Journal of Clinical Pharmacy and Therapeutics, 2013, 38, 350359

doi: 10.1111/jcpt.12077

Review Article

The kidney as a new target for antidiabetic drugs: SGLT2 inhibitors

S. Cangoz PharmD, Y.-Y. Chang PharmD, S. J. Chempakaseril PharmD, R. C. Guduru PharmD, L. M. Huynh PharmD, J. S. John PharmD,
S. T. John PharmD, M. E. Joseph PharmD, R. Judge PharmD, R. Kimmey PharmD, K. Kudratov PharmD, P. J. Lee PharmD, I. C. Madhani
PharmD, P. J. Shim PharmD, S. Singh PharmD, S. Singh PharmD, C. Ruchalski PharmD and R. B. Raffa PhD
Temple University School of Pharmacy, Philadelphia, PA, USA

Received 12 February 2013, Accepted 20 May 2013

Keywords: diabetes, sodium/glucose transport, inhibitor, pharmacotherapy

worldwide prevalence is estimated to reach nearly 370 million by

2030.4
A recent study found that less than half of newly diagnosed
type 2 DM patients achieve an HbA1c <7%, the American Diabetes
Association target.5 Another recent study found that less than half
of adolescents 1017 years of age reached the primary outcome
with current medications (metformin alone or plus rosiglitazone).6
The consequence of uncontrolled diabetes is signicantly increased
morbidity, including retinopathy, limb amputations, neuropathy
and nephropathy and mortality (in 2010, 6
8% of all deaths
worldwide were attributed to DM).7 For example, the risk of
cardiovascular complications increases with the duration of lack of
adequate glycaemic control.8,9
Diabetes is generally considered to result from either an
inadequate production of insulin or a hyporesponsiveness to
insulin at its receptors (insulin resistance). In either case, the
result is increased blood glucose (hyperglycaemia). Glucose, which
is a product of carbohydrate metabolism, is a main source of
energy for the central nervous system, muscle and fat and insulin
plays a key role in the effective use of glucose by tissues. Blood
glucose concentration increases following food intake, it is
detected, and insulin release is stimulated. Insulin facilitates
glucose uptake and converts glucose into its storage forms, viz.
glycogen and free fatty acids, which are utilized by muscle and fat,
respectively.
There are several types of DM, the most common being type 1
DM and type 2 DM. Type 1 DM, previously known as insulindependent diabetes, is linked with the formation of antibodies,
including insulin and the islet cells of the pancreas.1014 It results
from the destruction of insulin-producing b-cells, a type of islet
cell. Initially, patients with type 1 DM display postprandial
hyperglycaemia only, but these progresses to include fasting
hyperglycaemia by the time b-cell destruction are complete. Type 1
DM accounts for about 510% of the diabetic population. Because
it is mainly an autoimmune disorder resulting in progressive
destruction of pancreatic b-cells, patients usually have little insulin
reserve at the time of diagnosis and therefore require some form of
insulin pharmacotherapy for life. This can be a long period,
because type 1 DM is usually diagnosed during childhood or
adolescence. Type 2 DM, previously known as non-insulindependent diabetes, accounts for almost 90% of the diabetic
population.15 Type 2 DM is characterized by dysfunction of
pancreatic islet cells and insulin resistance and, secondarily, by an
increased glucose production resulting from feedback control
mechanisms.1618 In an effort to overcome insulin resistance at
tissue targets, additional insulin is produced in an effort to

