503626

research-article2013
AOPXXX10.1177/1060028013503626Annals of PharmacotherapyNigro et al

Review Article-New Drug Approvals

Annals of Pharmacotherapy

Canagliflozin, a Novel SGLT2 Inhibitor for

47(10) 1301­–1311
© The Author(s) 2013
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DOI: 10.1177/1060028013503626
aop.sagepub.com

Stefanie C. Nigro, PharmD, BCACP, BC-ADM1, Daniel M. Riche,

PharmD, BCPS, CDE2,3, Michelle Pheng, PharmD4, and
William L. Baker, PharmD, FCCP, BCPS5

Abstract
Objective: To evaluate the available clinical data on canagliflozin and provide formulary considerations as to its place in
the current treatment approach of type 2 diabetes mellitus (T2DM). Data Sources: A systematic review of the literature
in MEDLINE and Web of Science was performed through July 2013 using the key words and medical subject headings
canagliflozin, JNJ-28431754, TA-7284, and sodium-glucose co-transporter 2 inhibitor. A manual search of references from
reports of clinical trials or review articles was performed to identify additional relevant studies. Study Selection and
Data Extraction: Citations eligible for inclusion were in vitro or in vivo evaluations of canagliflozin with no restrictions
on patient population or indication used. Data related to the patient populations and outcomes of interest were extracted
from each citation. Data Synthesis: Five clinical trials (n = 2775 subjects) have been published evaluating canagliflozin
in patients with T2DM. A single study evaluated canagliflozin monotherapy, while the others included various add-on
therapies. Four studies included placebo groups with 2 others using sitagliptin as an active control. Compared with placebo
(+0.14%), canagliflozin monotherapy at doses of 100 to 300 mg/d decreases hemoglobin A1c by −0.77% to −1.03% from
baseline. Reductions in fasting plasma glucose, body weight, and systolic blood pressure were seen. Because of the increase
in glucosuria with the drug, patients (especially females) are at increased risk of genital mycotic infections. The overall
safety of canagliflozin (eg, cardiovascular, oncologic, pancreatic, bone) is also yet to be fully elucidated. Conclusions:
Canagliflozin is comparable to second-line oral medications in terms of effectiveness but has limitations in affordability and
long-term safety data.

Keywords
canagliflozin, SGLT2 inhibitor, type 2 diabetes mellitus

Introduction an expansion of the clinical utility of existing therapies (ie, bro-

Nearly 26 million Americans (8.3%) are diagnosed with
diabetes and an additional 79 million at risk for developing
the disease.1 Current clinical practice guidelines strongly
emphasize treatment and prevention strategies that include
individualized patient care planning, early lifestyle inter-
ventions, and the use of pharmacotherapy (Table 1)2,3 to
help minimize the growing burden of disease.4,5
The pathogenesis of type 2 diabetes mellitus (T2DM) is
complex and multifactorial. Characteristics of T2DM have
been expanded from diminished (or absent) insulin secretion,
increased gluconeogenesis and decreased peripheral uptake of
glucose to include a multitude of pathophysiologic abnormali-
ties.7 Discovery of neurotransmitter dysfunction and an
impaired incretin effect has led to the development of newer
drug therapies (ie, dipeptidyl peptidase-4 inhibitors [DPP-4]
inhibitors and glucagon-like peptide 1 [GLP-1] agonists) and
mocriptine, colesevelam). Most recently, the kidney has been
the target for drug development. It is estimated that >90% of
all filtered glucose is reabsorbed by the sodium-glucose trans-
porter 2 (SGLT2) in the kidney’s proximal tubule.8 Therefore,
glucose homeostasis can be maintained via decreased
1
Massachusetts College of Pharmacy and Health Sciences, Boston, MA,
USA
2
School of Pharmacy, The University of Mississippi, Jackson, MS, USA
3
Cardiometabolic Clinic, The University of Mississippi Medical Center,
Jackson, MS, USA
4
CVS Pharmacy, Middletown, CT, USA
5
University of Connecticut, Storrs, CT, USA
Corresponding Author:
William L. Baker, School of Pharmacy, University of Connecticut, 69 N.
Eagleville Rd, Unit 3092, Storrs, CT 06269-3092, USA.
Email: wbaker@uchc.edu

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1302 Annals of Pharmacotherapy 47(10)

Table 1.  Oral and Non-Insulin Injectables for Type 2 Diabetes.2,4,6.

