Review
Renal glucose reabsorption inhibitors
to treat diabetes
Clifford J. Bailey
Life and Health Sciences, Aston University, Birmingham B4 7ET, UK
Current therapies to reduce hyperglycaemia in type 2
diabetes mellitus (T2DM) mostly involve insulin-depen-
dent mechanisms and lose their effectiveness as pancre-
atic b-cell function declines. In the kidney, filtered
glucose is reabsorbed mainly via the high-capacity,
low-affinity sodium glucose cotransporter-2 (SGLT2) at
the luminal surface of cells lining the first segment of the
proximal tubules. Selective inhibitors of SGLT2 reduce
glucose reabsorption, causing excess glucose to be elim-
inated in the urine; this decreases plasma glucose. In
T2DM, the glucosuria produced by SGLT2 inhibitors is
associated with weight loss, and mild osmotic diuresis
might assist a reduction in blood pressure. The mecha-
nism is independent of insulin and carries a low risk of
hypoglycaemia. This review examines the potential of
SGLT2 inhibitors as a novel approach to the treatment of
hyperglycaemia in T2DM.
Treating hyperglycaemia
Treatment of hyperglycaemia in type 2 diabetes mellitus
(T2DM) is necessary to relieve acute symptoms and to
reduce the risk of chronic vascular complications. Lifestyle
interventions, notably diet and exercise, are important but
are generally insufficient to achieve or maintain glycaemic
control. Most current glucose-lowering therapies act to
address the underlying endocrine pathogenesis of insulin
resistance and b-cell dysfunction. However, these thera-
pies usually lose their effectiveness over time as b-cell
failure supervenes.
As a consequence, many patients receive multiple glu-
cose-lowering therapies and eventually require exogenous
insulin. Indeed, half or more of patients with T2DM do not
achieve guideline targets for glycaemic control [glycated
haemoglobin (HbA1c) of 6.5–7.0% (48–53 mmol/mol)] [1–4].
A majority of patients with T2DM are overweight or
obese [5], which increases insulin resistance and compli-
cates treatment [6]. However, several blood glucose-lower-
ing therapies (including insulin) are associated with
weight gain (Table 1), often of 2–5 kg [7]. This is predomi-
nantly due to reduced urinary glucose excretion, and ini-
tially approximates to the correction of glycaemia [8].
Except for a-glucosidase inhibitors, which slow the rate
of intestinal carbohydrate digestion, key antidiabetic
agents act, at least in part, through insulin-dependent
mechanisms (Table 1 and Figure 1). Thus, a new thera-
peutic approach without reliance on insulin or weight gain,
and suitable for use in combination with existing agents,
Corresponding author: Bailey, C.J. (c.j.bailey@aston.ac.uk).
0165-6147/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2010.11.011 Trends in Pharmacological Sciences, February 2011, Vol. 32, No. 2
would be a valuable addition to the treatment choices for
hyperglycaemia in T2DM. Renewed interest in the role of
the kidney in glucose homeostasis has prompted the de-
velopment of sodium glucose cotransporter-2 (SGLT2)
inhibitors that fulfil these criteria by reducing renal glu-
cose reabsorption. This review examines the insulin-inde-
pendent mechanism of action of these agents and recent
clinical studies that indicate their potential as a novel
approach in the treatment of T2DM.
Role of the kidney in glucose balance
The renal cortex produces glucose by gluconeogenesis, main-
ly for utilization in the renal medulla [9]. In T2DM, both the
liver and kidney contribute to excess glucose production,
and renal glucose production can contribute up to 20% of
the total glucose released into the circulation in the post-
absorptive state [9,10]. However, the kidneys substantially
affect the circulating glucose pool through reabsorption of
glucose filtered by the glomeruli. Renal glucose reabsorption
is a constitutive process that depends on the concentration of
glucose; it does not seem to be regulated by insulin and
might actually be increased in T2DM.
Almost all of the glucose entering the glomeruli in the
afferent glomerular arterioles is filtered into the nephron
fluid and enters the proximal convoluted tubule. Normal
kidneys (with a glomerular filtration rate of 125 mL/min)
filter approximately 180 L of plasma each day [11]. Thus, a
healthy individual with an average plasma glucose con-
centration of 5–5.5 mmol/L (90–100 mg/dL) will filter ap-
proximately 160–180 g of glucose daily, all of which will be
reabsorbed [12]. In theory, the amount of filtered glucose
that is reabsorbed will increase in proportion to the plasma
glucose concentration until the maximal reabsorptive
transport capacity of the tubules (Tm) is reached. Tm
usually occurs at an average filtered glucose load of ap-
proximately 375 mg/min, and all excess filtered glucose is
excreted in urine. In practice, however, some glucose usu-
ally escapes in the urine at plasma glucose concentrations
above 11 mmol/L (200 mg/dL), the renal threshold. There
is a gradual increase in glucosuria above the renal thresh-
old up to the Tm value for glucose, which is called the splay
effect. These features of renal glucose handling largely
reflect the properties of the sodium glucose cotransporters
(SGLTs) in the proximal tubules.
Sodium glucose co-transporters
SGLT proteins are encoded by the solute carrier 5 (SLC5)
subfamily of sodium/substrate symporter genes [12]. The
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Review Trends in Pharmacological Sciences February 2011, Vol. 32, No. 2

