Journal of

Clinical Medicine

Review
Sodium-Glucose Co-Transporter 2 Inhibitors: Mechanism of
Action and Efficacy in Non-Diabetic Kidney Disease from Bench
to Bed-Side
Aly M. Abdelrahman 1 , Alaa S. Awad 2 and Emaad M. Abdel-Rahman 3, *

1 Department of Pharmacology & Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos
University, Alkhod 123, Oman; abdelrahman@squ.edu.om
2 Division of Nephrology, University of Florida, Jacksonville, FL 32209, USA; alaa.awad@jax.ufl.edu
3 Division of Nephrology, University of Virginia, Charlottesville, VA 22908, USA
* Correspondence: ea6n@uvahealth.org; Tel.: +1-434-284-3825; Fax: +1-434-924-5848

Abstract: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are currently available for the
management of type 2 diabetes mellitus. SGLT2i acts by inhibiting renal SGLT2, thereby increasing
glucosuria and lowering serum glucose. Recent trials are emerging supporting a role for SGLT2i
irrespective of the diabetic status pointing towards that SGLT2i have other mechanisms
of actions beyond blood sugar control. In this review, we will shed light on the role of this group
of medications that act as SGLT2i in non-diabetics focusing on pre-clinical and clinical data
highlighting the mechanism of renoprotection and effects of SGLT2i in the non-diabetic kidneys.

Keywords: SGLT2i; non-diabetics; CKD; blood pressure; IgAN; FSGS; proteinuria; survival

1. Introduction
Chronic kidney disease (CKD) is defined as persistently reduced estimated glomerular
filtration rate (eGFR) <60 mL/min/1.73 m2 , persistently elevated urine albumin excretion,
Citation: Abdelrahman, A.M.; Awad, or both for more than 3 months. As of 2022, CKD was shown to affect more than 800 million
A.S.; Abdel-Rahman, E.M.
persons worldwide [1].
Sodium-Glucose Co-Transporter 2
The prevalence of end-stage kidney disease (ESKD) as a consequence of progressive
Inhibitors: Mechanism of Action and
CKD and other kidney diseases has more than doubled in the USA from 389,592 to 807,920
Efficacy in Non-Diabetic Kidney
between the years 2000 to 2020 [2] despite using current management. This continued
Disease from Bench to Bed-Side. J.
increase in the prevalence of ESKD poses a huge burden on patients with kidney diseases
Clin. Med. 2024, 13, 956. https://
doi.org/10.3390/jcm13040956
and the health care system. Trials to add new medications to our armamentarium are much
needed to improve the outcomes of patients with kidney diseases.
Academic Editor: Kent Doi Recent trials evaluating a new group of medications that act on the sodium-glucose
Received: 8 January 2024
co-transporters (SGLTs) have shown promising results for kidney disease patients,
Revised: 26 January 2024 especially in patients with diabetes mellitus (DM). Several trials confirmed the bene-
Accepted: 30 January 2024 fits of these medications in diabetic patients, yet little is known about their value in
Published: 7 February 2024 non-diabetic patients.

1.1. SGLT
SGLTs are transmembrane proteins that function to transport glucose and sodium
Copyright: © 2024 by the authors. across cell membranes in several tissues including the proximal renal tubules (PT). While
Licensee MDPI, Basel, Switzerland. SGLT1 contributes to the transport of glucose in the PT, it is SGLT2 that carries the burden
This article is an open access article of reabsorption of about 90% of filtered glucose in the PT. SGLT2 uses the
distributed under the terms and
electrochemical gradient of sodium ions to drive the transport of glucose against the
conditions of the Creative Commons
concentration gradient [3].
Attribution (CC BY) license (https://
In 2008, the US Food and Drug Administration mandated that SGLT2 inhibitors
creativecommons.org/licenses/by/
(SGLT2i) undergo outcome trials. These drugs were later approved to be among the newest
4.0/).

J. Clin. Med. 2024, 13, 956. https://doi.org/10.3390/jcm13040956 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2024, 13, 956 2 of 15

classes of medications currently available for the management of type 2 DM [4,5]. SGLT2i
act by inhibiting renal SGLT2, thereby increasing glucosuria and lowering serum glucose [6].
While their renoprotection in diabetics has been clearly documented [7], the potential for
SGLT2i use and the mechanisms of nephroprotection [8] in non-diabetic chronic kidney
disease is still not well defined. Yet, recent trials [9,10] weighed heavily in supporting the
benefits of using SGLT2i irrespective of the diabetic status point towards SGLT2i having
other mechanisms of action beyond blood sugar control.
In this review, we will shed light on the role of this group of medications that act
as SGLTi in non-diabetic patients focusing on pre-clinical and clinical data highlight-
ing the mechanism of renoprotection and effects of SGLT2i in the kidneys of patients
without diabetes.