Expected HbA1c Lowering With

Medication Class Proposed Site of Action Monotherapy (%)
Sulfonylureas (glyburide, glipizide, glimepiride Pancreas (beta cells) 1.0-2.0
Biguanide (metformin) Liver, peripheral tissue 1.0-2.0
α-Glucosidase inhibitors (acarbose, miglitol) Small intestine 0.5-0.8
Dipeptidyl peptidase-4 inhibitors (sitagliptin, GI tract 0.5-0.8
saxagliptin, linagliptin, alogliptin)
Amylin agonist (pramlintide) Pancreas (alpha cells) 0.5-1.0
Thiazolidinediones (pioglitazone, rosiglitazone) Adipose and peripheral tissue 0.5-1.4
Glinides (repaglinide, nateglinide) Pancreas (beta cells) 0.5-1.5
Glucagon-like, peptide-1 receptor agonists GI tract and liver 0.5-1.0
(exenatide, exenatide extended-release, liraglutide)
DA-2 agonist (bromocriptine) Brain <0.5
Bile acid sequestrant (colesevelam) Small intestine, liver <0.5
Sodium-glucose transport inhibitors (canaglifozin) Kidney ≤1.0

Abbreviations: HbA1c, glycosylated hemoglobin A1c; GI, gastrointestinal; DA, dopamine.

reabsorption. Because glucose is a viable source of energy, its
increased elimination will simultaneously lead to a caloric
deficit.
Canagliflozin (an SGLT2 inhibitor) was approved by the
US Food and Drug Administration (FDA) in March 2013 to
improve glycemic control in adult patients with T2DM as
an adjunct to diet and exercise.3,9 Unlike other currently
available oral agents, canagliflozin facilitates urinary glu-
cose excretion (UGE), thus decreasing plasma glucose con-
centrations.3 Canagliflozin exerts its therapeutic effect
independent of preserved β-cell function and insulin secre-
tion. While its clinical utility is yet to be fully elucidated,
this article will evaluate the available clinical data on cana-
gliflozin and provide formulary considerations as to its
place in the current treatment approach of T2DM.
Data Selection
A systematic review of the literature for all relevant articles
was performed through July 15, 2013 using MEDLINE
(beginning January 1950) and Web of Science (beginning
1974). The search strategy was developed using the key
words and medical subject headings (MeSH) canagliflozin,
JNJ-28431754, TA-7284, and sodium-glucose co-transporter 2
inhibitor. Citations were limited to those published in the
English language. A manual search of references from
reports of clinical trials or review articles was performed
to identify additional relevant studies. Citations were eli-
gible for inclusion in this review if they were in vitro or in
vivo evaluations of canagliflozin with no restrictions on
patient population or indication used. Product monographs
were retrieved from governmental Web sites (http://www.
fda.gov) and from the product sponsor (Janssen
Pharmaceuticals, Titusville, NJ). A search of ClinicalTrials.
gov (http://www.clinicaltrials.gov) was also conducted to
identify additional recently completed or ongoing studies
of relevance.
Chemistry and Pharmacology
Canagliflozin, (1S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-
thienyl]methyl]-4-methylphenyl]-d-glucitol hemihy drate, is
an orally active film-coated tablet with a molecular weight of
453.53 g/mol.3
The kidney plays a major role in glucose homeostasis
through gluconeogenesis and glomerular filtration and
reabsorption of glucose in the proximal convoluted tubules
.6(pp332-335),10-12 Nearly all of the glucose filtered by the glom-
eruli (>99%) is reabsorbed in a healthy adult and returned to
the circulation (Figure 1).6,7,10,13 At plasma glucose concen-
trations beyond the resorptive threshold (~180 g/d), glucose
begins to appear in the urine.6 In patients with T2DM, evi-
dence suggests that the renal glucose resorptive capacity is
increased.7 This means that, even in the presence of hyper-
glycemia, glucose is continuing to be resorbed into the cir-
culation, further increasing serum glucose concentrations.
This is key to the mechanistic benefits of canagliflozin and
could help explain its glucose-lowering potential (described
later).
Glucose reabsorption occurs primarily within the proxi-
mal renal tubule (Figure 1A).13 Because cell membranes are
impermeable to glucose, transport requires the assistance of
carrier proteins. Sodium-glucose transporter 1 (SGLT1) and
SGLT2 are proteins located within the brush border mem-
brane of the proximal renal tubule that catalyze the active
transport of glucose across the luminal membrane. The
SGLT2 transporter is found primarily in the S1 segment of
the proximal tubule and accounts for approximately 90% of