SUMMARY
What is known and objective: A novel class of antidiabetic drugs
SGLT2 (Na+/glucose cotransporter type 2) inhibitors target
renal reabsorption of glucose and promote normal glucose
levels, independent of insulin production or its action at
receptors. We review this new mechanistic approach and the
reported efcacy and safety of clinical testing of lead compounds.
Methods: Information was obtained from various bibliographic
sources, including PubMed and others, on the basic science and
the clinical trials of SGLT2 inhibitors. The information was then
summarized and evaluated from the perspective of contribution
to a fuller understanding of the potential and current status of
the lead clinical candidates.
Results and discussion: Diabetes mellitus is a spectrum of
disorders that involves inadequate insulin function resulting
in adverse health sequelae due to acute and chronic hyperglycaemia. Current antidiabetic pharmacotherapy primarily addresses
either insulin production at the pancreatic b-cells or insulin
action at insulin receptors. These drugs have less than full
clinical effectiveness and sometimes therapy-limiting adverse
effects. The third major component of glucose balance, namely
elimination, has not been a signicant therapeutic target to date.
SGLT2 inhibitors are a novel approach.
What is new and conclusion: A sufcient number of clinical
trials have been conducted on sufciently chemically diverse
SGLT2 inhibitors to reasonably conclude that they have efcacy
(HbA1c reductions of 0
41%), and thus far, the majority of
adverse effects have been mild and transitory or treatable, with
the caveat of possible association with increased risk of breast
cancer in women and bladder cancer in men.
WHAT IS KNOWN AND OBJECTIVE
Diabetes mellitus (DM) is a metabolic disorder of inadequate
glycaemic control, dened by the American Diabetes Association
as a haemoglobin A1C (HgA1c) level 6
5%.1 According to the
National Health and Nutrition Examination Survey (NHANES),2
the prevalence of DM in the United States is projected to increase
from nearly 26 million in 20103 to about 32 million by 2031. The
Correspondence: Robert B. Raffa, PhD, Department of Pharmaceutical
Sciences, Temple University School of Pharmacy, 3307 N. Broad St.,
Philadelphia, PA, USA. Tel.: +1 215 707 4976; fax: +1 215 707 3678;
e-mail: robert.raffa@temple.edu

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350

S. Cangoz et al.

SGLT2 inhibitors for type 2 DM

counteract the hyperglycaemia. This additional insulin contributes

to hyperinsulinemia and down-regulation (decreased number) of
insulin receptors located on target tissues. Although the exact
mechanism of insulin resistance is not known, it is believed to be
related to decreased insulin receptor binding afnity or to defects
in insulin receptor signal transduction mechanisms (2nd messengers).19 Genetics, obesity and sedentary lifestyle also play a role in
diabetes.2022
Currently, there are several pharmacotherapeutic classes of
antidiabetic agents approved for use in the United States (Table 1).
These drugs target organs involved in glucose control such as the
pancreas, liver, small intestine, skeletal muscle and adipose tissue.
But the currently approved drugs decrease HbA1C level by only
about 12%, and further, some have various side effects that
include gastrointestinal intolerability, hypoglycaemia and weight
gain among others.23 SGLT2 (Na+/glucose cotransporter type 2)
inhibitors act at a novel target the renal reabsorption of glucose
and by a novel mechanism: the inhibition of renal reabsorption of
glucose promotes normal glucose levels, independent of insulin
production or its action at receptors. We review the mechanism
and available clinical evidence related to the efcacy and safety of
SGLT2 inhibitors.

Analysis
Each of the sources was reviewed for relevance to the mechanism
of action or the clinical attributes of SGLT2 inhibition. In many
cases, the information was obtained from studies that did not have
investigation of the mechanism as the primary outcome, but the
results were determined either to reect on the mechanism or to
suggest further avenues of investigation. Each item was evaluated
for its relevance and strength of the evidence.

RESULTS AND DISCUSSION

Kidney as target of diabetes treatment
The kidney plays a major role in the regulation of glucose
homoeostasis.24 Contributing to this control are at least three of 12
or more SGLTs (gene name SLC5A, 11 genes) Na+/glucose
cotransporters: SGLT1, SGLT2 and SGLT3.2528 SGLT129 is
expressed in the distal proximal convoluted tubule (and in the
gastrointestinal tract)30 and acts as a transporter for dietary
glucose and galactose.31 SGLT2 accounts for about 90% of the
renally reabsorbed glucose; SGLT1 accounts for about 10%26,30,3234
(Table 2; Fig. 1).
In healthy individuals, approximately 180 g of glucose is
reabsorbed daily via the sodium/glucose transport (SGLT) transporters.35 That is, <1% of glucose is excreted in urine.36,37
However, in conditions of hyperglycaemia, SGLT transporters
become saturated, and a larger amount of glucose is excreted in
urine (glycosuria).30 This provides a physiological and molecular
target for development of new type 2 diabetes pharmacotherapy.
Because SGLT2 inhibitors block sodium reuptake in the proximal
tubule area of the kidneys,24 inhibiting SGLT2 should inhibit renal
glucose reabsorption, thereby increasing glucose excretion in the
urine and restore glucose levels to more normal levels.30,3854

METHODS
Identication of studies
Computerized literature searches (MEDLINE, PubMed) of articles
in English or having abstracts in English were conducted using
keywords related to mechanism of action, clinical trials and
potential deleterious properties of SGLT2 inhibitors (both in
general and for individual agents). Comprehensive reviews of
early literature were obtained, as well as an extensive collection of
primary literature.

