Clinical Therapeutics/Volume ], Number ], 2015

The Role of Sodium-Glucose Co-Transporter 2 Inhibitors in

the Treatment of Type 2 Diabetes
Karen Whalen, PharmD, BCPS, CDE1; Shannon Miller, PharmD, BCACP2; and
Erin St. Onge, PharmD2
1
Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy,
Gainesville, Florida; and 2Department of Pharmacotherapy and Translational Research, University of
Florida College of Pharmacy, Orlando Campus, Orlando, Florida

ABSTRACT (3 to 5 mm Hg). Genital mycotic infections and

Purpose: Diabetes is a chronic metabolic disorder
characterized by hyperglycemia that results from
insulin resistance, diminished or absent insulin secre-
tion, or both. Approximately one-half of patients with
diabetes fail to achieve acceptable glycemic control.
Consequently, morbidity and mortality associated
with diabetes is high, resulting from complications
such as cardiovascular disease and nephropathy. The
sodium-glucose co-transporter 2 (SGLT2) inhibitors
are a new class of medications for the treatment of
type 2 diabetes. This article provides an overview of
efcacy and safety data for the SGLT2 inhibitors and
outlines their role in the management of diabetes.
Methods: Relevant articles were identied through
searches of PubMed and International Pharmaceutical
Abstracts by using the key terms canagliozin, dapa-
gliozin, empagliozin, and sodium-glucose co-trans-
porter 2 inhibitor. A review of bibliographies of
retrieved articles was also performed to identify addi-
tional references. All identied trials published in
English and that involved the efcacy and safety of
SGLT2 inhibitors in the treatment of type 2 diabetes
were reviewed.
Findings: The SGLT2 inhibitors improve glucose
control by increasing urinary glucose excretion. Effec-
tiveness is decreased in the presence of renal dysfunc-
tion. These agents are efcacious as monotherapy and
add-on therapy for patients with type 2 diabetes
uncontrolled on metformin, sulfonylureas, insulin,
and other antihyperglycemic combinations. The
SGLT2 inhibitors lower glycosylated hemoglobin by
0.5% to 1% and fasting plasma glucose by
15 to 35
mg/dL, depending on the agent and the dosage used,
and are also associated with modest reductions in
weight (1.5 to 3.5 kg) and systolic blood pressure
increased urination, owing to the mechanism of
action, are the most common adverse effects. In
general, the class is well tolerated, and the risk of
hypoglycemia is low.
Implications: With their unique mechanism of
action and good safety and tolerability proles, the
SGLT2 inhibitors are an important addition to exist-
ing treatments for type 2 diabetes. Because of the lack
of data with this class of drugs when current treatment
guidelines for diabetes were published, the SGLT2
inhibitors are recommended as second- or third-line
therapies for diabetes. Forthcoming data on the long-
term efcacy and safety prole of these agents should
help to solidify the role of SGLT2 inhibitors in the
management of diabetes. (Clin Ther. 2015;]:]]]]]])
& 2015 Elsevier HS Journals, Inc. All rights reserved.
Key words: canagliozin, dapagliozin, empagliozin,
sodium-glucose co-transporter 2 inhibitor.
INTRODUCTION
Diabetes is a chronic metabolic disorder characterized
by hyperglycemia that results from insulin resistance,
diminished or absent insulin secretion, or both. Dia-
betes is estimated to affect 29.1 million Americans and
close to 350 million people worldwide.1,2 The most
common form of diabetes, accounting for 90% to
95% of cases, is type 2 diabetes mellitus (T2DM), or
diabetes attributed to insulin resistance. Chronic
complications of diabetes include both microvascular
Accepted for publication March 5, 2015.
http://dx.doi.org/10.1016/j.clinthera.2015.03.004
0149-2918/$ - see front matter
& 2015 Elsevier HS Journals, Inc. All rights reserved.

] 2015 1
 Clinical Therapeutics
complications such as nephropathy, neuropathy, and
retinopathy and macrovascular complications such as
heart disease and stroke. Cardiovascular (CV) risk is
signicant in T2DM, with heart disease or stroke
claiming the lives of 2 of 3 patients.2,3 Substantial
evidence indicates that controlling blood glucose
prevents the risk or reduces progression of micro-
vascular complications.4,5 Furthermore, controlling
other risk factors such as hypertension and dyslipide-
mia reduces the risk of both nephropathy and retin-
opathy and is paramount to decreasing the occurrence
of CV disease in diabetes.
First-line therapy for the management of T2DM
generally involves lifestyle modications, including
diet and exercise, along with metformin.6 Other oral
medications for the treatment of T2DM have tradi-
tionally included sulfonylureas, meglitinides, thiazoli-
dinediones (TZDs), dipeptidyl-peptidase-4 inhibitors,
-glucosidase inhibitors, bromocriptine, and coleseve-
lam. Injectable agents such as various forms of insulin,
glucagon-like peptide-1 (GLP-1) receptor agonists,
and amylin analogs are also used for the treatment
of T2DM. Despite the availability of a wide variety of
medications, almost one-half of patients with diabetes
fail to achieve acceptable glycemic control.7 Thus, the
search for effective medications for diabetes continues.
In 2013 a new class of antihyperglycemic medications,
the sodium-glucose co-transporter 2 (SGLT2) inhib-
itors, entered the market. Canagliozin was the rst of
these agents to obtain approval by the US Food and
Drug Administration (FDA) in March 2013. Subse-
quently, the FDA approved dapagliozin in January
2014 and empagliozin in August 2014. Each of these
agents is approved for the treatment of T2DM in
adults.810 This article provides an overview of ef-
cacy and safety data for the SGLT2 inhibitors and
outlines their role in the management of T2DM.
METHODS
Relevant articles were identied through searches of
PubMed (publication date range: 1966November
2014) and International Pharmaceutical Abstracts
(publication date range: January 1970November
2014) by using the key terms canagliozin, dapagli-
ozin, empagliozin, and sodium-glucose co-trans-
porter 2 inhibitor. A review of bibliographies of
retrieved articles was also performed to identify addi-
tional references. All identied trials published in
English and that involved efcacy and safety of
2 Volume ] Number ]
SGLT2 inhibitors in the treatment of T2DM were
reviewed.
RESULTS
Clinical Pharmacology
Under normal circumstances, the adult kidney
lters
180 g of glucose per day.11 Almost all of
the glucose ltered by the kidney is reabsorbed and
returned to the systemic circulation via the SGLT
proteins SGLT2 and SGLT1. Even though plasma
glucose levels are elevated in T2DM, the kidneys con-
tinue to reabsorb glucose through the SGLT proteins,
thereby contributing to hyperglycemia. SGLT2 is a
low-afnity, high-capacity transporter found exclu-
sively in the proximal renal tubule. It is responsible for
reabsorption of 90% of glucose ltered by the kidney.
SGLT1 is a high-afnity, low-capacity transporter
located further along the proximal tubule, and it
reabsorbs the remaining glucose.12 SGLT1 is also
expressed in the brush border of the small intestine
where it plays a signicant role in glucose absorption.
The available SGLT2 inhibitors differ in their relative
selectivity for SGLT2 versus SGLT1. For instance,
empagliozin is the most selective for SGLT2
(42500:1), followed by dapagliozin (41200:1)
and canagliozin (4250:1).13 The clinical signi-
cance of SGLT2 selectivity is not fully established.
Agents with lower selectivity for SGLT2 may
transiently inhibit SGLT1-mediated glucose absorp-
tion in the small intestine, thereby reducing postpran-
dial glucose.14
The SGLT2 inhibitors exert their main pharmaco-
logic action by preferentially inhibiting SGLT2. Inhibi-
tion of SGLT2 decreases reabsorption of glucose,
leading to an increase in urinary glucose excretion
(UGE) and a reduction in plasma glucose levels. The
increased UGE seen with SGLT2 inhibitors also results
in a loss of 200 to 300 kcal/d, which may contribute
to modest weight loss observed with these agents.12 In
addition, modest reductions in systolic blood pressure
may occur, likely attributable to the mild osmotic
diuresis produced by this class. Because SGLT2 inhi-
bitors depend on sufcient glomerular ltration to be
effective, they subsequently work best in patients with
normal renal function or mild renal impairment.15
Dapagliozin should not be used in patients with an
estimated glomerular ltration rate (eGFR) of o60
mL/min/1.73 m2. Canagliozin and empagliozin should
not be used if eGFR is o45 mL/min/1.73 m2.810

