflozin
on the primary outcome showed consistency among patients
with diabetic and non-diabetic nephropathies. In particular,
the patients with glomerulonephritis who were randomized
to dapagliflozin had a 57% lower HR (95% CI 0.26–0.71)
of reaching the primary endpoint in comparison to placebo.
The effect on the primary outcome favoring dapagliflozin
was also consistent for patients with ischemic/hypertensive
CKD or CKD of other or unknown cause (even if not statis-
tically significant in these two categories). This is in agree-
ment with the fact that the favorable effect of dapagliflozin
was independent of baseline proteinuria levels, as stated
above, reinforcing the concept that the favorable effects of
SGLT2is cannot be explained just by modifications of the
tubule-glomerular feedback.
Among the cases of glomerulonephritis, 270 (38.8%) sub-
jects had IgA nephropathy [254 (94%) were biopsy-proven].
In this subgroup, dapagliflozin reduced the risk of the pri-
mary outcome compared with placebo by 71% (HR: 0.29;
95% CI 0.12–0.73) [98]. Dapagliflozin also significantly
decreased the urinary albumin-to-creatinine ratio by 26%
in comparison with placebo (− 35.0% in the first 4 months)
[99]. Considering that this is an exploratory analysis, caution
is needed in interpreting the finding; however, it suggests
that in the future dapagliflozin has the potential to become
one of the most promising treatments of IgA nephropathy.
As outlined in the introduction, cardiovascular disease
is also a leading cause of morbidity and mortality in the
CKD population in the absence of diabetes; often it occurs
L. Del Vecchio et al.
well before the development of kidney failure. In this per-
spective, DAPA-CKD has provided the first information
on possible cardiovascular benefits of SGLT2is in non-
diabetic CKD.
As expected, the event rates for the composite outcome of
cardiovascular death or hospital admission for heart failure
were higher in T2D subjects than in non-T2D subjects. How-
ever, the benefit of dapagliflozin on this secondary outcome
was similar, as testified by the non-significant interaction for
diabetes status. Similarly, all-cause mortality was reduced
with dapagliflozin in participants with and without T2D.
Of note, in the overall trial population, the cardiovascular
benefits of dapagliflozin were confirmed in both primary and
secondary prevention [99]. Moreover, the efficacy on kidney
endpoints was maintained independently from the presence/
absence of cardiovascular disease at baseline.
Other than DAPA-CKD, only a small, short-term trial
tested the efficacy of SGLT2is in non-diabetic CKD. The
Effects of Dapagliflozin in Non-diabetic Patients With Pro-
teinuria (DIAMOND) was a randomized, double-blind,
placebo-controlled crossover trial conducted in Canada,
Malaysia, and the Netherlands [100]. Fifty-three subjects
with GFR > 25 mL/min/1.73 m ­ 2 and proteinuria between
500 and 3500 mg/day were randomized to either dapagliflo-
zin 10 mg or placebo over two 6-week periods with a 6-week
washout period in between. All patients were on stable RAS
inhibitors. The mean change in proteinuria from baseline
was similar in the two groups [difference of 0.9% (95% CI
− 16.6 to 22.1; P = 0.93)]. As expected, patients experi-
enced a significant drop in GFR during their dapagliflozin
period (− 6.3 mL/min/1.73 ­m2 in in the dapagliflozin arm);
this reduction in GFR was fully reversed after dapagliflozin
discontinuation.
A small pilot study tested the effect of dapagliflozin in ten
patients with focal segmental glomerulosclerosis [101]. Over
the 8 weeks of treatment, no significant changes in renal
hemodynamics or proteinuria were observed. At present, it is
difficult to reconcile the negative findings of these two small
studies with the significant and consistent nephroprotective
effects shown by DAPA-CKD.
The use of SGLT2is in non-diabetic CKD is a rapidly
evolving field; new and strong evidence is awaited in the
coming years. In particular, EMPA-KIDNEY (The Study
of Heart and Kidney Protection with Empagliflozin) is a
large, phase III, double-blind, parallel-group clinical trial
(NCT03594110) that will test the effect of empagliflozin on
CKD progression or cardiovascular death versus placebo
on top of standard of care in more than 6,000 CKD patients
with GFR ≥ 20 mL/min/1.73 ­m2. Subjects with polycystic
kidney disease, T1D or T2D and prior atherosclerotic car-
diovascular disease with an eGFR > 60 mL/min/1.73 m ­ 2 are
excluded. Active recruitment is still ongoing; study comple-
tion is expected in October 2022.
SGLT-2 Inhibitors in Non-diabetic CKD
6 Renal Outcomes in Trials of SGLT2
Inhibitors in Heart Failure
Two randomized controlled trials performed in patients with
heart failure with reduced ejection fraction (EF) also tested
renal outcomes: the EMPagliflozin outcomE tRial in Patients
With chrOnic heaRt Failure With Reduced Ejection Fraction
(EMPEROR-Reduced) [102] and the Study to Evaluate the
Effect of Dapagliflozin on the Incidence of Worsening Heart
Failure or Cardiovascular Death in Patients With Chronic
Heart Failure With Reduced Ejection Fraction (DAPA-HF)
[103].
