S P E C I A L

F E A T U R E

R e v i e w

Sodium Glucose Cotransporter 2 Inhibitors as a New

Treatment for Diabetes Mellitus
Sunil Nair and John P. H. Wilding
Diabetes and Endocrinology Research Unit, Clinical Sciences Centre, University Hospital Aintree,
Liverpool L9 7AL, United Kingdom

Context: Sodium-glucose cotransporter 2 (SGLT2) expressed in the proximal renal tubules accounts
for about 90% of the reabsorption of glucose from tubular fluid. Genetic defects of SGLT2 result
in a benign familial renal glucosuria. Pharmacological agents that block SGLT2 are being tested as
potential treatment for type 2 diabetes mellitus.
Evidence Acquisition: A Pubmed search was used to identify all relevant articles on the physiology
of SGLTs as well as published preclinical and clinical experimental studies with SGLT2 inhibitors; a
reference search of all retrieved articles was also undertaken.
Evidence Synthesis: SGLT2 is almost exclusively expressed in the proximal renal tubules. Preclinical
studies with selective SLGT2 inhibitors show dose-dependent glucosuria and lowering of blood
glucose in models of type 2 diabetes. Preliminary clinical studies of up to 3-month duration show
dose-dependent lowering of glycosylated hemoglobin up to 0.9% along with modest weight loss.
Side effects include an increase in genital fungal infection compared to placebo, increased urine
volume (300 400 ml/24 h), and evidence of volume depletion consistent with mild diuretic effect.
Conclusion: SGLT2 inhibitors are showing promise as a useful addition to the current therapeutic
options in type 2 diabetes mellitus. Results of ongoing phase III clinical trials are awaited and will
determine whether the risk-benefit ratio will allow approval of this new class of drug for the
management of type 2 diabetes mellitus. (J Clin Endocrinol Metab 95: 34 42, 2010)

anagement of type 2 diabetes mellitus (T2DM) remains complex and challenging. Although a wide
range of pharmacotherapy for T2DM is available, including
metformin, insulin secretagogues (predominantly sulfonylureas), thiazolidinediones, -glucosidase inhibitors, insulin,
and more recently glucagon like peptide-1 agonists and
dipeptidyl-peptidase-IV inhibitors, many patients do not
achieve glycemic targets, partly due to limiting side effects of
current therapies, including weight gain, hypoglycemia, fluid
retention, and gastrointestinal side effects. Hence, the search
for new treatment strategies is ongoing. Among the new therapies on the horizon, sodium-glucose cotransporter 2
(SGLT2) inhibitors seem promising, and there are a number
of ongoing phase II and III clinical trials with a variety of these
compounds. SGLT2 is almost exclusively expressed in the
renal proximal tubules and accounts for 90% of the renal

ISSN Print 0021-972X ISSN Online 1945-7197

Printed in U.S.A.
Copyright 2010 by The Endocrine Society
doi: 10.1210/jc.2009-0473 Received March 4, 2009. Accepted October 14, 2009.
First Published Online November 5, 2009

34

jcem.endojournals.org

glucose reabsorption (1). SGLT2 inhibitors work independently of insulin and lead to negative energy balance by enhanced urinary glucose excretion. This makes it mechanistically possible for this class of drugs to reduce glucose levels
without causing hypoglycemia and weight gain. However,
the side effect profile remains to be further elucidated in ongoing phase III trials, and these compounds will need to be
proven safe from a renal and cardiovascular perspective to meet
current regulatory requirements for new diabetes treatment.

Glucose Transport across Biological

Membranes
Glucose transporters
Glucose absorption at the enterocytes, reabsorption at the
renal tubules, transport across the blood-brain barrier, and
Abbreviations: GLUT, Glucose transporter; HbA1c, glycosylated hemoglobin; MAD, multiple ascending dose; SAD, single ascending dose; SGLT, sodium-glucose cotransporter;
SLC, solute carrier family; T2DM, type 2 diabetes mellitus; UTI, urinary tract infection.