No dosing considerations are required for hepatic
impairment.
All 3 agents are administered once daily in the
morning. Dapagliozin and empagliozin may be
administered with or without food.9,10 Although
canagliozin may be taken without regard to food,
the product information recommends administration
before the morning meal, because the SGLT1 activity
of this agent may delay intestinal glucose absorption
and reduce postprandial hyperglycemia.8,14
Drug Interactions
Drug interaction studies that examined the con-
current use of the SGLT2 inhibitors with other anti-
hyperglycemics such as metformin and sulfonylureas
have revealed no clinically signicant pharmacokinetic
changes.8,1619 When dapagliozin and glimepiride
are used together, there may be a slight increase in
the risk of hypoglycemia; therefore, patients should be
monitored appropriately.17 Dapagliozin was also
investigated in combination with pioglitazone and
sitagliptin.16 Results of these pharmacokinetic stu-
dies found that no dosage adjustment is needed for
either medication. The combination of empagliozin
with the dipeptidyl-peptidase-4 inhibitors sitagliptin
or linagliptin20,21 was examined. Although sitagliptin
slightly increases exposure to empagliozin, these
changes were not considered clinically relevant.
The concurrent administration of the SGLT2 in-
hibitors with simvastatin, warfarin, and digoxin re-
vealed no clinically signicant interactions, with the
exception of the combination of canagliozin and
digoxin.8,2225 If administered together, digoxin levels
should be closely monitored, because canagliozin
increases the exposure to digoxin.8 The use of the di-
uretic hydrochlorothiazide in combination with cana-
gliozin or empagliozin was also studied with no
clinically relevant interactions reported.26,27 Likewise,
dapagliozin and empagliozin were studied in com-
bination with antihypertensives such as valsartan,
verapamil, and ramipril with no clinically signicant
effects noted.22,25
Dapagliozin is mainly metabolized via uridine
diphosphate-glucuronosyltransferase 1A9 (UGT1A9).
Rifampin, an inducer of UGT1A9, reduces exposure
to dapagliozin, and mefenamic acid, a UGT1A9 inhi-
bitor, enhances exposure. However, changes in dapa-
gliozin levels are not clinically meaningful, and no
dosage adjustments are warranted.9,28 The concurrent
] 2015
K. Whalen et al.
use of canagliozin and rifampin was found to de-
crease the efcacy of canagliozin. Therefore, an
increase in the dose of canagliozin may be required
when coadministered with rifampin and other UGT
inducers, including phenytoin, phenobarbital, and
ritonavir.8,29 Exposure of canagliozin is increased
with cyclosporine and probenecid; however, these inter-
actions are not clinically relevant.30 No clinically mea-
ningful interaction was observed when empagliozin or
canagliozin were used with oral contraceptives that
contain ethinyl estradiol and levonorgestrel.8,31
The mechanism of action of the SGLT2 inhibitors
relies heavily on adequate kidney function. Drugs that
affect kidney function (eg, angiotensin-converting
enzyme inhibitors, angiotensin receptor blockers,
NSAIDs) should be used cautiously, because a de-
crease in the effect of the SGLT2 inhibitors may be
expected. Although no signicant pharmacokinetic
interaction exists with diuretics and the SGLT2 inhi-
bitors, pharmacodynamic interactions may occur. Pa-
tients who are particularly sensitive to volume changes
should be monitored closely for signs and symptoms
of dehydration and electrolyte abnormalities when
SGLT2 inhibitors are combined with diuretics.29 Cana-
gliozin use may lead to an increase in serum potas-
sium levels.32 Potassium levels should be monitored in
patients who take canagliozin in combination with
other medications that can increase potassium. Despite
similar mechanisms of action, no evidence supports
alterations in potassium with empagliozin or
dapagliozin.
Clinical Trials
Canagliozin, dapagliozin, and empagliozin were
each studied as monotherapy for T2DM and as add-on
therapy with other oral antihyperglycemic agents and/
or insulin. A summary of clinical trials performed with
canagliozin, dapagliozin, and empagliozin is pro-
vided in Table I,3339 Table II,4047 and Table III,4855
respectively. Selected trials for each agent are reviewed
below.
Canagliflozin Clinical Trials
Stenlf et al33 evaluated the efcacy and safety
prole of canagliozin monotherapy in a randomized,
double-blind, placebo-controlled phase 3 study. Eligi-
ble subjects included patients with T2DM who were
18 to 80 years of age and had a glycosylated
hemoglobin (HbA1c) between 7% and 10% on no
3
 4

Clinical Therapeutics
Table I. Phase 3 clinical trials with canagliflozin.