The EMPEROR-Reduced study randomized 3,730
patients (49.8% diabetic) with heart failure and an EF of
40% or less to receive empagliflozin or placebo [102]. The
mean baseline eGFR value was 62 mL/min/1.73 ­m2 and
48.3% of the patients had CKD (eGFR < 60 mL/min/1.73
­m2). Among the endpoints, the trial had a secondary, com-
posite renal outcome (chronic dialysis or renal transplanta-
tion or a sustained reduction of eGFR); it occurred in 1.6%
of patients in the empagliflozin group and 3.1% in the pla-
cebo group (HR 0.50; 95% CI 0.32–0.77). The decrease in
eGFR per year was − 0.55 versus − 2.28 mL/min/1.73 m ­ 2
in the empagliflozin group compared to the placebo group
(P < 0.001). Moreover, in 966 patients with paired measure-
ments before the start of the study and 23–45 days after the
discontinuation of the trial, the eGFR decreased by − 0.93
mL/min/1.73 ­m2 in patients taking empagliflozin and by
− 4.21 mL/min/1.73 ­m2 in the placebo group. According
to a prespecified analysis, the risk of the composite kidney
outcome was reduced similarly in patients with and with-
out CKD, including patients with eGFR as low as 20 mL/
min/1.73 ­m2 [104].
The DAPA-HF study evaluated the effects of dapagliflo-
zin versus placebo in 4744 patients with heart failure and
an EF ≤ 40% and elevated plasma N-terminal pro B-type
natriuretic peptide with and without diabetes [103]. Nearly
40% of the patients had an eGFR < 60 mL/min/1.73 m ­ 2. A
composite renal outcome (the first occurrence of 50% or
greater sustained reduction in eGFR, kidney failure, or death
from kidney-related causes) did not reach statistical signifi-
cance, neither in patients without nor in those with diabetes
mellitus (HR: 0.67; 95% CI 0.30–1.49 and HR: 0.73; 95%
CI 0.39–1.34, respectively). The incidence of adverse kidney
events did not differ significantly between dapagliflozin and
placebo in either group.
A meta-analysis, performed by pooling data from the
two trials, showed that the risk of the composite renal end-
point (50% or higher sustained decrease in eGFR, end-stage
renal disease, or renal death) was significantly reduced
in the SGLT2i group (HR: 0.62; 95% CI 0.43–0.90). The
eGFR modifications during follow-up were similar in the
EMPEROR-Reduced and DAPA-HF trials: the difference
in eGFR slope between the SGLT2i and placebo groups
was 1.73 mL/min/1.73 m ­ 2 for empagliflozin and 1.80 mL/
2
min/1.73 ­m for dapagliflozin (both P < 0.0001) [105].
Finally, a recent trial, enrolling 1222 diabetic patients
with a recent hospitalization for worsening heart failure ran-
domly assigned to take sotagliflozin (a combined SGLT1
and SGLT2 inhibitor) or placebo, showed that the between-
group difference in the change in eGFR over time was − 0.16
mL/min/1.73 ­m2 in favor of the placebo group. The median
eGFR of the study population was about 50 mL/min/1.73
­m2 [106].
7 Additional Potential Benefits
in Non‑diabetic CKD
SGLT2is may have benefits including those that one could
expect from increased natriuresis, activation of the tubular-
glomerular feedback, and vasoconstriction of the afferent
glomerular arteriole (Table 2). Some of them could be useful
in the overall management of CKD.
7.1 Blood Pressure Decrease
Hypertension is both a factor in worsening CKD and one
of its main complications. Among the causes leading to
an increase in blood pressure values, sodium-water reten-
tion has a strong contributory role. As a result of increased
natriuresis and diuresis, it is not then surprising that
SGLT2is also have antihypertensive effects. Interestingly,
osmotic diuresis occurring in the proximal tubule is rela-
tively mild; conversely, the diuretic action of SGLT2 inhi-
bition is mostly due to the inhibition of reabsorption in the
loop of Henle rather than that in the proximal tubule. This
is due to a reduced chloride concentration arriving at the
loop of Henle [107]. Apart from this, SGLT2is can decrease
arterial stiffness, reduce sympathetic nervous activity, and
possibly have a direct effect on endothelial nitric oxide (NO)
[108].