Table 1. Pharmacotherapeutic classes of antidiabetic agents approved for use in the United States
HbA1c

Drug

MOA

Metformin (po)

insulin sensitivity, hepatic glucose

production, glycogenolysis

12%

Sulfonylurea (po)

insulin secretion from the pancreas

12%

Thiazolidinediones (po)
DPP-4 Inhibitors (po)

insulin sensitivity
insulin secretion, glucagon secretion

12%
0
71
4%

Meglitinides (po)
Alpha glucosidase
inhibitors (po)
Insulin (sc)

insulin secretion from the pancreas

Delays absorption of glucose

0
52%
0
51%

Incretins/GLP-1
agonist (sc)

Amylin analogues (sc)

Increases glucose uptake by tissues;

increases glycogen levels; decreases
glycogen breakdown
Release of insulin from beta cells of
pancreas during hyperglycaemia;
prevents release of glucagon from
alpha cells of pancreas after eating;
increases satiety
Prevents release of glucagon after eating;
modulates gastric emptying; Increases satiety

No limit

Advantages

Disadvantages

Low risk of hypoglycaemia,

does not cause weight gain,
improves lipid panel
Low risk of GI side effects,
rapid onset of action
Low risk of hypoglycaemia
Lower risk of GI side effects
and hypoglycaemia
Rapid onset of action
Does not cause weight
gain or hypoglycaemia
Rapid onset of action

GI side effects, risk of lactic

acidosis especially pts w/HF
and kidney disease
Risk of hypoglycaemia, weight gain
Weight gain, oedema
Benets mainly seen as adjunctive
therapy
Hypoglycaemia, weight gain
GI side effects
Hypoglycaemia, injection site
reaction, weight gain

12%

Weight loss

Nausea, pancreatitis

0
30
6%

Weight loss

Nausea; hypoglycaemia in the

rst 4 weeks

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SGLT2 inhibitors for type 2 DM

Table 2. Selected characteristics of SGLT1 and SGLT225,30

Chromosome
Gene
Organ expression
Afnity for glucose
Mechanism of glucose transport
Cotransport
Glucose transport to blood
Capacity for glucose transport
% of renal glucose reabsorption

SGLT1

SGLT2

22 q13.1
SLC5A1
Mostly small intestine (ileum), kidney
(proximal straight tubules), heart
High (K = 0
4 mM)
Active (against concentration gradient)
Na+ (Na+/K+ ATPase-coupled)
Glucose transporters (GLUT)
Low
~10%

16 p11.2
SLC5A2
Mainly renal proximal convoluted tubules;
less in small intestine (ileum)
Low (K = 2 mM)
Active (against concentration gradient)
Na+ (Na+/K+ ATPase-coupled)
Glucose transporters (GLUT)
High
~90%

PCT

the kidney, SGLT1 plays only a minor role in the kidney. SGLT1 is
abundant in the gastrointestinal tract, where inhibition might lead
to undesirable adverse effects.56
A avonoid isolated in 1835 from root bark of apple trees,57
phlorizin (1-[2,4-dihydroxy-6-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6(hydroxymethyl)tetrahydropyran-2-yl]oxy-phenyl]-3-(4-hydroxyphenyl)propan-1-one),58 was observed to normalize insulin sensitivity in partial pancreatectomy-induced diabetic rats, whereas
insulin action in the control rats was not affected. The result was
glycosuria, which was observed to normalize glucose levels in
both fasting and fed states in rats. But additional study revealed
only poor absorption and low bioavailability of phlorizin. In
addition, decreased glucose and galactose absorption, dehydration
and diarrhoea were observed (for a review of phlorizin, see Ref.
58), so further studies were halted. Phlorizin was subsequently
found to be non-selective for SLGT2 vs. SLGT1 and to have poor
metabolic stability because of a rapid in vivo degradation by bglucosidase.58 Because it was evident that phlorizin would not be
applicable to human DM populations, compounds with greater
SGLT2 selectivity and metabolic stability have been sought.59
One such compound, sergliozin etabonate (2-(4-methoxybenzyl)phenyl 6-O-(ethoxycarbonyl)-b-D-glucopyranoside),60 demonstrated greater SLGT-2 selectivity and decreased serum glucose
and HbA1c levels in rats.61 Additionally, it produced a dosedependent reduction in weight compared with placebo and did
not show signicant inhibitory effects on glucose transporter 2
(GLUT2, a transmembrane carrier protein that facilitates the
passive movement of glucose across cell membranes).60 Both
single-dose design (in healthy volunteers and patients with type 2
DM) and multiple-dose design (in healthy overweight and healthy
obese subjects) pharmacokinetics and pharmacodynamics clinical
studies have been published.62,63 Remogliozin (5-methyl-4-[4-(1methylethoxy)benzyl]-1-(1-methylethyl)-1H-pyrazol-3-yl 6-O-(ethoxycarbonyl)-b-D-glucopyranoside) also produced dose-related
glycosuria and lower plasma glucose and HbA1c levels in rodent
models61 and a reduction in serum glucose in patients with type 2
DM.64 Although these agents demonstrated potential to control
glucose levels in rats, further investigation on them and other
compounds, such as AVE2268,65 T-1095,4553 TS-033 and YM-543,
was discontinued.66,67 Although the exact reasons are unknown,
the chemical structures of these compounds suggest that they
might be prone to hydrolytic degradation in the GI tract.
Current development continues to focus on increasing selectivity for SGLT2 vs. SGLT1 (Fig. 2)56,65,66 and greater bioavailability.