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Nigro et al 1303
Figure 1.  Renal handling of glucose transport (A) and the role
of sodium-glucose transporter 2 (SGLT2) (B). Reproduced with
permission from Chao and Henry.1,13
reabsorbed glucose, with expression limited to within the
kidney.14 SGLT1 is a low-capacity transporter found more
distal in the S2/S3 segment of the proximal tubule and is
involved with reabsorption of the remaining glucose load. It
is primarily involved with glucose absorption within the gas-
trointestinal tract. SGLT2 couples glucose with the transport
of sodium and actively pumps it against a concentration gra-
dient across the luminal membrane (Figure 1B).10,15 Glucose
passively diffuses out of the cell via facilitative glucose trans-
porters (GLUT) 1 and 2.16
Inhibition of SGLT has been the focus of drug develop-
ment since the isolation of phlorizin from the root bark of
the apple tree in 1835.17 Although phlorizin is an effective
inhibitor of SGLT2, its poor absorption following oral
administration does not allow for clinical use. Thus, various
SGLT2 inhibitors are in development. Canagliflozin is an
orally active agent exhibiting 250-fold greater inhibition of
SGLT2 versus SGLT1.18 Animal studies show that cana-
gliflozin inhibited sodium-dependent 13C-α-methyl-
glucoside uptake in cells expressing human SGLT2 or
SGLT1 with an IC50 (half-maximal inhibitory concentra-
tion) of 4.4 ± 1.2 and 84 ± 159 nmol/L, respectively.19 A
single-dose study in healthy volunteers showed that cana-
gliflozin 300 mg reduced postprandial plasma and insulin
glucose excursions, and increased UGE (5.9 and 12.2 g dur-
ing the 0- to 2-hour and 2- to 6-hour intervals) compared
with placebo (0.15 g).20 To evaluate the rate of intestinal
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glucose absorption, they tested the systemic appearance of
orally administered glucose (RaO).20 Canagliflozin reduced
the amount of oral glucose absorption (area under the curve
[AUC] RaO) by 31% and 20% over the 0- to 1-hour and 0-
to 2-hour intervals, respectively, although the difference
was no longer significant from 2 to 6 hours versus pla-
cebo.20 The observed reduction in gastrointestinal glucose
absorption is suggestive of transient SGLT1 inhibition.
A phase-1, dose-ranging study of healthy male subjects
by Sha et al21 showed that canagliflozin decreased the
24-hour renal threshold for glucose (RTG) in a dose-depen-
dent manner with the maximally effective dose (>400 mg
daily). The RTG is the glucose concentration below which
minimal UGE occurs, and above which UGE rises in direct
proportion to plasma glucose. It is calculated from the
plasma glucose profiles, UGE, and glomerular filtration
rate. Urinary glucose excretion was also similarly increased
in a dose-dependent manner by ~70 g with canagliflozin
doses >200 mg. Fasting plasma glucose (FPG) and serum
insulin concentrations were generally similar among the
treatment groups. These results were repeated in a phase 1b
study of patients with T2DM who were on stable doses of
insulin either alone or in combination with other oral anti-
hyperglycemic agents (AHA) and were not optimally con-
trolled.22 Subjects were randomized to receive either
canagliflozin 100 mg daily, 300 mg twice daily, or placebo
for 28 days in addition to their other therapies. The change
from baseline of UGE for canagliflozin 100 mg daily and
300 mg twice daily was 67 g/d and 153 g/d versus placebo
(P < .05 for both). The change from baseline of RTG was
similarly decreased versus placebo (P < .05 for both).
Canagliflozin 100 mg daily and 300 mg twice daily also
significantly reduced FPG (−38.0 mg/dL and −42.3 mg/dL)
and hemoglobin A1c (HbA1c) (−0.37% and −0.55%) from
baseline versus placebo (+8.6 mg/dL, and −0.19%, respec-
tively; P < .05 for both).
Pharmacokinetics
Following oral administration, canagliflozin has a mean
absolute oral bioavailability of approximately 65%.3
Administration with a high-fat meal does not affect this
absorption. Canagliflozin is extensively distributed into tis-
sues, with a mean steady-state volume of distribution of 119
L, and is 99% bound to plasma proteins.3 Hepatic conver-
sion of canagliflozin to two inactive O-glucuronide metabo-
lites (M5 and M7) is its primary mode of metabolism, with
minimal (~7%) additional metabolism by the CYP3A4 iso-
enzyme.3,23 Median tmax values for canagliflozin, M5, and
M7 were 1.5 to 2.0, 1.75 to 4.5, and 2.0 to 3.0 hours, respec-
tively, regardless of dose. The terminal elimination half-life
for canagliflozin was 14 to 16 hours, which was indepen-
dent of dose. Renal excretion of canagliflozin, M5, and M7
was <1%, 7% to 10%, and 21% to 32%, respectively.23 The
1304 Annals of Pharmacotherapy 47(10)
amounts found in the feces was 41.5%, 7.0%, and 3.2% for
canagliflozin, M5, and M7, respectively.3
In vitro studies have shown canagliflozin to have no
appreciable effect on either cytochrome P450 isoenzyme
induction or inhibition, although mild inhibition of
CYP2B6, SYP2C8, CYP2C9, and CYP3A4 was seen. The
manufacturer’s information also states that canagliflozin
may be a weak P-glycoprotein inhibitor. However, studies
have shown no clinically relevant effect on the AUC or Cmax