Table 1. Current antidiabetic agentsa [4,54–61]

Agent Insulin-dependent mechanisms Comments
Insulin Insulin Body weight
action release change
a-Glucosidase inhibitors – – Neutral  Reduce rate of carbohydrate digestion in small
intestine, lowering postprandial glucose levels
 Only oral antidiabetic class currently available
that does not have an insulin-dependent
mechanism of action
Amylin agonistsb (pramlinitide) H – Reduce  Injected subcutaneously before each meal in
insulin-treated patients
 Slow gastric emptying, inhibit postprandial
glucagon production in a glucose-dependent
manner, thereby reducing the increase in
postprandial glucose levels
 Although not directly dependent on insulin,
suppression of glucagon by amylin agonists
might indirectly enhance insulin action
Biguanides (metformin) H – Neutral  Decrease hepatic glucose output and improve
peripheral glucose disposal
 Metformin is the only biguanide available in most
of the world
 Efficacy requires the presence of insulin
DPP-4 inhibitors – H Neutral  Prevent degradation of endogenous incretins,
c
especially GLP-1, thereby raising incretin levels
 Increased GLP-1 levels potentiate glucose-dependent
insulin secretion and suppress glucagon release
Glinides – H Gain  Stimulate insulin secretion by binding to the
benzamido site of the sulfonylurea receptor SUR1
on pancreatic b-cells
GLP-1 receptor agonists – H Reduce  Bind to GLP-1 receptors on pancreatic b-cells and
potentiate glucose-dependent insulin secretion
and suppress glucagon release, resulting in
reduced postprandial hepatic glucose production
and enhanced peripheral glucose uptake
Sulfonylureas – H Gain  Stimulate insulin secretion by binding to the
sulfonylurea receptor SUR1 on pancreatic b-cells
TZDs H – Gain  Modulate PPAR-g activity to increase sensitivity
of muscle, fat and liver to insulin; reduce hepatic
glucose production
Bromocriptine d H – Neutral  Dopamine D2 receptor agonist
Colesevelam d – H? Neutral  Bile acid sequestrant
 Mechanism uncertain, induces GLP-1 secretion in
rat models
a
Abbreviations: DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; PPAR-g, peroxisome proliferator-activated receptor gamma; SUR1, sulfonylurea receptor;
TZDs, thiazolidinediones; –, no effect; H, increase or enhancement;?, not established.
b
Amylin is a neurohormone that is co-secreted with insulin in response to meals.
c
Incretins are hormones released from the gastrointestinal tract during meal digestion which enhance nutrient-induced insulin secretion.
d
The dopamine D2 receptor agonist bromocriptine and the bile sequestrant colesevelam have recently been licensed for treatment of T2DM in some territories.