Data coming from the trials performed in T2D patients
clearly showed a decrease in blood pressure values in those
treated with SLGT2is. According to a recent metanalysis,
combination therapy with an SGLT2i and ACEI/ARB lead
to an additional mean reduction in systolic blood pressure
(SBP) of − 3.84 mmHg and of − 1.06 mmHg of diastolic
blood pressure (DBP) compared with ACEI/ARB alone
[109]. Similar findings were obtained with 24-h ambulatory
blood pressure measurements. Recently, a secondary analy-
sis of the CREDENCE trial focused on the antihypertensive
efficacy of canagliflozin in people with T2D and CKD [110].
In this trial, canagliflozin reduced SBP by 3.50 mmHg.

Table 2  Potential benefits and risks of SGLT2 inhibitors in non-diabetic chronic kidney disease
Action Positive
Lower HR for ESKD or death from renal causes YES
Lower HR for CV death YES
Improved renal outcomes in HF with reduced EF YES
Blood pressure decrease YES
Hb increase and improved renal ­O2 content YES
Decrease of serum uric acid YES
Acute kidney injury Possibly protective
Hyperkalemia
Hyperphosphatemia and bone effects
Hypermagnesemia Increased magnesium
levels could be protec-
tive
Decreased urinary pH
HR hazard ratio, ESKD end-stage kidney disease, CV cardiovascular, HF heart failure, Hb hemoglobin, EF ejection fraction, CKD chronic kid-
ney disease
The experience accumulated so far in non-diabetic CKD
is still limited. Indeed, the data published so far of DAPA-
CKD did not show data of blood pressure trends during fol-
low-up [95]. Of note, no significant difference was observed
on the primary outcome in patients with SBP ≤ 130 mmHg
or > 130 mmHg.
The antihypertensive effect of SGLT2is is weaker in
patients with heart failure. According to a recent meta-anal-
ysis, the decrease in mean SBP is less than 1 mmHg [111].
However, this patient population is often characterized by
the presence of low rather than high blood pressure values.
For this reason, blood pressure control is not necessarily
needed, but rather avoided.
Considering that blood pressure control often requires the
use of several antihypertensive drugs in CKD patients, we
can foresee this new class of drugs as an additional tool for
helping to obtain adequate blood pressure control especially
for patients with salt-sensitive hypertension (as is the case
with CKD patients in many instances).
7.2 Decrease in Uric Acid
Hyperuricemia is observed in nearly 25–30% of CKD
patients. Once considered as a secondary consequence of
reduced kidney function, causing gout and nephrolithiasis
in some cases, it has become more clear over the years that
hyperuricemia may also contribute to CKD progression and/
or to increased cardiovascular risk [112]. Possible patho-
genic mechanisms include the worsening of oxidative stress
and inflammation. In addition to this, hyperuricemia is one
of the elements characterizing metabolic syndrome and
hyperinsulinemia. Both features are often observed in CKD
patients, especially if obese.
L. Del Vecchio et al.
Possibly negative
No increased risk
Minimal changes observed so far; more experience to be obtained
No significant increase in fracture risk to date; more information
has to be collected on bone markers
More experience to be obtained, especially in advanced CKD
Experimental observation; no clinical data
Although it is still a matter of debate whether hyperurice-
mia is a true risk factor or just a biomarker of renal and car-
diovascular damage, in everyday clinical practice it is now
treated more aggressively in comparison to the standard of
care of previous decades.
Among the effects of SGLT2is, there is an increase in
renal uric excretion and consequently a decrease in serum
acid uric concentration. This occurs because in the proximal
tubule glucose competes with urates for the glucose trans-
porter (GLUT) 9 isoform 2 (GLUT9b): in the presence of
glycosuria more glucose is available for the transporter and
less urate is thus reabsorbed [113]. At least in mice, the urate
transporter URAT1 is also required for the uricosuric effect
of SGLT2is [114].
Several clinical trials showed a decrease in uric acid lev-
els following therapy with SGLT2is. In particular, a meta-
analysis of 62 trials of T2D patients showed a weighted
mean difference on uric acid levels of − 37.73 μmol/L (95%
CI − 40.51 to − 34.95) between an SGLT2i and control, with
empagliflozin having the highest effect [115]. Apparently,
the decrease in serum uric acid levels did not occur in CKD
patients (eGFR < 60 mL/min/1.73 ­m2).
Interestingly, in a subanalysis of the EMPA-REG OUT-
COME, empagliflozin improved all cardiorenal outcomes
across tertiles of baseline serum acid uric levels, attenuating
the trend towards a higher HR for those with high acid uric
levels at baseline [116].
The experience accumulated so far in non-diabetic CKD
patients is still limited. According to a phase II, cross-over
study of subjects with asymptomatic hyperuricemia, dapa-
gliflozin added to verinurad, a selective URAT1 inhibitor,
and febuxostat further increased uric acid excretion and
decreased serum levels [117].
SGLT-2 Inhibitors in Non-diabetic CKD
Increased uricosuria may enhance crystallization in renal
tubules and cause nephrolithiasis. However, available evi-
dence does not currently show any significant concern from
this point of view [118]. Possibly, the increased urinary out-
put would partly prevent nephrolithiasis.
