2018, 65 (3), 335-344

Original

Efficacy and safety of sodium-glucose

cotransporter 2 inhibitors as add-on to metformin
and sulfonylurea treatment for the management of
type 2 diabetes: a meta-analysis
1) 2) 3) 1) 1) 1)
Jian Li *, Ying-hong Shao *, Xiao-gang Wang *, Yanping Gong , Chunlin Li and Yanhui Lu
1) Department of Geriatric Endocrinology, Chinese PLA General Hospital, Beijing 100853, China
2) Outpatient Department, Chinese PLA General Hospital, Beijing 100853, China
3) Department of Neurosurgery, Institute of Neurology, General Hospital of Shenyang Military Area Command, Shenyang,
Liaoning 110840, China

Abstract. This study evaluates the efficacy and safety of sodium-glucose cotransporter 2 (SGLT2) inhibitors as add-on to
metformin and sulfonylurea treatment for type 2 diabetes management. The literature search was conducted in electronic
databases and meta-analyses of mean differences in the changes from baseline in selected disease endpoints (efficacy endpoints)
or odds ratios (for safety endpoints) were performed to compare outcomes between SGLT2 inhibitor- and placebo-/ comparator-
2
treatments. Seven studies (5,143 patients; age 56.75 years [95% CI: 56.19, 57.37]; body mass index 29.53 kg/m [28.23, 30.83];
and 51.87% [50.46, 53.57] males) were included. Compared to placebo, SGLT2 inhibitors significantly ( p < 0.00001) reduced
glycated hemoglobin (HbA1c; –0.79% [95% CI: –0.90, –0.68]), fasting plasma glucose (FPG; –1.73 mmol/L [–1.86, –1.60]) and
body weight (–1.85 kg [–2.11, –1.59]) after 52–78 weeks of treatment. There were no significant differences in reduction of either
HbA1c, FPG or body weight between 18–24 weeks and after 52–76 weeks of treatment. Treatment with SGLT2 inhibitors as add-
on to metformin and sulfonylurea was also associated with significant reductions in blood pressure and triglycerides and increase
in high-density lipoprotein-cholesterol. Incidence of hypoglycemia was significantly higher, but incidence of hyperglycemia was
significantly lower in SGLT2 inhibitor group. Overall, drug-related adverse events were more common in SGLT2 group mainly due
to higher incidence of genital tract infections.

Key words: Sodium-glucose cotransporter 2 inhibitors, Metformin, Sulfonylurea, Type 2 diabetes mellitus