SCL5 genes code for several proteins (75 kDa) with >59%
amino acid identity, among which SGLT1 and SGLT2 are
the most well characterized [12]. SGLT1 is predominantly
expressed in enterocytes, where it mediates glucose and
galactose uptake from the gut lumen [12,13]. SGLT1 is also
expressed in the more distal segments (S2–3) of the proxi-
mal convoluted tubule, where it mediates the reabsorption
of glucose that has not been reabsorbed earlier in the
tubule by SGLT2. SGLT2 is almost entirely confined to
the first segment (S1) of the proximal tubules in the kidney
cortex [13,14], where it mediates reabsorption of most of
the filtered glucose [15].
SGLT1 and SGLT2 transport glucose across the luminal
membrane of epithelial cells lining the proximal tubules
against a concentration gradient by coupling with the
inward diffusion of sodium ions (Figure 2) [12]. This is a
secondary active process and is maintained by extrusion of
sodium across the basolateral membrane via the sodium-
potassium ATPase pump.
SGLT2 and SGLT1 exhibit different transport charac-
teristics [12]. SGLT2 transports glucose and sodium with a
1:1 stoichiometry, whereas SGLT1 transports one mole-
cule of glucose with two sodium ions. SGLT2 is a low-
affinity, high-capacity glucose transporter with K0.5 values
of 2 mM for glucose and 100 mM for sodium. By contrast,
SGLT1 is a high-affinity, low-capacity glucose transporter
with K0.5 values of 0.4 mM for glucose and 3 mM for sodium
[14]. Thus, SGLT2 in the S1 segment is suited to reabsorp-
tion of a high glucose concentration entering the proximal
tubule [16], whereas SGLT1 is suited to reabsorption of the
remaining lower glucose concentration in subsequent seg-
ments (Figure 3). After reabsorption from the lumen,
glucose within the proximal tubular cells passes into the
interstitium (and then to the plasma) by facilitative glu-
cose transporters in the basolateral membranes (GLUT2 in
S1 and GLUT1 in subsequent segments).
Although glucosuria is a feature of poorly controlled
diabetes, there is evidence that the renal threshold for

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()TD$FIG][ Review Trends in Pharmacological Sciences February 2011, Vol. 32, No. 2

GLP-1 receptor agonist

SU/glinide
DPP-4i
Pancreas

Insulin

tin
Metformin TZD

Incre
Liver
Adipose
Muscle
tissue

Blood
glucose
Gut
Kidney

AGI
SGLT2i
TRENDS in Pharmacological Sciences

Figure 1. Sites of action of antidiabetic agents, including SGLT2 inhibitors. Metformin targets both the liver and skeletal muscle [62]. The thiazolidinediones (TZDs) improve
insulin sensitivity, reduce hepatic glucose production, and improve glucose disposal indirectly by altering lipid metabolism in adipose tissue [57,58]. Sulfonylureas,
meglitinides (glinides) and GLP-1 receptor agonists target pancreatic b-cells and increase insulin secretion. GLP-1 agonists also reduce excess glucagon secretion by
pancreatic a-cells and slow gastric emptying. DPP-4 inhibitors reduce the breakdown and increase the levels of endogenous incretin hormones GLP-1 and GIP [59]. Amylin
agonists (not illustrated) slow gastric emptying and reduce postprandial glucagon secretion [61]. a-Glucosidase inhibitors slow the rate of carbohydrate digestion by the
small intestine [4]. The dopamine receptor agonist bromocriptine, which improves diurnal hypothalamic control of glucose homeostasis, and the bile sequestrant
colesevelam, which might affect the secretion of incretin hormones (not illustrated), have recently been approved for use in the treatment of hyperglycaemia in the USA
[54–56]. Selective SGLT2 inhibitors reduce glucose reabsorption by the kidney. Abbreviations: AGI, a-glucosidase inhibitor; DPP-4i, dipeptidyl peptidase-4 inhibitor; GIP,
glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; SGLT2i, sodium glucose cotransporter-2 inhibitor; SU, sulfonylurea.
" Stimulatory or positive effect
¢ Inhibitory effect.

