doi: 10.2169/internalmedicine.

6685-20
Intern Med 62: 681-688, 2023
http://internmed.jp

【 ORIGINAL ARTICLE 】

Nephroprotective Effects of Dapagliflozin in Patients with

Type 2 Diabetes

Yasuhiro Iijima 1-4, Masafumi Nakayama 5,6, Takashi Miwa 2, Fumiyoshi Yakou 1,2,
Hirofumi Tomiyama 7, Junpei Shikuma 2, Rokuro Ito 2, Akihiko Tanaka 1, Naoki Manda 4 and
Masato Odawara 2,3

Abstract:
Objective This study analyzed changes in the estimated glomerular filtration rate calculated using cystatin
C (eGFRcys) and sodium excretion in the urine after administering dapagliflozin as an add-on therapy to
conventional treatment for diabetes.
Methods This was a single-center, single-group, prospective interventional study. Dapagliflozin was admin-
istered to improve the plasma glucose control in 30 subjects with type 2 diabetes mellitus (age 53±8 years
old; 66.6% men). Blood and urine tests were performed before and 6 and 12 months after dapagliflozin ad-
ministration. The daily sodium excretion was estimated with the Kawasaki formula using second-morning
urine samples.
Results The eGFRcys did not markedly differ before and 6 months after the dapagliflozin administration
but was significantly increased after 12 months (p<0.001), and the estimated daily sodium excretion was also
significantly increased (p<0.001 at 6 months and p=0.002 at 12 months). The systolic and diastolic blood
pressures tended to decrease after administration. The HbA1c level after the administration of dapagliflozin
tended to be lower in the T3 group, showing the smallest increase in changes in the estimated daily sodium
excretion from baseline to 6 months (28.2-107.5 mEq/day), than in the combined groups of T1 (219.5-110.1
mEq/day) and T2 (101.4-28.9 mEq/day). In contrast, the eGFRcys was significantly higher in the combined
groups of T1 and T2 than that in the T3 group at both 6 and 12 months (p=0.031 and p=0.007, respectively).
Conclusions Add-on therapy with dapagliflozin increased the urinary sodium excretion and decreased the
blood pressure even in the early phase of this therapy. Our results suggest that dapagliflozin add-on therapy
may exert nephroprotective effects in subjects with type 2 diabetes mellitus.

Key words: dapagliflozin, diabetes mellitus, sodium glucose cotransporter-2, sodium excretion,
nephroprotective effects

(Intern Med 62: 681-688, 2023)

(DOI: 10.2169/internalmedicine.6685-20)

tions (1-3). Approximately 40% of subjects with T2DM de-

Introduction velop diabetic kidney disease, albuminuria, and a decreased
estimated glomerular filtration rate (eGFR). Diabetic kidney
Most subjects with type 2 diabetes mellitus (T2DM) will disease is associated with markedly increased risks of car-
die of or become disabled due to vascular complica- diovascular disease and death (4, 5). Some studies have

１
Department of Internal Medicine, Todachuo General Hospital, Japan, ２ Department of Diabetes, Endocrinology and Metabolism, Tokyo Medical
University Hospital, Japan, ３ Department of Shirakawa Community Medicine, Tokyo Medical University, Japan, ４ Diabetes Center, Manda Memo-
rial Hospital, Japan, ５ Cardiovascular Center, Todachuo General Hospital, Japan, ６ Cooperative Major in Advanced Biomedical Sciences, Joint
Graduate School of Tokyo Women’s Medical University and Waseda University, Japan and ７ Department of Cardiology, Tokyo Medical Univer-
sity Hospital, Japan
Received for publication November 10, 2020; Accepted for publication April 3, 2022
Correspondence to Dr. Masato Odawara, odawara@tokyo-med.ac.jp