of co-administered drugs such as metformin, glyburide,
warfarin, or oral contraceptives containing ethinyl estradiol
and levonorgestrel.3,24-26 Significant increases in the AUC
and Cmax of digoxin were seen (20% and 36%, respectively,
when given with canagliflozin.3 Diligent serum digoxin
monitoring is recommended when these drugs are used con-
comitantly. The inhibition of P-glycoprotein is likely the
mechanism behind this interaction.
Clinical Trials
Summary of Published Clinical Trials
To date, 7 clinical trials evaluating the effectiveness of
canagliflozin on outcomes in patients with T2DM have
been fully published.27-33 The characteristics of these trials
are summarized in Table 2. Two studies evaluated cana-
gliflozin monotherapy,27,33 while the others included vari-
ous add-on therapies.28-32 Add-on therapies generally
included metformin with or without concomitant sulfonyl-
urea therapy, although some studies allowed any AHA regi-
men (including both orals and insulin). While five of the
seven studies were placebo controlled,27,28,30,31,33 2 studies
included sitagliptin (a DPP-4 inhibitor) as an active con-
trol28,29 and another included glimepiride (a sulfonylurea).32
Study duration ranged from 12 to 52 weeks with enrollment
ranging from 269 to 1450 patients. Five studies had a mean
age around 50 to 57 years,27-29,32,34 while the mean age in 2
others were 64 to 69 years,30,31 one of which only enrolled
patients 55 to 80 years old.31 Each study used the change
from baseline in HbA1c as their primary outcome. Most
studies also evaluated changes from baseline in FPG, blood
pressure (both systolic and diastolic), body weight, and
lipid parameters as well as the proportion of patients reach-
ing an HbA1c or either <7% or <6.5%. Each of these will be
discussed in detail below.
Hemoglobin A1c and Plasma Glucose Control
When used as monotherapy in patients with T2DM inade-
quately controlled on diet and exercise for 26 weeks, cana-
gliflozin 100 mg/d and 300 mg/d reduced the HbA1c from
baseline by −0.77% and −1.03%, respectively, compared
with placebo (0.14%; P < .001 for both).27 Reductions were
found to be greater in patients with a higher baseline HbA1c.
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Compared with placebo (20.6%), a significantly greater
proportion of patients receiving canagliflozin 100 mg/d
(44.5%) and 300 mg/d (62.4%) achieved an HbA1c of <7%
(P < .001 for both). Similarly, canagliflozin 100 mg/d and
300 mg/d significantly reduced the FPG by 27 mg/dL and
34.2 mg/dL from baseline versus placebo (+9 mg/dL; P <
.001 for both). Reductions in 2-hour postprandial glucose
values were also seen with canagliflozin 100 mg/d (−43.2
mg/dL) and 300 mg/d (−59.5 mg/dL) versus placebo (+5.4
mg/dL; P < .001 for both). Maximal HbA1c lowering was
found at 12 weeks while maximal FPG lowering was found
at 6 weeks. Progressive, albeit smaller, decline continues
for both parameters through week 26.
A 12-week trial evaluated the impact of either varying
doses of canagliflozin (50 mg/d to 300 mg twice a day) or sita-
gliptin 100 mg/d when added to stable metformin. The HbA1c
was reduced by −0.70% to −0.95% from baseline by cana-
gliflozin, with the greatest reductions seen in the 300 mg/d
(−0.92%) and 300 mg twice per day groups (−0.95%) versus
placebo (P < .001 for all).29 Although not statistically com-
pared with canagliflozin, add-on sitagliptin 100 mg/d reduced
the HbA1c by 0.74% from baseline (P < .001 vs placebo). A
greater proportion of patients receiving canagliflozin at doses
above 100 mg/d (53% to 72%) and sitagliptin 100 mg/d (65%)
achieved an HbA1c <7.0% at week 12 (53% to 72%) versus
placebo (34%). Greater mean reductions in FPG were also
seen with all doses of canagliflozin (−16.2 to −27.0 mg/dL)
and sitagliptin (−12.6 mg/dL) compared with placebo (+3.6
mg/dL; P < .001 vs each canagliflozin dose).
After 52 weeks, canagliflozin 300 mg/d (−1.03%)
resulted in significantly greater reductions in HbA1c from
baseline versus sitagliptin 100 mg/d (−0.66%; P < .05)
when added to patients receiving metformin plus a sulfo-
nylurea.29 These differences were more notable in patients
with higher baseline HbA1c. Similarly, a greater proportion
of canagliflozin patients achieved an HbA1c <7.0% versus
sitagliptin (47.6% vs 35.3%; P value not provided).
Canagliflozin also reduced the mean FPG from baseline to
a greater degree then sitagliptin (−28.7 vs −0.3 mg/dL,
respectively; P < .001). Similarly greater reductions in
2-hour postprandial glucose levels were seen with cana-
gliflozin (−58.5 mg/dL) versus sitagliptin (−39.9 mg/dL).
This difference was considered statistically significant,
although no specific P value was provided.
Canagliflozin 300 mg/d (−0.93%; P < .05), but not 100
mg/d (−0.82%; P > .05), for 52-week resulted in signifi-
cantly greater reductions in HbA1c from baseline compared
with glimepiride (−0.81%) in a clinical trial of 1450
patients.32 Accordingly, a greater proportion of patients
receiving canagliflozin 300 mg/d (60%) achieved a HbA1c
<7.0% versus glimepiride (56%). Greater reductions in
FPG from baseline were also seen with canagliflozin 100
mg/d (−24.3 mg/dL) and 300 mg/d (−27.4 mg/dL) versus
glimepiride (−18.4 mg/dL). Statistical analyses comparing
Nigro et al 1305