1.2. Mechanism of Renoprotection in Non-Diabetic Kidney beyond Glucose Control (Table 1)

The protective effects of SGLT2i can occur independently of blood sugar levels [11].
In addition to their antihyperglycemic effects, SGLT2i have potential actions on the car-
diovascular and renal systems [12]. SGLT2i were shown to possess anti-inflammatory
and antioxidant actions [13,14]. SGLT2i act directly on the endothelial system leading to
decreased inflammatory cytokines and reactive oxygen species.
Changes noted in the tubule-glomerular (TG) feedback mechanism on using SGLT2i
may contribute to the beneficial effects of these drugs on kidney function. SGLT2i cause
natriuresis, promoting TG feedback and decreasing glomerular hyperfiltration [15].
Hawley et al. [16] showed that while canagliflozin significantly activates adenosine
mono-phosphate-activated protein kinase (AMPK), dapagliflozin and empagliflozin effects
on AMPK are significantly milder and require higher concentrations of these SGLT2i
drugs. AMPK, when activated, regulates the energy status and energy hemostasis and
stimulates autophagy, thus decreasing cellular stress and glomerular and tubular injury [17].
Furthermore, the increase in adenosine release by SGLT2i may lead to efferent arteriole
vasodilatation [18]. These hemodynamic changes by SGLT2i may mediate an albuminuria-
lowering action, further contributing to kidney protection [19]. Fioretto et al. [20] suggested
that improvement of the lipid profile and body-weight reduction by SGLT2i may also help
protect the kidneys.
Other effects of SGLT2i, not related to diabetes control, included the potential modest
reduction in both systolic [21] and diastolic [22] blood pressure, mainly due to natriuresis
and decreased circulating volume.
Furthermore, SGLT2i was shown to reduce serum uric acid. Zhao et al. [23] reviewed
trials examining the effect of SGLT2i on serum uric acid in diabetic patients with at least
4 weeks of follow-up (n = 62 studies) and showed that SGLT2i significantly decreased
serum uric acid compared with control, regardless of the SGLT2i drug used.
Yip et al. [24] showed similar results in reviewing 43 randomized controlled tri-
als evaluating the effects of SGLT2i on serum uric acid in both patients with and with-
out diabetes. They showed a reduction in serum uric acid by SGLT2i regardless of the
diabetes status.

Table 1. Renoprotective Mechanisms of Actions of SGLT2i.

-Antihyperglycemic
-Anti-inflammatory → Decreasing inflammatory and reactive oxygen species.
-Antioxidant
-Promote tubule-glomerular feedback → Decrease glomerular hyperfiltration
-Activate adenosine mono-phosphate-activated protein kinase → Decrease glomerular and tubular injury
-Hemodynamic changes → Decrease albuminuria
-Improve lipid profile
-Reduce body weight
-Natriuresis → Mild decrease in systolic and diastolic blood pressure
-Attenuate renal ischemia-reperfusion injury
-Decrease serum uric acid
J. Clin. Med. 2024, 13, 956 3 of 15

Rassaei et al. [25] studied the effect of SGLT2i in non-diabetic patients with CKD
stages 3–5 (n = 78) and showed a reduction in serum uric acid from 6.4 to 5.6 mg/dL
with an increase in fractional excretion of urate from 6.76% to 9.22% following the use
of dapagliflozin.

2. SGLT2i and Non-Diabetic Kidney Dysfunction-Preclinical Experiments (Table 2)

2.1. Dapagliflozin
Dapagliflozin (10 mg/kg/day) for two days attenuated renal ischemia-reperfusion
injury, improved renal function, reduced apoptotic cell death, and increased renal expres-
sion of hypoxia-induced factor 1 in C57BL/6 mice. The authors suggested that induction
of hypoxia-induced factor 1 may play a role in renoprotection in this model [26]. It was
also reported that dapagliflozin (1 and 10 mg/kg/day) for three weeks improved renal
function and ameliorated renal fibrosis in a model of adenine-induced (0.2% diet) renal
injury in C57BL/6J mice. This was associated with an increase in mitochondrial metabolism
and fatty acid oxidation and a reduction of inflammation and oxidative stress. This study
suggested that the renoprotective effect of dapagliflozin was related to mitochondrial
protection due to inhibition of the transforming growth factor-β1/mitogen-activated pro-
tein kinase (TGF-β1/MAPK) pathway activation and a reduction of inflammation and
oxidative stress [27]. Liu et al. [28] studied the effect of dapagliflozin on renal interstitial
fibrosis induced by unilateral ureteral obstruction in C57BL/6J mice. They found that
dapagliflozin (10 and 20 mg/kg/day) for two weeks improved renal function and renal
fibrosis independent of direct blood glucose control. This was associated with reduced
inflammation, apoptosis, oxidative stress, and mitochondrial injury in the kidneys. Deger
et al. [29] showed that in Balb\c albino mice treated with cyclosporine A, dapagliflozin
reduced oxidative stress, apoptosis, and histopathological damage in renal tissue caused by
cyclosporin A. In C57BL/6N mice with protein-overload proteinuria induced by unilateral
nephrectomy and injections of bovine serum albumin, dapagliflozin (1.5 mg/kg/day) treat-
ment for twenty-three days reduced proteinuria and ameliorated podocyte dysfunction
and loss and provided renal protection that was similar to lisinopril [30].
It was also shown that dapagliflozin has a renoprotective effect in a model of salt-
induced hypertension and cardiorenal disease in Dahl salt-sensitive rats. In this study,
dapagliflozin (0.1 mg/kg/day) for six weeks reduced albuminuria and attenuated renal
inflammation and oxidative stress [31]. Firat et al. [6] demonstrated that dapagliflozin
(0.1 mg/kg/day) for four weeks preserved the glomerular and mesangial structure and
reduced renal oxidative stress in an iron-overload rat model. Chang et al. [32] showed that
dapagliflozin (10 mg/kg/day) for six weeks attenuated doxorubicin-induced glomerular at-
rophy, renal fibrosis, and dysfunction and suppressed apoptosis and reactive oxygen species
production in rats. In spontaneously hypertensive rats, dapagliflozin (10 mg/kg/day) for
eight weeks reduced urinary albumin creatinine ratio but had no significant effect on serum
creatinine levels or renal histological changes. However, transcriptome analysis showed
that dapagliflozin therapy exerted protective effects on the renal tissues that were attributed
to the alleviation of abnormal metabolism and inflammation [33]. Xuan et al. [7] showed
that dapagliflozin (10 mg/kg/day) treatment for seven days reduced renal fibrosis in a uni-
lateral ureteral obstruction rat model. On the contrary, in 5/6 (subtotally) nephrectomized
rats, dapagliflozin (1 mg/kg/day) for twelve weeks did not attenuate heavy proteinuria,
declining glomerular filtration rate, the extent of glomerulosclerosis, tubulointerstitial fibro-
sis or overexpression of the profibrotic cytokines, transforming growth factor-ß1 mRNA in
the kidneys [34]. In subtotally nephrectomized rats, dapagliflozin (1 mg/kg/day) for eight
weeks did not modify renal hemodynamic function nor did it attenuate proteinuria. In
addition, dapagliflozin did not affect the increased glomerulosclerosis, increased glomeru-
lar collagen IV deposition, loss of glomerular capillaries, and increased infiltration of the
tubule-interstitium by macrophages [35].
J. Clin. Med. 2024, 13, 956 4 of 15