7.3 Anemia Improvement
Anemia is a common complication of CKD; it has been
associated with reduced quality of life, increased need for
blood transfusions, higher risk of hospitalization, CV events,
and mortality. Despite the data coming from observational
studies, the cause-effect relationship between anemia correc-
tion and improved outcomes has not been clearly established
so far. Moreover, after growing evidence showing possible
safety issues when aiming at near-to-normal hemoglobin
levels with erythropoiesis-stimulating agents (ESAs), the
hemoglobin target to aim for with these drugs is still a mat-
ter of discussion in the nephrology field.
Data from several clinical trials with SGLT2is have
shown a mild increase in hematocrit/hemoglobin levels fol-
lowing therapy with these drugs [119]. Recently, a post hoc
analysis of the CREDENCE trial evaluated the effects of
canagliflozin in subjects with diabetic CKD [120]. Among
the overall trial population, one-third of the participants had
anemia at baseline (defined as hemoglobin < 13.0 g/dL in
men or < 12.0 g/dL in women). During follow-up, the mean
hemoglobin concentration was 0.7 g/dL higher in the cana-
gliflozin group than the placebo group. Moreover, a lower
percentage of patients receiving canagliflozin had to start
iron or ESA therapy. No data about anemia and its treatment
from the DAPA-CKD trial have been published so far.
Several hypotheses have arisen to explain this ancillary
effect. The first and easiest one is hemoconcentration follow-
ing the decrease in plasma volume. However, the increase
in hemoglobin levels is anticipated by reticulocytosis and
increased erythropoietin (EPO) levels, suggesting increased
erythropoiesis [121].
Most of the available experimental data have been
obtained in diabetes and are not necessarily applicable to
non-diabetic patients. Indeed, in diabetic patients, increased
glucose reabsorption generates a high-glucose environment
in the renal tubule-interstitium, which may impair hypoxia-
inducible factor 1 (HIF-1), damage renal erythropoietin-
producing cells (REPs), and decrease EPO secretion and
erythropoiesis [122]. SGLT2is inhibit glucose reabsorption
and may thus attenuate glucotoxicity in the renal tubule-
interstitium, allowing REPs to resume their function and
increase EPO secretion. In addition to this, SGLT2is have
been shown to cause decreased macrophage infiltration, oxi-
dative stress, and inflammation [123]. On the other hand, by
blocking proximal tubular sodium reabsorption, SGLT2is
reduce oxygen consumption and improve renal hypoxia
[124]. As a result, HIF1-α is suppressed. Conversely, the
HIF2-α subunit, which is the main one involved in stimu-
lating EPO production, is not only regulated by hypoxia
but also activated by the low carbohydrate content follow-
ing SGLT2 inhibition [125]. Indeed, SGLT2is are known
to activate sirtuin-1 (SIRT1). This is both a redox rheostat
and a nutrient and/or oxygen sensor; its activation causes
relative changes in HIF-1α/HIF-2α activities (a downreg-
ulation of HIF-1α but an upregulation of HIF-2α) [126].
Whether this also applies to non-diabetic CKD is still to
be determined.
Another possible mechanism by which SGLT2is could
stimulate erythropoiesis is the suppression of serum hep-
cidin, as shown by a small, randomized clinical trial of 52
T2D patients [127]. In this patient population, the increase
in hemoglobin levels with therapy with dapagliflozin 10 mg/
day for 12 weeks was mediated by a 24% mean decrease of
serum hepcidin, together with a significant fall in ferritin
concentrations and an increase in erythroferrone levels.
Similar data were shown by a substudy of the EMPA-
HEART (Effects of Empagliflozin on Cardiac Structure
in Patients With Type 2 Diabetes) CardioLink-6 [128]. In
this trial, individuals with T2D and stable coronary artery
disease were randomized to either empagliflozin 10 mg
daily or placebo for 6 months. Hematocrit increased after
6 months by 2.34% in those receiving empagliflozin. This
accompanied an increase in EPO levels and a decrease in
serum ferritin.
Considering that hepcidin levels are often increased in
CKD, further confirmation is awaited in this setting.
At the moment it is still difficult to foresee whether the
observed increase of hemoglobin levels during therapy with
SGLT2is is meaningful from the clinical point of view in the
CKD population (whether with or without diabetes).
7.4 Metabolic Changes
Under conditions of stress, such as heart failure, glucose
utilization is impaired and heart metabolism depends more
on free fatty acid and ketone oxidation [129]; recently,
exogenous ketone administration has been proposed as a
possible therapeutic strategy for heart failure [130]. It has
been suggested that SGLT2is can modify fuel consump-
tion by increasing fatty acid oxidation and ketogenesis and
concomitantly reducing carbohydrate disposal [71, 131].