TYPE 2 DIABETES MELLITUS (T2DM) is charac‐
terized by chronic hyperglycemia frequently associated
with dyslipidemia, hypertension, and vascular complica‐
tions and is a major risk factor for cardiovascular vascu‐
lar disease [1]. Substantial morbidity and mortality is
linked to T2DM [2]. According to International Diabetes
Federation, 415 million adults have T2DM and by 2040
the prevalence will rise to 642 million [3]. The preva‐
lence of T2DM is not restricted to later age only rather it
Submitted Aug. 22, 2017; Accepted Dec. 2, 2017 as EJ17-0372
Released online in J-STAGE as advance publication Jan. 27, 2018
Correspondence to: Jian Li, Department of Geriatric Endocrinol‐
ogy, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian
District, Beijing 100853, China.
E-mail: jianli_med@126.com
*Jian Li, Ying-hong Shao and Xiao-gang Wang contributed
equally to this work.
©The Japan Endocrine Society
is increasing even in young groups. Early-onset T2DM is a
more aggressive phenotype with more rapid decline in β-cell
function associated with comorbid conditions [4, 5].
Developing countries may face a significant public
health crisis from T2DM because it is projected that
between 2010 and 2030 there can be a 70% increase in the
prevalence of T2DM there as compared to 20% increase
for developed countries [6]. Causal factors being the
population growth, increase in life expectancy,
urbanization, lack of physical inactivity and obesity [7].
For the management of T2DM, primary advice is to
adapt a healthy lifestyle and dietary pattern. Metformin,
which is an efficacious drug because of its glycemic con‐
trol, insulin sensitizing and body weight effects, is the first
line pharmacotherapy for T2DM [8]. However, met‐
formin cannot provide effect for very long periods which
necessitates use of additional drugs. Sulfonylurea drugs
336 Li et al.
(SU) are often added upon metformin’s inadequacy. Gly‐
cemic control improves with the addition of SU to met‐
formin, but the efficacy is not persistent in the longer run
[9]. Among the management options for T2DM, one
strategy recommended by the American Diabetes Asso‐
ciation (ADA) and the European Association for the Study
of Diabetes (EASD) is addition of sodium-glucose
cotransporter 2 (SGLT2) inhibitors to ongoing metformin
or SU plus metformin, if glycemic goals are not met [10].
Selective and reversible inhibition of SGLT2 lowers
blood glucose levels in an insulin-independent fashion
and is also found to be favorable for hypertension and
body weight control. Chemically, SGLT2 is a high-
capacity and low-affinity protein located abundantly in
the proximal renal tubules that reabsorb 80–90% of glu‐
cose from the glomerular filtrate [11]. Canagliflozin,
dapagliflozin, empagliflozin, ipragliflozin, luseogliflozin
and tofogliflozin are SGLT2 inhibitor drugs which are
well-studied for their efficacy, safety, bioavailability,
pharmacokinetic and pharmacodynamic characteristics
[12, 13].
In a recent network meta-analyses of several drugs
used for the management of T2DM after inadequacy of
metformin and SU, SGLT2 inhibitors were found as
effective as many other antidiabetic drugs in controlling
HbA1c levels but with regards to the incidence of hypo‐
glycemia, weight loss and blood pressure, SGLT2 inhibi‐
tors were better than other drugs [14, 15]. Similar results
were found in a meta-analysis of randomized controlled
trials (RCTs) in which SGLT2 inhibitors were used in
combination with metformin against placebo-controlled
trials [16]. To our knowledge, there is no systematic
review of trials which investigated the efficacy and safety
of SGLT2 inhibitors as add-on to metformin and SU
treatment. Objective of the present study was to con‐
duct a comprehensive literature search for the identifica‐
tion of trials which recruited T2DM patients to investigate
the efficacy and safety of SGLT2 inhibitors as add-on to
metformin and SU treatment and to perform meta-
analyses of important efficacy and safety endpoints that
could display the overall effectiveness of this thera‐
peutic combination.
Methods
This study was performed by following the Cochrane
Collaboration ’ s guidelines for conducting systematic
reviews and meta-analyses and is reported in
accordance with the PRISMA statement.
Inclusion and exclusion criteria
Inclusion criteria were: Study—a) recruiting adult T2DM
patients to evaluate the efficacy and safety of a SGLT2
inhibitor as add-on to metformin and SU treat‐ ment by
