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SGLT2 inhibition — a novel strategy

for diabetes treatment
Edward C. Chao and Robert R. Henry
Abstract | Inhibiting sodium–glucose co-transporters (SGLTs), which have a key role in the
reabsorption of glucose in the kidney, has been proposed as a novel therapeutic strategy
for diabetes. Genetic mutations in the kidney-specific SGLT2 isoform that result in benign
renal glycosuria, as well as preclinical and clinical studies with SGLT2 inhibitors in type 2
diabetes, support the potential of this approach. These investigations indicate that elevating
renal glucose excretion by suppressing SGLT2 can reduce plasma glucose levels, as well as
decrease weight. Although data from ongoing Phase III trials of these agents are needed to
more fully assess safety, results suggest that the beneficial effects of SGLT2 inhibition might
be achieved without exerting significant side effects — an advantage over many current
diabetes medications. This article discusses the role of SGLT2 in glucose homeostasis and the
evidence available so far on the therapeutic potential of blocking these transporters in
the treatment of diabetes.

Sodium-glucose
co-transporters
(SGLTs). A family of membrane
proteins that transport glucose,
as well as some ions, vitamins
and amino acids across the
brush-border membrane of
the proximal convoluted
tubules in the kidney and
epithelial cells in the intestine.
Section of Endocrinology,
Metabolism and Diabetes,
VA San Diego Healthcare
System and University of
California, San Diego School
of Medicine, 3350 La Jolla
Village Drive, 111 G San
Diego, California 92161,
USA.
Correspondence to E.C.C.
e-mail: edward.chao@va.gov
doi:10.1038/nrd3180
Published online 28 May 2010
The aetiology of type 2 diabetes mellitus (T2DM) is intri‑
cate and multifaceted, but virtually all patients contend
with both relative insulin deficiency and insulin resist‑
ance to varying degrees. The resulting hyperglycaemia
can facilitate β‑cell failure in the pancreas and worsen
insulin resistance, thus triggering a cycle of impaired
metabolism and glucotoxicity 1. Glucotoxicity can con‑
tribute to increased apoptosis of β‑cells, causing dimin‑
ished β‑cell mass and thus reduced gene transcription,
synthesis and secretion of insulin2.
The use of current agents for T2DM is often limited
by their potential to induce significant adverse effects.
For instance, metformin can cause gastrointestinal effects
such as diarrhoea and nausea, and rarely, lactic acidosis,
whereas sulphonylureas or insulin can induce hypogly‑
caemia as well as weight gain3. Thiazolidinedione use
is also associated with weight gain and oedema3. Newer
drugs, such as the incretin mimetics, may produce nausea,
vomiting and diarrhoea4. Glycaemic control can be dif‑
ficult to attain, even with a combination of multiple
oral agents, and with insulin added. Thus, the quest to
develop therapeutic agents with novel mechanisms of
action without these side effects continues.
The kidney has a key role in regulating glucose levels
— by mediating the reabsorption of glucose back into the
plasma — following filtration of the blood; this is a crucial
evolutionary adaptation to maintaining glucose homeo‑
stasis and to retaining calories. This process contributes
to the sustained elevated serum glucose levels observed
in individuals with diabetes, as they have an increased
capacity for renal glucose reabsorption5. Inhibiting this
glucose reabsorption, thereby allowing its excretion in
the urine (glycosuria), is therefore emerging as a potential
new approach to the treatment of diabetes. Glycosuria,
however, has historically been perceived as a sign of met‑
abolic decompensation and of adverse clinical sequelae.
Therefore, utilizing this manifestation as a therapeutic
strategy for diabetes represents a paradigm shift.
Sodium–glucose co-transporters (SGLTs) are responsible
for renal glucose reabsorption, with SGLT2 performing
most of this task and the remainder by SGLT1 (Ref. 6).
The development of inhibitors targeted against SGLTs
grew out of experiments with the compound phlorizin,
which was first isolated in the 1800s and was found to
improve blood glucose levels in laboratory animals. This
is in addition to observations in patients who had a rare
genetic abnormality in these transporters, those with a
condition termed familial renal glycosuria6.
As SGLT2 inhibitors do not target the major patho‑
physiological defects in T2DM — namely insulin resist‑
ance and impaired insulin secretion — they represent
a potentially promising new option in the treatment of
diabetes. This Review will provide an overview of the
function of the kidney in glucose homeostasis, focusing
on the pivotal role of SGLT2: its unique mechanism, as
well as its development as a novel therapeutic target for