SGLT2
~90%

Glucose
DCT

Gl

SGLT1
CD

~10%

LH

Fig. 1. The roles of SGLT2 and SGLT1 in the renal reabsorption of

glucose. GL, glomerulus; PCT, proximal convoluted tubule; LH,
loop of Henle; DCT, distal convoluted tubule; CD, collecting duct.

SGLT2 inhibitors
A major challenge of pharmaceutical innovation in diabetes
pharmacotherapy has been the development of medications that
are efcacious, but do not also produce the weight gain,
hypoglycaemia or gastrointestinal side effects associated with
many of the current agents.55 Due to their novel mechanism of
action, SGLT2 inhibitors represent a possible alternative. The
strategy is to inhibit glucose reabsorption via selective blockade of
SGLT2 and lower serum glucose secondary to increased renal
excretion of glucose. SGLT2 selectivity is desirable, because
whereas SGLT2 is primarily responsible for glucose regulation in

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S. Cangoz et al.

SGLT2 inhibitors for type 2 DM

Empagliflozin
Tofogliflozin
TS-071
Dapagliflozin

AVE2268
Ipragliflozin
Remogliflozin
Sergliflozin
Canagliflozin

T-1095
Phlorizin
0

500

1000

1500

2000

2500

3000

Selectivity (SGLT2 vs SGLT1)

Fig. 2. Selectivity of sodium/glucose transport inhibitors,

expressed as the ratio of in vitro IC50 (nM) values.56,65,66

Table 3. Clinical development of SGLT2 inhibitors in the United

States for the treatment of diabetes
Drug

Development company

Phase of development

Canagliozin
Dapagliozin
ASP-1941
BI 10773
BI 44847
R-7201
TS-071
LX4211
Remogliozin
YM-543
TS-033
AVE2268
Sergliozin
T-1095

JNJ/Mitsubishi Tanabe
Bristol-Myers Squibb/AstraZeneca
Astellas/Kotobuki
Boehringer Ingelheim
Boehringer Ingelheim/Ajinomoto
Roche/Chugai
Taisho
Lexicon
GlaxoSmithKline
Astellas/Kotobuki
Taisho
Sano-Aventis
GlaxoSmithKline/Kissei
Tanabe

Approved
Phase III
Phase III (Japan)
Phase II
Phase II
Phase II
Phase II
Phase II
Discontinued
Discontinued
Discontinued
Discontinued
Discontinued
Discontinued

SGLT2 inhibition in combination with other therapy has been

studied. For example, canagliozin has been studied and
approved for use in combination with sitagliptin and metformin
in patients with DM who are not adequately controlled; dapagliozin has been examined in combination with metformin and
insulin therapy in patients with DM who were not adequately
controlled on their drug regimens; and ipragliozin has been
tested in various combinations.67,89,90