J Clin Endocrinol Metab, January 2010, 95(1):34 42

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J Clin Endocrinol Metab, January 2010, 95(1):34 42

uptake and release by all cells in the body are effected by two
groups of transporters: glucose transporters (GLUTs) and
sodium-glucose cotransporters (SGLTs).
GLUTs are facilitative or passive transporters that
work along the glucose gradient. They belong to the SLC2
(solute carrier family 2) gene family, which has 13 members: GLUT 1-12 and the H-myoinositol cotransporters.
They are expressed in every cell of the body (2, 3).
SGLTs cotransport sodium and glucose into cells using
the sodium gradient produced by sodium/potassium
ATPase pumps at the basolateral cell membranes. They
belong to the SLC5 gene family, which has nine members
with known functions. Of these, six are plasma membrane
sodium/substrate cotransporters for solutes such as glucose, myoinositol, and iodide (SGLT 1-6). SGLT1 is primarily expressed in the small intestine but is also found in
the trachea, kidney, and heart, and its predominant substrates are glucose and galactose. SGLT2 is expressed in
the S1 and S2 segments of the proximal convoluted tubules
and is responsible for renal reabsorption of glucose (4).
SGLT2 RNA is minimally expressed in the ileum, the level
of which was insignificant by Northern blot analysis (5).
Although one study using real-time PCR suggests widespread SGLT2 RNA expression in a variety of tissues (6),
there is no published data to show that SGLT2 protein is
found outside the kidney. There have been attempts to
examine expression of SGLT proteins, but availability of
antibodies that are specific enough seems to be the limiting
factor. Therefore, the functional significance of mRNA
expression in nonrenal tissues has not been established.
However, there is some evidence for SGLT2 mRNA expression by real-time PCR as well as for SGLT2 protein
expression in the placenta by Western blot analysis (7).
SGLT1 gene mutations lead to glucose-galactose malabsorption, which causes potentially fatal diarrhea. The oral rehydration therapy that saves millions of lives from infectious
diarrheaworksviaSGLT1transportersintheenterocytes(8,9).
Much of the evidence for SGLT2 being a major pathway for renal glucose reabsorption comes from genetic
studies of individuals with familial renal glucosuria (10,
11). Mutations in the SLC5A2 gene encoding SGLT2 lead
to familial renal glucosuria, which is inherited as an autosomal recessive trait and is characterized by normal
blood glucose levels, normal oral glucose tolerance test
results, and isolated persistent glucosuria (10, 12, 13). A
study analyzing 23 families with index cases of renal glucosuria found that each family had a unique mutation in
the SGLT2 gene. Individuals who were found to be carriers
of two mutated alleles showed severe glucosuria, defined
by a urinary glucose of more than 10 g/1.73 m2 per 24 h
(55 mmol/1.73 m2 per 24 h). The index patients who presented with mild glucosuria and the family members of

jcem.endojournals.org

35

cases of severe glucosuria were shown to be heterozygous

carriers of SGLT2 mutations (11, 14). Another study
found 20 different SLC5A2 mutations within 17 pedigrees. Glucosuria was mild in heterozygotes ranging from
2.7 to 10 g/1.73 m2 per 24 h, whereas it was severe in
homozygotes ranging from 15.2 to 86.5 g/1.73 m2/24 h.
Two patients in the homozygous group had plasma renin
and serum aldosterone concentration raised to an average
of 4.6- and 3.1-fold, respectively, suggesting activation of
compensatory mechanisms (15).
Renal glucose transport in health
Kidneys play a very important role in glucose homeostasis. Blood glucose is freely filtered by the glomeruli
and is essentially completely reabsorbed from the proximal tubules via sodium-coupled transporters in the brush
border membrane. The glomeruli filter about 144 g of
glucose per 24 h, nearly 100% of which is reabsorbed in
the renal tubules. When blood glucose levels reach the
renal threshold for reabsorption, which is about 8 to 10
mmol/liter (180 mg/dl), glucosuria starts to develop (16).
The proximal tubule has traditionally been divided into
S1, S2, and S3 segments based on the cell morphologies,
although more recent ultra structural analyses of computerassisted three-dimensional reconstruction of mouse
proximal tubules revealed no obvious morphological segmentation of the proximal tubule (17). There is evidence,
however, for heterogeneity of sodium-dependent glucose
transport along the proximal tubule. The S1 and S2 segments of the proximal convoluted tubules show low affinity and high capacity for sodium-dependent glucose absorption, whereas the more distal parts show higher
affinity and low capacity for the same (18). SGLT2 is located in the S1 and S2 segments where the majority of
filtered glucose is absorbed, and SGLT1 is located in S3
segments responsible for reabsorbing the remaining glucose (4, 19). Combined in situ hybridization and immunocytochemistry with tubule segment-specific marker antibodies demonstrated an extremely high level of SGLT2
mRNA in proximal tubule S1 segments (1) (Fig. 1).
Renal glucose transport in diabetes
Renal tubular reabsorption is known to undergo adaptations in uncontrolled diabetes; particularly relevant in
this context is the up-regulation of renal GLUTs. The increase in extracellular glucose concentration in diabetes
lowers its outwardly directed gradient from the tubular
cells into the interstitium. Hence, up-regulation of SGLT2
is an important adaptation in diabetes to maintain renal
tubular glucose reabsorption. SGLT2 mRNA expression
is up-regulated in diabetic rat kidneys and this up-regulation is reversed by lowering blood glucose levels (20). Hu-