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REVIEWS
diabetes. Currently available preclinical and clinical data
Familial renal glycosuria
A genetic disorder of the renal
on SGLT2 inhibitors in the treatment of T2DM will be
tubules characterized by discussed.
persistent isolated glycosuria
without hyperglycaemia. Glucose transport in the kidney
The disorder results from
mutations in SLC5A2, the gene
Cell membranes, which are composed of lipids, are
encoding sodium–glucose impermeable to glucose, a polar compound. Therefore,
co-transporter 2. the transport of glucose across the cell membrane
requires the assistance of carrier proteins located within
the cell membrane. once plasma glucose has been filtered
in the kidney by the glomeruli, it is reabsorbed by the
SGLTs across the apical or luminal membranes of the
epithelial cells of the proximal tubule, coupling the trans‑
port of sodium with that of glucose (fIG. 1).
SGLT2 and SGLT1 actively transport glucose across
the proximal convoluted tubule (PCT) cells of the kidney
with varying capacities7 (TABLe 1). SGLT2 is a high‑capacity,
low‑affinity transporter found mainly in the S1 segment
of the PCT8. SGLT2 is thought to account for approxi‑
mately 90% of reabsorbed glucose and its expression is
limited to the kidney. By contrast, SGLT1, a low‑capacity,
high‑affinity transporter, is situated in the more distal
S2/S3 segment of the PCT and reabsorbs the remaining
percentage of the filtered glucose9,10. SGLT2 catalyses the
active transport of glucose against a concentration gradi‑
ent across the apical (luminal) membrane by coupling
it with the transport of sodium10,11 (fIG. 1). The inward
sodium gradient across the luminal epithelium is main‑
tained by ATP‑driven active extrusion of sodium across
the anti‑luminal surface into the blood8,9. Intracellular
glucose diffuses passively out of the cell, down a concen‑
tration gradient and across the anti‑luminal membrane
into the intercellular space — which is in equilibrium
with the blood — by basolateral (anti‑luminal) glucose
transporter type 2 (GLuT2; also known as SLC2A2)
and GLuT1 (also known as SLC2A1) facilitative glucose
transporters11.
Plasma glucose concentrations are normally main‑
tained within a narrow range, which is crucial for organs
such as the brain, which uses glucose almost exclusively
as its energy source. This balance involves the complex
Lumen Blood
Glucose GLUT2 Glucose
Na+ and Na+
S1 proximal
glucose at 1:1 SGLT2
tubule
stoichiometry Glucose
K+
Na+ ATPase
Na+
Figure 1 | sgLT2 mediates glucose reabsorption in the kidney. Sodium–glucose
co-transporter 2 (SGLT2) catalyses the active transport of glucose (against a
concentration gradient) across the luminal membrane by coupling it with the downhill
Nature Reviews | Drug Discovery
transport of Na+. The inward Na+ gradient across the luminal epithelium is maintained
by active extrusion of Na+ across the basolateral (anti-luminal) surface into the
intercellular fluid, which is in equilibrium with the blood. Glucose passively diffuses out
of the cell down a concentration gradient by basolateral facilitative transporters:
glucose transporter type 2 (GLUT2) and GLUT1.
552 | juLy 2010 | voLuMe 9
© 2010 Macmillan Publishers Limited. All rights reserved
interplay of numerous regulatory processes (fIG. 2).
Glucose uptake by the central nervous and peripheral
tissues is matched by glucose production, which is pri‑
marily mediated by the liver and to a lesser degree by the
kidney 10. The kidney also serves a unique function in
glucose homeostasis through filtration and reabsorption
of glucose. under normal circumstances, approximately
180 g of glucose per day is freely filtered and essentially
completely reabsorbed by the kidney, thus contributing
to maintaining this balance12 (fIG. 3). The filtered load of
glucose is the product of the plasma glucose concentra‑
tion and the glomerular filtration rate. So, as the plasma
concentration of glucose increases, the filtered load of
glucose increases in a linear manner. when the plasma
glucose concentration is greater than ~200 mg per 100 ml,
all of the filtered glucose is reabsorbed, as the reabsorp‑
tive capacity of the SGLTs is not yet saturated. In other
words, the threshold for glucose excretion has not been
reached (please refer to fIG. 4 for a graphical depiction)12.
The reabsorption curve is no longer linear at a plasma
glucose concentration of ~200–250 mg per 100 ml, as, at
this point, the co‑transporters are approaching saturation.
Some of the filtered glucose is therefore not reabsorbed,
but is excreted. Filtered glucose is reabsorbed in the
PCT, and healthy people do not exceed the maximum
amount of glucose that can be reabsorbed (the tubular
maximum or Tmax), which, on average, is approximately
375 mg per min12 (fIG. 4). when the filtered glucose load
surpasses the Tmax, the glucose excretion rate increases
linearly and parallels the curve for filtered load. Both the
reabsorption and excretion curves, by contrast, exhibit
nonlinear shapes as the glucose Tmax is approached. This
loss of linearity represents the threshold occurring at a
lower plasma glucose concentration than the Tmax, and is
termed splay 12. There are two reasons for splay: first, all
nephrons do not have the same Tmax, and nephrons with
a lower Tmax excrete glucose in the urine before those
with a higher Tmax (Ref. 12). Second, as the affinity of the
SGLT is low, if a glucose molecule becomes unattached
from its carrier, it will probably be excreted in the urine,
even if there are unoccupied binding sites remaining
on the co‑transporters10. Thus, any amount of filtered
glucose exceeding the Tmax is excreted and appears as
glucose in the urine.
Potential of SGLT inhibition in treating diabetes
The high plasma glucose levels that are characteristic
of uncontrolled T2DM exceed the maximum threshold
of glucose reabsorption, saturating the SGLT receptors,
and resulting in the increased excretion of glucose in the
urine5. Patients with T2DM also express a significantly
higher number of SGLT2 and GLuT2 than healthy
individuals, as shown by a preclinical study of cultured
PCT cells taken from human patients9. Renal glucose
uptake is also greatly elevated in these cells taken from
subjects with T2DM9. Patients with T2DM also face the
effects of the hyperglycaemic state, which further worsen
insulin deficiency and insulin resistance. The resultant
glucotoxicity can elevate the risk of developing long‑
