Review

doi: 10.1111/joim.12244

Lowering plasma glucose concentration by inhibiting renal

sodiumglucose cotransport
M. A. Abdul-Ghani & R. A. DeFronzo
Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

Abstract. Abdul-Ghani MA, DeFronzo RA. (University

of Texas Health Science Center at San Antonio, San
Antonio, TX, USA). Lowering plasma glucose
concentration by inhibiting renal sodiumglucose
cotransport (Review). J Intern Med 2014; 276:
352363.
Maintaining normoglycaemia not only reduces the
risk of diabetic microvascular complications but
also corrects the metabolic abnormalities that
contribute to the development and progression of
hyperglycaemia, that is insulin resistance and
beta-cell dysfunction. Progressive beta-cell failure,
in addition to side effects associated with many
current antidiabetic agents, for example hypoglycaemia and weight gain, presents major obstacles to the achievement of the recommended goal of
glycaemic control in patients with type 2 diabetes

Introduction
With the recognition that the kidney plays an
important role in the maintenance of normal
glucose homeostasis and pathogenesis of type 2
diabetes mellitus (T2DM), considerable attention
has been focused on the development of agents
that inhibit normal glucose reabsorption, a therapy
to improve glycaemic control and ameliorate glucotoxicity [1]. This topic has been the focus of a recent
review by our group [2]. Because of the publication
of numerous recent clinical trials concerning the
safety and efficacy of these novel inhibitors of renal
glucose transport, we felt that it was important to
update our previous review.
Hyperglycaemia is the principal risk factor for
diabetic microvascular complications, that is, retinopathy, nephropathy and neuropathy. Results
from the United Kingdom Prospective Diabetes
Study (UKPDS) and the Diabetes Control and Complications Trial (DCCT) have demonstrated that
every 1% decrease in haemoglobin A1c (HbA1c) is
associated with ~35% reduction in the risk of
microvascular complications [3, 4]. Hyperglycaemia

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2014 The Association for the Publication of the Journal of Internal Medicine

mellitus (T2DM). Thus, novel effective therapies are

needed for optimal glucose control in subjects with
T2DM. Most recently, specific inhibitors of the
renal sodiumglucose cotransporter 2 (SGLT2)
have been developed to produce glucosuria and
lower the plasma glucose concentration. Because
of the iR unique mechanism of action, which is
independent of insulin secretion and insulin
action, these agents are effective in lowering the
plasma glucose concentration in all stages of the
disease and can be combined with all other antidiabetic agents. In this review, we will summarize
the available data concerning the mechanism of
action, efficacy and safety of this novel class of
antidiabetic agents.
Keywords: kidney, SGLT2 inhibition, sodiumglucose
cotransport, type 2 diabetes.

also plays an important role in the pathogenesis of

insulin resistance and beta-cell failure, that is,
glucotoxicity [1, 5]. Studies in experimental animals
and in humans have demonstrated that hyperglycaemia worsens insulin resistance and impairs
beta-cell function [5, 6], thereby exacerbating the
hyperglycaemia and producing a vicious cycle that
perpetuates and aggravates the hyperglycaemia.
Thus, maintaining normoglycaemia in patients with
T2DM would be anticipated, not only to reduce the
risk of microvascular complications, but also to
slow the progressive beta-cell failure. Despite the
irrefutable evidence for the importance of maintaining optimal glycaemic control (HbA1c <6.57%),
many patients with T2DM in the United States
and worldwide fail to achieve this target level of
glycaemic control and manifest HbA1c >7% [6, 7]
due to progressive beta-cell failure; weight gain and
hypoglycaemia, which are common adverse events
associated with current antidiabetic therapies, further complicate the achievement of optimal glycaemic control [5]. Therefore, the development of novel
therapies that effectively lower the plasma glucose
concentration and produce durable glycaemic control, whilst avoiding hypoglycaemia and weight

M. A. Abdul-Ghani & R. A. DeFronzo

gain, is needed for the optimal management of

patients with T2DM. Most recently, specific inhibitors of the renal sodiumglucose cotransporter 2
(SGLT2) have been developed for the treatment of
T2DM [810]. In this review, we will summarize the
available data concerning the mechanism of action,
efficacy and safety of this novel class of antidiabetic
therapy. The reader is referred to several recent
reviews of this topic by our group [810].
Renal handling of glucose
In healthy individuals, all of the glucose filtered by
the kidney (~180 g day 1) is reabsorbed in the
proximal tubule, and no glucose is excreted in the
urine. Renal glucose reabsorption in the proximal
tubule is mediated by sodiumglucose cotransporters (SGLTs), which couple glucose reabsorption to sodium reabsorption. The maximum
glucose transport capacity (Tm) of the proximal
tubule, on average, is ~375 mg min 1. The sodium
electrochemical gradient generated by active
sodium transport provides the energy required for
glucose transport (Fig. 1) [9]. Two sodiumglucose
cotransporters are responsible for renal glucose
reabsorption. The SGLT2 transporter is primarily
expressed in the kidney and is responsible for the
reuptake of ~90% of the filtered glucose. It is
located in the proximal part (S3 segment) of the
proximal tubule and has a low affinity and high