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36

Nair and Wilding

SGLT2 Inhibitors for Diabetes

FIG. 1. Diagram of proximal renal tubular cell showing secondary

active transport of glucose by SGLT2. The sodium gradient, produced
by the Na/K ATPase pump at the basolateral cell membrane, is used for
sodium and glucose cotransport. Glucose is transported passively by
GLUT2 into the interstitium.

man exfoliated proximal tubular epithelial cells from fresh

urine of diabetic patients express significantly more
SGLT2 and GLUT2 than cells from healthy individuals
(21). There is also evidence for up-regulation of GLUT2
gene expression in renal proximal tubules in diabetic rat
models (2224). Uncontrolled diabetes leading to increased expression of SGLT2 has practical significance in
that the inhibitors are likely to produce greater degrees of
glucosuria in the presence of higher prevailing plasma glucose levels. This has been shown in preclinical studies with
the nonspecific SGLT inhibitor, T-1095 (25).
Interestingly, this up-regulation of SGLT2 receptors is
also seen in renovascular hypertensive rat models. The
authors speculated that angiotensin II-induced SGLT2
over expression probably contributes to increased absorption of Na and thereby development or maintenance of
hypertension. Rats treated with either ramipril or losartan
showed significant reduction in the intensity of immunostaining and levels of SGLT2 protein and mRNA (26).
This may have relevance in diabetes, given the high prevalence of hypertension in diabetes.

Therapeutic Potential of Inducing

Glucosuria
Phlorizin is a glucoside consisting of a glucose moiety and
two aromatic rings (aglycone moiety) joined by an alkyl
spacer. In the 19th century, French chemists isolated it
from the bark of apple tree to be used in treatment of fever
and infectious diseases, particularly malaria. Von Mering
observed in 1886 that phlorizin produces glucosuria. It
has been used as a tool for physiological research for more
than 150 yr (27). In 1975, DeFronzo et al. (28) showed
that infusion of phlorizin in dogs increased fractional excretion of glucose by 60%, whereas glomerular filtration
rate and renal plasma flow remained unchanged.