term complications, including microvascular disease
(such as neuropathy, nephropathy and retinopathy) as
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Table 1 | A comparison of selected characteristics of SGLT1 and SGLT2
site
renal location
Affinity for glucose
capacity for glucose
transport
Percent of renal
glucose reabsorption
SGLT, sodium–glucose co-transporter. Data from Ref. 11.
NATuRe RevIewS | Drug Discovery
sgLT1 sgLT2
Mostly small intestine, some Almost exclusively kidney
in kidney and heart
Late proximal straight tubule Early proximal convoluted
(S3 segment) tubule (S1 segment)
High (Km = 0.4 mM) Low (Km = 2mM)
Low High
~10% ~90%
well as macrovascular disease (such as cardiovascular,
cerebral and peripheral vascular disease)13. uncontrolled
hyperglycaemia is tightly linked to polyuria and glyco‑
suria, and contributes to both the pathophysiology and
complications of T2DM. Although both unchecked
hyperglycaemia and the therapeutic blockade of renal
glucose reabsorption share the manifestation of glyco‑
suria, only SGLT2 inhibition involves lowering of the
renal glucose excretion threshold, which functions to
reduce the level of hyperglycaemia.
Suppressing glucose reabsorption, through blockade of
SGLT, would increase urinary glucose excretion, thereby
reducing plasma glucose levels and potentially offering
a novel therapeutic strategy, without the adverse effects
that accompany currently available agents for T2DM.
one concern with inhibiting glucose reabsorption and
inducing glycosuria is a possible deleterious effect on
kidney function, resulting in excessive water loss in the
urine and dehydration. However, in individuals with
familial renal glycosuria, an autosomal genetic disorder
that leads to impaired function of SGLT2, renal function
remains normal, even when greater than 50 g of glucose
is lost in the urine each day 14. This suggests that even
long‑term impairment of SGLT function does not cause
significant adverse renal effects (see the Safety section
below for further discussion of this disorder).
Investigating the inhibition of SGLT could both fur‑
ther advance our continually evolving understanding of
diabetes, as well as the clinical application of this knowl‑
edge in patients with this disorder. Given the potential
of this novel therapeutic strategy, several SGLT inhibi‑
tors have been discovered and developed in recent years.
Late‑stage clinical trials are now in progress that could
clarify the efficacy and safety of this approach in large
numbers of patients.
Development of SGLT2 inhibitors
Phlorizin. Phlorizin (fIG. 5a) has played a vital role in
elucidating the mechanism of renal glucose reabsorp‑
tion and the role of hyperglycaemia in diabetes. This
agent was first isolated in 1835 by French chemists from
the root bark of the apple tree, and was subsequently
found to be a potent but relatively nonselective inhibi‑
tor of both SGLT2 and SGLT1 (Ref. 15). Rossetti and his
team compared the effects of phlorizin on blockade of
renal glucose reabsorption in diabetic rats — in which
© 2010 Macmillan Publishers Limited. All rights reserved
REVIEWS
diabetes had been induced by partial pancreatectomy
— with controls. using euglycaemic hyperinsulinaemic
clamp studies, phlorizin was found to normalize insulin
sensitivity in these diabetic rats, but did not influence
insulin action in controls16. Administration of phlorizin
resulted in glycosuria, which normalized both the fasting
and fed plasma glucose levels and completely reversed
insulin resistance. when phlorizin was discontinued,
hyperglycaemia and insulin resistance recurred. This
study was the first demonstration that hyperglycaemia
alone can lead to the development of insulin resistance
via glucotoxicity. Phlorizin was used in multiple subse‑
quent investigations that helped to establish that hyper‑
glycaemia contributes to the insulin resistance that
characterizes T2DM17.
Although studies revealed that phlorizin administered
orally to mice blunted the increase in blood glucose lev‑
els after ingesting a glucose solution, it was not further
developed as a possible anti‑diabetes therapy due to poor
intestinal absorption and resultant low bioavailability, as
well as rapid in vivo β‑glucosidase degradation15. Another
significant disadvantage is that phlorizin also acts on
SGLT1, which is mainly expressed in the gastrointestinal
tract. SGLT1 gene mutations lead to glucose and galac‑
tose malabsorption, dehydration, and diarrhoea15. A third
drawback is when phlorizin is hydrolysed in the gut, phlo‑
retin is produced, which inhibits facilitative glucose trans‑
porters, such as GLuT1 (Ref. 15). Suppression of intestinal
GLuT1 impairs intestinal transport of glucose and results
in gastrointestinal side effects, such as diarrhoea. This and
other studies fuelled the search for a phlorizin derivative
that would minimize these shortcomings.
Early agents. Given that phlorizin lacked specificity for
SGLT2 and was associated with substantial side effects,
efforts were made to develop new compounds to inhibit
SGLT2 with high potency and selectivity. other aims
included optimizing bioavailability through enhanced
stability, and improving safety profiles. The first orally
available phlorizin derivative reported was T‑1095
(fIG. 5a). Preclinical studies on this agent confirmed the
initial evidence that inhibition of renal SGLTs could be a
viable target for therapy in diabetes. Although this com‑
pound was more metabolically stable than phlorizin,
it too was nonselective18. T‑1095 was not developed
further, so no clinical data are available for this agent.
Subsequently, sergliflozin and remogliflozin (fIG. 5a),
which possessed greater SGLT2 selectivity, were tested
and sergliflozin progressed to clinical trials.
In a placebo‑controlled study of 18 subjects, treatment
with sergliflozin for 14 days produced sustained suppres‑
sion of renal glucose reabsorption and a dose‑related
glycosuria. A dose‑related reduction in body weight
was also observed over the study period, with mean
changes of –0.09 (placebo), –1.55 (500 mg sergliflozin)
and –1.74 kg (1,000 mg sergliflozin) from baseline19.
Remogliflozin also induced a dose‑dependent increase
in urinary glucose excretion, and lowered fasting plasma
glucose levels as well as glycated haemoglobin (HbA1c)
levels in mice and rats 20. For reasons not entirely
known, but most probably related at least in part to their
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REVIEWS