Indeed, SGLT2is significantly increase ketone body forma-
tion in patients with type 2 diabetes [132]. This improved
metabolic efficiency could result in less oxygen consumption
and improved myocardiocyte functioning [130].
Increased ketone body generation could also contribute
to nephroprotection, as shown in two mouse models of non-
proteinuric and proteinuric diabetic kidney disease [133]. In
these animals, ketone bodies prevented decreases in renal

ATP levels and lessened the podocyte damage mediated by
the hyperactivation of rapamycin complex 1 (mTORC1).
Moreover, SGLT2i can act directly on the adipose tis-
sue by increasing the percentage of brown adipocytes with
respect to the white ones [134]. This effect is probably
mediated by an increase in adiponectine and by polarization
towards M2 macrophages (with anti-inflammatory proper-
ties) [134].
Interestingly, cardiomyocytes express the glucagon recep-
tor, which contributes to cardiac inotropic and chronotropic
effects [135]. SGLT2is increase glucagon levels, possibly
due to glucose excretion and a direct effect on pancreatic
alpha cells. The improvement of arrhythmia and myocardial
function related to higher levels of glucagon may contribute
to a decrease in heart failure and cardiovascular mortality
risk [136, 137].
Of note, modestly elevated circulating levels of the ketone
β-hydroxybutyrate (βOHB) may induce beneficial effects on
the kidney, such as inhibiting inflammation, oxidative stress,
and fibrosis [138].
Finally, a growing body of evidence is indicating that
SGLT2is can also decrease oxidative stress through other
mechanisms, such as a decrease in activity of nicotinamide
adenine dinucleotide phosphate (NADPH) oxidase [139] or
by reducing the generation of advanced glycation end prod-
ucts (AGEs) [140].
8 SGLT2 Inhibitors in Combination
with Other Drugs
8.1 Combination with a Neprilysin Inhibitor
Sacubitril/valsartan is a drug containing the neprilysin
inhibitor sacubitril and the ANG-II receptor antagonist val-
sartan. Neprilysin inhibition enhances the bioavailability of
natriuretic peptides. The Prospective Comparison of ARNI
with ACEI to Determine Impact on Global Mortality and
Morbidity in Heart Failure (Paradigm-HF) trial compared
sacubitril/valsartan with enalapril in patients with heart
failure, and reduced EF and demonstrated that sacubitril/
valsartan was superior in reducing the risks of death and of
hospitalization [141]. A subanalysis of Paradigm-HF showed
that, compared with enalapril, sacubitril/valsartan led to a
slower rate of decrease in eGFR and improved cardiovascu-
lar outcomes, even in patients with CKD [142]. At the renal
level, sacubitril/valsartan induces preferential vasodilation
of the afferent arteriole and relative vasoconstriction of the
efferent arteriole. Its action on intra-renal hemodynamics
is therefore different from that hypothesized for SGLT2is,
which would induce afferent arteriolar vasoconstriction
through the tubule-glomerular feedback [143]. It is therefore
very interesting to know whether or not the positive effect
L. Del Vecchio et al.
of SGLT2is in patients with heart failure is preserved in the
subgroup of those taking sacubitril/valsartan. A subanalysis
of the DAPA-HF trial was aimed at assessing the efficacy
and safety of dapagliflozin in the subgroup of patients who
were taking sacubitril/valsartan at baseline (a total of 508
patients, 10.7%). Dapagliflozin had similar efficacy (HR:
0.75 vs. 0.74 in patients taking and not taking sacubitril/
valsartan) on the primary endpoint of cardiovascular death
or worsening of heart failure. Even safety results were com-
parable in the two groups [144]. These encouraging findings
suggest that the use of both drugs together could further
reduce morbidity and mortality in patients with heart failure
and reduced EF.
8.2 Combination Therapy with Selective
Mineralocorticoid Receptor Antagonists
Increased plasma aldosterone concentrations and mineralo-
corticoid receptor overactivation are known pathogenetic
factors for cardiovascular disease, heart failure, and kidney
damage. Mineralocorticoid receptor antagonists (MRAs)
have become the standard of care of symptomatic heart fail-
ure with low EF. In this setting, they also reduce the risk of
cardiovascular events and sudden death. In addition to this,
several studies have underlined the properties of this class of
drugs as antiproteinuric agents in diabetic and non-diabetic
nephropathies [145]. However, they are often poorly toler-
ated due to their side effects and their use is often limited by
the occurrence of hyperkalemia, especially in CKD patients.
Selective, non-steroidal MRAs are a new class of drugs;
finerenone is the most used and will be licensed for clinical
use next year in patients with T2D and CKD. As opposed to
non-selective antagonists, it is more selective for the miner-
alocorticoid receptor with similar potency to spironolactone.