2.2. Canagliflozin
Canagliflozin (10 and 25 mg/kg/day) treatment for five weeks attenuated adenine-
induced chronic kidney disease in rats. This action involved an anti-inflammatory effect as
shown by reducing the inflammatory markers, tumor necrosis factor (TNF)-α, interleukin
(IL)-6, and IL-1β as well as a reduction in oxidative stress [14]. In male C57BL/6 mice
fed with 0.2% adenine, canagliflozin (10 mg/kg/day) treatment for two weeks, started
after five weeks of an adenine diet, did not ameliorate renal damage; however, it reduced
the accumulation of uremic toxins, including p-cresyl sulfate. The authors suggested that
the lack of an effect on renal damage might be due to the administration period possibly
being too short [36]. Moreover, in adenine-induced chronic kidney disease, treatment
with canagliflozin (25 mg/kg/day) for four weeks failed to ameliorate the progressive
loss of kidney function and there was no decreased interstitial area percentage, nor was
there altered expression levels of genes related to fibrosis and inflammation. The authors
concluded that canagliflozin dosage was not effective in a therapeutic setting of established
non-diabetic CKD since canagliflozin treatment was started after four weeks of adenine
treatment [37]. Canagliflozin (5 mg/kg/day) for one week was also shown to improve
kidney function in isoprenaline-treated rats by stimulating antioxidant, anti-inflammatory,
and anti-apoptotic signaling pathways [38]. In high-salt (8% sodium chloride) diet-induced
Dahl salt-sensitive rats with hypertensive renal injury, canagliflozin (30 mg/kg/day) for
twelve weeks attenuated the increase in blood pressure and ameliorated the associated
hypertensive-induced renal injury. Canagliflozin increased sirtuin 3 expression, decreased
epithelial-mesenchymal transition and oxidative stress, and inhibited renal fibrosis [39].
In addition, canagliflozin (10 and 30 mg/kg/day) for ten days reversed the biochemical
and histopathological indices of cisplatin-induced nephrotoxicity in mice possibly through
its anti-inflammatory and antioxidant effects [40]. Park et al. [41] also showed that in
mice, canagliflozin (10 mg/kg/day) treatment for five days protected against cisplatin-
induced acute kidney injury by activating adenosine monophosphate-activated protein
kinase (AMPK) and autophagy in renal proximal tubular cells. Song et al. [42] also showed
that in mice, canagliflozin (20 mg/kg/day) for eight days had a nephroprotective effect
in cisplatin-induced nephrotoxicity. This effect mainly depends on Akt activation as well
as reduced uptake of cisplatin in the kidneys. Moreover, canagliflozin (20 mg/kg/day)
was effective in providing renal protection in unilateral ureteral occlusion and ischemia-
reperfusion renal fibrosis mouse models [43]. In rats with membranous nephropathy,
treatment with canagliflozin (10 mg/kg/day) for eight weeks decreased proteinuria and
improved the hyperplasia of glomerular mesangial cells and stroma, and the thickening
of the basement membrane and spiky structure. In addition, canagliflozin reduced renal
immune complex deposition and improved podocyte injury. The authors concluded that
canagliflozin exerts this renoprotective effect by reversing the imbalance in Helper T
1/Helper T 2 cells and restoring the autophagy of podocytes inhibited by the abnormal
immunoglobulin G secretion from B-cells [44].

2.3. Empagliflozin
In a 5/6 nephrectomy rat model, a model of chronic kidney disease, empagliflozin
(15 mg/kg/day) treatment for ninety-five days caused reduced proteinuria, improvement
in creatinine clearance and renal interstitial fibrosis and glomerulosclerosis. The authors
suggested two mechanisms of renoprotection: tubule-glomerular feedback-mediated ef-
fects and alterations of gene expression of key components of the complement system [8].
Lu et al. [45] also showed that empagliflozin (15 mg/kg/day) for six weeks had a benefi-
cial effect on kidney function and morphology in the 5/6 nephrectomy rat model. They
suggested that this beneficial effect might be due to an inhibition of CD206+ CD68+ M2
macrophage polarization by targeting mammalian targets of rapamycin (mTOR) and mi-
tophagy pathways and attenuating inflammatory signals from CD8+ effector T cells. Kim
et al. [46] showed that empagliflozin (20 mg/kg/day) for three weeks in a rat model with
salt-sensitive hypertension induced by uni-nephrectomy and 8% sodium chloride intake
J. Clin. Med. 2024, 13, 956 5 of 15