development can be found using the ClinicalTrials.gov

Glucagon Insulin Insulin identifiers listed in TABLe 2. Structures of some of the
SGLT2 inhibitors under development have been dis‑
Fat
closed and these can be seen in fIG. 5b.
Pancreas
+ – +
Dapagliflozin. Dapagliflozin (developed by Bristol‑Myers
Squibb and AstraZeneca), which is the furthest advanced
Liver compound in development in the SGLT2 inhibitor class, is
currently in Phase III trials as a once‑daily, oral treatment
90 mg per for T2DM (TABLe 2). A C‑aryl glucoside linkage found
Skeletal
100 ml muscle in dapagliflozin confers resistance to degradation in the
gastrointestinal tract by β‑glucosidase enzymes21 (fIG. 5b).
Consequently, dapagliflozin can be administered orally in
Fasting plasma an unmodified form, therefore carrying a more favour‑
Kidney glucose able pharmacokinetic profile than the earlier agents. In
addition, it is approximately 1,200‑times more selective
Figure 2 | Normal glucose homeostasis. This outlines the hormonal interactions for SGLT2 over SGLT1. An in vitro study revealed that
that are important in regulating normal glucose homeostasis. Normal fasting glucose
dapagliflozin exhibited around 30‑times greater potency
homeostasis involves the hormonal regulation of glucose Nature Reviews
utilization | Drug Discovery
and production,
as well as the filtration and reabsorption of glucose by the kidney10. Under basal against SGLT2 in humans than phlorizin, and approxi‑
conditions, glucose uptake by the tissues is matched by glucose production from mately 4‑fold less potency versus phlorizin against human
the liver; this enables fine regulation of glucose at a fixed level. Gluconeogenesis in the SGLT1 (Ref. 22).
liver helps prevent hypoglycaemia. In the rat, dapagliflozin administration resulted in an
acute increase in glycosuria, unaccompanied by hypogly‑
caemia21,22. In Zucker diabetic fatty rats, a doubling of
urine glucose levels was noted with all doses of dapagli‑
pharmacokinetic profiles, and possibly also due to flozin compared with vehicle22. Fasting and postprandial
an unfavourable efficacy and side‑effect profile, these glucose levels decreased, concomitant with the glycosuria.
agents did not undergo further development. Indeed, Similarly, fasting glucose was reduced in streptozocin‑
both sergliflozin and remogliflozin contain o‑glucoside induced diabetic rats following administration of a
linkages that render them susceptible to hydrolysis by single dose of dapagliflozin22. Such declines in fasting
β‑glucosidase enzymes in the gastrointestinal tract. glucose levels were sustained in Zucker diabetic fatty rats
after 15 days of repeated dosing of dapagliflozin. This
Agents currently under development and other preclinical studies suggested a potential novel
Although there are several SGLT2 inhibitors now in strategy of treating hyperglycaemia through a mecha‑
various stages of clinical development (TABLe 2), for many nism that did not directly affect insulin secretion or its
of these agents there is currently little published data actions. These observations of efficacy in animal models
available. Nevertheless, several clinical studies of dapagli‑ led to further clinical investigations in humans.
flozin, which is now in Phase III trials, have been pub‑ Komoroski and colleagues conducted the first clinical
lished and therefore can be discussed. Preliminary trial studies that evaluated the safety, pharmacokinetic and
data for canagliflozin are also accessible and are summa‑ pharmacodynamic parameters of single and multiple
rized below. Limited information for other agents under doses of dapagliflozin in healthy individuals23. In the
single‑ascending dose study, a single dose of 2.5 mg,
5 mg, 10 mg, 20 mg, 50 mg, 100 mg, 250 mg or 500 mg of
SGLT2 dapagliflozin, or placebo was randomly assigned. Subjects
were then enrolled at the next higher dose if results from
Glucose
the first trial indicated that dapagliflozin was safe and well
S1 segment tolerated in at least six subjects. The multiple‑ascending
of proximal dose study was similarly designed, with the administra‑
tubule tion of five sequential doses of 2.5 mg, 10 mg, 20 mg,
50 mg or 100 mg of dapagliflozin, or placebo. Doses
Collecting SGLT1 Distal S2/S3
duct segment
~90% reabsorption of 20–50 mg per day of dapagliflozin produced near‑
of proximal maximal SGLT2 blockade (a glucose excretion of up to
~10% reabsorption
tubule ~3 g per hour and ~60 g per day) for at least 24 hours.
The glycosuria observed was sustained, dose‑dependent,
and did not cause hypoglycaemia in these subjects. Renal
glucose reabsorption was inhibited by approximately
20–30% on day 1 and approximately 16–50% on day 14.
No glucose To define the entire dose–response curve for patients
Figure 3 | renal handling of glucose in a non-diabetic individual. Virtually all the with T2DM, Komoroski and colleagues examined quan‑
glucose filtered is reabsorbed, and none appears in the urine. The locations for tities of dapagliflozin up to 100 mg in a randomized,
sodium–glucose co-transporter 2 (SGLT2) and SGLT1 are shown. Adapted from Ref. 12. double‑blind Phase II clinical trial of 47 individuals24.