J Clin Endocrinol Metab, January 2010, 95(1):34 42

Phlorizin is a high-affinity competitive inhibitor of Nadependent glucose transport in renal and intestinal epithelia (29). Hence, it causes malabsorption of glucose and
galactose from the small intestines and of glucose from the
renal tubules. Phlorizin caused heavy glucosuria and
marked inhibition of glucose uptake in the small intestine
during enteric perfusion in normal rats. It also significantly reduces blood glucose on oral glucose tolerance test
in mice and lowers blood glucose in streptozotocin-induced diabetic rats (30). It improves counter-regulatory
responses reducing the risk of hypoglycemia in animal
models (31). In 1986, Ungers group (32) reported that iv
glucose failed to suppress the marked hyperglucagonemia
found in insulin-deprived alloxan-induced diabetic dogs;
however, when hyperglycemia was corrected by phlorizin,
the hyperglucagonemia became readily suppressible. Phlorizin treatment of partially pancreatectomized rats completely
normalized insulin sensitivity but had no effect on insulin
action in controls (33, 34), suggesting that the effect on insulin sensitivity was by reversal of glucotoxicity, rather than
by a direct effect on insulin sensitivity. Animal studies with
phlorizin have shown that its effect of changing the ambient
glucose independent of insulin levels can up-regulate the glucose transport response to insulin in adipose cells, which may
be as a result of changes in GLUT functional activity (35).
These findings provided important proof of concept
data, although phlorizin itself is unsuitable for development as a drug for the treatment of diabetes because of its
nonselectivity and low oral bioavailability (25, 36).
T-1095 is a synthetic phlorizin derivative, which unlike
phlorizin is absorbed into the circulation on oral administration and is metabolized to its active form T-1095A. It
suppresses the activity of SGLT1 and -2 in the kidney and
increases urinary glucose excretion in diabetic animals,
thereby decreasing blood glucose levels. With long-term
T-1095 treatment, both blood glucose and glycosylated
hemoglobin (HbA1c) levels were reduced in streptozotocin-induced diabetic rats and the obese insulin resistant
yellow KK rat models (25). Chronic administration of
T-1095 lowered blood glucose and HbA1c levels, partially
improved glucose intolerance and insulin resistance, and
prevented the development of diabetic neuropathy in the
diabetic insulin-resistant GK rat models. There were no
adverse side effects reported at the end of the study (37).
This drug, however, did not proceed to clinical development, presumably because it also inhibits SGLT1 (Fig. 2).

Development of Selective SGLT2

Inhibitors
Several specific and potent SGLT2 inhibitors have undergone preclinical testing. Most SGLT2 inhibitors are glu-

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J Clin Endocrinol Metab, January 2010, 95(1):34 42

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37

bonate, which are orally administered, are the ethyl carbonate prodrug esters of sergliflozin A and remogliflozin,
respectively. Creating a carbon-carbon bond between the
glucose and aglycone moiety converts o-glucosides to cglucosides, which have a different pharmacokinetic profile, making them unsusceptible to -glucosidase (38).
Dapagliflozin is the first c-glucoside to be discovered that
is currently in phase III trials. Several such structural alterations and new SGLT2 inhibitors have been reported
(39 42) (Table 1).

FIG. 2. Schematic representation of normal renal glucose reabsorption

and the effect of SGLT2 inhibition. The amount of glucose filtered
increases linearly with increasing plasma glucose concentration (gray
dotted line). The threshold at which glucose appears in the urine is a
plasma glucose concentration of around 8.3 mmol/liter, but some
variability in reabsorption by individual nephrons is thought to account
for the splay shown in the figure. Above the saturation threshold
(13.3 mmol/liter), glucosuria increases in a linear fashion with plasma
glucose. In diabetes due to up-regulation of SGLT2, the reabsorption
curve is shifted to the right. SGLT2 inhibitors lower both the saturation
threshold and the transport maximum (Tmax) for glucose. This results
in increased glucosuria for a given plasma glucose level, represented
here as a left shift of the glucosuria curve.

cosides, structurally related to phlorizin, which is an oglucoside. The o-glucosides have to be administered as
their prodrug esters to avoid degradation by -glucosidase
in the small intestine. Sergliflozin and remogliflozin eta-

Antisense oligonucleotide therapy

Preliminary findings of a novel method of SGLT2 inhibition have been presented in abstract form. ISIS
388626, an antisense oligonucleotide, reduces the expression of SGLT2 gene in the proximal renal tubules of
rodents and dogs. Once-weekly administration of ISIS
388626 reduced renal SGLT2 mRNA expression by up to
80%. It did not affect the expression of SGLT1 or GLUT
genes. Consistent with this, ISIS 388626 increased glucosuria and improved plasma glucose and HbA1c in Zucker
diabetic fatty rats. There was no accumulation in liver,
intestine, or cardiac tissues after 6 months of dosing in
Zucker diabetic fatty rats, whereas kidney antisense oligonucleotide concentration was high, confirming its tissue
specificity (43). A study examining the long-term effect of
ISIS 388626 in nonhuman primates showed dose-dependent reduction in SGLT2 expression, with more than 75%
reduction at the highest dose. This was accompanied by a