Review: SGLT2 inhibition and type 2 diabetes

capacity for glucose transport. The remaining 10%

of the filtered glucose is reabsorbed by SGLT1
which is located in the distal part (S3 segment) of
the proximal tubule. The SGLT1 transporter is a
low-capacity, high-affinity transporter. In addition
to the kidney, the SGLT1 transporter is expressed
in the gut, where it is responsible for intestinal
absorption of glucose and galactose.
In normal individuals, the filtered glucose load is
less than the maximal glucose transport capacity
(Tm, 375 mg min 1), and all of the filtered glucose
is reabsorbed and returned to the circulation.
However, if the filtered glucose load exceeds
375 mg min 1, as often occurs in poorly controlled
diabetic individuals, the Tm is exceeded and all of
the glucose in excess of the Tm is excreted in the
urine. The plasma glucose concentration at which
the filtered glucose load reaches the Tm
(375 mg min 1) is called the threshold, above
which the glucose excretion rate increases linearly
and parallels the filtered load. The reabsorption
and excretion curves display a nonlinear transition
as the Tm for glucose is approached. This rounding of the curves is termed splay (Fig. 2) and has
been explained by heterogeneity in the Tm of
individual nephrons and/or glomerulotubular
imbalance [9]. In healthy individuals, the plasma
glucose threshold above which glucosuria begins is
~180 mg dL 1. The renal Tm for glucose, as well as

Fig. 1 Schema of sodiumglucose reabsorption in proximal

renal epithelial cells.

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M. A. Abdul-Ghani & R. A. DeFronzo

Review: SGLT2 inhibition and type 2 diabetes

not only lower the plasma glucose concentration,

but also have additional metabolic benefits including a reduction in blood pressure and promotion of
weight loss. The specificity of drugs that inhibit
SGLT2 over SGLT1 (which is present in both the
gut and kidney) avoids impaired intestinal
glucose/galactose absorption and potential gastrointestinal adverse effects.
Clinical efficacy of SGLT2 inhibitors

Fig. 2 Kinetics of renal handling of glucose.

the threshold, is increased in subjects with T2DM

[10]. Studies in diabetic animals and humans [11,
12] have demonstrated that the increase in renal
glucose Tm is paralleled by an increase in SGLT2
gene expression. Further, correction of the hyperglycaemia reverses the increase in SGLT2 expression. The increase in renal Tm and threshold in
response to chronic hyperglycaemia can be viewed
as an adaptive mechanism to prevent glucosuria
and preserve glucose which is an essential fuel
source for the brain. However, in patients with
diabetes, it would be desirable for the kidney to
excrete the excess filtered glucose load and restore
normoglycaemia. Thus, the increase in renal Tm in
patients with diabetes contributes to the maintenance of hyperglycaemia, and the kidney contributes to the pathogenesis of hyperglycaemia in
T2DM.
It also should be noted that increased glucose
uptake in the proximal tubule in patients with
diabetes is expected to be accompanied by
increased sodium reabsorption. The increased
sodium reabsorption can lead to extracellular
volume expansion and contributes to an increase
in blood pressure that occurs in ~60% of T2DM
individuals. A recent micropuncture study in
experimental animals has demonstrated that acute
inhibition of SGLT2 causes a two- to threefold
increase in single nephron sodium excretion [13],
and treatment of T2DM patients with an SGLT2
inhibitor consistently is associated with a reduction in blood pressure [8, 10].
Based upon these pathophysiologic considerations, it follows that glucosuria, produced by
inhibition of renal glucose reabsorption, would
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2014 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2014, 276; 352363

Currently, there are two SGLT2 inhibitors, canagliflozin and dapagliflozin, available for the treatment of T2DM individuals, and empagliflozin has
been submitted to the FDA for approval. In the
present review, we will summarize the clinical
studies which have examined the efficacy of these
three drugs. Summary of other SGLT2 inhibitors
which are still in earlier stages of clinical development is available elsewhere [10, 14, 15].
Dapagliflozin
Dapagliflozin has a half-life of ~1718 h in
humans, making it suitable for once-daily administration [16, 17], and two doses are available 5 and
10 mg per day. Dapagliflozin has high bioavailability, and it is rapidly absorbed after oral administration, achieving maximal plasma concentrations
within 12 h. The clinical efficacy of dapagliflozin
has been studied in drug-nave patients with T2DM
and as add-on to other oral antidiabetic agents and
to insulin.
In initial dose-ranging studies (14-day duration) in
patients with T2DM, dapagliflozin (5, 25 and
100 mg day 1) produced a dose-dependent glucosuria (37, 62, 80 g/24 h, respectively) and significantly decreased both the fasting plasma glucose
concentration (by 19, 29 and 39 mg dL 1, respectively) and the incremental area under the glucose
concentration curve during an oral glucose tolerance test [15]. It does not inhibit or induce P450
enzymes. Dapagliflozin is highly protein bound
(9798%), and renal excretion is low (24%). An
inert glucuronide conjugate (M15) of dapagliflozin
is the major metabolite of the drug in vivo.
In a 12-week study in patients with T2DM
(n = 389), dapagliflozin reduced the HbA1c by
~0.7% from a baseline HbA1c of 7.88.0% without
any apparent dose dependency [18]. The reduction
in HbA1c was similar in magnitude to that observed
with metformin, and the reductions in fasting and