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Rate of glucose filtration/reabsorption/
Glucose excursion
This is usually defined as
the change in glucose
concentration from before
to after a meal. In research
settings this is pre- and post-
oral-glucose-tolerance tests.
NATuRe RevIewS | Drug Discovery
Tmax
375
excretion (mg per min)
200
Reabsorption
100
Actual
threshold
180 200
Plasma glucose (mg per 100ml)
Figure 4 | renal glucose handling before and following
inhibition of sgLT2. With gradual infusion of glucose,
as the plasma glucose concentration increases,
Nature Reviews | Drugthe
Discovery
reabsorption progressively increases following the line
marked reabsorption curve (in red). At plasma glucose
concentrations <200 mg per 100 ml, all the filtered glucose
is reabsorbed and there is no excretion. When glucose
reaches a threshold, around 200–250 mg per 100 ml, the
maximum capacity of the renal tubule to reabsorb glucose
— or theTmax — is exceeded and once it passes this,
glucose begins to be excreted into the urine (blue line,
labelled excretion). The breaking point, however, is not
abrupt. Splay (the curved dotted lines between the actual
and theoretical thresholds) represents glucose excretion
in the urine before saturation (Tmax) is fully attained, and is
explained by some nephrons releasing glucose at a slightly
lower threshold, others somewhat higher, and the relatively
low affinity of the sodium–glucose co-transporters (SGLTs).
The dotted lines underneath the arrows depict renal
glucose handling after SGLT2 inhibition. The SGLT2
inhibitors lower the Tmax of glucose, which in turn increases
the excretion of glucose by the kidneys.
These subjects were between the ages of 55–60 years
with unimpaired renal function, and were either drug‑
naive or on stable doses of metformin. The participants
were randomized to receive dapagliflozin at 5 mg, 25 mg
or 100 mg, or placebo once daily for 14 days. At the end
of the study, fasting serum glucose levels were signifi‑
cantly reduced across all dapagliflozin groups in a dose‑
dependent manner. Doses of up to 100 mg were well
tolerated by subjects for the 2 weeks of the study. Daily
urinary glucose excretion increased in a dose‑dependent
manner, although the amount of glucose excreted on day
14 was slightly lower than on day 1. Subjects receiving
placebo showed no change in the cumulative amount
of glucose excreted in the urine over 24 hours and no
significant reductions in fasting serum glucose levels.
Dapagliflozin also induced a significant decline in glucose
excursion after an oral‑glucose‑tolerance test, which
was measured as area under the plasma concentration–
time curve (0–4 hours) on day 2 (ranging from –9.6%
to –13.7% with P<0.001) and on day 13 (ranging from
–17.6% to –22.6% with P<0.001), as compared with
placebo. Dapagliflozin therefore demonstrated efficacy
in dose‑ranging studies in healthy subjects as well as in
those with T2DM.
© 2010 Macmillan Publishers Limited. All rights reserved
REVIEWS
Subsequent to this initial 2‑week study, List and
colleagues performed a 12‑week, double‑blind, ran‑
Tmax domized, parallel‑group, placebo‑controlled Phase II
trial in 389 treatment‑naive subjects with T2DM25.
Dapagliflozin given at 2.5 mg, 5 mg, 10 mg, 20 mg or
50 mg once daily was compared with placebo. extended
release metformin of 750 mg force‑titrated to 1,500 mg
at week 2 was also included as an active comparator.
Excretion
Statistically significant reductions from baseline in
HbA1c were observed in all dapagliflozin‑treated
Theoretical subjects, ranging from –0.55% to –0.9%, compared
threshold with –0.18% in the placebo group and –0.73% in the
300 metformin group. The effect of dapagliflozin on uri‑
nary glucose excretion was also assessed. In contrast to
metformin and placebo‑treated subjects, mean urinary
glucose levels rose from between 5.8 g to 10.9 g per
24 hours at baseline to 51.8 g to 85.0 g per 24 hours
at week 12 in the dapagliflozin group. These elevations
were sustained for the entire duration of the study.
weight was also lowered across all dapagliflozin groups
(ranging from –2.5% to –3.4%), with minor decreases
in weight detected within the metformin and placebo
groups. Fasting plasma glucose levels declined dose‑
dependently in all dapagliflozin groups, and reductions
were seen as early as the first week. The lowest dapagli‑
flozin dose of 2.5 mg yielded a near‑maximal effect
on postprandial glucose levels. After 12 weeks, fasting
plasma glucose was the sole metabolic parameter that
had a dose‑dependent response to dapagliflozin. SGLT2
inhibition exerted a relatively greater effect on postpran‑
dial glucose levels than on fasting plasma glucose levels,
which suggests that renal glucose excretion serves as a
mechanism to relieve postprandial hyperglycaemia.
Recently, wilding and colleagues published a study
investigating the effect of dapagliflozin on HbA1c, fast‑
ing plasma glucose, postprandial glucose and weight in
patients with T2DM, who were experiencing suboptimal
control on oral agents and high insulin doses26. A total of
71 individuals with T2DM were randomized in 26 cen‑
tres in the united States and in Canada. Patients were
on stable‑dose insulin‑sensitizing agents — metformin
≥1,000 mg and/or pioglitazone ≥30 mg, or rosiglitazone
4 mg — for ≥6 weeks and half of their usual insulin
dose (at least 50 units daily) for at least 12 weeks before
enrolment, with no change in dose for at least 6 weeks.
Twenty‑three patients were randomized to placebo, 24 to
the dapagliflozin 10 mg group, and 24 received 20 mg of
dapagliflozin. The primary end point — the change in
HbA1c from baseline at week 12 (last observation car‑
ried forward) — was reported to decrease 0.7% (10 mg)
and 0.78% (20 mg) in the dapagliflozin groups versus
placebo. Indeed, 65.2% of patients in both dapagliflozin
groups exhibited a ≥0.5% decline from baseline HbA1c
compared with 15.8% of the placebo cohort. The mean
changes in fasting plasma glucose levels from baseline
at week 12 were +17.8 mg per 100 ml (placebo), +2.4 mg
per 100 ml (10 mg dapagliflozin) and –9.6 mg per 100 ml
(20 mg dapagliflozin). The mean changes in total body
weight were –1.9 kg (placebo), –4.5 kg (10 mg dapagli‑
flozin) and ‑4.3 kg (20 mg dapagliflozin). Mean changes
in postprandial glucose at 120 minutes at week 12 (last
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REVIEWS