[()TD$FIG]

Glucose

SGLT2

S1 segment of
proximal tubule
SGLT1
Up to 90%
Collecting duct
Glucose reabsorption

≥10%

Distal S2/3
segment of
proximal tubule

Negligible glucose
in urine
TRENDS in Pharmacological Sciences

Figure 2. Glucose reabsorption from the glomerular filtrate in the renal proximal tubule. Glucose is reabsorbed from the glomerular filtrate and into the blood through
proximal tubule epithelial cells. In segment S1 of the proximal tubules, SGLT2 transports glucose into cells against a concentration gradient by coupling glucose with the
inward diffusion of sodium ions down their concentration gradient. The inward passage of sodium ions is maintained by an Na+/K+ ATPase pump, which extrudes Na+ ions
across the basolateral membrane of the cell in exchange for K+ ions in 3:2 stoichiometry. In segment S1, glucose is transported from the cells into the interstitial
compartment by the facilitative glucose transporter GLUT2. A similar mechanism operates with SGLT1 and GLUT1 in segment S3. Based on Bakris et al. [63].

65
()TD$FIG][ Review Trends in Pharmacological Sciences February 2011, Vol. 32, No. 2

Segment S1
Basolateral membrane

SGLT2 GLUT2

Glucose
Glucose

Na+

Glucose

Na+

Na+
K+
Tight K+
junction Na+/K+ATPase
pump

Lateral intercellular space

Segment S3
Basolateral membrane

SGLT1 GLUT1

Glucose Glucose

Na+

Glucose

Na+

Na+
K+
K+
Na+/K+ATPase
pump

Lateral intercellular space

TRENDS in Pharmacological Sciences

Figure 3. Reabsorption of glucose from the renal proximal tubules by the sodium glucose cotransporters SGLT2 and SGLT1. Almost all of the glucose entering glomeruli in the
afferent glomerular arterioles is filtered into the nephron fluid of the proximal renal tubules. Most (up to 90%) of this filtered glucose is reabsorbed in the initial proximal
convoluted segment (S1) by SGLT2 located at the luminal surface of proximal tubular cells. Remaining glucose is reabsorbed from the filtrate in the more distal convoluted and
straight segments by SGLT1. Glucose within the proximal tubular cells is then transported back to the interstitial compartment and thence to the plasma by the facilitative
glucose transporters GLUT2 and GLUT1 in the S1 and S3 segments, respectively. In normal individuals with an average plasma glucose concentration of 5–5.5 mmol/L (90–
100 mg/dL), approximately 160–180 g of glucose is filtered daily, with less than 0.5 g/day of glucose appearing in the urine. Based on Bakris et al. [63] and Bays [64].

glucose might be higher in diabetic states, thereby reduc-
ing urinary glucose excretion [17–19]. Animal studies sug-
gest that SGLT2 mRNA expression is increased by chronic
hyperglycaemia, and this effect is reversed during insulin
treatment, which is consistent with improved glycaemic
control [19]. There is also preliminary evidence that
SGLT2 mRNA levels are elevated in renal proximal cells
isolated from the urine of subjects with T2DM [18], but this
has not been confirmed in other studies [20].
Inhibition of SGLT2 seems to exceed the capacity of
SGLT1 to reabsorb all the filtered glucose in patients with
T2DM, such that enough glucose is excreted in the urine to
improve glycaemic control. Assuming a mean blood glucose
concentration of 10 mmol/L (180 mg/dL) and a normal rate of
glomerular filtration, approximately 324 g of glucose would
be filtered daily. If there were 20–25% inhibition of renal
glucose reabsorption, the body would lose 65–80 g of glucose
per day in urine. This equates to approximately 260–320
kcal of energy per day. If diet and exercise were maintained
and metabolic efficiency was unchanged, this would assist
weight loss and improve glycaemic control, which would
provide a rationale for selective SGLT2 inhibition.
Experiments of nature: familial renal glucosuria
Urinary glucose excretion can occur in the absence of either
generalized proximal tubular dysfunction or hyperglycae-
mia in inherited disorders of familial renal glucosuria (FRG)
[21–23]. Mutations in the SLC5A2 gene are responsible for