The most promising can be taken by mouth once daily. Several

SGLT2 inhibitors are currently undergoing testing in clinical trials
(Table 3; Fig. 3):

dapagliozin deters enzyme degradation in the GI tract, allowing

oral administration as a once-daily treatment. In addition to this
desirable dosing prole, it is >1000-fold more selective for the
SGLT2 transporter compared with SGLT1 (Fig. 2), and it apparently
does not cause hypoglycaemia.30 Dapagliozin has been approved
for use in Europe.
Empagliozin (1-chloro-4-(b-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yl-oxy)-benzyl]-benzene; BI 10773) improved glycaemic
control in diabetic rats 82 and demonstrated greater efcacy and
increase in urinary glucose excretion compared with remogliozin
in preclinical studies.30 In general, the C-glucoside SGLT inhibitors
such as empagliozin, canagliozin, dapagliozin, ipragliozin and
tofogliozin inhibit SGLT2 to a greater extent than do O-glucosides
such as sergliozin, phlorizin and remogliozin. Empagliozin
exhibited the highest selectivity for SGLT2 vs. SGLT156,65 (Fig. 2).
Ipragliozin (ASP-1941) is a novel benzothiophene derivative that
was discovered during optimization of a series of C-glycosides for
selective inhibitory activity against SGLT2 vs. SGLT1.83 It potently
(nM range) inhibits mouse, rat and human SGLT2 and produces
dose-dependent and sustained antihyperglycaemic effects in mouse
models of type 2 DM, but does not affect normoglycemia, intestinal
glucose absorption or electrolyte balance.84 It was well tolerated in
healthy subjects during a 10-day study85 and was reported to be
generally safe, well tolerated and effective at blocking renal glucose
reabsorption and decreasing plasma glucose levels in patients with
type 2 DM.86
LX4211 is a dual inhibitor of both SGLT2 and SGLT1. It has been
reported to dose-dependently increase the urinary excretion of
glucose and to improve fasting plasma glucose levels in patients
with type 2 DM.87
Tofogliozin ((1S,3R,4S,5S,6R)-6-[(4-ethylphenyl)methyl]-3,4,5,6-tetrahydro-6-(hydroxymethyl)-spiro[isobenzofuran-1(3H),2-[2H] pyran]3,4,5-triol; CSG452; R7201; RG7201) is a potent and selective inhibitor
of SGLT2 that has been reported to increase the renal clearance of
glucose and to lower blood glucose levels in Zucker diabetic fatty rats
and to improve glucose tolerance in db/db mice without affecting blood
glucose in normoglycaemic rats.88
TS-071((1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol) was selected from a series of derivatives of
the novel scaffold C-phenyl 1-thio-D-glucitol as a potent inhibitor of
SGLT2 (nM range) with 1650-fold selectivity over SGLT1.66 It
increased the urinary excretion of glucose in Zucker fatty rats and
in beagle dogs, improved glucose tolerance without stimulating
insulin secretion in Zucker fatty rats and reduced hyperglycaemia in
streptozotocin (STZ)-induced diabetic rats and db/db mice.67

Representative clinical trial data

Canagliozin ((2S,3R,4R,5S,6R)-2-{3-[5-[4-uoro-phenyl)-thiophen2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran3,4,5-triol)68 recently received FDA approval for type 2 DM. In

preclinical studies, canagliozin decreased plasma glucose levels in
mice on a hyperglycaemic diet. It has higher oral bioavailability and
longer half-life than T-109530 and is well tolerated, and the majority
of adverse effects appear to be mild.69 In premarketing studies, the
addition of canagliozin to metformin improved glycaemic control
with signicant weight loss.70
Dapagliozin
((2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)
methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol)71 is currently
in phase 3 clinical trials and is one of the most advanced SGLT2
inhibitors in development.7281 The C-aryl glucoside bond in

We identied 41 clinical studies of canagliozin registered at

ClinicalTrials.gov.91 In current phase 3 trials, canagliozin is being
compared with placebo in patients who have type 2 DM for 1 year
(NCT01106625) or 4 years (NCT01032629). It is also being compared with sitagliptin (a dipeptidyl peptidase-4 inhibitor) in two
phase 3 trials (NCT01106677 and NCT01081834). In an exploratory
phase 2 study, 29 subjects with type 2 DM not optimally controlled
on insulin and up to one oral agent were randomized to
canagliozin 100 mg daily or 300 mg twice daily or placebo.
After 28 days, a decrease in A1c and body weight was noted in
patients administered canagliozin (A1c: 0
19%, 0
73%, 0
92%;