M. A. Abdul-Ghani & R. A. DeFronzo

Review: SGLT2 inhibition and type 2 diabetes

postprandial plasma glucose concentrations

accounted approximately equally for the decline
in HbA1c [18]. Dapagliflozin also caused a 2.2
3.1 kg weight loss and produced a modest reduction in both systolic and diastolic blood pressure.
The amount of glucosuria observed with dapagliflozin (5060 g day 1) is equivalent to a daily
caloric loss of ~200240 cal day 1 (4 calories per
gram) that, over the course of 12 weeks, explains
the 23 kg weight loss.
Phase III trials with dapagliflozin include 6798
patients with diabetes randomized to dapagliflozin
and placebo in a 2 : 1 ratio [19]. Treatment with
dapagliflozin (5 and 10 mg day 1) consistently
caused a significant decrease in HbA1c (~0.7
0.8%) compared with placebo, independent of the
background therapy. A comparable decrease in
HbA1c was observed when dapagliflozin was given
to drug-nave patients with diabetes or was added
to metformin, sulphonylurea, thiazolidinedione or
insulin. A decrease in both fasting and postprandial plasma glucose concentrations equally contributed to the decrease in HbA1c. The decrease in
the fasting and postprandial plasma glucose concentrations with 10 mg day 1 dapagliflozin dosage
was ~25 mg dL 1 and ~55 mg dL 1, respectively.
The decrease in HbA1c caused by dapagliflozin was
independent of gender, ethnicity, race, body mass
index or duration of T2DM. As expected, dapagliflozin produced a greater reduction in HbA1c in
patients with higher baseline HbA1c. In a subgroup
(n = 78) of patients with baseline HbA1c of 10.1
12.0%, dapagliflozin (5 and 10 mg day 1) reduced
the HbA1c by 2.88% and 2.66%, respectively, over
24 weeks [20]. Similar impact of baseline HbA1c on
dapagliflozin efficacy has recently been reported in
Asian T2DM individuals [21] (Table 1).
Because the mechanism of action of dapagliflozin
is independent of insulin secretion and insulin
Table 1 SGLT2 inhibitors under development
Drug

Stage

References

Dapagliflozin

Approved by FDA and EMA

27

Canagliflozin

Approved by FDA and EMA

38

Empagliflozin

Phase III

43

Ipragliflozin

Phase III

47

LX4211

Phase II

49

PF04791729

Phase II

51

TS-071

Phase II

50

action, the efficacy of dapagliflozin is independent

of beta-cell function or diabetes duration. Thus,
dapagliflozin is also effective in reducing the HbA1c
in patients with insulin therapy. Wilding et al. [22]
randomized 71 insulin-treated (50 units day 1)
patients with type 2 diabetes who also were
receiving an insulin sensitizer (metformin and/or
thiazolidinedione) to add-on therapy with dapagliflozin (5 and 10 mg day 1) or placebo. The insulin
dosage was reduced by 50% at the start of therapy,
whilst the insulin sensitizer dosage was
unchanged. After 12 weeks, the placebo-subtracted declines in HbA1c were 0.70% and 0.78%,
respectively (P < 0.01 vs. placebo) despite the 50%
reduction in insulin dosage. The placebo-subtracted reductions in body weight were 2.6 and
2.4 kg, respectively (P < 0.01 vs. placebo), reflecting both the loss of glucose in the urine and
reduction in insulin dosage. In a larger study
(n = 800), the addition of dapagliflozin (5 and
10 mg day 1) to insulin-treated T2DM individuals
(receiving ~7080 units day 1 for a mean of
~6 years) caused a dose-dependent decrease in
HbA1c ( 0.49 and 0.57%, respectively) compared
with placebo over 24 weeks of treatment, and the
decrease in HbA1c was maintained at 48 weeks
[23]. The reduction in HbA1c was independent of
diabetes duration. In a 12-week study, 151
patients with new-onset diabetes (<1 year) and 58
patients with long-standing (11 years) type 2 diabetes were randomly assigned to 10 or
20 mg day 1 of dapagliflozin [24]. Although
patients with long-standing diabetes were in poor
glycaemic control (HbA1c = 8.4%), were older and
more obese, and were taking a large dosage of
insulin (>50 units day 1) plus metformin and a
thiazolidinedione, dapagliflozin was equally effective in decreasing the HbA1c.
In a head-to-head comparison of dapagliflozin
with sulphonylurea as add-on therapy in poorly
controlled T2DM patients on metformin therapy
[25], both groups exhibited the same decline in
mean HbA1c ( 0.52%) over 52 weeks. Two studies
with longer duration of therapy with dapagliflozin
(2 years) recently have been reported [26, 27]. In
one study, dapagliflozin was added to metformin,
and the decrease from baseline in HbA1c was
0.54% at 1 year and 0.80% at 2 years. Similarly, in a head-to-head study of dapagliflozin
versus glipizide, an additional 0.34% decrease
in HbA1c was observed in the second year in
subjects treated with dapagliflozin compared with
a
0.12% decrease in subjects treated with
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M. A. Abdul-Ghani & R. A. DeFronzo