Baseline Background Treatment Change in Change in FPG Change in

Study Age (y) HbA1c (%) Duration therapy groups* HbA1c (%) (mg/dL) weight (kg)

Stenlf et al33,34
Main study (N = 584) 55.4 8.0 26 weeks None CANA 100 mg 0.77 27.0 2.5
CANA 300 mg 1.03 34.2 3.4
PBO 0.14 9.0 0.5
High glycemic substudy 49.3 10.6 26 weeks CANA 100 mg 2.13 81.0 3.0
(N 91) CANA 300 mg 2.56 86.4 3.8
Extension study (N 451) Weeks CANA 100 mg 0.81 27.4 3.1
2752 CANA 300 mg 1.11 39.1 4.1
Lavalle-Gonzalez35
Period I (N 1284) 55.4 7.9 26 weeks MET CANA 100 mg 0.79 27.0 3.3
CANA 300 mg 0.94 37.8 3.6
SITA 100 mg 0.82 19.8 1.1
PBO 0.17 2 1.1
Period II (active-control) Weeks CANA 100 mg 0.73 27.0 3.3
(N 1103) 2752 CANA 300 mg 0.88 36.0 3.7
SITA 100 mg 0.73 18.0 1.2
Cefalu et al36 (N 1250) 56.2 7.8 52 weeks MET CANA 100 mg 0.82 24.3 3.7
CANA 300 mg 0.93 27.4 4.0
GLIM 68 mg 0.81 18.4 0.7
Wilding et al37
Core period (N 469) 56.8 8.1 26 weeks MET SU CANA 100 mg 0.85 18.0 1.9
CANA 300 mg 1.06 30.6 2.5
PBO 0.13 3.6 0.8
Extension period Weeks CANA 100 mg 0.74 19.8 2.0
2752 CANA 300 mg 0.96 27.0 3.1
PBO 0.01 10.8 1.0
Volume ] Number ]

Schernthaner et al38 56.7 8.1 52 weeks MET SU CANA 300 mg 1.03 28.7 2.3
(N 755) SITA 100 mg 0.66 2.2 0.1
Forst et al39
Core period (N 342) 57.4 7.9 26 weeks MET PIO CANA 100 mg 0.89 26.8 2.6
CANA 300 mg 1.03 33.2 3.7
PBO 0.26 2.5 0.2
(continued)
 K. Whalen et al.

antihyperglycemic medication. Patients who had an

CANA canagliozin; FDA Food and Drug Administration; FPG fasting plasma glucose; GLIM glimepiride; HbA1c glycosylated hemoglobin; MET
weight (kg)
Change in HbA1c of 6.5% to 9.5% on antihyperglycemic mono-

2.5
3.6
0.3
therapy or metformin/sulfonylurea combination ther-
apy were also eligible. However, the subjects on
antihyperglycemic therapy underwent an 8-week
washout before starting the study period. The trial
Change in FPG

also conducted a high glycemic substudy that eval-

(mg/dL)

26.7
31.5
12.6
uated canagliozin in patients with an HbA1c of 10%
to 12%. Exclusion criteria included a history of type 1
diabetes mellitus (T1DM) or CV disease; use of a
TZD, insulin, or another SGLT2 inhibitor within 12
weeks of the study; and eGFR o50 mL/min/1.73 m2.
HbA1c (%)
Change in

0.92
1.03
0.37

Patients in the main study group were randomly

assigned to receive canagliozin 100 mg, canagliozin
300 mg, or placebo daily. The high glycemic substudy
group received active treatment with canagliozin 100
CANA 300 mg
CANA 100 mg

mg or 300 mg. Placebo treatment was avoided in these

SITA 100 mg
Treatment
groups*

patients because of the high HbA1c levels. The proto-

col required the use of rescue therapy with metformin
if fasting plasma glucose (FPG) exceeded 270 mg/dL
in weeks 1 through 6, 240 mg/dL in weeks 7 to 12,
and 200 mg/dL in weeks 13 to 26. Patients were
Background

followed for 26 weeks. The primary outcome was the

metformin; PBO placebo; PIO pioglitazone; SITA sitagliptin; SU sulfonylurea.
therapy

change in HbA1c from baseline. Secondary outcomes

included the percentage of patients who achieved an
HbA1c o7% and changes in FPG and systolic blood
pressure.
Duration

2752

The main study consisted of 584 participants, and

Weeks

91 patients participated in the high glycemic substudy.

In the main study the changes in HbA1c at 26 weeks
were 0.77%, 1.03%, and 0.14% for the canagli-
FDA-approved dosage of canagliozin 100 mg, 300 mg.
HbA1c (%)
Baseline

ozin 100-mg, canagliozin 300-mg, and placebo

groups, respectively (P o 0.001 for both canagliozin
doses versus placebo). Greater reductions in HbA1c
occurred in the high glycemic subgroup, with an
average reduction in HbA1c of 2.13% with canagli-
Age (y)

ozin 100 mg and 2.56% with canagliozin 300 mg.

The percentage of patients who achieved an HbA1c
o7% was higher in the canagliozin groups (44.5%
P o 0.0001 versus glimepiride.

canagliozin 100 mg, 62.4% canagliozin 300 mg

P o 0.001 versus sitagliptin.
Extension study (active-

P o 0.001 versus placebo.

control) (N 289)

versus 20.6% placebo; P o 0.001). Signicant

Table I. (continued).

P value not calculated.

changes in FPG (27 to 34 mg/dL) and systolic

blood pressure (3.7 to 5.4 mm Hg) were also
noted with the active treatment groups. When the
main study group was extended by an additional 26
weeks, markers of glycemic control remained similar
for the canagliozin arms.34 The incidence of adverse
Study

events was slightly greater in the canagliozin groups,

*

particularly the occurrence of urinary tract infections

] 2015 5
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Clinical Therapeutics
Table II. Phase 3 clinical trials with dapagliflozin.