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 Intern Med 62: 681-688, 2023 DOI: 10.2169/internalmedicine.6685-20
demonstrated that improving lifestyles through sodium re-
duction, protein restriction, and glycemic control effectively
prevent the progression of diabetic nephropathy (6-9).
Renin-angiotensin system inhibitors have been shown to be
medically effective in preventing the progression of nephro-
pathy (10, 11).
Several studies have suggested that sodium glucose
cotransporter-2 (SGLT2) inhibitors can reduce the incidence
of cardiovascular events (12-14). SGLT2 inhibitors suppress
glucose and sodium reabsorption at the early proximal tu-
bule (15). The nephroprotective effects of SGLT2 inhibitors
have received substantial attention, as proximal tubules are
thought to play a significant role in the pathophysiology of
diabetic nephropathy (12, 16, 17). This may be associated
with amelioration of hyperfiltration but has not yet been
fully investigated. Cystatin-C measurement, compared to se-
rum creatinine, improves clinical sensitivity as a screening
test for early renal damage (18).
We therefore analyzed the changes in the eGFR calculated
using cystatin C and sodium excretion in the urine of sub-
jects with T2DM after dapagliflozin treatment.
Materials and Methods
Study subjects
The present study was conducted in subjects treated for
diabetes at the Todachuo General Hospital. The inclusion
criteria were as follows: 1) subjects diagnosed with T2DM;
2) subjects not taking diuretics; and 3) subjects who agreed
to receive treatment with 5 mg dapagliflozin per day for fur-
ther plasma glucose reduction. The subjects were subse-
quently asked to participate in the study protocol from Sep-
tember 2014 to February 2015 based on these inclusion cri-
teria. We excluded subjects with renal dysfunction (serum
creatinine level of !2.0 mg/dL) from the study.
In this study, the effects of the dapaglifrozin administra-
tion on the improvement of the plasma glucose level and re-
nal function were examined as the primary and secondary
endpoints, respectively. This was a single-center, single-
group, prospective interventional study. The difference in the
GFR values using cystatin C before and after the dapagli-
flozin administration was hypothesized to be 3.0±2.2 from
our small pilot study. To ensure a significance level (α) of
0.05 and power factor (1-β) of 90%, a sample size of at
least 30 patients was necessary. However, all subjects who
had provided their informed consent before reaching the tar-
get sample size were added to the study, so we ultimately
enrolled 32 subjects.
Study protocol
After obtaining the subjects’ written informed consent,
blood pressure and laboratory examination results were
measured and analyzed, respectively, before prescribing da-
pagliflozin. All subjects were followed monthly at the outpa-
tient department of Todachuo General Hospital. At 6 and 12
682
months after the initiation of 5 mg dapagliflozin per day,
blood pressure measurements and laboratory analyses were
repeated. During this study, there were no changes in dia-
betic drugs or in drugs for hypertension and dyslipidemia.
The Ethics Committee of Todachuo General Hospital ap-
proved the study protocol, which was conducted in accor-
dance with the tenets of the 1964 Declaration of Helsinki
and its later versions. In addition, this study was conducted
after registration with UMIN, a public clinical trial registra-
tion institution (ID No. UMIN000028153).
Physical and blood pressure measurements
Body weight and abdominal circumference were meas-
ured at baseline and at 6 and 12 months post-treatment.
Height was measured at baseline. Blood pressure at the
medical examination was determined as the mean of two
measurements obtained with the conventional cuff method
using a mercury sphygmomanometer. These two measure-
ments were performed with participants in the seated posi-
tion after resting for at least 5 minutes.
Laboratory measurements and estimation of the
GFR using cystatin C
Blood and urine samples were obtained after overnight
fasting. Enzymatic methods were used to measure serum
electrolyte (sodium, potassium, and chloride), low-density
lipoprotein cholesterol, triglycerides, creatinine, uric acid,
HbA1c, plasma glucose, and cystatin C (CysC), urine so-
dium and creatinine, and urine albumin levels.
Glomerular filtration rates were estimated using CysC
(eGFRcys) as follows: (104×CysC-1.019×0.996age)-8 for men
and (104×CysC-1.019×0.996age×0.929)-8 for women (19). All
blood samples were obtained in the morning after overnight
fasting.
Estimation of daily salt excretion
Daily sodium excretion was calculated with the Kawasaki
formula using the second-morning urine (20, 21). The for-
mula used to estimate the daily sodium excretion (mEq/day)
was as follows: 16.3×[second-morning urine sodium concen-
trations (mEq/L)/second-morning urine creatinine concentra-
tions (mg/L)/10× estimated 24-hour urine creatinine excre-
tion]0.5. The formula used to estimate the 24-hour urine cre-
atinine excretion from the demographic data was as follows:
15.1×body weight (kg)+7.4×height (cm)-12.6×age (years)-
79.9 for men and 8.6×body weight (kg)+5.1× height (cm)-
4.7×age (years)-75.0 for women.
Data and statistical analyses
Numerical values were expressed as the mean±standard
deviation (SD). Categorical data were expressed as percent-
ages and compared using the chi-square test. The paired t-
test was used to calculate statistical significances of differ-
ences in values measured before and after the addition of
dapagliflozin. To assess the different status of each variable
among groups, a one-way analysis of variance and the
 Intern Med 62: 681-688, 2023 DOI: 10.2169/internalmedicine.6685-20