Review: SGLT2 inhibition and type 2 diabetes

glipizide [27], suggesting a more durable decrease

in HbA1c with dapagliflozin compared with glipizide.
It should be noted that only ~70% and ~90% of
subjects in these two studies [26, 27], respectively, entered the second-year extension study.
Thus, more data are required before making
definitive conclusions about the durability of
SGLT2 inhibitors. Nevertheless, the results of
both studies demonstrate that the glucose-lowering effect of dapagliflozin does not wane with time
up to 2 years.
Canagliflozin
Canagliflozin also is approved by the FDA and
European Medical Agency (EMA) for the treatment
of patients with T2DM in combination with oral
antidiabetic therapy (Table 2) as well as with GLP1 receptor agonists and insulin. Canagliflozin
produced a dose-dependent increase in urinary
glucose excretion in T2DM individuals, with a
maximal effect at 400 mg day 1 [28]. The glucosuria was accompanied by a dose-dependent
decrease in the incremental area under both the
plasma glucose and insulin concentration curves
during a mixed meal [28]. In clinical studies,
canagliflozin was effective in lowering the plasma
glucose concentration in drug-nave patients with
T2DM and as add-on therapy in patients inadequately treated with metformin, insulin and combination of metformin plus sulphonylurea
(Table 2). In a 12-week, placebo-controlled trial in
drug-nave patients with diabetes, canagliflozin
produced a dose-dependent decrease in HbA1c
with a maximal placebo-subtracted decrease in
HbA1c of 0.99% with a dosage of 300 mg day 1
[29]. In a 26-week placebo-controlled study, 678
subjects were randomized in 1 : 1 : 1 ratio to
receive 100 and 300 mg canagliflozin or placebo.
The decrease in HbA1c at 26 weeks was 0.77%,
1.03%, +0.14%, respectively. A total of 451

subjects entered a 26-week extension, and the

decrease in HbA1c was maintained at 52 weeks
( 0.81 and 1.11% for 100 and 300 mg day 1
doses, respectively) [30]. In a double-blind, placebo-controlled, dose-ranging study in metformintreated patients with T2DM (n = 451), canagliflozin
in dosages 50, 100, 200 and 300 mg day 1
reduced the HbA1c by 0.70.9% from baseline,
whilst placebo and sitagliptin-treated patients
experienced 0.22 and 0.74%, respectively, over
12 weeks [31]. Two other large studies compared
the efficacy of canagliflozin to sitagliptin and glimepiride in poorly controlled patients with T2DM
treated with metformin. In one study [32], 1284
patients with T2DM were randomized to receive
100 and 300 mg of canagliflozin, sitagliptin and
placebo. The placebo-subtracted decrease in
HbA1c at 52 weeks was
0.73%,
0.88%,
0.73% for 100, 300 mg canagliflozin and sitagliptin, respectively, and the decrease in HbA1c with
300 mg dose was significantly greater than that
with sitagliptin [32]. In a second study [33], 1450
patients with diabetes were randomized to 100,
300 mg canagliflozin or glimepiride for 52 weeks.
The
decrease
in
HbA1c
(from
baseline
HbA1c = 7.8%) was
0.82%,
0.93% and
0.81%, respectively, and the decrease with
300 mg canagliflozin dose was significantly greater
than that with glimepiride [33]. The 300 mg dosage
of canagliflozin produced a greater decrease in
HbA1c than sitagliptin in subjects receiving metformin plus sulphonylurea. In 755 poorly controlled T2DM subjects receiving metformin plus
sulphonylurea, 300 mg of canagliflozin caused
significantly greater reduction in HbA1c and fasting plasma glucose at 52 weeks compared to
sitagliptin ( 1.03% vs.
0.66%, P < 0.05, and
1.7 mmol L 1 vs. 0.3 mmol L 1, P < 0.001,
respectively) [34]. The addition of canagliflozin
(100 and 300 mg day 1) to insulin-treated patients
with diabetes (n = 29) caused
0.54% and

Background
therapy

Canagliflozin

Dapagliflozin

Empagliflozin

Drug nave

1.03

0.66

0.69

Metformin

0.93

0.54

0.71

Sulphonylurea

1.03

0.59

0.60

Pioglitazone
Insulin

NT
0.73

0.55

0.61

0.55

0.62

NT, not yet tested/reported.

356

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Table 2 Placebo-subtracted
decrease in HbA1c (%) with
different SGLT2 inhibitors in
T2DM subjects receiving
various background therapy

M. A. Abdul-Ghani & R. A. DeFronzo

0.73%, respectively, placebo-subtracted decreases in HbA1c after 28 days of treatment [35].