As a result, it has shown remarkable protective effects on
fibrosis and inflammation in animal models [146]. Recently,
the Finerenone in Reducing Cardiovascular Mortality and
Morbidity in Diabetic Kidney Disease Trial (FIDELIO
DKD) showed that treatment with finerenone obtained a
lower risk of reaching the primary renal endpoint (kidney
failure, a decrease > 40% in the eGFR from baseline, or
death from renal causes) or cardiovascular events than pla-
cebo [147]. Hyperkalemia developed in a small percentage
of patients. A second large trial, FIGARO, is still ongoing; it
will primarily give information on cardiovascular endpoints
in a trial population similar to that of the FIDELIO-DKD
study and test renal endpoints as secondary ones.
Finerenone could be shown to be nephroprotective in the
future in non-diabetic CKD as well.
Little information is available at the moment on the effi-
cacy and safety of the combined use of selective MRAs and
SGLT2is. However, considering the entrance of finerenone
SGLT-2 Inhibitors in Non-diabetic CKD
in clinical practice and expected wider use of SGLT2is, it is
something that we need to consider.
Theoretically, SGLT2is could enhance aldosterone syn-
thesis as a consequence of natriuresis and osmotic diuresis.
However, according to available data, they do not seem to
alter plasma aldosterone levels significantly [148]. Apart
from this aspect, the mechanism of action of SGLT2is and
MRAs displays potential synergistic renoprotective and car-
diovascular properties if given in combination.
A secondary analysis of DAPA-HF investigated the effi-
cacy and safety of dapagliflozin in patients with heart fail-
ure and reduced EF [149]. Of the total 4744 patients, 71%
received an MRA. Dapagliflozin showed similar efficacy on
the primary endpoint compared to placebo in patients either
taking or not taking an MRA; similar findings were observed
for secondary endpoints. In both MRA subgroups, safety
outcomes were similar in patients randomized to dapagli-
flozin or placebo.
Following a protocol amendment, SGLT2is were allowed
as concomitant medications during FIDELIO-DKD and
FIGARO trials. A secondary analysis giving information
about the combined use of these two classes of drugs is very
likely to be performed. Conversely, treatment with MRA
was not admitted in the CREDENCE and DAPA-CKD trials.
Recently, a consensus statement by the European Renal
and Cardiovascular Medicine (EURECA-m) working group
of the European Renal Association—European Dialysis and
Transplant Association (ERA-EDTA) and the Hyperten-
sion and Kidney working group of the European Society of
Hypertension (ESH) recommended the use of finerenone in
addition to an ACEi or an ARB in maximum tolerated doses
and independent of the use of an SGLT2i in patients with
T2D and CKD (eGFR 25–75 mL/min/1.73 m ­ 2), albuminuria,
and normal serum potassium [150].
Of note, a clinical trial has just started aimed at com-
paring the efficacy and safety of a new, selective MRA
(AZD9977, AstraZeneca) alone and in combination with
dapagliflozin in participants with heart failure with low EF
and severe CKD (at least 30% of participants with eGFR
< 30 mL/min) (NCT04595370).
9 Safety Issues of Particular Interest
for Non‑Diabetic CKD
9.1 Acute Kidney Injury
Given that SGLT2is cause osmotic diuresis and an acute
drop in GFR in the first weeks of treatment, AKI was con-
sidered as a possible safety concern at the very beginning.
However, expanding experience with SGLT2is not only
did prove this concern [151], but also suggested a possi-
ble protective effect in this respect. According to a recent
meta-analysis of 18 trials enrolling more than 150,000 T2D
subjects, SGLT2is were associated with a lower risk of AKI
compared to placebo (odds ratio, 0.76; 95% CI 0.66–0.88)
[152]. Similar findings were reported from real-life observa-
tions [153].
Patients with CKD could be more susceptible to AKI
development. In this respect, a secondary analysis of the
CREDENCE trial did not show an increased risk of AKI at
different levels of baseline GFR [154]. However, for baseline
GFR between 30 and ≤ 45 mL/min/1.78 ­m2, a higher num-
ber of patients receiving canagliflozin were reported as hav-
ing volume depletion compared to placebo. Of note, nearly
half of the participants had an acute drop in eGFR of > 10%
without impairing the clinical benefit of canagliflozin [155].
A more acute drop exceeding 30% occurred infrequently.
Similarly, more patients randomized to dapagliflozin
developed volume depletion compared to placebo in DAPA-
CKD; however, renal-related adverse events (including AKI)
occurred with a lower frequency.
Of note, a case report showed an association between
empagliflozin use and the development of acute interstitial
nephritis [156].
9.2 Hyperkalaemia
The kidney has an important role in potassium homeostasis;
accordingly, hyperkalaemia is one of the most common com-
plications of CKD. Among the contributory factors, reduced
­K+ urinary excretion, metabolic acidosis, and hyperinsulin-
ism are the most important causes.
For a similar degree of kidney function, it is more likely
to develop in diabetic than in non-diabetic CKD patients.
Hyperkalemia is not only associated with an increased
risk of cardiovascular events and mortality, but it often pre-
vents full use of RAS blockers as kidney- and cardioprotec-
tive therapies.