a OH
modification of diet in renal disease‑estimated glomer‑
OH O
ular filtration rates at the end of the study were normal
HO OH compared with baseline.
O Dapagliflozin was also examined as an add‑on
H3C O
OH agent to metformin over 24 weeks in 546 patients with
OH
O O O O T2DM who were not being sufficiently controlled on
O O stable doses of metformin alone at 1,500 mg per day or
H3C OH
HO OH greater 27. In a multicentre, randomized, double‑blind,
O OH
OH placebo‑controlled clinical trial that has been reported
Phlorizin T-1095
in abstract form, subjects were equally divided into four
groups, all on open‑label metformin, to which dapagli‑
O O
O flozin 2.5 mg, 5 mg or 10 mg, or placebo were added. For
O O the primary end point — the change in HbA1c at the
O
end of the study — all groups with dapagliflozin added
O O O
O O HO
HO O on to metformin demonstrated statistically significant
OH reductions from baseline HbA1c, which were greater
HO OH N N
than those observed with metformin treatment alone.
OH
weight also revealed a dose‑dependent decrease, ranging
Sergliflozin Remogliflozin from –2.66% to –3.43%.
b F
Canagliflozin. Canagliflozin (developed by johnson &
HO
johnson) (fIG. 5b; TABLe 2) is also currently undergoing
S O Phase III trials, with results in abstract form anticipated for
HO HO Cl presentation at the 2010 American Diabetes Association
O H Scientific Sessions. In preclinical studies, a single oral
HO HO OH O administration of 3 mg per kg of canagliflozin decreased
H
plasma glucose levels independent of food intake in mice
HO OH Canagliflozin Dapagliflozin
on a high‑fat, hyperglycaemic diet. In normoglycaemic
mice, canagliflozin administration led to a minimal
H
O N NH2 change in plasma glucose levels. Canagliflozin had a
HN
N
longer plasma half‑life and greater oral bioavailability
O
HO compared with its predecessor, T‑1095 (Ref. 28).
O O
O An example of one of the double‑blind, Phase III
HO OH
HO clinical trials currently underway is the CANTATA‑Su
H
HO OH O (canagliflozin treatment and trial analysis‑sulfonylurea)
DSP-3235
trial, which is examining the efficacy and safety of canag‑
liflozin 100 mg or 300 mg once a day for 104 weeks com‑
O Cl
HO O pared with glimepiride 1 mg titrated to a maximum of
H S
O O 6 mg or 8 mg once a day for 104 weeks in patients with
HO
T2DM, who are not optimally controlled on stable‑dose
H
HO OH
HO OH O
metformin monotherapy 29. The primary end point is
OH the change in HbA1c; the secondary end point is the
LX-4211 TS-071 percentage change in body weight. Studies are also being
Figure 5 | Available structures of sgLT inhibitors. a | Early agents. Phlorizin and conducted on canagliflozin as monotherapy (100 mg and
T-1095 are nonselective for the sodium–glucose co-transporters
Nature(SGLTs),
Reviewswhereas
| Drug Discovery 300 mg) compared with placebo in patients with T2DM
sergliflozin and remogliflozin exhibit markedly increased selectivity for SGLT2. who are inadequately controlled with diet and exercise30;
b | Agents currently in development. All agents are selective for SGLT2, except for not controlled with metformin and sulphonylurea31; and
DSP-3235, which targets SGLT1. canagliflozin 100 mg and 300 mg compared with placebo
and an active‑control (sitagliptin 100 mg) in patients
with T2DM not controlled with metformin32.

observation carried forward) were +18.7 mg per 100
ml with placebo and insulin; –34.3 mg per 100 ml for
10 mg dapagliflozin and insulin; and –41.9 mg per
100 ml for 20 mg dapagliflozin and insulin. The urinary
glucose excretion at week 12 for those receiving pla‑
cebo was –1.5 g per 24 hours, compared with 83.5 g per
24 hours in the 10 mg dapagliflozin group, and 85.2 g
per 24 hours for those given 20 mg dapagliflozin. Mean
decreases in standing systolic and diastolic blood pres‑
sure were detected in both dapagliflozin cohorts. The
BI‑10773 and BI‑44847. BI‑10773 (developed by
Boehringer Ingelheim) is a selective SGLT2 inhibitor
that is currently in Phase II trials. Preclinical data have
demonstrated greater blockade of SGLT2 compared with
remogliflozin, with an IC50 value of 3.1–0.7 nM compared
with an IC50 value of 12–4 nM. In addition, the increase
in urinary glucose excretion over 24 hours was signifi‑
cantly higher in Zucker diabetic fatty rats and db/db mice
given BI‑10773 than in those administered with remo‑
gliflozin33. Boehringer Ingelheim is also investigating a