Table 2.  Canagliflozin Phase 3 Clinical Trials Available in Full Publication.

Patients Primary Secondary

Reference Design (n) Inclusion Criteria Dosage Duration Outcome Outcomes
Stenlof et al R, DB, PC 584 18-80 years old CANA 100 mg QD 26 weeks Change from Proportion of
(2012)27 with inadequately vs baseline in patients reaching
controlled T2DM CANA 300 mg QD HbA1c to HbA1c <7.0%,
vs week 26 change from
Placebo baseline in FPG,
BP, body weight,
HDL-C, and TG
Rosenstock R, DB, PC, AC 451 18-65 years old withCANA 50 mg QD 12 weeks Change in Change from
et al T2DM, HbA1c vs HbA1c from baseline in FPG,
(2012)28 7.0% to 10.5%, on CANA 100 mg QD baseline to body weight,
stable metformin vs week 12 and urinary
≥1500 mg/d, stableCANA 200 mg QD glucose-to-
body weight (BMI vs creatinie ratio, %
25-45 kg/m2), Scr CANA 300 mg QD of subjects with
<1.5 mg/dL (men) vs HbA1c <7.0%
or <1.4 mg/dL CANA 300 mg BID and <6.5%, and
(women) vs serum lipids
SITA 100 mg QD
vs
Placebo
Schernthaner R, DB, AC 755 >18 years old with CANA 300 mg QD 52 weeks Change in Change from
et al T2DM using stable vs HbA1c from baseline in FPG,
(2013)29 metformin + SITA 100 mg QD baseline to BP, body weight,
sulfonylurea week 52 TG, and HDL-C,
therapy and HbA1c and proportion
7.0% to 10.5% of subjects
reaching HbA1c
<7.0% and <6.5%
Yale et al R, DB, PC 269 >25 years old with CANA 100 mg QD 26 weeks Change from Proportion of
(2013)30 inadequately vs baseline in patients reaching
controlled T2DM CANA 300 mg QD HbA1c to HcA1c <7.0%,
(HbA1c 7.0% to vs week 26 change from
10.5%) and stage 3 Placebo baseline in FPG,
CKD (eGFR 30-50 BP, body weight,
mL/min/1.73 m2) and serum lipids
Bode et al R, DB, PC 716 55-80 years old CANA 100 mg QD 26 weeks Change from Proportion of
(2013)31 with inadequately vs baseline in patients reaching
controlled T2DM CANA 300 mg QD HbA1c to HcA1c <7.0%,
vs week 26 change from
Placebo baseline in FPG,
BP, body weight,
and serum lipids
Cefalu et al R, DB, AC 1450 18-80 years old with CANA 100 mg QD 52 weeks Change from Proportion of
(2013)32 T2DM, HbA1c vs baseline in patients reaching
7.0% to 9.5%, on CANA 300 mg QD HbA1c to HcA1c <7.0%
stable metformin vs week 52 or <6.5% and
(≥2000 mg/d, or GLI 1-8 mg QD experiencing
(≥1500 mg/d if hypoglycemic
unable to tolerate episodes, change
higher dose) for at from baseline in
least 10 weeks FPG, BP, body
weight, and
serum lipids
(continued)

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1306 Annals of Pharmacotherapy 47(10)

Table 2. (continued)

Patients Primary Secondary

Reference Design (n) Inclusion Criteria Dosage Duration Outcome Outcomes
Inagaki et al R, DB, PC 383 20- to 80-year-old CANA 50 mg QD 12 weeks Change from Proportion of
(2013)33 Japanese patients vs baseline in patients reaching
with T2DM, CANA 100 mg QD HbA1c to HcA1c <7.0%,
HbA1c 6.6% to vs week 12 change from
9.9% despite diet CANA 200 mg QD baseline in
and exercise vs FPG, BP, body
therapy CANA 300 mg QD weight, serum
vs lipids, waist
Placebo circumference,
urinary glucose/
creatinine ratio,
insulin levels, and
HOMA-β

Abbreviations: AC, active controlled; AHA, antihyperglycemic agent; BID, twice a day; BP, blood pressure; CANA, canagliflozin; CKD, chronic kidney
disease; DPP-4, dipeptidyl peptidase-4; DR, dose-ranging; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; GLI, glimepiride;
HbA1c, glycosylated hemoglobin A1c; HOMA-β, homeostasis model assessment of β-cell function; MC, multicenter; MET, metformin; PBO, placebo;
PC, placebo controlled; PG, parallel-group; PIO, pioglitazone; PPARγ, peroxisome proliferator-activated receptor-γ; QD, once a day; R, randomized;
SITA, sitagliptin; SU, sulfonylurea.