The 300-mg day 1 dosage appeared to be slightly
more effective than the 100-mg day 1 dosage. In a
16-day trial, canagliflozin was shown to improve
beta-cell function in patients with type 2 diabetic
using a model-based method to calculate insulin
secretion [36].
Empagliflozin
Similar to dapagliflozin and canagliflozin, empagliflozin produced a dose-dependent glucosuria in
both normal and T2DM subjects [37, 38], and the
24-h urinary glucose excretion with 100 mg day 1
was 74 g [39]. In a dose finding 12-week study, 495
metformin-treated diabetic subjects with poor
glycaemic control (baseline HbA1c ~8.0%) were
randomized to receive five different doses of empagliflozin, placebo or sitagliptin. The maximal
placebo-subtracted decrease in FPG and HbA1c
was observed with 10, 25 and 50 mg doses, was
27 mg dL 1 and 0.71%, respectively, and was
greater than that observed with sitagliptin
(22 mg dL 1 and 0.58%) [40]. Empagliflozin also
effectively reduced the HbA1c in drug-nave
patients and as add-on to metformin plus sulphonylurea and metformin plus pioglitazone. In a 24week study, 899 drug-nave patients with T2DM
were randomized to receive 10 (n = 224) and 25
(n = 224) mg empagliflozin, sitagliptin (n = 223) or
placebo
(n = 228).
The
placebo-subtracted
decrease in empagliflozin-treated subjects was
0.78% and 0.85% with 10 and 25 mg doses
compared with 0.73% in sitagliptin-treated subjects [41]. In a 24-week study [42], 10 mg (n = 217)
and 25 mg (n = 213) empagliflozin caused a 0.57%
and 0.64% decrease in HbA1c in metformin-treated
subjects with baseline HbA1c = ~7.9%. In a
24-week study [43], 10 mg (n = 225) and 25 mg
(n = 216) empagliflozin produced a placebo-subtracted decrease in HbA1c of -0.65 and -0.60%,
respectively. In a 12-week study [44], 10 mg
(n = 165) and 25 mg (n = 168) empagliflozin was
added to patients with diabetes treated with pioglitazone with or without metformin. The placebosubtracted HbA1c after 12 weeks was 0.48 and
0.61%, respectively.

Review: SGLT2 inhibition and type 2 diabetes

this class of drugs will be effective in lowering the

plasma glucose concentration in T1DM. In an
8-week study [45], 40 patients with type 1 diabetes (HbA1c = 8.0%, FPG = 9.0 mmol L 1, insulin
dose = 55 units per day) received open-label
empagliflozin (25 mg) for 8 weeks. Addition of
empagliflozin reduced HbA1c by 0.40% decrease
and fasting plasma glucose by 2.0 mmol L 1,
whilst the insulin dose was decreased by ~10
units per day. Despite the decrease in FPG and
HbA1c by empagliflozin, the incidence of symptomatic hypoglycaemia was reduced by two-thirds,
and body weight and systolic blood pressure both
decreased. This study demonstrates that SGLT2
inhibitors are likely to be effective in patients with
T1DM.
SGLT2 inhibitors and renal function
Studies with dapagliflozin demonstrated that treatment of SGLT2 inhibitor has no adverse effect on
renal function. Moreover, because the drug primarily is cleared via the liver, no dose adjustment
is necessary in patients with renal impairment.
Because of their mechanism of action, the efficacy
of SGLT2 inhibitors to reduce the plasma glucose
level is highly dependent upon renal function. As
the GFR decreases, there is a decrease in filtered
glucose load and a progressive decline in the drugs
glucose-lowering effect. In subjects with a mild
decrease
in
renal
function
(GFR = 60
90 mL min 1), the glucosuria produced by dapagliflozin [19] was decreased by 40%, and the
reduction in HbA1c was decreased by ~22% (Fig. 3).
In subjects with moderately impaired renal
function (GFR = 3059 mL min 1), the glucosuria

SGLT2 in type 1 diabetes

Because SGLT2 inhibitors lower the plasma
glucose concentration independent of insulin
action and insulin secretion, it is anticipated that

Fig. 3 Impact of reduced renal function on the glucoselowering efficacy of dapagliflozin (Adapted from Bristol
Myers-Squibb NDA [28]).
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357

M. A. Abdul-Ghani & R. A. DeFronzo

produced by dapagliflozin was markedly reduced

(by ~80%), and the decrease in FPG and HbA1c was
clinically insignificant (4 mg dL 1 and 0.11%,
respectively). Of note, although the decrease in
HbA1c in subjects with GFR = 3059 mL min 1
was significant, dapagliflozin caused significant
glucosuria and decrease in both body weight and
blood pressure [46]. In subjects with eGFR = 30
50 mL min 1, although the decrease was modest,
~0.4% canagliflozin (100 and 300 mg day 1) produced significant decrease in HbA1c compared
with placebo [47].
Mechanism of glucosuria
Glucosuria can be promoted by lowering the Tm or
increasing the glucose splay. A study in rodents
with sergliflozin demonstrated that SGLT2 inhibition markedly reduces the Tm without significant
change in the glucose splay [48]. Dapagliflozin
produced a marked decrease in both the Tm and
splay in diabetic and nondiabetic individuals.
However, the decrease in Tm caused by dapagliflozin cannot explain the glucosuria produced by
dapagliflozin with fasting plasma glucose concentrations in the normal range, that is, 80
90 mg dL 1. The major action of dapagliflozin and
other SGLT2 inhibitors is to markedly reduce the
threshold at which plasma glucose appears in the
urine. Thus, during treatment with dapagliflozin,
the renal threshold for glucosuria declined from
~180 to ~40 mg dL 1 [49].
Although SGLT2 is responsible for the reabsorption
of ~8090% of the filtered glucose load, the
increase in urine glucose excretion (6080 g day 1)
observed with maximal dosages of SGLT2 inhibitors currently in clinical trials represents inhibition
of less than 50% of the filtered glucose load. Under
physiologic conditions, because SGLT1 is located
in the distal part of the proximal tubule, only small
amount of glucose reaches that part of the proximal tubule and SGLT1 operates at submaximal
transport capacity. Complete inhibition of SGLT2
forces SGLT1 to reabsorb glucose in full capacity,
and therefore, only the fraction of filtered glucose
that escapes SGLT1 will be excreted in the urine
[50].
Nonglycaemic benefits of SGLT2 inhibitors
In addition to the beneficial effects related to
improved glycaemic control, the SGLT2 inhibitors
have a number of nonglycaemic effects that make
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Review: SGLT2 inhibition and type 2 diabetes