Table 1. Clinical Characteristics.

Number of patients (male） 30 (20)

Age, years 53.5±7.6
Height, cm 166.4±8.2
Body weight, kg 78.2±14.0
BMI, kg/m2 28.1±3.7
Abdominal circumference, cm 98.7±8.8
Systolic BP, mmHg 139±19
Diastolic BP, mmHg 86±11
Time since diagnosis of type 2 diabetes, year 7.1±3.4
HbA1c, % 7.6±1.1
UACR, mg/g･CRE 112.0±69.5
Estimated sodium excretion, mEq/day 231.2±62.4
eGFRcys, mL/min/1.73m2 92.8±18.5

Current or past smoker (%) 13 (43.3)

Medications (%)
for diabetes
Dipeptidyl peptidase-4 inhibitor 24 (80.0)
Biguanide 25 (83.3)
Sulfonylurea 13(43.3)
Glinide 1 (3.3)
Thiazolidinediones 0 (0)
α -glucosidase inhibitor 4 (13.3)
Insulin 5 (16.7)

for hypertension
Agents acting on renin–angiotensin system (ARB or ACE) 17 (56.7)
Calcium channel blocker 8 (26.7)
β -blocker 0 (0)
for hyperuricemia 3 (10.0)
for dyslipidemia 20 (66.7)
BMI: body mass index, BP: blood pressure, UACR: urine albumin-to-creatinine ra-
tio, eGFRcys: estimated glomerular filtration rate calculate using cystatin C

Kruskal-Wallis test were used. A subgroup analysis was also
performed using the same method. A probability (p) value
of <0.05 was considered to indicate a statistically significant
difference. All statistical analyses were performed using the
IBM SPSS Statistics software program for Windows, version
23.0 (IBM Corporation, Armonk, USA).
Results
The subjects’ clinical characteristics are shown in Table 1.
A total of 32 subjects agreed to participate in this study, but
2 of them dropped out due to side effects of dapagliflozin
during the follow-up period (1 with vomiting and the other
with urinary tract infection). Data were thus ultimately ob-
tained from 30 participants for 12 months after the initiation
of dapagliflozin treatment. The mean age was 53.5±7.6
years old, and 20 (66.6%) of them were men. The majority
of study participants were taking dipeptidyl peptidase-4 in-
hibitors and biguanide for plasma glucose control (80.0%
and 83.3%, respectively), and 5 of them were receiving in-
sulin. A total of 56.7% were taking hypertension medica-
tions. No medications were changed during the follow-up
period in these 30 subjects.
Variable changes before and after adding dapagliflozin (5
mg), including in the HbA1c, body weight, body mass in-
dex, and abdominal circumference, are shown in Table 2.
The C-peptide levels significantly decreased after six months
of dapagliflozin treatment but were still quite high. During
the medical examination, both systolic and diastolic blood
pressures were significantly decreased, and the estimated
daily sodium excretion was significantly increased after six
months of dapagliflozin treatment (Table 2, Fig. 1). How-
ever, the serum sodium levels also significantly increased
(Table 2). None of the subjects had serum sodium abnor-
malities. Serum hemoglobin and hematocrit levels were sig-
nificantly increased at six months. However, uric acid levels
were significantly decreased after 12 months of dapagli-
flozin treatment.
The subjects were divided into tertiles according to differ-
ences in the estimated daily sodium excretion levels at base-
line and 6 months (i.e. 6 months - baseline), as follows: T1,
219.5-110.1 mEq/day; T2, 101.4-28.9 mEq/day; T3, 28.2-