Baseline Duration Background Treatment Change in Change in Change in

Study Age (y)* HbA1c (%) (wk) therapy groups HbA1c (%) FPG (mg/dL) weight (kg)

Ferrannini et al40
Primary cohort (N 199) 52.6 7.92 24 None DAPA 2.5 mg 0.58 15.2 3.3
DAPA 5 mg 0.77 24.1 2.8
DAPA 10 mg 0.89 28.8 3.2
PBO 0.23 4.1 2.2
Exploratory cohort (N 211) 53.2 7.82 24 DAPA 2.5 mg 0.83 25.6 3.8
DAPA 5 mg 0.79 27.3 3.6
DAPA 10 mg 0.79 29.6 3.1
High glycemic cohort (N 73) 48.1 10.82 24 DAPA 5 mg 2.88 77.1 2.1
DAPA 10 mg 2.66 84.3 1.9
Kaku et al41 (N 279) 58.1 7.48 24 None DAPA 5 mg 0.41 8.6 2.13
DAPA 10 mg 0.45 13.7 2.22
PBO 0.06 5.8 0.84
Bailey et al42 (N 282) 53 7.9 24 None DAPA 1 mg 0.68 11 2.4
DAPA 2.5 mg 0.72 22 2.6
DAPA 5 mg 0.82 28 2.7
PBO 0.02 4.1 0.96
Nauck et al43 (N 801) 58 7.7 52 MET DAPA 2.510 mg 0.52 NR 3.22
GLIP 520 mg 0.52 1.44
Bailey et al44 (N 546) 53.9 8.0 24 MET DAPA 2.5 mg 0.67 17.8 2.2
DAPA 5 mg 0.7 21.6 3.0
DAPA 10 mg 0.84 23.4 2.9
PBO 0.3 5.9 0.9
Strojek et al17 (N 592) 59.8 8.1 24 GLIM DAPA 2.5 mg 0.58 16.8 1.18
DAPA 5 mg 0.63 21.3 1.56
DAPA 10 mg 0.82 28.5 2.26
Volume ] Number ]

PBO 0.13 2.0 0.72

Rosenstock et al45 (N 420) 53.5 8.37 48 PIO DAPA 5 mg 0.95 22.8 1.35
DAPA 10 mg 1.21 33.1 0.69
PBO 0.54 13.1 2.99
Jabbour et al46 (N 451) 54.8 7.9 48 SITA MET DAPA 10 mg 0.5 24.1 2.1
PBO 0 3.8 0.3
(continued)
 K. Whalen et al.

(UTIs) and genital mycotic infections. Few adverse

weight (kg)

DAPA dapagliozin; FDA Food and Drug Administration; FPG fasting plasma glucose; GLIM glimepiride; GLIP glipizide; HbA1c glycosylated
Change in
events led to discontinuation of treatment during

0.96
1.00
1.61
0.82
the trial.
The efcacy of canagliozin as add-on to back-
ground therapy with metformin was evaluated in a
FPG (mg/dL)

randomized, double-blind, placebo- and active-

Change in

controlled phase 3 study.35 The trial included 1284

patients who were 18 to 80 years of age and had an
20
20
12

HbA1c of 7% to 10.5% on a therapeutic dose of

NR

metformin. Exclusion criteria were similar to the study

by Stenlf et al33 detailed earlier in this section.
HbA1c (%)
Change in

0.79
0.89
0.96
0.39

Participants were randomized to receive canagliozin

hemoglobin; INS insulin; MET metformin; NR not reported; PBO placebo; PIO pioglitazone; SITA sitagliptin.

100 mg, canagliozin 300 mg, sitagliptin 100 mg

(active control), or placebo daily for 26 weeks (period I).
At the end of period I, patients in the placebo group
were switched to the sitagliptin arm (other patients
DAPA 2.5 mg
Treatment

DAPA 10 mg
groups

DAPA 5 mg

maintained current treatments), and the study was

continued for an additional 26 weeks. The primary
outcome measure was the change in HbA1c from
PBO

baseline at week 26. Secondary outcomes at week

26 included the percentage of patients who achieved
Background

INS MET

an HbA1c o7% and changes in FPG, weight, and

therapy

systolic blood pressure. The change in HbA1c at week

Data reported as compilation of doses; most patients were receiving maximum dose.

52 was another secondary end point.

Signicant reductions in HbA1c at week 26 were
observed for both canagliozin 100 mg (0.79%) and
Duration

canagliozin 300 mg (0.94%) compared with pla-

(wk)

24

cebo (P o 0.001) with metformin background ther-

apy. The percentage of patients who achieved an
HbA1c of o7% was 29.8% with placebo, 45.5%
HbA1c (%)
Baseline

with canagliozin 100 mg, and 57.8% with canagli-

8.55

ozin 300 mg (P o 0.001 for both canagliozin

FDA-approved dosage of dapagliozin 5 mg, 10 mg.

arms). Reductions in FPG (27 to 38 mg/dL),

weight (3.7% to 4.2%), and systolic blood pres-
Age (y)*

sure (3.8 to 5.1 mm Hg) were also signicant (P o

59.3

0.001). At week 52, canagliozin 300 mg lowered

HbA1c by 0.88%, compared with 0.73% with
Average age of all treatment groups.

both canagliozin 100 mg and sitagliptin 100 mg.

Genital mycotic infections and adverse events related
to osmotic diuresis (eg, polyuria and pollakiuria
Wilding et al47 (N 800)

P o 0.0001 versus placebo.

P o 0.001 versus placebo.

[increased urinary frequency]) were more common in

Table II. (continued).

the canagliozin treatment groups. The incidence of

hypoglycemia was low, but slightly higher with can-
agliozin (6.8%) compared with patients who re-
ceived sitagliptin (4.1%) or placebo/sitagliptin (2.7%).
P 0.0007.
P o 0.01.