canagliflozin to glimepiride for these last 2 endpoints were
not undertaken, as part of the statistical plan of the study.
Body Weight
After 26 weeks, monotherapy with canagliflozin 100 mg/d
and 300 mg/d reduced mean body weight from baseline by
2.8% (2.5 kg) and 3.9% (3.4 kg) versus placebo (−0.6%,
−0.5 kg; P < .001 for both).27 The 300 mg/d group saw pro-
gressive decreases in body weight over the 26-week period,
while the 100 mg/d group saw a plateauing after week 18.
In a dose-ranging, 12-week study, when canagliflozin was
added to stable metformin therapy, significant reductions in
mean body weight from baseline were seen across doses
(−2.3% [−2.0 kg] to −3.4% [−2.9kg]; P < .001 vs placebo).28
The greatest weight reductions were seen with canagliflozin
300 mg/d and 300 mg twice a day doses and was progres-
sive over the 12-week period. Patients receiving sitagliptin
100 mg/d saw only a −0.6% (−0.4 kg) reduction in body
weight. When used in addition to metformin plus a sulfo-
nylurea for 52 weeks, canagliflozin 300 mg/d use signifi-
cantly reduced patients’ mean body weight from baseline
(−2.5% [−2.3kg]) versus sitagliptin 100 mg/d (+0.3% [+0.1
kg]; P < .001).29 As compared with glimepiride (+1.4%, 0.8
kg) over 52 weeks when added to metformin, numerically
lower body weights were seen with canagliflozin 100 mg/d
(−5.0%, 4.4 kg) and 300 mg/day (−4.9%, −4.2 kg), although
statistical analyses were not performed.32
Blood Pressure
Monotherapy with canagliflozin 100 mg/d (−3.6 mm Hg, P
< .001) and 300 mg/d (−5.4 mm Hg, P < .001) for 26 weeks
resulted in statistically significant reductions in systolic
blood pressure from baseline versus placebo (+0.4 mm
Hg).27 Diastolic blood pressure was also reduced with cana-
gliflozin (−1.6 and −2.0 mm Hg, respectively) versus pla-
cebo (−0.1 mm Hg) although formal statistical testing was
not performed. When added to a background of metformin
plus sulfonylurea, canagliflozin 300 mg/d significantly
decreased systolic blood pressure (−5.1 mm Hg) and dia-
stolic blood pressure (−3.0 mm Hg) compared with sita-
gliptin 100 mg/d (0.9 and −0.3 mm Hg, respectively; P <
.05 for both) over a 52-week period.29 Similar reductions in
systolic blood pressure were seen in a 52-week trial com-
paring canagliflozin 100 mg/d (−3.3 mm Hg) and 300 mg/d
(−4.6 mm Hg) with glimepiride (+0.2 mm Hg). No statisti-
cally or clinically meaningful changes in heart rates were
seen for any of the above evaluations.
Lipid Parameters
When used as monotherapy for 26 weeks, canagliflozin 100
mg/d and 300 mg/d resulted in significant increases in high-
density lipoprotein (HDL-C) versus placebo (+6.8% and
+6.1%; P < .01 for both).27 Reductions in triglycerides
(−14.2 mg/dL [−7.6%] and −15.9 mg/dL [−9.7%], respec-
tively; P = not significant vs placebo) and increases in low-
density lipoprotein (LDL-C) (0 mg/dL [+0.4%] and +4.6
mg/dL [+3.1%], respectively; statistical comparisons were
not performed) from baseline were seen.27 When added to
metformin therapy for 12 weeks, canagliflozin 300 mg
twice a day significantly increased HDL-C (+4.0 mg/dL)
from baseline versus placebo (P < .001), while the 300
mg/d (−28.5 mg/dL, P < .025) and 300 mg twice a day
(−35.3 mg/dL, P = .001) groups significantly decreased