66
 Review
most FRG; heterozygous individuals usually develop mild
glucosuria (<10 g/1.73 m2/day) or sometimes no glucosuria,
whereas those with homozygous or compound heterozygous
SCL5A2 mutations show more severe glucosuria [21–23].
Twenty different mutations of the SCL5A2 gene have been
reported, including missense, nonsense and splicing muta-
tions [22,23]. Possible effects (other than glucosuria) have
been suggested for some patients with FRG, such as auto-
antibodies (but without clinical evidence of autoimmune
disease) and bacteriuria, which is usually asymptomatic
[24–26]. However, FRG does not seem to be associated with
significant clinical consequences and is considered a benign
condition [27]. This supports the potential safety of life-long
glucosuria by loss of SGLT2 function.
Development of SGLT inhibitors
Phlorizin (Figure 4) is a naturally occurring phenol glyco-
side first isolated from the bark of apple trees in 1835 [28].
In the late 19th and early 20th centuries, it was shown that
orally administered phlorizin increases urinary glucose
excretion and loss of body weight. By the 1960s, it was
known that phlorizin inhibits glucose transport by erythro-
cytes and cells in the kidney and small intestine [28]. Proof
of principle that promotion of renal glucose excretion could
be used in the treatment of diabetic states was provided by
Rossetti and colleagues in 1987 [29]. Phlorizin restored
euglycaemia and insulin sensitivity in partially pancre-
atectomized rats, and the hyperglycaemia and insulin
resistance returned if phlorizin was discontinued [29]. In
the same diabetic animal model, restoration of euglycae-
mia with phlorizin also improved insulin secretion, which
indicates that hyperglycaemia itself (i.e. glucotoxicity)
makes an important contribution to insulin resistance
and reduced b-cell function [30]. It was subsequently
shown that oral administration of phlorizin improves glu-
cose tolerance in normal mice without significantly affect-
ing the insulin response [31].
It was not until the genes for SGLT1 and SGLT2 were
cloned in the 1990 s that phlorizin was identified as a
potent, competitive inhibitor of both transporters. Howev-
er, the lack of selectivity towards SGLT2 is one reason why
phlorizin was precluded as a drug candidate for the treat-
ment of T2DM [28]. In addition, phlorizin is poorly
absorbed in the small intestine and it has a short half-life,
because the O-glucoside bond is highly susceptible to hy-
drolysis by intestinal glucosidases. From a therapeutic
perspective, an ideal renal glucose reabsorption inhibitor
for T2DM treatment would selectively inhibit SGLT2, but
could exert some non-selective inhibition of SGLT1, pro-
[()TD$FIG]
(a)
HO OH
O OH
HO O F
O HO
HO OH
HO
Phlorizin
Figure 4. Structure of (a) phlorizin, (b) dapagliflozin and (c) canagliflozin. The structure of BI 10773 is not available at this time.
Trends in Pharmacological Sciences February 2011, Vol. 32, No. 2
vided that the compound is absorbed early in the upper
small intestine so that it does not prevent complete ab-
sorption of glucose by the small intestine. In addition, it
would require good bioavailability, safety and tolerability,
and preferably a plasma half-life that would suit once-daily
oral administration.
Selective SGLT2 inhibitors
The first orally active SGLT inhibitor was T-1095, devel-
oped by Tanabe Seiyaku and Johnson & Johnson [32]. This
O-glucoside prodrug is converted in the intestine to an
active form, T-1095A, which inhibits human SGLT2 (IC50
50 nM) with four-fold greater selectivity than SGLT1 (IC50
200 nM) [33]. Administration of T-1095 to diabetic animal
models increased urinary glucose excretion and reduced
hyperglycaemia [33]. However, T-1095 and several other
early SGLT2 inhibitors (e.g. sergliflozin and remogliflozin)
have not proceeded to clinical development, owing at least
partly to the lability of the O-glucosidic linkage and the
resulting short half-life and poor bioavailability. Orally
active SGLT2 inhibitors now in clinical development in-
clude BI 10733, canagliflozin (TA7284) and dapagliflozin
(Figure 4). BI 10773 is a C-glucoside inhibitor with >2500-
fold selectivity for SGLT2 (IC50 3.1 nM) over SGLT1 (IC50
7.7 mM) and it is not hydrolyzed by intestinal glucosidases
[34]. Canagliflozin (TA7284) is also a C-glucoside and has
200-fold selectivity for SGLT2 (IC50 2.2 nM) over SGLT1
(IC50 0.44 mM) [35]. Dapagliflozin is a C-aryl glucoside with
1200-fold selectivity for SGLT2 (IC50 1.1 nM) over SGLT1
(IC50 1.32 mM) [36,37]. It has been reported that each of
these agents induces significant urinary glucose excretion,
reduces blood glucose and reduces body weight in obese
diabetic rodent models.
Clinical studies: pharmacokinetics and
pharmacodynamics
To date, papers describing clinical trial data have only
been published for dapagliflozin. This agent displayed
dose-proportional plasma concentrations in single-dose
(2.5–500 mg) and multiple-dose (2.5–100 mg daily for 14
days) studies in healthy and T2DM subjects [38,39]. The
amount of glucose excreted in urine increased with the
dose, and a near-maximal rate of urinary glucose excretion
(3 g/h) occurred for 25 mg of dapagliflozin [38]. This
represented approximately 20–25% inhibition of renal glu-
cose reabsorption. It is estimated that the maximum inhi-
bition of glucose reabsorption by SGLT2 inhibition is self-
limiting at approximately 30–40%. This probably reflects
the number of fully functional nephrons at any given time,
(b) (c)
CH3 HO
HO OH
O HO
O
CI
O S
HO
HO
OH
Dapagliflozin Canagliflozin
TRENDS in Pharmacological Sciences
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Review Trends in Pharmacological Sciences February 2011, Vol. 32, No. 2