comparing it with either placebo or a suitable non-SGLT2
comparator drug controlled group; and b) reported at
least one indicator of disease condition of interest (study
endpoints). Exclusion criteria were: rele‐ vant studies—a)
of less than 16 weeks duration; b) examined the efficacy of
SGLT2 inhibitors as add-on to metformin and SU in a
single arm trial; c) compared SGLT2 inhibitor
monotherapy with metformin and/or SU either alone or in
combination with other antidiabetic drugs; and d)
compared SGLT2 inhibitors in combination with other
non-SGLT2 drugs with any other combination or
monotherapy as add-on to metformin and/or SU.
Literature search
Literature search was conducted in Embase, Google
Scholar, Medline/PubMed, Scopus, Ovid SP, and Web of
Science databases. Medical subject headings (MeSH) and
keywords used in different combinations were: sodium-
glucose cotransporter-2 inhibitor, SGLT2 inhibi‐ tor,
dapagliflozin (DAPA), canagliflozin (CANA), ipra‐ gliflozin
(IPRA), empagliflozin (EMPA), tofogliflozin (TOFO),
luseogliflozin (LUSEO), metformin, sulfonyl‐ urea, type 2
diabetes, randomized trial, efficacy, safety, tolerability,
adverse effects, add-on treatment, glycosyla‐ ted
hemoglobin (HbA1c), fasting plasma glucose (FPG), blood
pressure, body weight, body mass index (BMI),
postprandial glucose (PPG), cholesterol, high density lip‐
oprotein cholesterol (HDL-chol), low density lipoprotein
cholesterol (LDL-chol), triglyceride, and estimated glo‐
merular filtration rate (eGFR). The cross references of
important articles were also searched. Search encom‐
passed research articles published before October 2017 in
English language.
Primary and secondary endpoints
Participants of the included studies were T2DM
patients having inadequate control on disease with met‐
formin and SU therapy. Primary outcome measures of
interest were the changes from baseline in percent
HbA1c, FPG) levels, and body weight. Secondary end‐
points were the changes from baseline in systolic and
diastolic blood pressure (SBP and DBP), and the blood
levels of HDL‐chol, LDL‐chol, and triglycerides, and eGFR.
Safety endpoints were the incidence of hypogly‐ cemia
and hyperglycemia, incidence of genital and uri‐
 SGLT2 Inhibitors, metformin and sulfonylurea for diabetes
nary tract infections, and incidence of ketoacidosis
during treatment period.
Quality assessment and data synthesis
Quality assessment of the RCTs included in this meta-
analysis was carried out by using the Cochrane Collabo‐
ration ’ s Tool for Quality Assessment of Randomized
Controlled Trials. Data pertaining to the participants ’
demographic and clinical characteristics, interventions,
trial eligibility criteria, outcome measures, and outcomes
were extracted from the selected research articles by
adapting a standardized procedure. Changes from base‐
line in the selected endpoints were either extracted raw
from the respective research articles if provided, or cal‐
culated from baseline and week 18, 24, 52 and 76 of
treatment duration values reported as outcomes of the
treatments.
Statistical analysis
Data and Analyses module of RevMan software (ver‐
Fig. 1  A flowchart of study screening and selection process.
337
sion 5.3; Cochrane Collaboration) was used for the meta-
analyses of weighted mean differences (WMD) between
SGLT2 inhibitors and control groups in changing effi‐
cacy endpoints or weighted odds ratios (OR) for safety
endpoints where overall effect size or subgroup size was
an inverse variance weighted average of the individual
effect sizes. Between-studies inconsistency (heterogene‐
2
ity) was tested by I statistics. Subgroup analyses were
performed with regards to control group (placebo vs.
DPP4 inhibitors). Subgroup analyses were also per‐
formed to examine the effect of BMI (over 30 vs. under
30) in the changes from baseline in % HbA1c, FPG, and
body weight between SGLT2 inhibitor- and placebo-
treated groups.
Results
Literature search
Seven studies fulfilled the eligibility criteria and were
included in this meta-analysis [17-23] (Fig. 1). These
338 Li et al.
studies recruited 3,321 patients to treat with a SGLT2
inhibitor by comparing the outcomes with 1,318
placebo-treated patients and 504 comparator
(dipeptidyl dipepti‐ dase 4 (DPP4) inhibitors) treated
patients as add-on to metformin and SU treatment.
Meta-analysis results
Important characteristics of the included studies are
presented in Table 1. Age, percentage of males and BMI
of the SGLT2 inhibitor treated patients were 56.85 years