TABLE 1. SGLT2 inhibitors with published preclinical studies

T-1095

Drug

Chemical structure
O-Glucoside

AVE2268

Substituted glycopyranoside

Remogliflozin etabonate

O-glucoside

Sergliflozin

O-glucoside

Dapagliflozin

C-aryl glucosides

JNJ-28431754/TA-7284
BI 10773

Preclinical studies
T-1095, an inhibitor of renal SGLTs, may provide a novel approach
to treating diabetes (25)
Long-term treatment with the SGLT inhibitor T-1095 causes
sustained improvement in hyperglycemia and prevents diabetic
neuropathy in Goto-Kakizaki rats (37)
Effects of AVE2268, a substituted glycopyranoside, on urinary
glucose excretion and blood glucose in mice and rats (59)
Remogliflozin etabonate, in a novel category of selective low-affinity
SGLT2 inhibitors, exhibits antidiabetic efficacy in rodent models (41)
Sergliflozin, a novel selective inhibitor of low-affinity SGLT2,
validates the critical role of SGLT2 in renal glucose reabsorption
and modulates plasma glucose level (36)
Discovery of dapagliflozin: a potent, selective renal sodiumdependent glucose cotransporter 2 (SGLT2) inhibitor for the
treatment of T2DM (46)
Dapagliflozin, a selective SGLT2 inhibitor, improves glucose
homeostasis in normal and diabetic rats (60)
Dapagliflozin, a selective SGLT2 inhibitor, improves glucose
homeostasis in normal and diabetic rats (61)
JNJ-28431754/TA-7284, an SGLT inhibitor, lowers blood glucose
and reduces body weight in obese and T2DM animal models (62)
In vitro properties and in vivo effect on urinary glucose excretion of
BI 10773, a novel selective SGLT2 inhibitor (63)

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38

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SGLT2 Inhibitors for Diabetes

J Clin Endocrinol Metab, January 2010, 95(1):34 42

In a phase IIa study, 47 patients

with T2DM were randomized to receive 5, 25, or 100 mg of dapagliflozin
or placebo for 14 d. Those receiving
25 and 100 mg dapagliflozin had approximately 40% inhibition of renal
glucose reabsorption as compared
with baseline resulting in glucose excretion of up to 70 g per 24 h. Two of
the 24 women who received dapagliflozin were diagnosed with mild vulvovaginal mycotic infections that reFIG. 3. A, Mean change in HbA1c over time. B, Mean change from baseline in total body
solved in 4 d with treatment. The most
weight over time. Error bars represent 95% confidence intervals. DAPA, Dapagliflozin; INS,
frequently reported treatment emerinsulin; PLA, placebo. [Reproduced with permission from Wilding et al.: Diabetes Care
gent adverse events were gastrointes32:1656 1662, 2009 (49).]
tinal, including constipation, nausea,
and diarrhea. There were no drug dismore than 1000-fold increase in glucosuria without any
continuations
due
to adverse events (47).
associated hypoglycemia, and the glucosuria persisted for
A phase IIb multiple-dose study to evaluate safety
several weeks after treatment cessation (44).
and
efficacy of dapagliflozin-randomized T2DM paThis novel approach is of potentially great interest,
tients
to five dapagliflozin doses (2.5, 5, 10, 20, or 50
and ISIS Pharmaceuticals (San Diego, CA) recently anmg),
metformin
extended release, or placebo for 12 wk
nounced that translation into human phase I studies is
about to commence using a 12-nucleotide antisense oli- has recently been reported. Dapagliflozin improved hygonucleotide, ISIS-SGLT2RX although very careful safety perglycemia and caused weight loss by inducing conevaluation will need to be undertaken given the novelty of trolled glucosuria with urinary loss of approximately
200 300 kcal/d. There was a weight loss of 2.5 to 3.4
this approach.
kg in the dapagliflozin-treated patients, compared with
1.2 kg with placebo and 1.7 kg with metformin. DapaSGLT2 inhibitors in clinical development
gliflozin treatment was not associated with clinically
significant osmolarity, volume, or renal status changes.
Dapagliflozin
Dapagliflozin is a potent and highly selective SGLT2 There was also no compensatory increase in hunger as
inhibitor. The elimination half-life after intraarterial assessed by visual analog scales. The rates of bacterial
administration was 4.6, 7.4, and 3.0 h in rats, dogs, and urinary tract infections (UTIs) were similar in the treatmonkeys, respectively (45). Single and multiple ascend- ment and placebo arms, but there was higher incidence
ing dose (SAD and MAD) studies with dapagliflozin of genital infections in the dapagliflozin vs. placebo,
confirmed that it has a pharmacokinetic profile consis- especially at higher doses (48).
A double-blind, three-arm parallel group, placebo-content with once-daily dosing and produces a dose-depentrolled
study randomized 71 patients 1:1:1 to placebo, 10
dent increase in glucosuria in humans. Dapagliflozin
was rapidly absorbed after oral administration, and and 20 mg dapagliflozin, plus oral antidiabetic agents and
maximum plasma concentrations (Cmax) were observed 50% of their prestudy daily insulin dose. At wk 12, dapawithin 2 h of administration. The mean half-life after gliflozin 10- and 20-mg groups demonstrated 0.70%
the last dose in the MAD study ranged from 11.2 to and 0.78% mean differences in HbA1C change from
16.6 h, and the data were similar for the SAD study with baseline vs. placebo. Mean changes from fasting plasma
high dose. In the MAD study, a dose of 100 mg produced glucose were 17.8, 2.4, and 9.6 mg/dl, and mean
urine glucose of 58.3 g per 24 h and 55.4 g per 24 h on changes in total body weight were 1.9, 4.5, and
d 14. Dapagliflozin had no effect on urine and serum 4.3 kg (placebo, 10-, and 20-mg dapagliflozin groups,
electrolytes, serum albumin, osmolality, or renal tubu- respectively). The baseline HbA1c in the three groups
lar markers such as N-acetyl-b-D-glucosaminidase and were 8.4 0.9, 8.4 0.7, and 8.5 0.9, respectively.
2-microglobulin. Two events of mild asymptomatic Overall, adverse events were balanced across all groups,
hypoglycemia were reported in the SAD study. No treat- but more genital infections occurred in the dapagliflozin
ment-related serious adverse events were reported in 20-mg group than placebo. Also total hypoglycemic
either study (46).
events were more frequently reported with dapagliflo-