In addition, canagliozin was examined as add-on

Study

therapy to a variety of background treatments,

including sulfonylureas,56 metformin/sulfonylurea

*

combination therapy,37,38 metformin/pioglitazone

] 2015 7
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Clinical Therapeutics
Table III. Clinical trials with empagliflozin.
Baseline HbA1c Duration Background Treatment Change in Change in Change in
Study Age (y) (%) (wk) therapy groups* HbA1c (%) FPG (mg/dL) weight (kg)

Kanada et al48 (N 100) 59.5 8 4 Not provided EMPA 1 mg 0.66 28.1 NP

EMPA 5 mg 0.72 35.3
EMPA 10 mg 0.85 41.6
EMPA 25 mg 0.82 42.7
PBO 0.42 15.5
Ferrannini et al49 (N 408) 58 7.9 12 None EMPA 5 mg 0.4 23.2 1.81
EMPA 10 mg 0.5 28.9 2.33
EMPA 25 mg 0.6 31.0 2.03
PBO 0.1 0.72
Kadowaki et al50 (N 547) 57.5 7.95 12 None EMPA 5 mg 0.42 22.65 2.5
EMPA 10 mg 0.40 25.28 2.6
EMPA 25 mg 0.65 33.7 2.9
EMPA 50 mg 0.61 32.54 3.1
PBO 0.3 4.06 0.9
Rosenstock et al51 (N 495) 5660 7.88.1 12 MET EMPA 1 mg 0.09 2.0 1.6
EMPA 5 mg 0.23 16.0 2.3
EMPA 10 mg 0.56 22.0 2.7
EMPA 25 mg 0.70 27.0 2.6
EMPA 50 mg 0.49 28.0 2.9
PBO 0.15 5.0 1.2
Hring et al52 (N 669) 57.1 8.1 24 MET SU EMPA 10 mg 0.82 23.22 2.16
EMPA 25 mg 0.77 23.22 2.39
PBO 0.17 5.58 0.39
Kovacs et al53 (N 499) 54.5 8.1 24 PIO MET EMPA 10 mg 0.59 16.92 1.62
EMPA 25 mg 0.72 21.96 1.47
PBO 0.11 6.48 0.34
Rosenstock et al54 (N 563) 56.7 8.3 52 MDI insulin MET EMPA 10 mg 1.18 23.76 1.95
EMPA 25 mg 1.27 25.74 2.04
Volume ] Number ]

PBO 0.81 11.34 0.44

Ferrannini et al55,
Study 1 (N 271) 59 7.898.15 78 None EMPA 10 mg 0.34 30 2.2
EMPA 25 mg 0.47 28 2.6
MET 0.56 26 1.3

(continued)
 K. Whalen et al.

combination therapy,39 and insulin therapy (with or

weight (kg)

78-week open-label extension of two 12-week studies: study 1, continuation of empagliozin 10 mg, empagliozin 25 mg, or metformin monotherapy; study 2,
EMPA empagliozin; FDA Food and Drug Administration; FPG fasting plasma glucose; HbA1c glycosylated hemoglobin; MDI multiple daily injections;
Change in without other antihyperglycemic agents).57 In each
case, signicant reductions in HbA1c, FPG, and weight

4.0
0.4
3.1 were seen when canagliozin was used as add-on
therapy. Compared with an active control as add-on
FPG (mg/dL)

therapy (eg, sitagliptin or glimepiride), canagliozin

Change in

demonstrated noninferiority in lowering HbA1c.36,38

Positive effects on weight and systolic blood pressure
32
21

16

were noted, similar to the above-mentioned trials.

Dapagliflozin Clinical Trials

HbA1c (%)
Change in

Ferrannini et al40 evaluated the safety prole and

0.34
0.63
0.40

efcacy of dapagliozin in treatment-naive patients

continuation of background metformin therapy with empagliozin 10 mg, empagliozin 25 mg, or sitagliptin 100 mg.
with T2DM. Patients inadequately controlled on diet
MET metformin; NP not published; PBO placebo; PIO pioglitazone; SITA sitagliptin; SU sulfonylurea.

and exercise alone were randomly assigned in this

EMPA 10 mg
EMPA 25 mg
Treatment

24-week, double-bind, parallel-group, placebo-con-

groups*

trolled study. Patients, aged 18 to 77 years, were

SITA

enrolled at 85 sites in the United States, Canada,

Mexico, and Russia. Patients were eligible if they had
a body mass index (BMI; calculated as weight divided
by height squared; kg/m2) r45 and fasting C-peptide
Background

Z1.0 ng/mL. History of T1DM, signicant renal or

therapy

hepatic impairment, a CV event (including New York

Heart Association Class III/IV heart failure) within the
MET

past 6 months, and severe uncontrolled hypertension

(systolic blood pressure Z180 mm Hg and/or dia-
stolic blood pressure Z110 mm Hg) excluded patients
Duration
(wk)

from entering the study.

The study design involved 3 cohorts. Patients with
an HbA1c of 7% to 10% were randomly assigned to
receive placebo or dapagliozin 2.5 mg, 5 mg, or
Baseline HbA1c

FDA-approved dosage of empagliozin 10 mg, 25 mg.

10 mg once daily in the morning (main cohort) or

7.888.03
(%)

once daily in the evening (exploratory cohort). A third

cohort (high HbA1c exploratory cohort) included
patients with an HbA1c between 10.1% and 12%.
These patients were assigned to 5 mg or 10 mg once
Age (y)

daily in the morning. No placebo arm was used

60

secondary to the elevated HbA1c levels. Patients were

P o 0.05 compared to placebo.

allowed a rescue medication (metformin) when FPG

was 4270 mg/dL at week 4, 4240 mg/dL at week 8,
P o 0.0001 versus placebo.
P o 0.001 versus placebo.

or 4200 mg/dL at weeks 12 to 24. The primary

P o 0.01 versus placebo.

outcome was change in HbA1c from baseline in the

Table III. (continued).

main cohort. Secondary end points included changes

Study 2 (N 388)

from baseline in FPG and total weight.

In total, 485 patients were randomly assigned to
the main and exploratory cohorts, whereas 74 pa-
tients were assigned to the high HbA1c exploratory
Study