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Nigro et al 1307
triglycerides versus placebo.28 Increases in LDL-C were
seen in the canagliflozin 300 mg twice daily group (+7.8
mg/dL), with lesser affects seen with lower doses and a 8.0
mg/dL reduction seen with sitagliptin. As compared with
sitagliptin 100 mg/d in patients receiving metformin plus
sulfonylureas over 52 weeks, canagliflozin 300 mg/d sig-
nificantly increased both HDL-C (0.6% vs 7.6%; P < .05)
and LDL-C (5.2% vs 11.7%; P < .05) from baseline with no
data on triglycerides reported.29 Given the changes seen in
LDL-C with canagliflozin use, the manufacturer recom-
mends routine monitoring and treatment, if appropriate.
Given the relatively modest increases seen in clinical trials,
this recommendation may not be warranted.
Beta-Cell Function
To better evaluate the impact of canagliflozin on glucose
parameters, indices of β-cell function have been evaluated.
These include the homeostasis model assessment of β-cell
function (HOMA2-%B), proinsulin/insulin ratio, and the
proinsulin/C-peptide ratio.27,29 The HOMA2-%B, a mea-
sure of fasting insulin secretion, was increased by cana-
gliflozin 100 mg/d (+9.9) and 300 mg/d (+20.3) monotherapy
compared with placebo (−2.5; n = not reported).27 Dose-
related decreases in proinsulin/insulin and proinsulin/C-
peptide ratio were also seen compared with placebo.
Although these changes reflect improvements in β-cell
function, this likely reflects either the reversal of glucotox-
icity or the “unloading” of the β-cell as systemic glucose
levels are decreased.34 Since SGLT-2 transporters are not
located on β-cells, a direct mechanism for improvement is
not likely.
Unpublished Data
In addition to the clinical comparisons that have been fully
published and discussed thus far, information regarding
combination of canagliflozin with both the thiazolidinedi-
one (TZD) pioglitazone and insulin, with or without other
AHAs, is available in the prescribing information.3 In 342
patients with T2DM inadequately controlled on metformin
and pioglitazone, canagliflozin 100 mg/d (−0.89%) and 300
mg/d (−1.03%) significantly reduced HbA1c over 26 weeks
versus placebo (−0.26%; P < .001 for both).3 Significant
reductions in FPG (−27 mg/dL, −33 mg/dL) and body
weight (−2.8%, −3.8%) were seen with canagliflozin 100
mg/d and 300 mg/d, respectively, versus placebo (+3 mg/
dL, −0.1%). Smaller effects on HbA1c were seen when
canagliflozin was added to patients with T2DM inade-
quately controlled on insulin (>30 units/d) in 1718 patients
over an 18-week period. Significant reductions in HbA1c of
−0.63% and −0.72% were seen with canagliflozin 100 mg/d
and 300 mg/d, respectively, versus +0.01% with placebo (P
< .001 for both).3 Significant reductions in FPG (−19 mg/
Downloaded from aop.sagepub.com at Library - Periodicals Dept on October 6, 2014
dL, −25 mg/dL) and body weight (−1.8%, −2.3%) were
seen with canagliflozin 100 mg/d and 300 mg/d, respec-
tively, versus placebo (+4 mg/dL, −0.1%).
Special Populations
The efficacy and safety of canagliflozin 100 mg/d and 300
mg/d was tested versus placebo in patients with T2DM and
concomitant stage 3 chronic kidney disease (estimated glo-
merular filtration rate [eGFR] 30-50 mL/min/1.73 m2; mean
eGFR = 39.4 mL/min/1.73 m2) over a 26-week period.30
Changes from baseline in HbA1c were −0.33% (P < .05)
and 0.44% (P < .001) for canagliflozin 100 mg/d and 300
mg/d, respectively, versus placebo (−0.03%). These are
noticeably lower values than in the above-mentioned stud-
ies in patients without appreciable chronic kidney disease.
This is likely because of the reduced UGE in patients with
lower eGFRs, thus attenuating the potential impact of cana-
gliflozin on glycemic markers.30 A higher proportion of
canagliflozin 100 mg/d and 300 mg/d patients achieved an
HbA1c <7.0 versus placebo (27.3%, 32.6%, and 17.2%,
respectively). Patients receiving canagliflozin also had
reductions in body weight of 1.2% to 1.5% whereas placebo
patients generally gained weight (0.3%). Significant reduc-
tions in systolic (−6.1 to −6.4 mm Hg) and diastolic blood
pressure (−2.6 to −3.5 mm Hg) were seen in the cana-
gliflozin 100 mg/d and 300 mg/d groups versus placebo
(−0.3 and −1.4 mm Hg, respectively).
Canagliflozin treatment was evaluated in a population of
716 older patients aged 55 to 80 years (mean 63.6 years)
with T2DM who were inadequately controlled on their cur-
rent AHA.31 Changes in HbA1c from baseline were similar
in this study compared with those discussed prior, with
reductions of 0.60% and 0.73% with canagliflozin 100
mg/d and 300 mg/d, respectively, versus placebo (−0.03%;
P < .001 for both). Reductions in FPG were also seen (−25.2
and −27 mg/dL, respectively) versus placebo (P < .001).
Significant reductions in body weight, FPG level, and sys-
tolic BP, and increased HDL-C levels were seen with both
canagliflozin doses compared with placebo (P < .001) while
LDL-C levels were increased with both canagliflozin doses
versus placebo.
A recently published study evaluated the efficacy and
safety of canagliflozin in 383 Japanese patients with type 2
diabetes.33 Patients were randomized to receive either cana-
gliflozin 50, 100, 200, or 300 mg/d or placebo for 12 weeks.
Each dose of canagliflozin (−0.61% to −0.88%) decreased
the HbA1c significantly more than placebo (+0.11%; P <
.01 for all). Significant reductions in FPG were also seen
with each canagliflozin dose (−24.7 to −38.3 mg/dL) versus
placebo (−3.0 mg/dL; P < .01 for all). Canagliflozin had
similar effects on other metabolic parameters as popula-
tions in studies discussed earlier. Moreover, the overall
safety of canagliflozin was similar to other studies (see
1308 Annals of Pharmacotherapy 47(10)
Adverse Events section). The authors concluded that the
efficacy of canagliflozin was similar to non-Japanese popu-
lations, particularly at doses higher than 100 mg/d.
Dosage and Administration
Canagliflozin is supplied as film-coated tablets for oral
administration in strengths of 100 mg and 300 mg.3 The
recommended starting dose is 100 mg/d taken before the
first meal of the day. Despite the lack of appreciable effect
of food on canagliflozin’s bioavailability, taking the dose