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J Clin Endocrinol Metab, January 2010, 95(1):34 42

zin than placebo, although none of them was major

(49) (Fig. 3).
A number of phase III clinical trials with dapagliflozin,
mostly as add-on therapies to existing antidiabetic drugs,
are now under way.
Sergliflozin
A phase I study with 50 500 mg of sergliflozin in 14
healthy volunteers and a phase IIa study where the same
dose range was given to eight subjects with T2DM showed
a dose-dependent increase in urinary glucose excretion
that plateaued at higher doses. It did not cause hypoglycemia in nondiabetic subjects, and there was a 1.5-kg
weight loss from baseline to d 15 compared with placebo.
There were no clinically significant effects on serum electrolytes or calculated creatinine clearance (50, 51). Development of sergliflozin has been discontinued in favor of
remogliflozin.
Remogliflozin etabonate
Remogliflozin etabonate is metabolized to its active
form remogliflozin, which is a benzylpyrazole glucoside. Its skeleton differs from that of phlorizin,
T-1095, or sergliflozin, and hence is from a new category of SGLT2 inhibitors. Its inhibitory effect for human SGLT2 is approximately three times greater than
that of phlorizin, but for SGLT1 it was only 1/20 that of
phlorizin in in vitro studies. Animal studies have shown
good linearity between urinary glucose excretion and
the dose of remogliflozin etabonate. It did not significantly alter the plasma glucose level in 16-h fasted normal rats (41).
A study with 13 T2DM patients supported its coadministration with metformin in patients with T2DM
with minimal risk of hypoglycemia. There was no drug
interaction affecting the pharmacokinetics of either
drug (52). In another study, remogliflozin etabonate
administered to 10 healthy subjects (doses ranging from
20 to 1000 mg) and six subjects with T2DM (doses
ranging from 50 to 500 mg) was rapidly absorbed and
converted to remogliflozin, which had a plasma half-life
of 120 min across doses and groups. It caused a dosedependent increase in urinary glucose excretion in all
subjects. There were no effects on plasma electrolytes
and no serious adverse events (53).
AVE2268
A phase II study with AVE2268 recruited 300 patients
with T2DM not adequately controlled by metformin to assess the effects of several doses of AVE2268 on glycemic
control and to assess safety and tolerability. The results of
this study are awaited.