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 Intern Med 62: 681-688, 2023 DOI: 10.2169/internalmedicine.6685-20

Table 2. Changes Occurring in Variables after the Add-on Therapy of 5 mg Dapagliflozin in

All Study Participants (n=30).
p value (vs. before)
Baseline 6 months 12 months
6 months 12 months
Body weight (kg) 78±14 75±14 74±14 <0.001 <0.001
BMI (kg/m2) 28.1±3.7 26.9±3.7 26.5±3.6 <0.001 <0.001
Abdominal circumference (cm) 98.7±8.8 93.2±10.4 93.6±9.6 <0.001 <0.001
HbA1c (%) 7.6±1.1 7.2±0.6 7.0±0.7 0.031 <0.001
C-peptide (ng/mL) 4.1±3.0 2.8±1.5 2.8±1.5 0.017 0.018
Systolic BP (mmHg) 139±19 130±16 131±16 0.005 0.024
Diastolic BP (mmHg) 86±11 79±10 83±8 0.006 0.061
eGFRcys (mL/min/1.73m2) 92.8±18.5 90.0±20.7 101.9±20.5 0.125 <0.001
24-hour sodium excretion (mEq/day) 231±62 290±99 284±96 <0.001 0.002
UACR (mg/g･CRE) 69.2±21.4 49.2±14.5 56.4±16.9 0.055 0.304
Serum Sodium (mEq/L) 140±2 141±2 140±2 0.027 0.441
Hemoglobin (g/dL) 14.4±1.3 15.0±1.4 15.1±1.5 <0.001 <0.001
Hematocrit (mg/dL) 41.9±3.3 44.0±3.6 44.7±3.7 <0.001 <0.001
Uric acid (mg/dL) 5.0±1.0 4.6±1.2 4.5±1.0 0.107 0.014
BMI: body mass index, BP: blood pressure, eGFRcys: estimated glomerular filtration rate calculate using cystatin C,
UACR: urine albumin-to-creatinine ratio

Figure 1. Significantly increased estimated daily sodium excretion in subjects with type 2 diabetes
after 6 months of dapagliflozin treatment. The estimated glomerular filtration rate calculated using
cystatin C (eGFRcys) did not significantly change within the first 6 months but was significantly in-
creased after 12 months. Hence, the eGFRcys may be improved by a reduced kidney load. The urine
albumin-to-creatinine ratio showed a decreasing trend with dapagliflozin treatment.

107.5 mEq/day. As shown in Table 3, at 12 months, al-
though HbA1c levels were significantly decreased due to the
add-on dapagliflozin therapy in T2 and T3, the eGFRcysC
was significantly increased in T1 and T2 after add-on ther-
apy, and the serum sodium levels were significantly de-
creased in T3 (p=0.041). The estimated daily sodium excre-
tion was increased in T1 and T2 at 6 months; however, the
serum sodium level was not significantly different among
groups, and none of the subjects had hyponatremia.
When the subjects were divided into two groups (T3 vs.
T1/2), the HbA1c levels after dapagliflozin treatment tended
to be lower in the T3 group than in the T1/2 group. By con-
trast, the changes in eGFRcys from the baseline were sig-
nificantly greater in the T3 group than in the T1/2 group at
both 6 and 12 months (p=0.031 and p=0.007, respectively).
Furthermore, the eGFRcys was higher at 12 months than
at 6 months in both groups. In addition, the urine albumin-
to-creatinine ratio showed a decreasing trend in T1/2 com-
pared with T3, albeit without significance (at 6 months, T1/
2: -34.3±65.5, T3: 3.7±25.8, p=0.091; Fig. 2).

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 Table 3. Changes in Parameters before and after the Add-on Therapy of 5 mg Dapagliflozin among Groups Categorized by Tertile Ranges of 24-h Sodium Excretion.