[95% confidence interval (CI): 56.24, 57.45], 52.12%
2
[50.46, 53.77], and 29.72 kg/m [28.39, 31.06] and those
of control patients were 56.69 years [56.11, 57.26],
2 BMI) in mean differences in the changes in % HbA1c,
51.55% [49.91, 53.20] and 29.36 kg/m [28.06, 30.65],
respectively. Quality of the included RCTs was high when
these studies were subjected to the Cochrane Col‐
laboration’s Tool for Quality Assessment of Randomized
Controlled Trials (Table 2).
In these studies, canagliflozin was used in 3 studies,
and empagliflozin in 2 and dapagliflozin in 2 studies.
Five studies compared a SGLT2 inhibitor against a
placebo-controlled group whereas two studies used a
DPP4 inhibitor drug as a comparator. Five studies
inves‐ tigated 2 doses of SGLT2 inhibitors.
As add-on to metformin and SU treatment, SGLT2
inhibitors significantly reduced percent HbA1c after
18– 24 weeks (–0.64% [–0.71, –0.58]; p < 0.00001) as
well as after 52–78 weeks (–0.79% [–0.90, –0.68]; p <
0.00001) in comparison with placebo. There was no
sig‐ nificant difference in reduction of HbA1c after 18–
24 weeks and after 52–76 weeks of treatment (Fig. 2).
Although, SGLT2 inhibitors treatment also reduced
HbA1c significantly more than DPP4 inhibitors (–0.28%
[–0.36, –0.19]; p < 0.00001), but decrease in HbA1c
was significantly more (p < 0.00001) against placebo
treated than in DPP4 inhibitors-treated patients.
Compared to placebo-controlled patients, the
SGLT2 inhibitors significantly reduced FPG after 18–
24 weeks (–1.58 mmol/L [–1.75, –1.42]; p < 0.00001)
as well as after 52–78 weeks (–1.73 mmol/L [–1.86, –
1.60]; p < 0.00001) (Fig. 3). There was no significant
difference in the reduction of FPG after 18–24 weeks
and after 52–76 weeks of treatment. Although, SGLT2
inhibitors treat‐ ment also reduced FPG significantly
more than DPP4 inhibitors (–1.14 mmol/L [–1.52, –
0.77]; p < 0.00001), but decrease in FPG was
significantly more (p < 0.00001) against placebo than in
DPP4 inhibitors treated patients.
The SGLT2 inhibitors also significantly reduced body
weight after 18–24 weeks (–1.75 kg [–1.99, –1.51]; p <
0.00001) as well as after 52–78 weeks (–1.85 kg [–
2.11, –1.59]; p < 0.00001) in comparison with placebo
treated group. There was no significant difference in
reduction of body weight after 18–24 weeks and after
52–76 weeks of treatment. Not only the SGLT2
inhibitors treatment reduced body weight significantly
more than DPP4 inhibitors (–2.23 kg [–2.56, –1.90]; p
< 0.00001), but also the decrease in body weight was
significantly more (p < 0.00001) against DPP4
inhibitors than in placebo treated patients (Fig. 4).
No significant differences were found between
placebo-controlled subgroup (under 30 BMI vs. over 30
FPG, and body weight.
The SGLT2 inhibitor treatment was also associated
with significantly reduced SBP, DBP, and blood triglyc‐
erides (Table 3). Whereas, SGLT2 inhibitors increased
HDL-chol levels, there was no significant change in
LDL-chol levels (Table 3). These outcomes did not
differ with respect to placebo- and DPP4 inhibitors-
treated sub‐ groups.
In safety meta-analysis, incidence of hypoglycemia was
significantly higher in SGLT2 inhibitors treated patients
whereas the incidence of hyperglycemia was significantly
higher in the placebo-treated group. Over‐ all, drug-
related adverse events were more common in SGLT2
group especially the genital tract infections (Table 4).
These outcomes did not differ with respect to placebo-
treated and DPP4 inhibitors-treated subgroups.
Discussion
This meta-analysis finds that SGLT2 inhibitors as add-
on to metformin and SU treatment are significantly more
efficacious in controlling T2DM disease indices includ‐ ing
HbA1c, FPG, body weight, SBP/DBP, HDL-chol and
triglycerides than placebo or DPP4 inhibitors. However,
drug-related adverse events were found to be signifi‐
cantly more in SGLT2 inhibitor treated group than in
comparators mainly due to the higher incidence of geni‐
tal tract infections in SGLT2 inhibitor group. Moreover,
incidence of hypoglycemia was significantly higher, but the
incidence of hyperglycemia was significantly lower in
SGLT2 inhibitor-treated patients.
For the management of T2DM, when lifestyle and
dietary interventions remain inadequate to control
disease, metformin is the first line drug [8]. However,
disease progression usually makes metformin use in‐
Table 1 Characteristics of the included studies
Study TD n   Drug & dose (mg)   Age (years)   Males (%)   White (%)   Black (%)   Asian (%)