Table 2. Effects of dapagliflozin in clinical trials in subjects with T2DMa

Trial Treatment Treatment effect Reference
(duration) (change from baseline and
placebo subtracted)
Phase IIa Dapagliflozin (5–100 mg/day)  FSG #19–39 mg/dLb [39]
(14 days) vs placebo  OGTT AUC #10–23% a
n = 47
Phase IIb Dapagliflozin (2.5–50 mg/day)  HbA1c #0.37–0.72%b [40]
(12 weeks) vs placebo vs metformin c  FPG #10–25 mg/dLb
n = 348  PPG AUC #7050–10,150 mg min/dLb
 Body weight #1.3–2.0 kg b
Phase III (24 weeks) Dapagliflozin (2.5, 5, and  HbA1c #0.35–0.66%b [41]
n = 485 10 mg/day) vs placebo  FPG #11–25 mg/dLb
 Body weight #1.0–1.1kg
Phase III Dapagliflozin (2.5–10 mg/day)  HbA1c #0.37–0.54%b [42]
(24 weeks) + metformin vs placebo + metformin d  FPG #12–18 mg/dLb
n = 546  Body weight #1.3–2.1kg
Phase IIb Dapagliflozin (10 and 20 mg/day)  HbA1c #0.61% and 0.69% [45]
(12 weeks) n = 68 + insulin vs placebo + insulin e  FPG "2 and #10 mg/dL
 Body weight #4.5 kg and 4.3 kg
Phase III (24 weeks) Dapagliflozin (2.5–10 mg/day)  HbA1c #0.45–0.60%b [46]
n = 807 + insulin  OADs vs placebo  FPG #9–18 mg/dLb
+ insulin  OADs  Body weight #1.0–1.69 kg b
Phase III (24 weeks) Dapagliflozin (2.5, 5,10 mg/day)  HbA1c #0.45–0.69%b [44]
n = 597 + glimepiride vs placebo + glimepiride f  Body weight #0.46-1.54kg b
Phase III (52 weeks) Dapagliflozin (2.5–10 mg/day)  HbA1c #0.52%g [43]
n = 814 + metformin vs glipizide (5 mg/day  Body weight #3.2 kg h
up to  20 mg/day) + metformin
a
Abbreviations: AUC, area under the plasma concentration time curve; FSG, fasting serum glucose; FPG, fasting plasma glucose; OADs, oral antidiabetic drugs; OGTT oral
glucose tolerance test; # decrease; " increase.
b
Statistically significant versus placebo (P<0.05).
c
Metformin 1500 mg/day.
d
Pretreatment dose of metformin continued.
e
Pretreatment dose of insulin 50 U/day, halved during treatment phase of study.
f
Glimepiride 4 mg/day.
g
Statistically significant versus baseline and same reduction from baseline as glipizide group.
h
Statistically significant versus glipizide group (P < 0.0001).