T1: 219.5~101.4 mEq/day (n=10) T2: 100.5~29.6 mEq /day (n=10) T3: 28.2~−107.5 mEq /day (n=10)
p value p value p value p value p value p value
Baseline 6M 12M Baseline 6M 12M Baseline 6M 12M
0vs6M 0vs12M 0vs6M 0vs12M 0vs6M 0vs12M
Age, years 53.8±7.4 71.8±2.4 67.4±2.9
Number of patients 10 (8) 10 (5) 10 (7)
(male)
BMI, kg/m2 28.2±3.3 27.1±3.4 26.7±3.3 0.012 0.002 26.5±3.5 25.3±3.4 24.9±3.8 0.002 <0.001 29.6±4.0 28.4±3.9 27.9±3.3 <0.001 0.001
Systolic BP, mmHg 140±22 131±16 131±17 0.019 0.027 137±21 131±17 129±13.8 0.323 0.180 139±14 129±16 134±17 0.102 0.516
Diastolic BP, mmHg 83±13 81±11 82±9 0.705 0.801 88±12 77±8 83±7 0.016 0.147 86±9 80±12 83±8 0.074 0.162
HbA1c, % 7.3±1.2 7.3±1.0 7.1±0.8 0.910 0.515 7.7±1.0 7.2±0.3 6.9±0.5 0.176 0.022 7.8±1.1 7.0±0.4 6.9±0.7 0.041 0.002
Intern Med 62: 681-688, 2023

eGFRcys, mL/ 94.1±20.6 96.7±19.2 107.5±20.8 0.325 <0.001 98.1±14.1 95.2±15.0 110.0±17.4 0.295 0.009 86.3±20.1 78.2±23.5 88.1±17.5 0.032 0.590
min/1.73 m2

685
Increase eGFRcys, 5 (50%) 10 (100%) 4 (40%) 9 (90%) 2 (20%) 5 (50%)
mL/min/1.73 m2
(VS baseline, %)
Na, mEq/L 139.6±2.9 140.4±2.8 139.5±2.2 0.137 0.872 139.7±1.5 140.4±1.3 139.8±2.1 0.153 0.872 139.9±2.0 140.6±0.8 140.8±2.1 0.354 0.215
K, mEq/L 4.5±0.3 4.4±0.4 4.5±0.3 0.675 0.601 4.4±0.3 4.5±0.4 4.4±0.3 0.437 0.818 4.5±0.2 4.5±0.4 4.5±0.2 0.823 0.879
Cl, mEq/L 104±2 104±1 103±2 0.847 0.343 104±4 103±3 103±3 0.944 0.815 103±3 104±2 104±2 0.077 0.040
Serum osmolality, 289±5 291±4 292±3 0.292 0.078 288±3 291±4 293±4 0.011 0.001 291±7 294±6 294±4 0.113 0.213
mOsm/kg･H2O
Urinary osmolality, 601±194 601±183 573±235 0.997 0.757 690±12 770±206 700±195 0.027 0.829 660±253 782±193 689±213 0.140 0.774
mOsm/kg･H2O
UACR, mg/g･CRE 43.5±58.2 21.9±31.1 29.1±55.2 0.056 0.064 107.5±184.2 60.6±103.6 77.7±127.2 0.125 0.316 56.5±67.8 66.8±82.5 62.6±83.4 0.534 0.798
24-h sodium 249±75 389±93 346±100 <0.001 0.012 192±46 251±55 228±66 <0.001 0.145 252±49 229±69 277±86 0.127 0.293
excretion, mEq/L/day
DOI: 10.2169/internalmedicine.6685-20

T1-3: tertile ranges of estimated 24-h sodium excretion by the Kawasaki method, DM: diabetes mellitus, BMI: body mass index, BP: blood pressure, eGFRcys: estimated glomerular filtration rate calculate using cys-
tatin C, Na: serum sodium, K: serum potassium, Cl: serum chloride, UACR: urine albumin-to-creatinine ratio
 Intern Med 62: 681-688, 2023 DOI: 10.2169/internalmedicine.6685-20

Figure 2. Changes in HbA1c and eGFRcys levels and the urine albumin-to-creatinine ratio after
add-on treatment with dapagliflozin between subjects with increased urine sodium excretion and
those with almost no increase in urine sodium excretion. The change in HbA1c level was high, but not
significantly so, in the T3 group, whereas the increase in the eGFRcys was significantly higher in the
T3 group at both 6 and 12 months after treatment than before. Furthermore, the eGFRcys was high-
er at 12 months than at 6 months in both groups. In addition, the urine albumin-to-creatinine ratios
tended to be lower in T1/T2 than in T3.