cohort. HbA1c reductions were apparent by week 4

*

and maintained throughout the trial. The main cohort

] 2015 9
 Clinical Therapeutics
saw mean HbA1c reductions from 0.58% to
0.89% with dapagliozin treatment compared with
0.23% with placebo. The dose-ordered reductions in
HbA1c afforded by dapagliozin were statistically
signicant for the 5- and 10-mg groups (P 0.005,
P o 0.001, respectively). Patients in the high HbA1c
exploratory cohort (10.1%12%) saw the greatest
reduction in HbA1c (1.90% to 1.98%); the P value
was not reported.
Dapagliozin was tolerated well and was not
discontinued in the study secondary to hypoglycemia.
Reductions were statistically signicant for FPG in the
5- and 10-mg arms. Reductions in weight and both
systolic and diastolic blood pressures were observed
but did not reach statistical signicance. Signicant
changes in serum electrolytes or renal function were
not observed in the active treatment. Consistent with
other SGLT2 inhibitors, patients in the treatment arm
experienced more events suggestive of genital infec-
tions and UTIs (7.7%12.9% vs 1.3% placebo and
4.6%12.5% vs 4% placebo, respectively). Of note,
weight reductions did not plateau by the end of the
study. Long-term studies may identify a greater weight
reduction. Results of other monotherapy trials found
similar reductions in HbA1c, weight, and FPG and are
summarized in Table II.4042
The safety prole and efcacy of dapagliozin was
evaluated in a 48-week placebo-controlled, multicen-
ter trial in patients inadequately controlled on insulin
(with or without other oral antidiabetic agents).47 A
total of 808 patients with T2DM inadequately
controlled on at least 30 units of insulin daily were
randomly assigned to treatment with dapagliozin 2.5
mg, 5 mg, 10 mg or placebo. Enrolled patients were
between 18 and 80 years of age, had a BMI r45, and
an HbA1c between 7.5% and 10.5%. During the 8
weeks before enrollment, patients must have been on
at least 1500 mg of metformin daily or at least one-
half the maximum dose of other oral antidiabetic
agents. Exclusion criteria included T1DM, eGFR
o50 mL/min/1.73 m2, serum creatinine (SCr) 42
mg/dL, or SCr Z1.5 mg/dL for men or Z1.4 mg/dL
for women if on metformin. Study medications and
oral antidiabetic drugs were not modied except when
hypoglycemia was a concern, and the dose of the oral
antidiabetic drugs were subsequently decreased. Up
titration of insulin was allowed if FPG was 4240 mg/dL
between weeks 0 and 12, 4220 mg/dL between weeks
12 and 24, or 4180 mg/dL between weeks 25 and 48
10
with 3 self-reported readings. The primary end point
was change in HbA1c from baseline. Secondary out-
comes included change in mean insulin dose, weight,
and FPG.
A statistically signicant reduction in HbA1c from
baseline was observed (0.32%, 0.49%, 0.54%;
P o 0.001 all groups) in the 2.5-, 5-, and 10-mg
groups, respectively. The most rapid decrease in
HbA1c occurred within the rst 8 weeks and was
maintained at 48 weeks. Total weight decreased in all
groups (0.96 to 1.61 kg), compared with an
increase in the placebo arm (0.82 kg). FPG was
reduced in all treatment arms. Patients in the dapagli-
ozin treatment arms did not necessitate an increase in
insulin requirement throughout the trial; however, the
placebo group requirements did increase progressively
(with an up titration mean of 10.54 units/d). Reduc-
tions of systolic blood pressure (3.8 to 5.4 mm Hg)
along with diastolic reductions (2.3 to 3.1 mm Hg)
were noted in the dapagliozin treatment groups.
Orthostatic hypotension was not observed in the
treatment arms.
Similar to other clinical trials, dapagliozin was
well tolerated, and the overall adverse event rate was
similar between the treatment arms. A larger number
of patients experienced hypoglycemia in the dapagli-
ozin arms (56.6%) compared with placebo (51.8%).
In addition, more patients in the treatment arms
experienced UTIs and genital infections. Data suggest
treatment with dapagliozin improves glycemic con-
trol, produces sustained weight loss, and appears to be
insulin sparing.
Consistently, dapagliozin 5 and 10 mg daily, im-
proved glycemic control in patients with inadequately
controlled T2DM as monotherapy and as add-on com-
bination therapy with metformin,44 glimepiride,17 pio-
glitazone,45 sitagliptin,46 and insulin47 (Table II). In
each trial, signicant reductions were noted in HbA1c
and FPG. Combination trials saw greater reductions in
weight compared with placebo, with similar trends ob-
served in monotherapy trials. In addition, dapagliozin
established noninferiority compared with glipizide in
patients inadequately controlled on 1500 to 2500 mg/d
metformin.43 Results of this 1-year study found no
treatment differences for markers of glycemic control
and found a more favorable effect on weight in the
dapagliozin arm. Consistent with the above-mentioned
trials, reductions in both systolic and blood pressure
were observed.
Volume ] Number ]