in Sprague Dawley rats decreased blood pressure and ameliorated renal inflammation.
The beneficial renal protective effect of empagliflozin (10 mg/kg/day) for eight weeks
was also shown in spontaneously hypertensive rats expressing human C-reactive protein
and it was suggested that it was mediated by reduced renal lipid accumulation, inflam-
mation, and oxidative stress [47]. In addition, empagliflozin (10 mg/kg/day) for four
weeks reduced blood pressure and had a nephroprotective effect in cyclosporine A-induced
nephropathy in rats [48]. In rats with angiotensin II-induced hypertension, empagliflozin
(10 mg/kg/day) for two weeks prevented the development of renal fibrosis, an effect that
was caused by a reduction in inflammatory infiltrates [49]. Reyes-Pardo et al. [50] showed
also that empagliflozin (10 mg/kg/day) treatment for two weeks attenuated oxidative
stress, proteinuria, and glomerular filtration rate reduction associated with angiotensin
II infusion; thereby, reducing kidney damage development in a rat model of angiotensin
II-dependent kidney damage. In hypertensive and proteinuric renin-transgenic (mRen2)27
rats with additional administration of N(ω)-nitro-L-arginine methyl ester (a nitric oxide syn-
thase inhibitor), treatment with empagliflozin (3 and 10 mg/kg/day) dependently reduced
proteinuria and induced protection for renal vasculopathy, glomerulopathy, and tubular
degeneration [51]. The combination of the low dose (3 mg/kg/day) of empagliflozin
and finerenone, a non-steroidal mineralocorticoid receptor antagonist, resulted in effi-
cacious reduction in proteinuria, plasma creatinine and uric acid and renal lesions [51].
Empagliflozin (10 mg/kg/day), but not canagliflozin (30 mg/kg/day), for seven days was
able to reduce renal tubular dilatation and necrosis in a renal ischemia-reperfusion injury
model in rats. Empagliflozin did not have a significant effect on serum creatinine and
blood urea nitrogen (BUN) levels while canagliflozin increased both parameters compared
to the placebo-treated group. In addition, the increased renal kidney injury molecule
(KIM)-1 expression and decreased urinary microRNA-26a excretion were alleviated by
empagliflozin only [52]. Ala et al. [53] also showed that empagliflozin (10 mg/kg/day)
for two days attenuated renal ischemia-reperfusion injury in rats that was associated with
reduced oxidative stress, inflammation, and apoptosis. In C57/BL6 mice subjected to
renal ischemia-reperfusion injury, empagliflozin (1 mg/kg) given twice protected against
renal injury as shown by decreased serum levels of creatinine, attenuated tubular damage,
reduced inflammatory markers, and inhibited apoptosis [54]. Ge et al. [55] showed that
empagliflozin (70 mg/kg/day in the chow) for four weeks reduced podocyte lipotoxicity,
prevented renal lipid accumulation, and improved renal function in a mouse model of
Alport syndrome [55]. In a mouse model with vascular calcification induced by an oral
high-phosphorus diet following a 5/6 nephrectomy in Apo E−/− mice, empagliflozin
(10 mg/kg/day) treatment for eight weeks improved renal function [56]. Empagliflozin
(10 mg/kg/day) treatment for fourteen days did not affect chronic kidney disease pro-
gression in oxalate-related nephrocalcinosis in C57BL/6N mice. This was demonstrated
as empagliflozin had no effect on reduced glomerular filtration rate, crystal deposition,
tubular injury, and markers of interstitial fibrosis [57]. In three models of chronic kidney
disease, fawn-hooded hypertensive rats, uni-nephrectomized salt-loaded rats, and rats
with Goldblatt hypertension (two-kidney, one-clip 2K1C), empagliflozin (10 mg/kg/day)
for eight weeks did not provide renoprotection because it did not ameliorate proteinuria,
elevated plasma urea and creatinine, oxidative stress, or inflammation [58].

2.4. Ipragliflozin
Ipragliflozin (0.3 and 0.1 mg/kg/day) treatment for four weeks was shown to have a
renoprotective effect that was independent of plasma glucose levels and urinary glucose
excretion in adenine-induced (0.25% w/w in the diet) chronic kidney disease in C57BL/6JJcl
mice. The anti-inflammatory and antioxidant effect of ipragliflozin might have contributed
to the protective effect [59]. In addition, ipragliflozin (1 mg/kg/day) for twelve weeks
improved the pathogenesis of chronic kidney disease by reducing ectopic lipid deposition
in renal tubules, endoplasmic reticulum stress in a mouse (FLS-ob/ob) model of non-
alcoholic steatohepatitis [60]. Ipragliflozin (0.04%) monotherapy during eight weeks of a
J. Clin. Med. 2024, 13, 956 6 of 15

high-salt diet did not improve renal glomerulosclerosis or creatinine clearance in Dahl salt-
sensitive rats. However, the combination therapy of ipragliflozin and losartan significantly
ameliorated glomerulosclerosis compared with ipragliflozin or losartan monotherapy [61].
In conclusion, preclinical trials showed that dapagliflozin, canagliflozin, empagliflozin,
or ipragliflozin had renoprotective effects in various animal models of acute kidney injury
and chronic kidney diseases.

Table 2. Effects of SGLT2i on Experimental Animals.

Drug Animal Effects of SGLT2i Ref.