anticipated competition for SGLT2 transporters by in-
creased glucose concentrations in proximal convoluted
tubule versus the SGLT2 inhibitor, and the compensating
capacity of SGLT1 in the S3 segment.
Clinical studies in subjects with T2DM
Improved glycaemic control in T2DM has been observed for
dapagliflozin as monotherapy [39–41] and for combination
therapy with metformin [42,43] or glimepiride [44] and as
combination therapy for subjects treated with insulin plus
oral antidiabetic agents (Table 2) [45,46]. In a randomized,
double-blind, placebo-controlled (RDBPC) 12-week study,
348 previously untreated subjects with T2DM received
2.5–50 mg/day dapagliflozin, placebo, or 1500 mg/day met-
formin (as a therapeutic benchmark) [40]. Dapagliflozin
increased urinary glucose excretion from 6–11 g/day at
baseline to 52–85 g/day at study end, whereas placebo-
and metformin-treated patients continued to excrete
6 g/day. HbA1c levels were reduced by 0.55% to 0.90%
(6–10 mmol/mol) with dapagliflozin compared with 0.18%
(2 mmol/mol) for placebo and 0.73% (8 mmol/mol) for
metformin. The reduction in body weight was 1.3–2.0 kg
more with dapagliflozin than with placebo, a difference
that was particularly evident during the first week. This
might reflect an initial diuretic effect of SGLT2 inhibition,
whereas continued weight loss is consistent with the calo-
rific value of ongoing glucose elimination in urine. Further
RDBPC or parallel-group studies in T2DM for up to 52
weeks with dapagliflozin (2.5–10 mg/day) as monotherapy
or an adjuvant to other antidiabetic agents have noted
similar improvements in glycaemic control and reductions
in body weight. In patients receiving insulin, the reduc-
tions in HbA1c and body weight during concomitant dapa-
gliflozin administration were achieved with a modest
reduction in insulin dose [44,45].
The mild osmotic diuresis observed with dapagliflozin,
as evidenced by initial increases in urinary volume up to
450 mL/day, was accompanied by small increases in
blood urea nitrogen and haematocrit and a modest de-
crease in systolic blood pressure (–3 to –6 mm Hg) [40–
42]. A long-term increase in urinary glucose can predispose
patients to genitourinary infections, and although dapagli-
flozin increased the incidence of these infections, they were
transient and none was severe. More patients also reported
symptoms of hypoglycaemia with dapagliflozin than with
placebo, but these were mild and similar to those in
metformin-treated subjects [40].
Further clinical trials to examine the effects of dapagli-
flozin in conjunction with other anti-diabetes medications
are in progress; there are additional clinical trial pro-
grammes with canagliflozin, BI 10773 and other candidate
SGLT2 inhibitors. Details are available on the clinical
trials website at http://clinicaltrials.gov/.
Concluding remarks
Because T2DM is a progressive disease, glucotoxicity poses
an insidious cumulative risk that requires early and effec-
tive intervention to prevent, defer and ameliorate chronic