Data coming from clinical trials with SGLT2is and
everyday use are quite reassuring in this respect, showing
minimal increases in potassium levels (in addition to RAS
blockers). The observed increase in potassium levels is pos-
sibly explained by small transient changes in GFR or vol-
ume status resulting in less sodium exchanged for potassium
[157]. Reduced glucose levels and improvement of insulin
resistance could also result in a redistribution of potassium
out of the cells [157]. Conversely, SGLT2 inhibition may
determine enhanced aldosterone activity with increased
kaliuresis, possibly counterbalancing the mechanisms men-
tioned above.
Focusing on CKD, data from the CREDENCE trial
showed that a lower number of patients randomized to
canagliflozin developed hyperkalemia as an adverse event
in comparison to those on placebo [6.8% vs. 8.2%, respec-
tively; HR 0.80 (95% CI 0.65–1.00)] [54].

Unfortunately, available publications of DAPA-CKD do
not give detailed information on serum potassium changes
during follow-up.
9.3 Mineral Bone Metabolism
The inhibition of sodium-glucose co-transport increases
­Na+ availability in the proximal tubule and, in turn, influ-
ences renal phosphate handling by enhancing its reabsorp-
tion [158]. Moreover, osmotic diuresis produces a decline
in medullary osmolarity causing a moderate impairment
of calcium reabsorption in the ascending limbs of Henle’s
loop [159]. Accordingly, data on healthy volunteers showed
increased levels of serum phosphate, fibroblast growth fac-
tor 23 (FGF-23), and parathyroid hormone (PTH), as well
as decreased 1,25(OH) vitamin D levels following treatment
with canagliflozin [160]. However, some of these changes
could only be transient. Similar changes were reported by a
post hoc analysis of the IMPROVE trial in T2D patients and
albuminuria [161]. Compared with placebo, dapagliflozin
significantly increased serum phosphate, PTH, and FGF23,
with a non-statistically significant trend towards decreased
serum 1,25(OH) vitamin D. Calcium and 25(OH) vitamin
D were unaffected. Some of the patients considered in the
study had a certain degree of kidney insufficiency (eGFR
> 45 mL/min/1.73 m ­ 2). Despite this, the overall changes
were of a mild degree. Changes in bone biomarkers could
be more intense and become of clinical relevance in patients
with more advanced CKD. No detailed information is avail-
able to date for the non-diabetic CKD population at different
stages of CKD.
Apart from the CANVAS study, data from clinical stud-
ies are quite reassuring with respect to an increased risk of
bone fractures following SGLT2 inhibition [162]. Moreover,
according to the DAPA-CKD study, there is no difference in
fracture risk among the patients receiving dapagliflozin or
placebo in both the diabetic- and non-diabetic groups [95].
However, the follow-up period of all these trials could be too
short with respect to the time needed to develop clinically
significant bone fragility leading to fractures.
9.4 Hypermagnesemia
A meta-analysis including 18 studies demonstrated a signifi-
cant increase in plasma magnesium levels in T2D patients
taking SGLT2is compared with placebo. This association
has been described for four different molecules (canagliflo-
zin, dapagliflozin, empagliflozin, and ipragliflozin) in the
absence of CKD [163]. Furthermore, it was found that cana-
gliflozin induced a higher increase in serum magnesium in
patients with eGFR < 60 mL/min/1.73 ­m2 [164]. A post hoc
analysis based on pooled data from four randomized con-
trolled trials comparing canagliflozin with placebo showed
L. Del Vecchio et al.
that canagliflozin was associated with normalization of
serum magnesium in hypo-magnesemic patients with T2D
[165], who frequently have low magnesium levels due to
renal magnesium wasting.
A number of mechanisms have been hypothesized to
explain this effect of SGLT2is on plasma magnesium values.
Among others, the reduced insulin resistance observed with
SGLT2i administration may be associated with a decrease
in renal magnesium excretion and may induce a redistribu-
tion of magnesium out of the cells to the extracellular space
[166]. It has been hypothesized that this effect may play
a role in the beneficial cardiovascular outcomes observed
in the SGLT2 trials. However, a recent post hoc analysis
pooling data from CANVAS and CANVAS-R trials did not
confirm this hypothesis; the authors concluded that change
in serum magnesium was not a mediator of the effects of
canagliflozin on cardiovascular outcomes [167].
The kidney is crucial in the maintenance of normal mag-
nesium levels; when renal function declines, the ability of
magnesium excretion is then reduced [168]. However, a
number of compensatory mechanisms are put in place. As
a consequence, CKD patients often in reality have normal
serum levels or even hypomagnesemia. How much increased
magnesium levels can have a positive effect in CKD patients
is still a controversial topic. Experimental data suggest a
protective effect of magnesium on vascular calcifications
[169]. Moreover, two recent metanalyses showed that plasma
magnesium concentration was inversely associated with all-
cause mortality, cardiovascular mortality, and cardiovascular
events in CKD patients [170, 171], indirectly suggesting a
potential positive effect rather than a safety concern.