them desirable agents as monotherapy and combination treatment.

1 Weight loss: Weight gain is a major problem with
currently available antidiabetic medications
including sulphonylureas, thiazolidinediones and
insulin. The urinary loss of 6080 g day 1 of glucose equates to 240320 cal day 1 or 23 lbs per
month if this caloric deficit is not offset by an
increase in caloric intake. Consistent with this,
weight loss was observed in diabetic subjects
treated with SGLT2 inhibitors in all clinical studies.
2 Blood pressure: A consistent finding in all
dapagliflozin, and canagliflozin, studies has been
a reduction in systolic/diastolic blood pressure of
45/12 mmHg [18]. Although this has been
attributed to the mild fluid/sodium deficit that
occurs during the first several days of dapagliflozin
treatment [16, 18], an alternative explanation is
local inhibition of the reninangiotensin system
secondary to enhanced sodium delivery to the
juxtaglomerular apparatus [51, 52]. In one study,
treatment with dapagliflozin caused ~1 l decrease
in extracellular volume which persisted during
treatment with the drug. Because uric acid and
sodium reabsorption in the proximal tubule are
coupled, it is not surprising that a decrease in
serum uric acid concentration (~1 mg dL 1) has
been observed in patients with diabetes treated
with dapagliflozin [52].
3 SGLT2 inhibitors and diabetic nephropathy:
Hyperglycaemia is the principal risk factor for
diabetic microvascular complications (retinopathy,
nephropathy and neuropathy), and improved glycaemic control no matter how achieved would
be expected to reduce the risk of microvascular
complications in subjects with type 2 diabetes [3,
4]. Enhanced sodiumglucose reabsorption in the
proximal tubule has been shown to play an
important role in the development of diabetic
nephropathy [51, 52]. Thus, the SGLT2 inhibitors
might be expected to have an additional beneficial
renoprotective action above and beyond their glucose-lowering effect [51, 52]. The increased filtered
glucose load in diabetic individuals results in
increased glucose and sodium reabsorption by
the SGLT2 transporter in the proximal tubule [53,
54] and decreased sodium delivery to the
juxtaglomerular apparatus. This activates the
reninangiotensin system, resulting in increased
intraglomerular pressure and increased GFR [55].
By inhibiting sodium transport in the proximal

M. A. Abdul-Ghani & R. A. DeFronzo

tubule and increasing sodium delivery to the

juxtaglomerular apparatus, renin and angiotensin
secretions are inhibited, leading to a reduction in
the introglomerular pressure and amelioration of
the hyperfiltration. Consistent with this, increased
GFR and increased kidney size can be reversed by
6 weeks of intensive insulin therapy that normalizes the plasma glucose concentration [56]. With
regard to this, it is noteworthy that chronic T-1095
administration decreased HbA1c levels in diabetic
mice and stopped the progression of diabetic
nephropathy, with prevention of proteinuria and
expansion of glomerular mesangial area [57].
Safety
The pharmacological properties of the SGLT2
inhibitors suggest that they should have a good
safety profile. Because of their high selectivity for
SGLT2 over SGLT1, no inhibition of glucose or
galactose transport in the intestinal mucosa is
anticipated and, unlike phlorizin, gastrointestinal
side effects are not anticipated. Furthermore,
because subjects with homozygous mutations in
the SGLT2 gene are asymptomatic, have normal
kidney function despite large amounts of glucosuria (>50100 g/24 h) and have a normal life expectancy, pharmacological inhibition of SGLT2 would
not be expected to affect kidney function or cause
significant volume depletion. Indeed, none of those
adverse events have been observed with SGLT2
inhibitors in clinical trials. With dapagliflozin,
1224 weeks of treatment caused a 200
400 mL day 1 increase in urine volume during
the first 23 days after initiation of therapy without
excessive urine losses of sodium, potassium or
other electrolytes [18]. Consistent with mild volume
contraction, a small rise in haematocrit (12
volume %) and plasma urea nitrogen-to-creatinine
ratio have been observed. Plasma electrolyte concentrations did not change following dapagliflozin
treatment [16, 18]. No increase in the incidence of
hypoglycaemia was observed with SGLT2 inhibitors in the absence of concomitant sulphonylurea
or insulin therapy. This is explained by the lack of
effect of SGLT2 inhibitors on insulin secretion or on
the glucose counter-regulatory mechanisms.
Although the SGLT2 inhibitors promote glucosuria, which could result in an increased incidence
of urinary tract infections, patients with uncontrolled blood sugar already have significant
glucosuria. Moreover, T2DM individuals may have
increased susceptibility to infections compared