jcem.endojournals.org

39

Adverse effects
Increased urine volume (up to 400 ml) was observed
in clinical studies with dapagliflozin, associated with
increased hematocrit and urea, suggesting slight volume
depletion. Electrolyte imbalance is also a consideration
because physiological studies have shown increased sodium loss with phlorizin. A phase II trial reported one
case of dehydration and prerenal azotemia, which resolved with oral rehydration and withholding angiotensin-converting enzyme inhibitor and diuretic therapy (49). Whether patients with diabetes mellitus who
have neuropathy, hyporeninemic hypoaldosteronism,
and nephropathy could be rendered more vulnerable to
sodium wasting and hypovolemia will need to be assessed further. A statistically significant increase in
magnesium (0.18 0.16 mEq/liter; P 0.001) and
decrease in uric acid levels (1.14 1.15 mg/dl; P
0.001) were reported in a phase II trial with dapagliflozin compared with placebo. In terms of bone metabolism, an increase in parathormone concentration
(range, 0.6 7.0 pg/ml above baseline of 31.135.0 pg/
ml) has been noted, which was greater than the 0.8
pg/ml increase for placebo. There was no change in serum 1,25-dihydroxyvitamin D and 25-hydroxyvitamin
D values from baseline, and the mean changes in the
24-h urinary calcium-to-creatinine ratio were similar to
those with placebo (48). The long-term effects on bone
health will also need to be clarified by ongoing phase
III trials.
The apparent presence of SGLT2 in the placenta does
raise concern about its safety in women of child-bearing
age.
Another important question is whether increased glucosuria would predispose to UTIs or genital fungal infections.
In vivo studies have not shown a higher prevalence of
bacteriuria among diabetic patients with glucosuria
compared with patients without glucosuria. Defects in
the local urinary cytokine secretions and an increased
adherence of the microorganisms to the uroepithelial
cells have been proposed to increase the incidence of
UTI in patients with diabetes (54, 55). This suggests that
risk of UTI may not be increased in patients taking
SGLT2 inhibitors, and this has been borne out by the
available clinical data.
Symptomatic vulvovaginal candidiasis is more prevalent in patients with diabetes compared with the normal
population (56, 57), and this increased prevalence is associated with poor glycemic control (58), but it is unknown whether circulating glucose concentrations or the
presence of glucosuria is the critical factor. Both reported
phase II studies with dapagliflozin suggest an increase in

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40

Nair and Wilding

SGLT2 Inhibitors for Diabetes

genital fungal infection, so this will need close observation

in the future.

Future Potential
SGLT2 inhibitors have a unique mechanism of action
and have the potential to become a new treatment for
T2DM. Several phase III trials with these compounds
are ongoing and if their efficacy and safety profile are
proven to be adequate, these agents may gain a place in
the management of T2DM, particularly where weight
gain is a concern. The potential for use as an insulinsparing agent in patients on insulin has been highlighted
in a recent trial (49) and a future role in the management
of type 1 diabetes mellitus cannot be ruled out, although
SGLT2 inhibitors have not yet been tested for this
indication.

J Clin Endocrinol Metab, January 2010, 95(1):34 42

9.

10.

11.

12.

13.
14.

15.

Acknowledgments
16.

Address all correspondence and requests for reprints to: John

P. H. Wilding, Diabetes and Endocrinology Research Unit, Clinical Sciences Centre, University Hospital Aintree, Longmoore
Lane, Liverpool L9 7AL, United Kingdom. E-mail: j.p.h.wilding@
liv.ac.uk.
Disclosure Summary: J.P.H.W. is a consultant to Bristol Myers
Squibb/AstraZeneca (BMS/AZ), GlaxoSmithKline, and Johnson &
Johnson in relation to SGLT2 inhibitors for diabetes treatment and
is an investigator for ongoing trials with dapagliflozin (BMS/AZ).
S.N. is a coinvestigator in an ongoing clinical trial of dapagliflozin
(BMS/AZ).

17.

18.

19.

20.

21.

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42

Nair and Wilding

SGLT2 Inhibitors for Diabetes

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