-Attenuated renal ischemia-reperfusion injury, improved
-C57BL/6 mice with renal-reperfusion
renal function, reduced apoptotic cell death and increased [26]
injury
renal expression of hypoxia induced factor 1
-Improved renal function and ameliorated renal fibrosis,
-C57BL/6J mice with adenine (0.2% diet)
increased mitochondrial metabolism and fatty acid oxidation, [27]
-induced renal injury
reduction of inflammation and oxidative stress.
-Unilateral ureteral obstruction in -Improved renal function and renal fibrosis independent of
[28]
C57BL/6J mice direct blood glucose control
-Balb\c albino mice treated with -Reduced oxidative stress, apoptosis, and histopathological
[29]
cyclosporine A damage in renal tissue
-C57BL/6N mice with protein-overload
proteinuria induced by unilateral -Reduced proteinuria and ameliorated podocyte dysfunction
[30]
nephrectomy and injections of bovine and loss and provided renal protection
serum albumin
- Dahl salt sensitive rats with
Dapagliflozin -Reduced albuminuria and attenuated renal inflammation
salt-induced hypertension and [31]
and oxidative stress
cardiorenal disease
- Preserved the glomerular and mesangial structure and
-Iron-overload rat model [5]
reduced renal oxidative stress
-Rats with doxorubicin induced -Attenuated glomerular atrophy, renal fibrosis, and
[32]
glomerular atrophy dysfunction
-Reduced urinary albumin creatinine ratio but had no
-Spontaneously hypertensive rats significant effect on serum creatinine levels or renal [33]
histological changes
-Rats with unilateral ureteral obstruction -Reduced renal fibrosis [7]
-Did not attenuate heavy proteinuria, declining glomerular
-Rats with 5/6 (subtotally)
filtration rate, the extent of glomerulosclerosis or [34]
nephrectomized
tubulointerstitial fibrosis
-Did not modify renal hemodynamic function nor attenuated
-Rats with subtotally nephrectomized [35]
proteinuria
-Attenuated adenine induced chronic kidney disease,
-Rats with adenine-induced chronic
anti-inflammatory effect as well as reduction in oxidative [13]
kidney disease
stress
-Male C57BL/6 mice fed with 0.2% -Did not ameliorate renal damage, however it reduced the
[36]
adenine accumulation of uremic toxins including p-cresyl sulfate
-Failed to ameliorate the progressive loss of kidney function
-Rats with adenine-induced chronic and there was no decreased interstitial area percentage, nor
[37]
kidney disease was there altered expression levels of genes related to fibrosis
and inflammation
-Improve kidney function by stimulating antioxidant,
-Rats, isoprenaline-treated [38]
anti-inflammatory and anti-apoptotic signaling pathways
-Attenuated the increase in blood pressure and ameliorated
-Dahl salt-sensitive rats with high-salt the associated hypertensive-induced renal injury, decreased
[39]
diet-inducing hypertensive renal injury. epithelial-mesenchymal transition and oxidative stress and
Canagliflozin
inhibited renal fibrosis
-Reversed the biochemical and histopathological indices of
-Mice with cisplatin-induced
possibly through its anti-inflammatory and antioxidant [40]
nephrotoxicity.
effects
-Protected against cisplatin-induced acute kidney injury by
-Mice with cisplatin-induced
activating adenosine monophosphate-activated protein [41]
nephrotoxicity.
kinase and autophagy in renal proximal tubular cells
-Mice with cisplatin induced -Nephroprotective effect by Akt activation, reduced uptake
[42]
nephrotoxicity. of cisplatin in the kidneys.
-Mice with unilateral ureteral occlusion
-Renal protection [43]
and ischemia-reperfusion renal fibrosis
-Decreased proteinuria and improved the hyperplasia of
-Rats with membranous nephropathy glomerular mesangial cells and stroma, the thickening of [44]
basement membrane and spiky structure.
J. Clin. Med. 2024, 13, 956 7 of 15

Table 2. Cont.

Drug Animal Effects of SGLT2i Ref.

-Reduced proteinuria, improved in creatinine clearance and
-Rats with 5/6 nephrectomy [7]
renal interstitial fibrosis and glomerulosclerosis.
-beneficial effect on kidney function and morphology due to
an inhibition of CD206+CD68+ M2 macrophage polarization
-Rats with 5/6 nephrectomy by targeting mammalian target of rapamycin (mTOR) and [45]
mitophagy pathways and attenuating inflammatory signals
from CD8+ effector T cells.
-Sprague Dawley rats with
-Decreased blood pressure and ameliorated renal
uni-nephrectomy and salt sensitive [46]
inflammation.
hypertension.
-Beneficial renal protection by reducing renal lipid
-Spontaneously hypertensive rats [47]
accumulation, inflammation and oxidative stress
-Rats with cyclosporine A induced
-Reduced blood pressure [48]
nephropathy
-Rats with angiotensin II induced -Prevented the development of renal fibrosis by reducing
[49]
hypertension inflammatory infiltrates
-Reduced kidney damage by attenuating oxidative stress,
-Rats with angiotensin II dependent
Empagliflozin proteinuria and glomerular filtration rate reduction [50]
kidney damage
associated with angiotensin II infusion
-Hypertensive and proteinuric
renin-transgenic (mRen2)27 rats with -Reduced proteinuria and induced protection for renal
[51]
additional administration of nitric oxide vasculopathy, glomerulopathy, and tubular degeneration
synthase inhibitor
-Rats with renal ischemia-reperfusion
-Reduced renal tubular dilatation and necrosis [52]
injury
-Rats with renal ischemia-reperfusion -Attenuated renal injury with reduced oxidative stress,
[53]
injury inflammation an apoptosis
-C57/BL6 mice subjected to renal -Protected against renal injury, attenuated tubular damage,
[54]
ischemia-reperfusion injury reduced inflammatory markers and inhibited apoptosis
-Reduced podocyte lipotoxicity prevented renal lipid
-Mouse model of Alport syndrome [55]
accumulation and improved renal function
-Apo E−/− mice with vascular
-Improved renal function [56]
calcification and 5/6 nephrectomy
-C57BL/6N mice with oxalate-related -Did not affect chronic kidney disease progression in
[57]
nephrocalcinosis oxalate-related nephrocalcinosis
-Fawn-hooded hypertensive -Did not provide renoprotection because it did not
rats-Uni-nephrectomized salt-loaded ameliorate proteinuria, elevated plasma urea and creatinine, [58]
rats-Rats with Goldblatt hypertension oxidative stress or inflammation
-C57BL/6JJcl mice with adenine -Renoprotective effect that was independent from plasma
[59]
induced chronic kidney disease glucose levels and urinary glucose excretion
-Improved the pathogenesis of chronic kidney disease by
-Mouse (FLS-ob/ob) model of
Ipragliflozin reducing ectopic lipid deposition in renal tubules, [60]
non-alcoholic steatohepatitis
endoplasmic reticulum stress
-Did not improve renal glomerulosclerosis or creatinine
-Dahl Salt sensitive rats [61]
clearance