Review: SGLT2 inhibition and type 2 diabetes

with nondiabetic individuals [58]. It remains to be

determined whether the additional glucosuria will
promote bacterial growth. In one study in which
midstream urine was collected, treatment with
SGLT2 did not increase the prevalence of urinary
bacteriuria [59]. In diabetic subjects receiving
placebo or dapagliflozin at dosages of 5 mg day 1
(n = 1145) and 10 mg day 1 (n = 1193), the incidence of urinary tract infection was 3.7%, 5.7%
and 4.3%, respectively [19]. In females receiving
placebo and dapagliflozin at 5 and 10 mg dL 1, the
incidence of vulvovaginitis was increased: 1.5%,
8.3% and 6.4%, respectively [1922]. The incidence
of balanitis in males is increased, and the penile
infection primarily is observed in uncircumcised
men [1922]. As previously stated, SGLT2 inhibitors do not adversely affect renal function as
manifested by change in serum creatinine [19]. A
very small reduction in eGFR (45 mL min 1 per
1.73 m2) may be observed during the initial 1
2 months after institution of therapy due to the
modest decrease intravascular volume. However,
with autoregulation, the small decrease in eGFR
returns to baseline. SGLT2 inhibitors do not cause
or aggravate proteinuria, and in some studies,
reduced urinary albumin excretion was observed.
In phase III trials, canagliflozin, 300 mg day 1,
increased LDL cholesterol by 10% and produced a
significant increase in plasma HDL cholesterol
concentration and decrease in plasma triglyceride
concentration in drug-naive subjects and in
patients with T2DM poorly controlled with metformin [60]. The increase in plasma LDL was independent of background therapy with statins.
Although the increase in plasma HDL and decrease
in triglyceride concentration could be explained by
the weight loss and/or improved glycaemic control,
the cause for the increase in LDL cholesterol
remains unknown, but most likely results from
the transfer of LDL cholesterol from VLDV triglyceride to apoB-100. The impact of these small
changes in lipid profile on cardiovascular events
is not known. The incidence of total cardiovascular
events in canagliflozin-treated subjects in phase III
trials was similar to that in subjects receiving other
antidiabetic agents. However, there was a modest
increase in the incidence of CVAs in canagliflozintreated subjects in the initial months after starting
therapy. However, the increased incidence of CVA
events primarily was due to a decreased number of
events in placebo-treated subjects, rather than an
increased number of events in canagliflozin-treated
subjects. Nonetheless, this signal warrants further
2014 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2014, 276; 352363

359

M. A. Abdul-Ghani & R. A. DeFronzo

investigation, and the ongoing CANVAS study with

4330 subjects randomized to receive 100, 300 mg
canagliflozin or placebo will provide more definitive
information about the cardiovascular safety/benefit of canagliflozin [61]. A similar 4-year study for
cardiovascular safety with empagliflozin is ongoing
[62]. A meta-analysis of phase III dapagliflozin
studies revealed no increase in cardiovascular
events [8].
In phase III studies of dapagliflozin, an increased
incidence of bladder and breast cancer was
observed; however, the total number of cases
was small (10 for each cancer). This finding was
surprising because neither breast nor bladder
tissues express the SGLT2 transporter, and 2-year
carcinogenic studies in animals failed to demonstrate any preneoplastic or neoplastic activity.
Further, there could have been detection bias for
bladder cancer due to the frequent testing for
urinary tract infections, which could have led to
the discovery of microscopic haematuria. Because
breast and especially bladder cancer take many
years to develop, whereas the exposure to dapagliflozin was short (generally less than 1 year), the
significance of the increased incidence of these two
tumours remains to be determined. Nonetheless,
because of this potential carcinogenic signal, the
FDA has asked for additional safety data regarding
cancer risk with dapagliflozin treatment. Results
from additional clinical trials with dapagliflozin
have reported more balanced incidence of cancer
cases in dapagliflozin-treated versus placebo-treated patients. Based on this additional information,
the FDA recently approved the drug for the treatment of T2DM in the United States. Dapagliflozin
also has been approved by the European Medical
Agency (EMA).
The place of SGLT2 inhibitors in the management of T2DM
individuals
All major organizations (American Diabetes Association/European Association for the Study of
Diabetes, the American Association of Clinical
Endocrinologists) recommend metformin as the
first-line therapy in individuals with new-onset
diabetes. However, because metformin does not
affect beta-cell function, metformin-treated individuals experience a progressive increase in HbA1c.
SGLT2 inhibitors can provide a good therapeutic
option in inadequately controlled (A1c >7.0%)
metformin-treated
diabetic
individuals.
An
increase in the plasma glucagon-like peptide-1
360