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 REVIEWS

Table 2 | SGLT2 inhibitors currently in development

Drug company Highest clinicalTrials.gov identifier
(alternative name) development
status
Dapagliflozin Bristol-Myers Squibb/ Phase III NCT01055691; NCT00643851; NCT00528372;
(BMS-512148)21–27 AstraZeneca NCT01095666; NCT01095653; NCT00673231;
NCT00528879; NCT00660907; NCT00680745
Canagliflozin Johnson & Johnson/ Phase III NCT01064414; NCT01081834; NCT01106625;
(TA-7284, Mitsubishi Tanabe NCT01106677; NCT01106690; NCT01106651;
JNJ-28431754)28–32 Pharma NCT01032629; NCT00968812
ASP-1941 Astellas/Kotobuki Phase III NCT01054092; NCT01057628
BI-10773 (Ref. 33) Boehringer Ingelheim Phase II NCT01011868
BI-44847 Boehringer Ingelheim Phase II Not applicable
(under license from
Ajinomoto)
TS-071 Taisho Pharmaceutical Phase II Not applicable
CSG-452 Roche/Chugai Phase II Not applicable
(R-7201, RG-7201) Pharmaceutical
LX-4211 Lexicon Phase II NCT00962065
Pharmaceuticals
DSP-3235 GlaxoSmithKline/ Phase I NCT00976261
(KGA-3235, Dainippon Sumitomo
GSK-1614235, (under license from Kissei
1614235)* Pharmaceuticals)
ISIS-SGLT2Rx Isis Pharmaceuticals Phase I NCT00836225
(ISIS-388626)34,35
Unknown Sirona Biochem (under Discovery Not applicable
license from TFChem)
SGLT, sodium–glucose co-transporter. *Selective for SGLT1; all other agents are selective for SGLT2.

second SGLT2 inhibitor from this series, BI‑44847, which
is undergoing Phase II trials, although most of the clinical
activity appears to be centred on BI‑10773.
Other agents. other SGLT2 inhibitors currently
being studied in Phase II trials include TS‑071
(Taisho Pharmaceutical), CSG‑452 (Roche/Chugai
Pharmaceutical) and LX‑4211 (Lexicon Pharmaceuticals)
(fIG. 5b; TABLe 2). ASP‑1941 (Astellas/Kotobuki) is now
in Phase III clinical studies in japan, and Phase II trials
in europe and the united States (TABLe 2). DSP‑3235
(GlaxoSmithKline/Dainippon Sumitomo) is an SGLT1
inhibitor that is currently being evaluated in Phase I trials.
However, clinical data for these compounds have not yet
been published.
mRNA expression without affecting SGLT1 expression35.
These findings were observed in studies in dogs over
6 weeks; Sprague Dawley rats over 3 months; and Zucker
diabetic fatty rats over 6 months35. ISIS‑388626 selec‑
tively targeted kidney proximal tubules and there was no
accumulation of this agent in cardiac, liver or intesti‑
nal tissues after 6 months of administration in Zucker
diabetic fatty rats35. In these rats, HbA1c significantly
decreased from 10.9 ± 0.3% in controls given saline to
6.3 ± 0.8% in animals treated with the antisense oli‑
gonucleotide. Marked glycosuria and plasma glucose
reductions were also noted. Blood urea nitrogen, serum
creatinine, plasma electrolytes and urine electrolytes did
not change significantly. The results of Phase I studies
are forthcoming.

Antisense oligonucleotide
inhibitor
When the sequence of a
particular gene is known to
cause a particular disease,
a strand of nucleic acid can be
synthesized (DNA, RNA or a
chemical analogue) that will
bind to the mRNA produced
by that gene and inactivate
that gene. Antisense is
complementary to the ‘sense’
sequence of the target gene’s
mRNA.
SGLT2 antisense oligonucleotide inhibitors. ISIS‑388626
(also know as ISIS‑SGLT2Rx and is being developed by
Isis Pharmaceuticals) represents a novel approach to
SGLT2 inhibition — the use of an RNAase H chimeric
antisense oligonucleotide inhibitor to block the expres‑
sion of the SGLT2 gene in vivo. Normoglycaemic mice
responded to ISIS‑388626 with a 14‑fold to 130‑fold
increase in urine glucose excretion at 1–30 mg per kg
per week, and 7‑fold to 125‑fold elevation at greater than
3 mg per kg per week34. wancewicz and colleagues dem‑
onstrated that administration of ISIS‑388626 once a week
yielded an approximately 80% reduction of renal SGLT2
Safety of SGLT2 inhibition
one of the major safety concerns of many diabetes
agents is the potential development of hypoglycaemia.
However, given that SGLT2 inhibitors act independ‑
ently of glucose‑dependent insulin secretion by the
pancreatic β‑cells, and that they incompletely inhibit
glucose reabsorption, this type of adverse effect is not
expected. Indeed, results from the dapagliflozin clinical
trials so far have reported virtually no instances of major
hypoglycaemic events24–26. Further results are pending
from larger trials of longer duration. Although the risk
of hypoglycaemia is low, it is important to investigate its