SGLTI COMP SGLTI COMP SGLTI COMP SGLTI COMP SGLTI COMP SGLTI COMP SGLTI COMP
Cha 2017 24 60 124 DAPA LINA/GLEMI 52.6± 6.5 53.4 ± 7.1 58.3 50 100 100

SGLT2 Inhibitors, metformin and sulfonylurea for diabetes

Haring 2013 24 225 225 EMPA 10 PBO 57± 9.2 56.9 ± 9.2 50.22 50 39.56 39 1.33 1 57.33 56

Haring 2013 24 216 225 EMPA 25 PBO 57.4± 9.3 56.9 ± 9.2 53 50 39 39 1 1 58 56

Haring 2015 52 225 225 EMPA 10 PBO 57± 9.2 56.9 ± 9.2 50.22 50 39.56 39 1.33 1 57.33 56

Haring 2015 52 216 225 EMPA 25 PBO 57.4± 9.2 56.9 ± 9.2 53 50 39 39 1 1 58 56

Haring 2015 76 225 225 EMPA 10 PBO 57± 9.2 56.9 ± 9.2 50.22 50 39.56 39 1.33 1 57.33 56

Haring 2015 76 216 225 EMPA 25 PBO 57.4± 9.2 56.9 ± 9.2 53 50 39 39 1 1 58 56

Ji 2015 18 223 226 CANA 100 PBO 56.5± 8.3 55.8 ± 9.4 55.60 55.31 100 100

Ji 2015 18 227 226 CANA 300 PBO 56.4± 9.2 55.8 ± 9.4 49.78 55.31 100 100

Matthaei 2015 24 108 108 DAPA 10 PBO 61.1± 9.7 60.9 ± 9.2 42.59 55.56 96.23 94.44

Wilding 2013 24 157 156 CANA 100 PBO 57.4± 10.5 56.8 ± 8.3 48.41 48.72 84.08 82.05 3.18 6.41 1.27 1.28

Wilding 2013 24 156 156 CANA 300 PBO 56.1± 8.9 56.8 ± 8.3 55.77 48.72 81.41 82.05 7.05 6.41 0 1.28

Wilding 2013 52 157 156 CANA 100 PBO 57.4± 10.5 56.8 ± 8.3 48.41 48.72 84.08 82.05 3.18 6.41 1.27 1.28

Wilding 2013 52 156 156 CANA 300 PBO 56.1± 8.9 56.8 ± 8.3 55.77 48.72 81.41 82.05 7.05 6.41 0 1.28

Schrenthaner 2013 24 377 378 CANA 100 SITA 56.6± 9.3 56.7 ± 9.3 54.91 56.88 64.98 63.49 11.40 11.90 17.77 17.19

Schrenthaner 2013 52 377 378 CANA 300 SITA 56.6± 9.3 56.7 ± 9.3 54.91 56.88 64.98 63.49 11.40 11.90 17.77 17.19

Abbreviations: CANA, canagliflozin; COMP, comparator; DAPA, dapagliflozin; EMPA, empagliflozin; IPRA, ipragliflozin; PBO, placebo; SGLTI, SGLT2 inhibitor; SITA, sitagliptin; TD, trial duration (weeks).
339
340 Li et al.
Table 2 Risk of bias assessment in the included studies

Selective Incomplete Blinding of Blinding of Allocation Random

Other bias outcome participants/ sequence
reporting outcome data concealment
assessment personnel generator
Cha et al., 2017 L L L H H H H
Haering et al., 2013/2015 L L L L L L L