preserve the renal function. The Na+/H+ exchanger (NHE3),

Discussion
This study investigated the association between sodium
excretion and the eGFRcys after add-on therapy with da-
pagliflozin. The addition of SGLT2 inhibitors suppresses
urinary sugar reabsorption in the proximal tubule and inhib-
its excessive sodium reabsorption. As a result, the glomeru-
lar overfiltration situation is corrected by restoring the failed
tubuloglomerular feedback mechanism. Such treatment has
also been shown to reduce oxygen demand and improve oxi-
dative stress in the renal cortex (22). Therefore, in this
study, we investigated the effect of the degree of increased
urinary sodium excretion on the renal function.
After the initiation of dapagliflozin treatment, the esti-
mated daily sodium excretion was significantly increased. In
addition, the reduction in the HbA1c level in the subjects
with increased urine sodium excretion was relatively small;
however, the eGFRcys was significantly improved. Sodium
excretion was increased, and the eGFRcys was not signifi-
cantly different at 6 months after the initiation of dapagli-
flozin add-on therapy, but the eGFRcys was significantly
improved at 12 months after the initiation. Wanner et al.
also reported that the eGFR was decreased at one month af-
ter the start of empagliflozin administration and then gradu-
ally improved (16). During the early stage of treatment, this
phenomenon might be due to the normalization of the eGFR
because of glomerular hyperfiltration.
Appropriate therapeutic intervention at the early stage of
incipient nephropathy and overt nephropathy are required to
which coexists with SGLT2 on the luminal side of the
proximal tubules, is responsible for approximately 30% of
sodium reabsorption in the kidney, and SGLT2 inhibition re-
sults in the downregulation of NHE3 activity, which pro-
motes natriuresis. This means that SGLT2 inhibitors sup-
press sodium reabsorption in the proximal tubules, and natri-
uresis is promoted by increased sodium levels in tubular
fluid, which is sensed by the macula densa (23, 24). There-
fore, sodium excretion may be important for the renoprotec-
tive action of SGLT2 in a mechanism independent of plasma
glucose levels. Previous reports have suggested that the uri-
nary sodium excretion increases in the early stages of
SGLT2 inhibitor administration (25). We therefore con-
ducted a subgroup analysis based on the amount of change
over six months, which is the early stage of data collection.
We classified the subjects into three groups according to the
degree of urinary sodium excretion as follows: T1, increased
urine sodium excretion group; T2, mildly increased urine so-
dium excretion group; and T3, almost no or decreased urine
sodium excretion group. We then examined the effects of
changes in urine sodium excretion on the improvement in
the plasma glucose level and renal function. Increased urine
sodium excretion did not exert a strong hypoglycemic effect.
In addition, the eGFRcys was significantly elevated after
12 months of dapagliflozin treatment, independent of its
plasma glucose-lowering effect in this study. To investigate
the effect of urinary sodium excretion, we compared the
T1/2 (increased urine sodium excretion) group and T3 (al-
most no increase in urine sodium excretion) group.