3. SGLT2 and Non-Diabetic Kidney Dysfunction-Clinical Trials (Table 3)

3.1. Effects of SGLT2i on CKD
Several original trials and meta-analysis studies were conducted to elicit the effects of
SGLT2i on patients with CKD. These studies included both patients with and without DM.

Table 3. Renal Beneficial Effects of SGLT2i in Non-Diabetic Patients.

- Delay progression of CKD

- Role in management of IgA nephropathy
- Potential role in the management of focal segmental glomerulosclerosis
- Decrease blood pressure
- Decrease proteinuria
- Improve renal-related survival

We looked to tease the effect of SGLT2i on non-diabetics in these metanalyses. A recent

study [62] underwent a systemic review and metanalysis of large placebo-controlled trials
 - Decrease proteinuria
- Improve renal-related survival

We looked to tease the effect of SGLT2i on non-diabetics in these metanaly

J. Clin. Med. 2024, 13, 956 8 of 15
cent study [62] underwent a systemic review and metanalysis of large placebo-c
trials using SGLT2i and identified 13 studies with 90,413 participants (Figure 1)
the number of non-diabetic patients was 15,605/47,845 participants (32.6%).
using SGLT2i and identified 13 studies with 90,413 participants (Figure 1). Of those, the
number of non-diabetic patients was 15,605/47,845 participants (32.6%).

Figure 1. Diabetics versus non-diabetics in metanalysis.

Of the four CKD

Figure 1. studies,
Diabeticstwoversusstudies involved
non-diabetics in most of the non-diabetic patients.
metanalysis.
The study by Heerspink et al. [63] (DAPA-CKD) included 1398/4304 (32.5%) non-diabetic
patients while the EMPA-CKD
Of the four trialCKD[10] had 3569/6609
studies, two studies (54.0%) withmost
involved no DM. Their
of the mean
non-diabetic pat
baseline eGFR study
rangedby from 37–56 mL/min/1.73 m 2 with a follow-up of 1.3–2.6 years.
Heerspink et al. [63] (DAPA-CKD) included 1398/4304 (32.5%) non-di
The studytients
by Heerspink
while theetEMPA-CKD
al. [63] was prematurely
trial [10] hadstopped
3569/6609as dapagliflozin
(54.0%) with no proved
DM. Their m
its efficacy versus placebo over a median of 2.4 years. They showed a reduced risk of a com-
line eGFR ranged from 37–56 mL/min/1.73 m with a follow-up of 1.3–2.6 years
2
posite of a sustained decline in the estimated GFR of at least 50%, ESKD, or death from renal
The study by Heerspink et al. [63] was prematurely stopped as dapaglifloz
or cardiovascular causes with dapagliflozin than with placebo. Similarly, empagliflozin
its efficacy versus placebo over a median of 2.4 years. They showed a reduced
showed a similar superiority over placebo in decreasing the composite progression of
kidney diseasecomposite
[10]. In bothofstudies,
a sustained decline
the diabetic in the
status, theestimated GFR and
baseline eGFR, of attheleast 50%, ESKD
primary
from renal or cardiovascular
cause of CKD had no impact on the renal outcomes. causes with dapagliflozin than with placebo. Simi
Four out ofpagliflozin
the 5 heart showed a similar
failure studies superiority
included over placebo
non-diabetic patients in [64–67].
decreasing the comp
Their
gression of kidney disease [10]. In both
2 studies,
mean eGFR ranged from 62 to 68 mL/min/1.73 m , with a follow-up ranging between the diabetic status, the baseline e
the primary cause of CKD had no impact on the renal
0.8–and 2.2 years. Analyzing these studies showed that SGLT2i decreased the risk of CKD outcomes.
progression regardless Fourofoutthe of the 5 heart
presence failureofstudies
or absence included
DM, baseline eGFR,non-diabetic patients [64–
or the primary
etiology of CKD. mean eGFR ranged from 62 to 68 mL/min/1.73 m2, with a follow-up ranging bet
A year later,
andRassaei et al.Analyzing
2.2 years. [25] addedthesefive more studies
studies to thethat
showed prior metanalysis
SGLT2i and the ris
decreased
studied the impact of SGLT2i on renal parameters focusing on non-diabetic
progression regardless of the presence or absence of DM, baseline eGFR, patients. Out of or th
46 full texts, they reviewed 7
etiology of CKD. studies in depth [9,36,64,68–71]. Studies reviewed had a follow-
up period ranging A from
year6 weeks to 2.4 years;
later, Rassaei 6 trials
et al. [25] addedusedfive
dapagliflozin
more studies [9,35,64,68–70]
to the prior metan
while one trial used empagliflozin [71]. Their review demonstrated that SGL2i had a
studied the impact of SGLT2i on renal parameters focusing on non-diabetic pat
reno-protective effect as demonstrated by delaying the reduction of eGFR and decreasing
of 46 full texts, they reviewed 7 studies in depth [9,36,64,68–71]. Studies review
urine albumin/creatinine ratio (UACR). Vart et al. [72] further suggested that adding RAAS
follow-up period ranging from 6 weeks to 2.4 years; 6 trials used dapagliflozin [9
blockers to SGLT2i in non-diabetic albuminuric patients may increase kidney failure-free
survival. While70] while
in one one[59],
study trialdapagliflozin
used empagliflozin
was shown [71].
to Their
cause areview demonstrated
reversible decrease in that SG
reno-protective effect as demonstrated by delaying
eGFR in six weeks after the washout period following stopping the drug, another study the reduction of [35]
eGFR and d
failed to show urine albumin/creatinine
that dapagliflozin ratio (UACR).
benefits patients who hadVart et al. kidney
preserved [72] further suggested th
function.
RAAS blockers to SGLT2i in non-diabetic albuminuric patients may increase ki
3.2. Effects of SGLT2i on survival.
ure-free GlomerularWhile
Disorders
in one study [59], dapagliflozin was shown to cause a
3.2.1. IgA Nephropathy (IgAN)
decrease in eGFR in six weeks after the washout period following stopping
Wheeler et al. [69] analyzed the DAPA-CKD study based [9] on the primary etiology
of CKD. The studied outcome was the effects of dapagliflozin on sustained decline in eGFR
of 50% or more, ESKD, or death from a kidney disease-related or cardiovascular cause.
The study included 270 participants with investigator-reported IgAN (confirmed by renal
biopsy in 94% of the participants). Only 14.1% of the cohort had DM. Participants receiving
dapagliflozin (n = 137) and those receiving placebo (n = 133) were followed for a median
of 2.1 years (0.025–3.2 years). Mean eGFR and median UACR were 44.3 (12.4) mL/min/
1.73 m2 and 889.5 (557.5–1472.0) mg/g and 43.2 (12.0) mL/min/1.73 m2 and 902.5
(500.5–1633.0) mg/g in the dapagliflozin and placebo, respectively. The study showed the
superiority of dapagliflozin over placebo on primary composite (p = 0.005) and secondary
J. Clin. Med. 2024, 13, 956 9 of 15