9.5 Risk of Infectious Complications
A significantly higher risk of genital infections has been
described in diabetic patients taking SGLT2is compared
with placebo and other antidiabetic treatments [172].
Comprehensive data on urinary infections in patients with
non-diabetic glomerular disease treated with SGLT2is are
currently lacking. However, considering that patients with
glomerulonephritis are often treated with immunosuppres-
sive drugs, it is possible that the use of immunosuppressive
therapy in combination with SGLT2is may increase the risk
of infectious complications.
10 Future Perspectives
SGLT2is can provide nephroprotection to non-diabetic CKD
thanks to the combined contribution of several mechanisms
(Fig. 1). In the coming years, SGLT2is are likely to enter on
a large scale in everyday clinical practice for the treatment
of patients with diabetic and non-diabetic CKD. Indeed,
SGLT-2 Inhibitors in Non-diabetic CKD
clinical trials have given remarkable and consistent find-
ings in terms of reno- and cardiovascular protection. This
efficacy was obtained on top of RAS inhibition and with a
good safety profile. Data from the ongoing EMPA-KIDNEY
are likely to further reinforce the evidence supporting the use
of SGLT2is in non-diabetic CKD.
In addition to this, several treatment indications may open
in the future with SGLT2is.
It is well known that the antidiabetic efficacy of SGLT2is
progressively decreases as CKD worsens. Accordingly, the
initial treatment indication in T2D patients was for eGFR
> 45/mL/min/1.73 ­m2. However, accumulating evidence
has shown that the nephroprotective and CV efficacy is
also maintained at lower levels of GFR. However, to which
degree of kidney function SGLT2is remain effective is still
an open question. Data from the CREDENCE trial showed
consistent efficacy across all levels of kidney function down
to an eGFR of 30 mL/min/1.73 ­m2. A recent subgroup analy-
sis of this trial of 174 participants who had an eGFR < 30
mL/min/1.73 ­m2 indicated that the effects of canagliflozin
on kidney, cardiovascular, and mortality outcomes were
consistent with those of patients with higher GFR [173].
According to its inclusion criteria, DAPA-CKD gave evi-
dence of efficacy up to GFR values of 25 mL/min/1.73 ­m2
Fig. 1  Possible mechanisms of nephroprotection of SGLT2 inhibi-
tors in non-diabetic chronic kidney disease. The left panel of the fig-
ure describes the clinical effects of SGLT2 inhibitors, the right one
in both diabetic and non-diabetic CKD [95]. The ongoing
EMPA-KIDNEY will include patients with eGFR ≥ 20 mL/
min. It is difficult to imagine significant nephroprotection for
stage V CKD patients. However, it is possible that SGLT2is
also maintain their beneficial effects on the CV system at the
final stages of CKD, providing diuresis conservation.
In addition to this, SGLT2i-induced osmotic diuresis can
be helpful in conditions of fluid retention (as is often the
case in advanced CKD) alone or in combination with other
diuretics. However, the combined use with loop diuretics
should be done with caution and avoided in subjects with
unstable volume status or hypovolemia. Of note, the effects
of SGLT2is on kidney and cardiovascular outcomes are quite
consistent in patients receiving or not receiving diuretics
[174]. In the future, the diuretic properties of SGLT2is could
be used in cases of acute decompensated heart failure, as
suggested by preliminary experiences [175] or in patients
with nephrotic syndrome. Interestingly, the intraperitoneal
administration of SGLT2is has been proposed to reduce peri-
toneal fibrosis and ultrafiltration failure in patients receiving
peritoneal dialysis [176].
The use of SGLT2is could also offer benefits for reduc-
ing/preventing the nephrotoxic effects of contrast media,
reports possible pathophysiological mechanisms. IL1β interleukin 1β;
TGF- β1 tumor growth factor β1

considering their direct anti-inflammatory and antifibrotic
nephroprotective effects.
Finally, the combined use of SGLT1 and SGLT2 inhibi-
tion could have additional advantages in non-diabetic CKD,
given that in this subset there is no significant risk of devel-
oping ketoacidosis [177].
Declarations  a network meta-analysis of randomised clinical trials. Drugs.
Funding  This article received no funding.
Conflicts of interest/Competing interests  Lucia Del Vecchio received
speaker fees from Mundipharma. Simonetta Genovesi received speak-
er fees from Astra-Zeneca. Angelo Beretta, Carlo Jovane and Silvia
Peiti have no conflicts of interest to declare. All the Authors contrib-
uted to the writing and revision of the manuscript.
Ethics approval, Consent to participate, Consent for publication, Avail‑
ability of data and material, Code availability  Not applicable.
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