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SGLT2 inhibitors for type 2 DM

R1

R2

Phlorizin

T-1095

Canagliflozin

Sergliflozin

Remogliflozin

Dapagliflozin

TS-071

Fig. 3. Chemical structures of representative SGLT2 inhibitors.

body weight: +0
03 kg, 0
73 kg, 1
19 kg for placebo, 100 mg
once daily and 300 mg twice daily groups, respectively) (Devineni,
2012). In another randomized phase 2 trial (NCT00642278), 451
patients with type 2 DM were randomized to canagliozin 50, 100,
200 or 300 mg once daily, or 300 mg twice daily, or sitagliptin
100 mg once daily, or placebo twice daily. A greater reduction in
HbA1c was noted in treatment groups that received 300 mg of
canagliozin once or twice daily compared with sitagliptin at
12 weeks (0
71%, 0
73% vs. 0
56%, respectively). In this
study, the patients receiving sitagliptin gained weight, in contrast
to the signicant weight loss in the patients treated with canagliozin (1
3% to 2
3% for canagliozin compared with +0
4% for

sitagliptin). The rate of symptomatic genital infections was more

common (38% vs. 2%), and urinary tract infections were more
common (39% vs. 2%) for canagliozin than for sitagliptin. The
FDA is requiring post-marketing trials to investigate cardiovascular outcomes and pharmacovigilance studies for suspected adverse
effects. One such study underway is CANVAS (Canagliozin
Cardiovascular Outcomes Assessment) for major cardiovascular
adverse effects.
We found 53 studies for dapagliozin registered at ClinicalTrials.gov,92 including 21 phase 1, 8 phase 2, and 24 phase 3 trials. In
patients were
one phase 2 study, 389 type 2 DM treatment-nave
randomized to receive 2
5, 5, 10, 20 or 50 mg of dapagliozin,

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placebo or metformin XR 750/1500 mg as active comparator. After

12 weeks of therapy, the dapagliozin group had a signicant
decrease in fasting blood glucose levels and HbA1C (adjusted
mean reductions of 0
55 to 0
90%, 0
18% and 0
73% in the
dapagliozin group, placebo group and metformin group, respectively, and decrease in adjusted mean fasting plasma glucose levels
of 16 to 31 mg/dL, 6 mg/dL and 18 mg/dL in the
dapagliozin, placebo and metformin groups, respectively).80 In
a phase 3 trial (NCT00680745), dapagliozin was studied as
adjunctive to sulfonylurea therapy (specically glimepiride) at
doses 2
5, 5 and 10 mg daily compared with glimepiride alone. At
the completion of the study (24 week), the adjusted mean HbA1C
was signicantly decreased in all dapagliozin treatment arms
more than with monotherapy or placebo (0
13%, 0
58%,
0
63%, 0
82% in placebo and dapagliozin 2
5-, 5- and 10-mg
groups, respectively). Secondary outcome measures, such as body
weight and fasting plasma glucose values, were also reduced from
baseline in all treatment groups (0
72 kg, 1
18 kg, 1
56 kg,
2
26 kg and 0
11 mM, 0
93 mM, 1
18 mM and 1
58 mM in
the placebo and dapagliozin 2
5-, 5- and 10-mg groups, respectively) (note: mM 9 18 mg/dL).73 Regarding adverse events,
effects on renal hemodynamics were noted in clinical trials. In
particular, increased diuresis and blood pressure lowering effects
were noted in patients receiving dapagliozin.80 Signicant weight
loss also was noted (which is a possible new indication
(NCT00297180)). Dapagliozin is metabolized in the liver to an
inactive glucuronidated metabolite that is subsequently eliminated
renally.93 The pharmacokinetic parameters were within US FDA
(Federal Drug Administration) limits in mild and moderate hepatic
impairment, but in patients with severe hepatic impairment, the
need for long-term studies has been suggested, with careful
assessment of riskbenet ratio.94 As expected from the compounds mechanism of action,76 the excreted glucose per day was
decreased substantially in patients with reduced renal function.95
Dapagliozin had no clinically signicant effect on QT prolongation in healthy volunteers.96
A summary of clinical measures outcomes is presented in
Table 4 for canagliozin,97 dapagliozin,75 empagliozin 98 and
ipragliozin.99