kidney-specific outcomes (p = 0.002). There was a 76% reduction in ESKD and a >50%
reduction in eGFR decline and renal death. These effects did not differ based on eGFR
or UACR with an annual decline in eGFR less in the dapagliflozin group versus placebo
(−2.2 +/− 0.5 vs. −4.6 +/− 0.47 mL/min/1.73 m2 ).
Similar results were found after analyzing the EMPA-KIDNEY trial [10] with
817 patients in the study having IgAN. Empagliflozin reduced the kidney endpoint of
IgAN patients (progression of CKD disease) by about 30% vs. placebo. Combining results
of these 2 studies showed a 51% decrease in CKD progression in patients with IgAN [73].
Dong et al. [74] followed a cohort of Chinese patients with biopsy-proven IgAN for
three and six months after being treated with SGLT2i. Most of the IgAN cohort were non-
diabetic (81.7%). The authors observed a significant reduction in proteinuria in their patient
cohort independent of immunosuppressive agents and baseline eGFR and proteinuria
levels, again confirming the role of SGLT2i in the management of IgAN.

3.2.2. Focal Segmental Glomerulosclerosis (FSGS)

Rajasekeran et al. studied [35] the effect of eight weeks of dapagliflozin on GFR in
humans (n = 10) and in experimental FSGS. The secondary endpoints were related to
changes in renal hemodynamic function, proteinuria, and blood pressure. They noted
no statistical difference in PAH-based GFR. When stratified into two subgroups based on
GFR, the researchers noted a significant decrease in GFR in the group of patients with
GFR > 90 m/min/1.73 m2 . They further showed that dapagliflozin failed to modify kidney
hemodynamics or attenuate proteinuria.
Two years after the prior study, Cherney et al. [68] performed a short-term crossover,
randomized controlled trial (DIAMOND) at six hospitals in three countries. Their goal
was to investigate the efficacy of SGLT2i in proteinuric kidney disease without diabetes.
Eleven patients with FSGS were randomly assigned (1:1) to receive a placebo followed by
dapagliflozin 10 mg per day or vice versa. Each treatment period lasted six weeks with a
six-week washout period in between. The primary outcome was the effect of dapagliflozin
on proteinuria and other hemodynamic parameters. While the researchers demonstrated
a nonsignificant reduction in proteinuria compared with placebo, GFR was temporarily
decreased during the six weeks of dapagliflozin.
A larger study analyzing patients with biopsy-proven FSGS (n = 104) in the DAPA-
CKD trial [63] showed a reduced rate of eGFR decline versus placebo but failed to show
any statistically significant difference between the drug and the placebo group [75]. It
is postulated that this negative result could be attributed to the small number of events
(4 primary outcomes in dapagliflozin versus 7 in the placebo group).
Thus, data remains non-conclusive as to the role of SGLT2i in managing patients with
FSGS. The lack of long-term data and a larger study population to address the potential
efficacy of SGLT2i in FSGS leave a knowledge gap that begs for further studies.