2014 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2014, 276; 352363

Review: SGLT2 inhibition and type 2 diabetes

(GLP-1) concentration has been observed in some

clinical studies following initiation of therapy with
SGLT2 inhibitors. This observation makes the
combination of SGLT2 inhibitors plus dipeptidyl
peptidase-IV (DPP-IV) inhibitors an attractive therapeutic option in metformin-failing individuals. In
newly diagnosed T2DM individuals with very high
HbA1c (e.g. >9.0%), metformin alone will not lower
the HbA1c below the treatment goal (<7.0%). Thus,
SGLT2 in combination with metformin provides an
attractive therapy. In one study, initiation of therapy with metformin plus dapagliflozin in subjects
with new-onset diabetes produced an additive
decrease in HbA1c versus either therapy alone,
and more subjects (~60%) with the combination
therapy achieved the target glycaemic therapy
(HbA1c <7.0%) than with either therapy alone [6].
About 1020% of subjects with new-onset diabetes
do not tolerate metformin, because of gastrointestinal side effects cannot receive metformin because
of an increased serum creatinine. Thus, SGLT2
inhibitors, as monotherapy or in combination with
DPP-IV inhibitors, can provide an effective initial
therapy in metformin-intolerant individuals.
Lastly, because SGLT2 inhibitors are effective in
lowering the HbA1c at all stages of diabetes, they
can be added in subjects who fail on multiple oral
therapies or in insulin-treated individuals who do
not reach the target glycaemic control. Lastly, in
newly diagnosed T2DM subjects with an A1c
>10.0%, dapagliflozin reduced the A1c by ~2.8%
[20]. Thus, a combination of dapagliflozin with any
other oral agent or GLP-1 receptor agonist should
reduce the A1c to less than 7.0%.
Summary and conclusion
Current data in experimental animals and humans
indicate that inhibition of renal glucose reabsorption with SGLT2 inhibitors is a novel and effective
strategy to reduce the plasma glucose concentration in type 2 diabetic subjects. Dapagliflozin and
canagliflozin the most clinically advanced of the
SGLT2 inhibitors have demonstrated good efficacy with a reduction in HbA1c of 0.70.8% from a
starting HbA1c ~8.0% and a good safety profile.
Empagliflozin shows similar efficacy and safety
and is expected to be approved by both the United
States and FDA and EMA. In addition, SGLT2
inhibitors produce additional nonglycaemic benefits, which include modest weight loss and
decrease in blood pressure. Because the SGLT2
inhibitors have a mechanism of action that is
independent of insulin secretion or insulin action,

M. A. Abdul-Ghani & R. A. DeFronzo

the efficacy of this class of drugs is not anticipated

to decline with progressive beta-cell failure or in
the presence of severe insulin resistance. Thus,
this class of drugs can be administered in combination will all other antidiabetic drugs with anticipated additive efficacy on glycaemic control at all
stages of T2DM. Although initial studies have
demonstrated durable decrease in HbA1c over
52102 weeks compared with placebo and superiority over DPP-IV inhibitors, longer follow-up is
warranted to define the durability of HbA1c reduction by this class of drugs.
Because of their mechanism of action, the efficacy
of SGLT2 inhibitors declines with decreased renal
function, such that in subjects with eGFR <45
60 mL min 1 per 1.73 m2, the decrease in HbA1c
produced by SGLT2 inhibitors is significantly
reduced and is not clinically meaningful in diabetic
subjects with an eGFR <45 mL min 1 per 1.73 m2.
The SGLT2 inhibitors also are effective as monotherapy in newly diagnosed patients with diabetes.
To the extent that glucotoxicity contributes to the
demise in beta-cell function in subjects with
impaired glucose tolerance and impaired fasting
glucose, these drugs also may prove useful in the
treatment of prediabetes. Currently available data
indicate that the SGLT2 inhibitors have a good
safety profile.
Conflict of interest statement
RAD is a member of the Advisory Board of Takeda,
Bristol Myers Squibb, Janssen, Boehringer Ingelheim, Novo Nordisk, Astra Zeneca and Lexicon.
RAD is a member of the Speakers Bureau of Novo
Nordisk, Astra Zeneca, BMS and Janssen. RAD has
grant support from Takeda, Amylin, Astra Zeneca
and BMS.
Acknowledgements
Ralph DeFronzo (5R01DK240923) and Muhammad Abdul-Ghani (R01 DK097554-01) receive NIH
grant support. The authors meet criteria for
authorship as recommended by the International
Committee of Medical Journal Editors (ICMJE).
The authors received no direct compensation
related to the development of the manuscript.
Proofreading and manuscript formatting assistance was provided by Geraldine Thompson of
Envision Scientific Solutions, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). BIPI was given the

Review: SGLT2 inhibition and type 2 diabetes

opportunity to review the manuscript for medical

and scientific accuracy, as well as intellectual
property considerations.

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Correspondence: Muhammad Abdul-Ghani MD, PhD, Diabetes

Division, University of Texas Health Science Center, 7703 Floyd
Curl Drive, MS 7886, San Antonio, TX 78229, USA.
(fax: (210) 567-6554; e-mail: abdulghani@uthscsa.edu).

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