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 Intern Med 62: 681-688, 2023 DOI: 10.2169/internalmedicine.6685-20
The blood pressure at 6 months after the initiation of da-
pagliflozin therapy was significantly lower than that at base-
line (systolic: 139±19 to 130±16 mmHg; p=0.005, and dia-
stolic; 86±11 to 79±10 mmHg; p=0.006), and the antihyper-
tensive effect persisted at 12 months. Blood pressure man-
agement at <130/80 mmHg is recommended for subjects
with T2DM (26).
This decreased blood pressure is induced by the natriu-
retic effect of dapagliflozin and might also be associated
with renal protection, because subjects with diabetic nephro-
pathy have high-salt-sensitivity hypertension (27, 28). Thiaz-
ide diuretics are effective for the treatment of salt-sensitive
hypertension, but hyponatremia rarely occurs (29-31). In this
study, the estimated daily sodium excretion was significantly
increased; however, none of the subjects developed hypona-
tremia. Blood concentration changes caused by increased
urine volume affect the increased serum sodium level, as the
body weight and excretion of large amounts of free water
accompanying sodium excretion were significantly reduced.
SGLT2 also acts as a diuretic and has been reportedly useful
for subjects with heart failure (32). However, SGLT2 differs
from thiazide diuretics in reducing serum uric acid levels,
suggesting that the nephroprotective effect of dapagliflozin
might be achieved by multiple factors, including reduced
blood sugar levels, serum uric acid levels, and blood pres-
sure, via increased urinary sodium excretion.
In a previous experimental study, urinary sodium excre-
tion was increased after administration of an SGLT2 inhibi-
tor to mice that developed progressive diabetic nephropa-
thy (33). However, there is some controversy regarding the
albuminuria-reducing effect of SGLT2 inhibitors in experi-
mental studies. One experimental study reported that SGLT2
inhibition failed to reduce albuminuria in diabetic db/db
mice, although it did attenuate renal tubulointerstitial fibro-
sis (34). In contrast, several experimental studies have
shown a reduction in albuminuria by SGLT2 inhibition in
the same mouse model (35, 36). In addition, several clinical
studies have reported a reduction in albuminuria by long-
term SGLT2 inhibitor treatment in subjects with
T2DM (12, 37). The factors that cause these differences
have not yet been clarified. And ipragliflozin treatment con-
tributed to the amelioration of proximal tubular protein over-
load, mitochondrial morphological abnormality, and renal
oxidative stress and tubulointerstitial fibrosis in progressive
diabetic nephropathy. These findings suggest the existence
of a novel crosstalk mechanism between SGLT2 inhibition
and megalin underlying the potential renal benefits of SGLT
2 inhibition.
In the present study, the subjects included many patients
with type 2 diabetes and diabetic nephropathy. Therefore,
similar effects may have been achieved in subjects with in-
creased urinary sodium excretion after the administration of
dapagliflozin. Further studies are needed to elucidate the
long-term renal benefits of SGLT2 inhibition in diabetic
nephropathy.
687
Study limitations
Several limitations associated with the present study war-
rant mention. First, the number of subjects was relatively
small. Second, a urine analysis to estimate sodium excretion
was performed using second-morning urine, not the urine
collected after a 24-hour fast. However, early second-
morning urine is more accurate than spot urine for estimat-
ing the sodium excretion. In addition, the sodium excretion
was estimated through interviews of dietary content, not
based on actual measurements. Third, as this was a single-
group prospective study, the possibilities of a placebo effect
and behavior changes triggered by participation in the study
cannot be ruled out.
Conclusion
Even in the early phase of this study, add-on dapagliflozin
therapy increased the urinary sodium excretion and reduced
the blood pressure compared with the baseline values. As a
result, the eGFRcys was improved. In addition, the urine
albumin-to-creatinine ratio showed a decreasing trend. Our
results thus suggest that add-on dapagliflozin therapy may
exert nephroprotective effects in subjects with T2DM. Fur-
ther large-scale studies should be conducted to confirm the
relationship between the urinary sodium excretion and neph-
roprotective effects after add-on dapagliflozin therapy.
Author’s disclosure of potential Conflicts of Interest (COI).
Masato Odawara: Honoraria, Daiichi Sankyo, MSD, Ono, Novar-
tis, Astellas, Sanwa Kagaku Kenkyusho, AstraZeneca, Kyowa
Hakko Kirin, Kowa, Takeda, Tanabe Mitsubishi, Eli Lilly, Nip-
pon Boehringer, Sanofi, Novo Nordisk, Dainippon Sumitomo and
Taisho Toyama; Research funding, Dainippon Sumitomo, Eli
Lilly, Daiichi Sankyo, Ono, Astellas, Kyowa Hakko Kirin,
Takeda, Tanabe Mitsubishi and Nippon Boehringer.
Acknowledgement
We thank Helena Popiel (Department of International Medical
Communications, Tokyo Medical University) for the English lan-
guage editing and review of our manuscript.
Yasuhiro Iijima and Masafumi Nakayama contributed equally
to this work.
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