Empagliflozin Clinical Trials
In a 12-week trial, 408 patients with T2DM were
randomized to receive empagliozin, placebo, or
metformin.49 The multicenter trial was conducted at
75 centers in 13 countries. After a 4-week washout
period, patients were randomized to receive one of the
following: empagliozin 5 mg, empagliozin 10 mg,
empagliozin 25 mg, placebo, or open-label metfor-
min at a maximum dose of 1000 mg twice daily.
The following patients were included in the study:
men and women aged 18 to 79 years with T2DM,
treatment-naive for Z10 weeks or on 1 diabetes
medication (except TZDs, GLP-1 receptor agonists,
or insulin) at a stable dose for Z10 weeks, HbA1c
6.5% to 9% for patients on 1 medication or HbA1c
7% to 10% for treatment-naive patients, and BMI
r40. Patients were excluded from the study for the
following reasons: acute myocardial infarction, stroke,
or transient ischemic attack within the past 6 months;
impaired hepatic function; impaired renal function
(SCr 41.5 mg/dL for men and 41.4 mg/dL for
women); unstable or acute heart failure; acute or
chronic acidosis; diseases of the central nervous
system, psychiatric disorders, or clinically relevant
neurologic disorders; chronic or acute infection; cur-
rent or chronic urogenital infection; dehydration;
history of clinically relevant allergy/hypersensitivity;
intolerance to metformin; hereditary galactose intol-
erance; treatment with TZDs, GLP-1 receptor ago-
nists, or insulin within the past 3 months; use of
antiobesity medications; current treatment with sys-
temic steroids; alcohol abuse; treatment with an
investigational drug within the past 2 months; and
pregnancy, breast-feeding, or not using acceptable
birth control methods (women). The primary efcacy
end point was the change in HbA1c from baseline to
week 12. Secondary end points included change in
FPG from baseline to week 12, change in HbA1c from
baseline over time, proportion of patients who
achieved HbA1c r7% after 12 weeks, proportion of
patients who achieved a decrease in HbA1c Z0.5%
after 12 weeks, change in weight from baseline to 12
weeks, and pharmacokinetic parameters of empagli-
ozin. Safety and tolerability were assessed from the
following data: incidence and intensity of adverse
events, withdrawal from treatment due to adverse
events, clinically relevant changes in physical exami-
nation, vital signs, electrocardiogram, or laboratory
results.
] 2015
K. Whalen et al.
Baseline characteristics were similar between
groups, and the mean nal dose of metformin was
1668 mg/d. Compared with placebo, the mean HbA1c
decrease after 12 weeks was greater in all empagli-
ozin groups (P o 0.0001). In patients with a baseline
HbA1c Z8%, the change in HbA1c was 0.6%,
0.7%, and 1.1% in the empagliozin 5-mg, 10-
mg, and 25-mg groups, respectively. For patients with
a baseline HbA1c of o8%, HbA1c changes of 0.5%,
0.4%, and 0.5% were seen in the empagliozin
5-mg, 10-mg, and 25-mg groups, respectively. In
addition, more patients in the empagliozin groups
achieved an HbA1c r7% and a decrease in HbA1c of
Z0.5% compared with placebo. FPG and mean
weight decreased in all empagliozin groups com-
pared with placebo. The incidence of adverse events
was similar between all groups, including placebo.
The most common adverse events reported with
empagliozin were pollakiuria, thirst, and nasophar-
yngitis. Seven patients reported adverse events consis-
tent with UTIs, and 5 patients reported adverse events
consistent with genital infections. No cases of hypo-
glycemia occurred in patients who took empagliozin.
No clinically signicant changes in physical examina-
tion, vital signs, electrocardiogram, or laboratory
values were noted.
A 12-week study examined the safety prole and
efcacy of empagliozin in 495 patients inadequately
controlled on metformin.51 Patients were randomized
to receive one of the following regimens in addition to
metformin: empagliozin 1 mg, 5 mg, 10 mg, 25 mg,
or 50 mg daily; or placebo; or open-label sitagliptin
100 mg daily. Patients meeting the following criteria
were included in the study: age of 18 to 80 years, BMI
r40, previous treatment with metformin alone or in
combination with 1 additional agent, unchanged
diabetes therapy for at least the past 10 weeks, HbA1c
6.5% to 9% for patients on metformin plus 1 addi-
tional agent (additional agent was stopped at study
entry), or HbA1c 7% to 10% for patients on metfor-
min monotherapy. The exclusion criteria for this study
included history of acute myocardial infarction,
stroke, or transient ischemic attack in the past 6
months; impaired hepatic or renal function; diseases
of the central nervous system; chronic or acute
infection; history of allergy/hypersensitivity; and treat-
ment with TZDs, GLP-1 receptor agonists, or insulin
within the past 3 months. The primary end point was
change in HbA1c from baseline to week 12.
11
 Clinical Therapeutics
Secondary end points included change in HbA1c over
time, change in FPG and weight from baseline to week
12, and proportion of patients achieving HbA1c
r7% or HbA1c lowering of Z0.5% at week 12.
Assessments for safety and tolerability involved labo-
ratory parameters, vital signs, and adverse event
reporting.
Of 495 patients randomly assigned, 63% were
taking metformin alone and 37% were taking met-
formin plus 1 additional antidiabetic drug. The
placebo-adjusted mean decrease in HbA1c was
0.24%, 0.39%, 0.71%, 0.7%, and 0.64%
for the empagliozin 1-mg, 5-mg, 10-mg, 25-mg, and
50-mg groups, respectively. The changes in HbA1c
were statistically signicant for all doses except
empagliozin 1 mg daily. More patients in the
empagliozin 10-mg, 25-mg, and 50-mg groups
achieved an HbA1c r7% than placebo. FPG and
weight were also signicantly decreased in patients
taking empagliozin compared with placebo, except
in the 1-mg group. The most commonly reported
adverse events in patients taking empagliozin were
UTI and pollakiuria. Fourteen patients taking empa-
gliozin reported symptoms consistent with UTI and
genital infections. Hypoglycemia was reported in 4
patients taking empagliozin; however, no patients
experienced a blood glucose level o54 mg/dL.
Empagliozin was also studied in combination with
a sulfonylurea,52 pioglitazone (with or without met-
formin),53 and insulin.54 The results of these studies
consistently revealed signicant reductions in HbA1c,
FPG, and weight. A long-term, active control trial that
involved empagliozin 10 mg or 25 mg as monothe-
rapy or add-on to metformin found empagliozin pro-
vides sustained glycemic control and continued weight
loss over 90 weeks with a low risk of hypoglycemia in
patients with T2DM.55
CV Safety Profile
SGLT2 inhibitors are associated with a reduction in
systolic and diastolic blood pressures when used as
both monotherapy or in combination with other
glucose-lowering agents.5860 A meta-analysis of 21
placebo-controlled trials indicated a mean drop in
systolic blood pressure of 3.77 mm Hg. The same
analysis reported a drop of 1.75 mm Hg in diastolic
blood pressure across 16 placebo-controlled trials.59
Although the mechanism is not completely understood,
these effects are likely attributed to a glucose-induced
12
osmotic diuresis. Symptomatic hypotension may
occur in patients with an eGFR o60 mL/min/
1.73 m2, patients on diuretics or medications that
interfere with the renin-angiotensin-aldosterone sys-
tem, the elderly, or patients with low systolic blood
pressure.810 Small changes in fasting lipid proles
were reported with the SGLT2 inhibitors, including an
increase in high-density and low-density lipoproteins
and a decrease in triglycerides.15,59 Whether this
represents a clinically signicant effect remains un-
known. Weight loss of
1 to 5 kg was observed in all
studies with SGLT2 inhibitors and appears to be
sustained at 48 to 52 weeks of follow-up.45 Weight
loss is predominately because of loss of fat, parti-
cularly visceral adipose tissue, rather than lean
mass.58,61 Both monotherapy and combination ther-
apy trials have reported weight reduction that may
mitigate weight gain associated with insulin and/or
TZDs.45
CANVAS (CANagliozin cardioVascular Assess-
ment Study) is an ongoing CV safety study of cana-
gliozin in 4330 persons with CV disease or at high
risk. Preliminary results suggest that canagliozin is
not associated with an increased risk of CV events.62
However, an elevated stroke risk was found within the
rst 30 days of canagliozin therapy. Final results of
CANVAS are not expected until sometime in 2015.63
An updated meta-analysis of dapagliozin, consistent
with previous meta-analyses, found no unacceptable
increase in CV risk.64,65 A CV outcome trial with
empagliozin is also currently under way.66
Adverse Events
SGLT2 inhibitors did not lead to signicant changes
in renal function in phase 2 and 3 studies.810 Although
no signicant changes were observed, elevations in SCr
and blood urea nitrogen may occur. Patients with
hypovolemia are more susceptible and may require
more frequent monitoring of renal function.810 This
class of drugs is primarily renally eliminated, and
exposure to these agents is increased in renal impair-
ment. Paradoxically, however, glucose lowering is
decreased in severe renal impairment.810,58 Because
the ability to enhance UGE is diminished with severe
renal impairment, the SGLT2 inhibitors are expected to
be ineffective in patients with an eGFR o30 mL/min/
1.73 m2.
Promotion of glucosuria with the SGLT2 inhibitors
may be anticipated to increase the incidence of
Volume ] Number ]
 K. Whalen et al.