3.3. Effects of SGLT2i on Blood Pressure

Miyata et al. [11] reviewed the mechanisms of decreasing blood pressure upon using
SGLT2i. They suggested that the decrease in plasma volume as a result of their diuretic
and natriuretic effects, weight loss, and the anti-inflammatory action of these drugs may
contribute to the anti-hypertensive effects. Other mechanisms identified that may contribute
to the SGLT2i effects on blood pressure were the noted improvement in arterial stiffness
and endothelial function [21,76].
While the effect of SGLT2i in lowering blood pressure in diabetics is well estab-
lished [77], studies of the role of SGLT2i in lowering blood pressure in non-diabetics
did not show the same effect [36,68]. Cherney et al. [68] studied non-diabetic patients
(n = 53, GFR > 25 mL/min, proteinuria 500–3500 mg/g) comparing dapagliflozin effects
on blood pressure versus placebo over six weeks. Patients who started on dapagliflozin
(n = 27) were switched to a placebo, and patients on a placebo (n = 26) were switched to
receive dapagliflozin. The researchers showed no change in systolic (SBP) and diastolic
J. Clin. Med. 2024, 13, 956 10 of 15

(DBP) blood pressure with no hypoglycemic episodes. The decrease in body weight with
dapagliflozin was 1.5 kg (p = 0.046).
Zanchi et al. [78] performed a randomized control study on non-diabetic normotensive
patients (n = 39) comparing the effect of empagliflozin (n-26) versus placebo (n = 13) on
blood pressure. Their results were different than the prior studies where empagliflozin
was shown to decrease SBP/DBP (−5 ± 7 and −2 ± 6, respectively) over a one-month
study period. Similarly, Bays et al. [79] underwent a randomized, double-blinded study
comparing the canagliflozin effect in three different dosages on blood pressure in non-
diabetics versus placebo (n = 376). At the end of the study (12 weeks), the researchers
demonstrated a decrease in blood pressure in both canagliflozin and placebo groups. While
the reduction in SBP was more in the canagliflozin groups (−2.0 to −3.3 vs. −1.4 mmHg),
the reduction in DBP was more in the placebo group (−1.8 vs. −0.7 to −1.4 mmHg).
Diaz-Cruz et al. [80] were also able to show a decrease in both SBP and DBP on using
dapagliflozin in patients who were pre-diabetics.

3.4. Effects of SGLT2i on Nephrotic Proteinuria

Kalay et al. [81] reviewed studies examining the effects of SGLT2i on patients with
nephrotic range proteinuria and identified nine studies. While most patients in these
studies were diabetics, two studies included non-diabetic patients with FSGS [82,83].
Boeckhaus et al. [82] reported 2 cases with FSGS where SGLT2i reduced the UACR
ratio by 84% at 11 months in one patient and by 18% at 3 months in another. The same data
was reported in another study [83] on a patient with FSGS where UACR was decreased by
61% after one month and by 37% after 9 months of using SGLT2i.

4. Effects of SGLT2i on Survival

Awad et al. [84] reviewed randomized clinical trials (12 studies) focusing on the effect
of SGLT2i on mortality in both diabetic and non-diabetic patients. While mortality risks
were decreased in both groups, it was not statistically significant in the non-diabetic patients
(RR = 0.93, 95% CI 0.70–1.23).
Heerspink et al. [9] showed that dapagliflozin decreased the risk of both renal and
cardiovascular mortality, and when RAAS blockers were added to dapagliflozin, patients’
survival was further increased. More recently, McEwan et al. [85] used a model analysis on
the DAPA-CKD trial and showed that dapagliflozin may reduce all-cause mortality.

5. SGLT2i Side Effects

While using SGLT2i was not associated with hypoglycemia in non-diabetic patients,
several significant side effects were noted when using these drugs.
Hypotension secondary to diuresis [9], natriuresis, and volume depletion has been
reported. Furthermore, excessive diuresis may impact poorly on patients’ quality of life.
Urinary tract infections (UTIs) mainly secondary to yeast infections have been associated
with the use of SGLT2i [86]. UTIs can range from mild to severe infections. A more severe
form of infection, genital mycotic infection, has been described in diabetics, but not in
non-diabetics [87].
Other side effects were suggested to be associated with SGLT2i as bone fractures,
amputations, and malignancies, but results are controversial [88].

6. Future Directives
The addition of newer agents that showed benefits in managing patients with kidney
diseases to SGLT2i may be beneficial. Zhang et al. [89] performed a systemic literature
search of randomized control trials comparing mineralocorticoid receptor antagonists
(finerenone), SGLT-2i, and glucagon-like peptide-1 receptor agonists (GLP-1 RA) in diabet-
ics with CKD. They identified 18 studies (n = 51,496) that demonstrated that while SGLT2i
significantly decreased the risk of renal events compared with finerenone and GLP-1 RA,
their cardiac outcome effects were comparable.
J. Clin. Med. 2024, 13, 956 11 of 15

Trials comparing additive effects of SGLT2i with GLP-1 RA, mineralocorticoid, or

endothelin receptor antagonist to SGLT2i alone in both diabetics and non-diabetics may
prove to be very helpful in improving renal outcomes.

7. Conclusions
SGLT2i play a major role in managing non-diabetic patients with kidney diseases. This
group of drugs can achieve their role through different mechanisms unrelated to glycemic
control. More studies looking at the effects of SGLT2i on different renal pathologies causing
CKD, examining the effects of SGLT2i alone or in combination with other therapeutic
groups, their possible side effects, and their mechanism of action are very much needed.
It is important to note that many studies reviewed were small studies, open labeled
with little reports on control variables that may affect the outcomes of the study. It is crucial
to have more well-designed randomized placebo-controlled studies.

Author Contributions: Conceptualization: A.M.A., A.S.A. and E.M.A.-R.; data curation A.M.A. and
E.M.A.-R.; writing-original- draft preparation: A.M.A. and E.M.A.-R.; writing review and editing:
A.M.A., A.S.A. and E.M.A.-R. All authors have read and agreed to the published version of the
manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflicts of interest with no ties to any pharmaceutical
or drug-related industry.

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