68
Review
complications [47]. Glucotoxicity represents a pathogenic
spiral that is caused by insulin resistance and b-cell dys-
function and also aggravates these conditions. Indeed,
chronic hyperglycaemia can accelerate the loss of b-cell
function and mass by generating reactive oxygen species
and through wide daily fluctuations in blood glucose [48–50].
Selective inhibition of SGLT2 decreases plasma glucose by
increasing urinary glucose excretion, which offers a novel
mechanism that is independent of the amount of circulating
insulin and the degree of insulin resistance. This approach is
additive and complementary with other blood-glucose-low-
ering therapies and carries low risk of hypoglycaemia be-
cause SGLT1 can reabsorb an increasing proportion of
filtered glucose at low plasma glucose concentrations. More-
over, inhibition of SGLT2 does not impede counter-regula-
tory mechanisms of glucose homoeostasis.
Urinary elimination of excess glucose by inhibiting
SGLT2 facilitates body weight reduction. Obesity is a
strong risk factor for insulin resistance and T2DM, and
each of these conditions is an independent risk factor for
cardiovascular disease [51]. Weight loss in obese patients
with T2DM can reduce the risk of all-cause mortality [52],
and weight management is therefore a valuable component
of diabetes management [5,6,53]. Patients with T2DM
typically require escalating insulin doses, often in combi-
nation with oral agents to counter the progressive increase
in hyperglycaemia [4]. This frequently promotes weight
gain and potentially compromises the value of glycaemic
control to reduce long-term vascular complications [4].
Thus, a reduced insulin dose requirement with SGLT2
inhibition constitutes an additional mechanism to assist
weight reduction alongside the caloric dissipation of extra
glucose in urine [44]. Weight loss plus a modest decrease in
plasma volume during SGLT2 inhibition could at least
partly account for a reduction in blood pressure.
Diabetes is typically associated with a deterioration in
renal function, especially in the elderly. Inhibition of SGLT2
does not interfere with the glomerular filtration of glucose,
but does require a filtration rate that is sufficient to deliver
substantial amounts of glucose into the proximal tubules.
Thus, SGLT2 inhibition should not adversely affect the
progression of diabetic glomerular pathology, but this ther-
apy is not suitable for patients with a severely reduced
glomerular filtration rate. SGLT2 inhibition might reduce
the availability of glucose as an energy source within cells
lining the S1 segment of the proximal tubules, which could
potentially influence active transport functions in this part
of the tubule. The nephron retains considerable spare ca-
pacity to compensate for small changes in sodium reuptake
in the S1 segment, but initial transient changes in renal
sodium handling might not be unexpected. Evidence from
patients with FRG suggests that protracted exposure to
glucose along subsequent regions of the nephron and to
the urothelium of the urinary tracts does not have detri-
mental effects. However, renal glucose elimination does
generate modest osmotic diuresis (although there has been
no evidence of dehydration in trials to date), and diuresis
might explain the small but consistent reduction in blood
pressure. High levels of urinary glucose excretion increase
the risk of genitourinary infections in uncontrolled diabetes,
and the incidence of genital infections was approximately
Trends in Pharmacological Sciences February 2011, Vol. 32, No. 2
doubled during administration of dapagliflozin. However,
the incidence of urinary tract infections was not consistently
increased [42–44]. In most cases, genital infections were
recognized and dealt with by patients such that they re-
solved before the patient attended the next clinic visit. Few
patients required medical intervention or discontinued the
SGLT2 inhibitor.
In summary, selective SGLT2 inhibition is a novel
approach for reducing hyperglycaemia in patients with
T2DM through increased renal glucose elimination. Al-
though natural mutations that inactivate SGLT2 are gen-
erally well tolerated in patients with FRG, long-term
clinical trials with pharmacological inhibitors of SGLT2
are awaited to confirm safety in patients with T2DM.
Selective SGLT2 inhibitors have potential advantages
conferred by their independence from insulin secretion
or action; notably, their glucose-lowering efficacy should
not decrease significantly with disease progression. Weight
loss is a further benefit of SGLT2 inhibition, and there is
low potential to cause hypoglycaemia due to glucose reab-
sorption by SGLT1 and lack of interference with counter-
regulation. SGLT2 inhibition is compatible with other
antidiabetic therapies, including insulin, and might there-
fore benefit any stage in the natural history of T2DM.
Disclosure statement
Professor Bailey has received research grants from and
provided remunerated ad hoc consultancy to pharmaceu-
tical companies that produce antidiabetic and antiobesity
agents. He has undertaken research on dapagliflozin (Bris-
tol-Myers Squibb and AstraZeneca) but records no conflict
of interest for this review.
Acknowledgements
The author gratefully acknowledges the assistance of Dr Ann P. Tighe of
Parexel, which receives funding from Bristol-Myers Squibb and
AstraZeneca.
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