genitourinary infections (Table IV).15,57,67 The in-
creased incidence (approximately double) of genital
infections appears more pronounced in women, although
uncircumcised men were also at a higher risk of
infection such as balanitis and balanoposthitis. Pa-
tients with a prior history of genital mycotic infections
were more likely to encounter subsequent mycotic
infections.9 The frequency of UTIs was inconsistent
among trials but also appeared to be increased.15,58
Genital infections were not dose dependent and led to
discontinuation of therapy in o1% of patients. The
occurrence of both mycotic infections and UTIs in
clinical trials appears to be reduced over time. Dis-
continuations due to UTIs and genital infections
occurred within the rst year of treatment, with no
discontinuation observed in the second year.61
A small increase in the number of bladder tumors
(10 of 6045 patients) was reported in clinical trials with
dapagliozin.65 Five of these cases occurred during the
rst 6 months of therapy, which may cast doubt on the
direct link between the medication and the
development of cancer. In addition, baseline
hematuria was observed in 9 of the 10 patients. Two
of the patients had a history of hematuria before
dapagliozin therapy. In any case, the FDA has
proposed continued clinical and statistical
surveillance; package labeling includes a warning for
bladder cancer in patients with prior or active history
of bladder cancer.9,65 Risk factors associated with
reported cases include male sex, advanced age, and
pioglitazone use.65 Of note, dapagliozin was not
initially approved by the FDA in 2011, secondary to
an increased incidence of bladder cancer. An increase in
bladder cancer was not observed with empagliozin or
canagliozin. However, after-marketing surveillance
data is being collected on all of the SGLT2 inhibitors.68
ROLE IN THERAPY
On the basis of available data from clinical trials,
SGLT2 inhibitors appear to be effective as monotherapy
and add-on therapy for patients uncontrolled on met-
formin, sulfonylureas, insulin, or other antihyperglyce-
mic combinations. The class lowers HbA1c by
0.5%
to 1% and is potentially useful for patients with an
HbA1c o9%. SGLT2 inhibitors have a unique mecha-
nism of action that promotes weight loss and reductions
in blood pressure, with a low risk of hypoglycemia.
These agents are well suited for obese or hypertensive
patients and patients at risk of hypoglycemia. One
caveat, however, would be in combining SGLT2 inhib-
itors with insulin and sulfonylureas, because hypoglyce-
mia may be more likely to occur. Inhibiting SGLT2
receptors and increasing UGE facilitates the pathogenesis
of and may lead to UTIs and genital mycotic infections.
Patients with a history of these infections should avoid
SGLT2 inhibitors. In addition, patients with postural
hypotension and renal impairment are not ideal candi-
dates for these drugs. SGLT2 inhibitors increase low-
density lipoprotein; whether this is clinically meaningful
remains to be determined.
Despite proven efcacy, questions are still unan-
swered, and the exact role of these agents is unclear.
In the most recent American Diabetes Association
guidelines on the management of hyperglycemia in

Table IV. Common adverse effects with SGLT2 inhibitors.810

Canagliozin* Dapagliozin Empagliozin

Adverse effect (%) 100 mg 300 mg 5 mg 10 mg 10 mg 25 mg

Female genital mycotic infections 10.4 11.4 8.4 6.9 5.4 6.4
Male genital mycotic infections 4.2 3.7 2.8 2.7 3.1 1.6
Increased urination 5.3 4.6 2.9 3.8 3.4 3.2
Urinary tract infections 5.9 4.3 5.7 4.3 9.3 7.6

SGLT2 sodium-glucose co-transporter 2.

*
Pooled data from 4 placebo-controlled trials that reect exposure of 1667 patients to canagliozin.

Pooled data from 12 placebo-controlled trials that reect exposure of 2338 patients to dapagliozin.

Pooled data from 5 placebo-controlled trials that reect exposure of 1976 patients to empagliozin.

] 2015 13
 Clinical Therapeutics
T2DM, SGLT2 inhibitors are 1 of 6 treatment options
that may be considered as combination therapy with
metformin if the HbA1c target is not achieved after 3
months of metformin monotherapy at maximum tol-
erated doses. In addition, if a patient has an intolerance
or contraindication to metformin therapy, SGLT2
inhibitors may be considered as initial drug therapy
according to the American Diabetes Association.6 The
American Association of Clinical Endocrinologists lists
SGLT2 inhibitors as agents that may be used cautiously
either as monotherapy or dual/triple combination
therapy.69 This is because of the lack of evidence
available at the time the American Association of
Clinical Endocrinologists guidelines were published in
2013. Expense, adverse events, and lack of long-term
efcacy data may limit the use of these agents. Long-
term safety end points, including cancer and CV
outcomes, need to be explored. Data thus far are
reassuring; however, after-marketing studies may help
quantify any potential associations with these adverse
outcomes. Studies that examine the clinical signicance
of inhibition of SGLT1 are also under way. In addition,
the use of SGLT2 inhibitors in persons with T1DM and
children is currently being investigated.15
CONCLUSION
The SGLT2 inhibitors represent a new class of antihy-
perglycemics that improve glucose control by increasing
UGE. The mechanism of action renders them effective as
monotherapy or add-on therapy in combination with a
variety of other medications for diabetes. Added benets
of the SGLT2 inhibitors include a modest reduction in
weight and systolic blood pressure and a low risk of
hypoglycemia. The decision to use these agents should be
based on patient-specic factors such as reduction in
HbA1c needed, renal function, tolerability, and cost issues.
ACKNOWLEDGMENT
Dr. Miller was primarily responsible for researching
and writing the sections pertaining to dapagliozin.
Dr. St. Onge was primarily responsible for prepara-
tion of the sections pertaining to empagliozin.
Dr. Whalen was responsible for preparation of the
sections pertaining to canagliozin and for compila-
tion and review of the nal manuscript.
CONFLICTS OF INTEREST
The authors have indicated that they have no conicts
of interest regarding the content of this article.
14
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