Haring et al., 2015 L L L L L L L

Ji et al., 2015 L L L L L L L

Matthaei et al., 2013 L L L L L L L

Schrenthaner et al., 2013 L L L L L L L

Wilding et al., 2013 L L L L L L L

Legends: H: high risk; L: low risk; U: unclear risk

Fig. 2  Forest graph showing the mean differences in the changes in percent HbA1c between SGLT2 inhibitors and comparators.

adequate. Addition of a SU drug to metformin is reported
to reduce HbA1c by up to 0.8% after 1 year of treatment
[24]. A meta-analysis of 6 studies (1,364 patients)
revealed that decrease in HbA1c from baseline was
0.9% but the odds of experiencing a hypoglycemic
event was significantly higher in SU treated than in
comparator treated patients [25].
Efficacy of SGLT2 inhibitors in improving glycemic
control, blood pressure and body weight is also reported
in other meta-analytical reviews and is now well-defined
[26-28]. Safety concerns, especially with regards to
higher incidence of genital tract infections, are also well-
pursued in literature and generally glucosauria is consid‐
ered as the main causal factor; although, immune
weakness may also play a role in the etiology [29, 30].
Serious safety issues such as bone fractures,
pyelonephri‐ tis, urosepsis, and ketoacidosis, are rarely
reported with SGLT2 inhibitors. Rather, a robust
improvement in car‐ diovascular outcomes in T2DM
patients treated with SGLT2 inhibitor, empagliflozin,
supports the use of this therapeutic regimen. Therefore,
overall this class of oral anti‐diabetic medication is a
valuable addition to availa‐ ble treatment options for
T2DM that can be a prominent therapy in future [28]. A
simulation study conducted in Canada revealed that
canagliflozin treatment was associ‐ ated with better
health outcomes and lower costs than
 SGLT2 Inhibitors, metformin and sulfonylurea for diabetes 341

Fig. 3  Forest graph showing the mean differences in the changes in percent fasting plasma glucose between SGLT2 inhibitors and
comparators.

Fig. 4  Forest graph showing the mean differences in the changes in body weight between SGLT2 inhibitors and comparators.

sitagliptin as a third-line therapy added-on to
metformin and sulfonylurea in T2DM patients [31].
Sulfonylurea use is found to be associated with signifi‐
cantly higher incidence of hypoglycemia than with met‐
formin [32]. Incidence and severity of hypoglycemia is
reported to be associated with increased patient anxiety
about hypoglycemia and lower health-related quality of
life in T2DM patients under metformin and a SU treat‐
ment [33]. In comparison with SU, a SGLT2 inhibitor
(dapagliflozin) is reported to cause significantly lower
incidence of hypoglycemia (7% vs. 29%) [34]. Other RCTs
have also found that in combination with metfor‐ min,
SGLT2 treatment is associated with significantly lower
incidence of hypoglycemia in comparison with
 342 Li et al.
Table 3 Outcomes of secondary efficacy endpoints showing mean differences between SGLT2

inhibitors-treated and placebo-treated groups

Endpoint Mean difference [95% CI] Significance
Systolic blood pressure (mm Hg) –2.85 [–3.51, –2.19] p < 0.00001
Diastolic blood pressure (mm Hg) –0.76 [–1.19, –0.34] p < 0.0001
HDL-chol (%) 5.98 [4.64, 7.32] p < 0.00001
LDL-chol (%) 1.79 [–1.05, 4.63] p = 0.22
Triglycerides (%) –5.25 [–9.12, –1.38] p = 0.008
2 0.11 [–0.79, 1.01] p = 0.81
eGFR (mL/min/1.73 m )
Abbreviations: chol, cholesterol; CI, confidence interval; eGFR, estimated glomerular filtration rate;
H/LDL, high/low density lipoprotein.