NATuRe RevIewS | Drug Discovery voLuMe 9 | juLy 2010 | 557

© 2010 Macmillan Publishers Limited. All rights reserved

REVIEWS
potential development if SGLT2 inhibitors are admin‑
istered in combination with other anti‑diabetic agents,
such as metformin or the insulin secretagogues.
Given the mechanism of action of SGLT2 inhibitors,
other safety issues include the development of urinary
tract infections and fungal genitourinary infections, as
well as deterioration of renal function. Clinical studies
so far on dapagliflozin have found that the rates of uri‑
nary tract infections were comparable in treatment and
placebo groups. elevated urine volume of 400–600 ml
per day was detected in the studies of dapagliflozin, and
was associated with a dose‑related elevation in haemato‑
crit (range 1.5–2.9%)25, and increased urea. The diuresis
may be due more to an osmotic effect than to sodium
loss. Two recent clinical studies noted an increased inci‑
dence in fungal genitourinary infections, most occurring
in the higher dosage groups25–26.
In addition, in all the three larger trials of the cur‑
rently most advanced SGLT2 inhibitor, dapagliflozin, no
deaths have occurred24–26 and no serious adverse events
related to dapagliflozin were observed in the studies by
Komoroski and colleagues23,24 and List and colleagues25.
Although two subjects experienced a serious adverse
event in the study by wilding and colleagues26, one was
on placebo, while the other received the higher dose
(20 mg) of dapagliflozin.
Perhaps the most compelling evidence for the long‑
term safety of this class of agents that affect glucose
reabsorption is found from studying individuals with
familial renal glycosuria — an autosomal genetic disorder
resulting from mutations in the gene encoding SGLT2;
its mode of transmission is thought to be co‑dominant
with incomplete penetrance36,37. Familial renal glycosu‑
ria is characterized by persistent isolated glycosuria of
approximately 10–120 g per day, in the face of normal
fasting serum glucose, normal glucose tolerance tests, the
absence of any signs of general renal tubular dysfunction
or other pathological changes, and normal life expectan‑
cies36,37. Individuals with familial renal glycosuria usually
report no complaints, and only rarely have hypoglycae‑
mia or hypovolaemia.
Future directions and concluding remarks
of the SGLTs, inhibition of SGLT2 offers the most
promise as a therapeutic strategy because it is respon‑
sible for most of the renal glucose reabsorption and
since it is expressed exclusively in the kidney. Clinical
trials of many of the SGLT2 inhibitors are in the early
stages; nevertheless, data from investigations so far are
encouraging. Currently, all published clinical studies
of SGLT2 inhibitors have been performed in individu‑
als with T2DM, although they may also be beneficial
in the treatment of T1DM. Acute administration of
SGLT2 inhibitors reduces both preprandial and post‑
prandial blood glucose, and chronic administration
may decrease glucotoxicity 38. Inhibition of SGLT2 rep‑
resents a particularly appealing approach to treating
diabetes, as, in contrast to many other current diabetes
therapies, SGLT2 inhibitors do not directly influence
insulin secretion, thereby utilizing a novel mechanism
of action. Thus, there is a low risk of hypoglycaemia, as
558 | juLy 2010 | voLuMe 9
© 2010 Macmillan Publishers Limited. All rights reserved
these agents selectively target renal glucose transporters,
without affecting the counter‑regulatory hormones39.
The energy deficit induced by excretion of calories in
the urine can lead to weight loss, or at a minimum, result
in a weight‑neutral effect. The prospective aetiology of a
slight diuretic‑like effect awaits further determination,
and includes glucose inducing an osmotic diuresis, or
may be secondary to sodium loss. Hypertension could
therefore possibly be concomitantly improved. As the
target tissue is limited to the kidney, the potential for
off‑target adverse effects is also minimized, and the data
from the studies completed so far indicate that this class
of agents has been generally safe and well tolerated.
Their novel mechanism of action suggests that
SGLT2 inhibitors might have the potential to be used
in combination with oral anti‑diabetic agents as well as
insulin to exert additive or synergistic effects on lower‑
ing glucose levels in T2DM, although the results of such
investigations are awaited. In addition, the potential for an
increase in side effects, such as hypoglycaemia, following
such combination therapy is unknown.
A question that has also not yet been answered is
whether — and to what extent — inhibiting SGLT1
activity along with inhibiting SGLT2 would yield addi‑
tional clinical improvement. Theoretically, greater
glycaemic control and weight loss could reasonably be
expected if both were blocked. However, owing to its
presence in the small intestine, blocking SGLT1 could
generate less desirable effects that accompany the delayed
absorption of carbohydrates. Mutations of SGLT1 pro‑
duce little or no glycosuria; thus, the role of SGLT1 in
the kidney would seem to be much more limited than
that of SGLT2 (RefS 38,39). Studies on dual inhibition of
SGLT2 and SGLT1 are ongoing. SGLT1 is also expressed
in large numbers in human cardiac myocytes, but any
potential effects on the heart are not yet known40. of
note, cardiomyopathy has not been reported in indi‑
viduals with the genetic disorder of glucose and galac‑
tose malabsorption41. In addition, the potential effect of
SGLT suppression on SGLTs found elsewhere, such as
the hypothalamus, is unclear. Indeed, SGLT inhibitors
are lipid‑soluble, and can therefore cross the blood–
brain barrier, warranting additional research.
Another area of uncertainty involves the contributions
of diuresis versus reduction in adiposity to total weight
loss. one study postulated that the larger reduction in
weight during week 1 of dapagliflozin administration,
coupled with a partial, rapid resurgence in weight after
discontinuation of higher doses, might represent the
effect of diuresis, whereas more sustained weight loss is
due to decreased adipose tissue25. The safety of this class
of agents in women of child‑bearing age also is unknown,
as is the impact of these inhibitors on bone metabolism.
In summary, increasing urinary glucose excretion
represents a new approach to addressing the challenge of
hyperglycaemia. SGLT2 inhibitors may have indications
both in the prevention and treatment of T2DM, and
perhaps T1DM, with a possible application in obesity.
Further studies in large numbers of human subjects are
necessary to delineate efficacy, safety and how to most
effectively use these agents in the treatment of diabetes.
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Acknowledgements
This project was supported by the Veterans Administration
Medical Center, San Diego and the University of California,
San Diego, USA.
Competing interests statement
The authors declare competing financial interests: see web
version for details.
DATABASES
OMIM:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
Familial renal glycosuria
UniProtKB: http://ca.expasy.org/sprot
GLUT1 | GLUT2 | SGLT1 | SGLT2
FURTHER INFORMATION
ClinicalTrials.gov: http://clinicaltrials.gov
Division of Endocrinology and Metabolism, UCSD
Department of Medicine: http://endocrinology.ucsd.edu
The Center for Metabolic Research, VA San Diego
Healthcare System: http://www.vacmr.org
ALL LiNks Are AcTive iN THe oNLiNe PDf
voLuMe 9 | juLy 2010 | 559