WHAT IS NEW AND CONCLUSION

Current and future clinical trials will continue to delineate the
therapeutic efcacy of the concept of SGLT2 inhibition in general
and specic inhibitors in particular. Likewise, the clinical efcacy
of combinations of SGLT2 inhibitors together with current or
developmental DM agents and insulin is being, or will be, assessed
in clinical trials.
The more pressing issue, as with any new therapeutic approach,
is the question of the adverse effect prole of such an approach
or of specic agents if all or some of the adverse effects are not
class effects. As summarized in the recent review by Ferrannini
and Solini,100 the adverse effect concerns noted thus far were as
follows:

An increased incidence of genitourinary infections (possibly as a

consequence of the higher glucose levels that result from SGLT2
inhibition providing a more favourable environment for bacterial or
fungal growth). This adverse effect seems to occur more often in
female patient (particularly post-menopausal) and in more susceptible patients (e.g. patients with a history of such infections). The
extent, seriousness and possible adaptation with continued treatment still need to be better dened. But the infections thus far
appear to be treatable and, albeit inconvenient, outweighed by the
benets of better glycaemic control.
An increased incidence of genital infections (vulvovaginitis, balanitis, prostatitis). These appear to be responsive to standard treatment,
have led to considerable dropout rates in the clinical trials and,
similar to genitourinary infections, likely outweighed by the benets
of better glycaemic control.
Possible small (<2
0 ng/L) increase in parathyroid hormone (PTH)
and in phosphate plasma levels.
Other reported adverse effects included increased urine volume,
elevated haematocrit, dehydration, nasopharyngitis, diarrhoea and
headache. Hypoglycaemia has been rare.
Adverse effects on other tissues that express SGLT2 might also
manifest themselves in greater patient exposure.

The most serious concerns are the ndings of a possible excess

number of cases of breast cancer in females and of bladder cancer
in males. Citing from an FDA brieng document101: In summary,
the nding that the age-specic incidence rates of breast cancer
were higher than those reported in the literature could be a safety
signal that dapagliozin may be associated with an increased risk

Table 4. Changes in clinical measures for individual SGLT2 compounds

Drug
Canagliozin97
100 mg
300 mg
Dapagliozin75
2
5 mg
5 mg
10 mg
Empagliozin98
5 mg
10 mg
25 mg
Ipragliozin99
12
5 mg
50 mg
150 mg
300 mg

HbA1C (%)

Fasting glucose (mM)

Weight (kg)

BP (mm Hg)

Lipids (%)

2 (LDL); 6
8 (HDL); 5
4 (Triglycerides)

6
1 (LDL); 6
1 (HDL); 10
2 (Triglycerides)

0
77
1
03

2
0
2
4

1
9
2
9

3
7/1
6
5
4/2
0

0
58
0
77
0
89

15
2
24
1
28
8

3
3
2
8
3
2

4
6/2
8
2
3/1
7
3
6/2
0

0
4
0
5
0
6

1
29
1
61
1
72

1
81
2
33
2
03

0
49
0
65
0
73
0
81

0
84
1
1
1
3
1
68

1
08
1
67

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S. Cangoz et al.

SGLT2 inhibitors for type 2 DM

of breast cancer. It is not feasible to establish the relative risk with

any degree of certainty at this time given the small number of
events (nine cases in the dapagliozin treatment groups and zero
in the comparator groups) and a wide condence interval for the
incidence rate ratio that includes 1
0 and innity. Therefore, it is
uncertain whether dapagliozin treatment is associated with an
increased risk of breast cancer. Continued follow-up of all
participants in the dapagliozin trials for breast cancer and further
analysis with a direct comparison between the dapagliozin
treatment arms and the comparator arms should be conducted to
evaluate the relative risk of breast cancer associated with dapagliozin treatment. And further from the same source: In the
clinical trials of dapagliozin, no cases of bladder cancer were
observed in female patients. Nine cases occurred during a total
follow-up of 2237
1 subject-years in males in the dapagliozin
arms, amounting to a rate of 402 (95% CI, 184764) per 100 000
subject-years. This compared to one case during 989
8 subjectyears in male controls, or 101 (95% CI, 1
3562) new cases per
100 000 subject-years the clinical trials were not powered to
statistically distinguish between nine cases of bladder cancer in the
active treatment arms compared to one case in the control arms.
However, event rates for males observed in the active treatment
arms signicantly exceeded the rates expected in an age-matched
reference diabetic population.
As of this writing, it is unclear whether there is an increased risk
of breast or bladder cancer and if so, whether it is unique to a
particular agent or agents or whether it is inherent in the SGLT2
mechanism of action. In an effort to gain some insight into this
question, we searched the literature for possible connection
between SGLT and cancer. The rst study to measure the levels
of SGLT1 and SGLT2 gene expression in cancer cells102 found no
signicant differences in the level of either gene expression
between the primary lung cancers and normal lung tissues. The
expression of SGLT1 was the same in primary lung cancers and
their metastatic lesions, but the expression of SGLT2 was significantly higher in the metastatic lesions than in the primary lung
cancers. Based on this, the authors posit that SGLT inhibitors
might be useful for the treatment of cancers. Other ndings include
the following:

SGLT1 expression was found to be higher in colorectal cancer tissues

than in normal tissues, related to clinical stage but not to other
clinical characteristics, objective response rate, disease control rate or
overall survival.110

It is clear from the above that there is an absence of much

information about SGLT2 and cancer. What little there is suggests
that there might be a possible protective benet from a selective
and exclusive inhibition of SGLT2, but the information is too
sparse and such projections are too speculative. A relationship
between SGLT1 and cancer is even more ambiguous, but a case
could be made that SGLT1 promotes cancer growth in some way.
It is also possible that it is not the absolute level of SGLT1 or
SGLT2 that is important, but rather the ratio of the two or even the
up- or down-regulation of one secondary to the under- or
overexpression of the other.

Summary and conclusion

Currently available drugs provide less than fully adequate therapy
for the majority of patients with DM. As a result, they have greater
morbidity and mortality compared with age-matched non-diabetics. The current drugs have individual shortcomings in efcacy
and/or limiting adverse effects, but they are also limited in their
physiological approaches (targets), mainly the inhibited insulin
secretion or insulin receptor resistance characteristic of the
disorder. An important factor in the control of glucose homoeostasis has largely been overlooked, namely elimination in the
urine. Canagliozin, which is now FDA-approved, and other
SGLT2 inhibitors currently in clinical trials or other stages of
development target this important site.
A sufcient number of clinical trials have been conducted on a
sufcient number of relatively chemically diverse SGLT2 inhibitors to reasonably conclude that they have efcacy in type 2 DM,
that is, they improve glycaemic control to a therapeutically useful
extent, lower HbA1c levels about 0
51% do not cause hypoglycaemia, and thus far, the majority of adverse effects have been
mild and transitory or treatable. The morbidity and mortality of
DM plus the absence of fully adequate therapy have led some to
suggest that these agents are worth considering. As a cautionary
note, however, more serious adverse effects might have gone
undetected in the clinical trials to date due to the relatively small
number of trial participants compared with the exposure population (the total population of patients with DM). The sites of
these adverse effects might be related to tissues in which SGLT2
(or SGLT1) is expressed (e.g. heart, blood-brain barrier, etc.).
Another, as yet unresolved, area of concern is the apparent excess
cases of breast and bladder cancer that have been at least
speculated to be associated with one SGLT2 inhibitor. We found
no obvious connection between cancer and inhibition of SGLT2 or
inhibition of SGLT1 by non-specic inhibitors, but up-regulation
of SGLT1 in response to inhibition of SGLT2 is a theoretical
possibility. Only careful evaluation will elucidate whether this
effect is real and, if so, is limited to a single agent or chemical
family, or is an inherent unavoidable adverse effect of inhibition
of SGLT2.

Epidermal growth factor (EGFR) and SGLT1 coexpression may

contribute to the growth and survival of oral squamous cell
carcinoma.103
High SGLT1 expression in pancreatic adenocarcinomas is signicantly correlated with disease-free survival, and a trend was found
for overall survival, especially in younger patients.104
SGLT1-mediated increase in glucose uptake is important for the
repair of plasma membrane injury.105
SGLT1, but not SGLT2, expression was observed in short-term
cultures of squamous cell carcinomas of the head and neck.106
Overexpression of SGLT1 protein levels correlates with poor
prognosis of patients with ovarian carcinoma.107
Phlorizin inhibits the cytoprotection of SGLT1-mediated increase in
anti-apoptotic proteins and protection of enterocytes from lipopolysaccharide-induced apoptosis and barrier defects.108
EGFR prevented autophagic cell death in a human metastatic
prostate cancer cell line by maintaining intracellular glucose level
through interaction with and stabilization of SGLT1.109

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