Table 4 Outcomes of the safety meta-analysis (odds ratios [95% confidence interval]) between SGLT2 inhibitors-treated and placebo-
treated groups in the incidence of adverse events (AEs).
Safety endpoint n Overall Low dose High dose
Any AE/s 2,695 1.02 [0.88, 1.17]; p = 0.82 0.98 [0.80, 1.19]; p = 0.82 1.07 [0.86, 1.32]; p = 0.56
Drug-related AEs 2,695 1.61 [1.37, 1.89]; p < 0.0001 1.63 [1.30, 2.05]; p < 0.0001 1.58 [1.25, 2.00]; p < 0.00001
Serious AEs 2,695 0.68 [0.51, 0.90]; p = 0.007 0.76 [0.52, 1.11]; p = 0.16 0.58 [0.38, 0.89]; p = 0.01
AEs causing discontinuation 2,695 1.09 [0.78, 1.52]; p = 0.62 0.95 [0.59, 1.52]; p = 0.82 1.25 [0.78, 1.99]; p = 0.35
Male genital tract infections 2,695 2.73 [1.29, 5.75]; p = 0.009 3.04 [1.10, 8.38]; p = 0.03 2.38 [0.79, 7.20]; p = 0.12
Female genital tract infections 2,695 4.71 [2.63, 8.44]; p < 0.00001 6.59 [2.57, 16.93]; p < 0.0001 3.63 [1.71, 7.70]; p = 0.00008
Urinary tract infections 2,680 1.31 [1.02, 1.67]; p = 0.03 1.37 [0.98, 1.91]; p = 0.06 1.24 [0.87, 1.77]; p = 0.24
Hypoglycemia 2,244 1.75 [1.43, 2.15]; p < 0.00001 1.88 [1.42, 2.50]; p < 0.001 1.62 [1.20, 2.187]; p < 0.001
Hyperglycemia 1,284 0.30 [0.22, 0.42]; p < 0.00001 0.30 [0.19, 0.47]; p < 0.00001 0.31 [0.20, 0.48]; p < 0.00001

DPP-4 inhibitors [35, 36] and incretin-based therapies
[37, 38]. However, in the present study, the incidence of
hypoglycemia was significantly higher in SGLT2 inhibi‐ tor
group than in the placebo group. Whether there can be
any synergistic relationship between SGLT2 inhibitors and
SU in this regard needs to be further researched.
Taken together, the SGLT2 inhibitors have insulin-
independent mechanisms of action whereas the efficacy of
SU drugs depends on adequate insulin-secretory capacity
of pancreas. Generally, the SGLT2 inhibitors lowers the
risk of hypoglycemia, whereas, SU drugs increase
hypoglycemia risk. Using both these regimens in
combination may need to adjust SU dosage to mitigate the
risk of hypoglycemia. Moreover, increasing concerns
about of the safety of SU drugs in the long-run also needs
due considerations. Thus, the identification of patients
who can be potentially benefitted with such a combination
of drugs keeping in view the efficacy as well as safety
should be an important consideration of a
patient-centered approach to T2DM management.
Conclusion
As add-on to metformin and sulfonylurea, SGLT2
inhibitors are found significantly more efficacious than
placebo and DPP4 inhibitors in improving HbA1c, FPG,
and body weight. Systolic and diastolic blood
pressures, HDL-cholesterol and triglyceride levels also
signifi‐ cantly improved with SGLT2 inhibitor
treatment in com‐ parison with placebo controlled
patients. Incidence of genital tract infections and
hypoglycemic events was sig‐ nificantly higher in
SGLT2 inhibitor treated group whereas hyperglycemic
events were significantly higher in control group.
Acknowledgements
None.
 SGLT2 Inhibitors, metformin and sulfonylurea for diabetes
Authors Contributions
J.L., Y.H.S. and X.G.W. conceptualized and designed
the study; Y.P.G. and C.L.L. extracted and analyzed data,
and drafted the manuscript; Y.H.L. provided technical
support in the analyses and writing. All authors agree to
be accountable for all aspects of the work.
Funding
No fund was received for this research.
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Conflicts of Interest
There is no conflict of interests.
Ethical Privacy Statement
No approval was required for ethical privacy because
the study does not involve direct contact with patients or
their personal information.
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