before the first meal potentially reduces postprandial plasma
glucose excursions as a result of delays in intestinal glucose
absorption.3 The dose can be increased to 300 mg/d in
patients who have an eGFR of 60 mL/min/1.73 m2 or greater
and require additional glycemic control. For those who
have an eGFR of 45 to <60 mL/min/1.73 m2, administer at
a dose of 100 mg/d. It is also recommended that any preex-
isting volume depletion be corrected prior to initiation.
Administration of canagliflozin is not recommended in sub-
jects with an eGFR of <45 mL/min/1.73 m2.3 The recom-
mendations for dose adjustment based on renal function
reflects not only the reduced efficacy in this population, but
the increase in adverse events seen.30 The incidence of
increased urine frequency as well as postural dizziness and
orthostatic hypotension (reflecting reduced intravascular
volume) were higher with canagliflozin 100 mg and 300 mg
doses versus placebo (no statistics provided). Similarly,
greater reductions in eGFR from baseline were seen with
canagliflozin 100 mg (−9.1%) and 300 mg (−10.1%) versus
placebo (−4.5%; P values were not provided).
Adverse Events
Despite the fact that canagliflozin was generally well toler-
ated in published clinical trials,27-33 a number of safety con-
cerns exist. Withdrawals due to adverse events ranged from
2.0 % to 5.3% across various canagliflozin doses, as com-
pared with 0% to 2.9% with sitagliptin 100 mg/d and 1% to
2% with placebo.27-29 Serious adverse events occurred in
2.0% to 6.4% with canagliflozin 100 mg/d or 300 mg/d, 0%
to 2.9% with sitagliptin 100 mg/d, 8% with glimepiride, and
2.1% to 3.0% with placebo.27-33 None of the studies pro-
vided definitions of these serious events (beyond serious
hypoglycemia as those events requiring the assistance of
another or resulting in seizure or loss of consciousness).29
The most frequently worrisome adverse event with cana-
gliflozin is the occurrence of genital mycotic infections,
which occurred in 15.3% of females and 9.2% of males
with the 300-mg dose in a phase 3 study by Schernthaner et
al.29 The manufacturer’s information reports incidences of
10.4% to 11.4% in women and 3.7% to 4.2% in men.3 It has
been hypothesized that the elevated levels of glucosuria
with canagliflozin increases the risk of bacteriuria
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and genitourinary infections.35 A substudy of a 12-week
dose-ranging trial28 showed the incidence of bacteriuria did
not differ from baseline between canagliflozin patients
(regardless dose) and the control patients (placebo or sita-
gliptin).35 The incidence of urinary cultures positive for
Candida species was 4.4% in the canagliflozin group versus
1.1% in the control group (P = .19). A separate evaluation of
the same clinical trial28 evaluated the incidence of valvu-
vaginal candidiasis in female patients.36 Twelve percent of
female patients had vaginal cultures positive for Candida
species at baseline. After 12 weeks of treatment, 31% of
female patients had positive vaginal cultures for Candida in
the canagliflozin group versus 14% in the control group
(placebo or sitagliptin, P = .04). No evidence of dose depen-
dence was seen with canagliflozin. Vulvovaginal adverse
events were reported in 10% of canagliflozin patients and
3% of control patients (P = .11).
Clinical studies defined hypoglycemia as any blood
sugar reading less than 70 mg/dL and severe hypoglycemia
as an event requiring the assistance of another person or an
event resulting in a seizure of loss of consciousness. When
used as monotherapy, rates of hypoglycemia with cana-
gliflozin 100 and 300 mg/d were similar to placebo (3.6%,
3.0%, and 2.6%, respectively).27 There were no reports of
severe hypoglycemia. When added to metformin therapy,
canagliflozin 100 and 300 mg/d had appreciably lower inci-
dences of hypoglycemia (6% and 5%, respectively) as com-
pared with glimepiride (34%).32 The incidence of
hypoglycemia when canagliflozin was added to metformin
and a sulfonylurea was 43.2% compared with 40.7% for
sitagliptin.29 Severe hypoglycemia occurred in 4.0% of
canagliflozin and 3.4% of sitagliptin patients. The prescrib-
ing information for canagliflozin warns about the potential
for hypoglycemia, potentially when combined with other
insulin secretagogues or insulin itself.3 Thus, these popula-
tions should be appropriately monitored and counseled
when canagliflozin is initiated.
Clinical trials have shown that initiation of canagliflozin
is associated with an osmotic diuresis and volume-related
adverse events. These include pollakiuria (increased urine
frequency) and polyuria (increased urine volume) with a
frequency generally in the 2% to 5% range, and similar to
its comparators.27-30 Occurring less frequently, but of greater
concern, are the risk of postural dizziness and orthostatic
hypotension. These have been reported in a dose-related
fashion, occurring in 2.3% to 3.4% of patients with cana-
gliflozin 100 mg/d and 300 mg/d, respectively, versus 1.5%
with comparators.3,27-33 Risk factors for development of
volume-related adverse events includes those receiving
loop diuretics, with moderate renal impairment (GFR 30-60
mL/min/m2), or age 75 years or older.3
Although not discussed in the published clinical trials,
the prescribing information for canagliflozin warns about
the increased risk of hyperkalemia which they defined as a
Nigro et al 1309
serum potassium of greater than 5.4 mEq/L or a 15%
increase above baseline.3 Incidences of 12.4% and 27.0%
with canagliflozin 100 mg/d and 300 mg/d, respectively,
were reported compared with 16.1% for placebo.3 Patients
with moderate renal impairment or those taking medications
that may increase potassium (eg, aldosterone antagonists,
potassium-sparing diuretics, rennin–angiotensin–aldosterone
system inhibitors) may require more frequent laboratory
monitoring.
During the approval process for canagliflozin, cardio-
vascular safety was evaluated. Preliminary data from the
Canagliflozin Cardiovascular Assessment Study (CANVAS;
NCT01032629) was pooled with the other studies that had
been completed to that point.37,38 Although the incidence of
major adverse cardiac events (cardiovascular death, myo-
cardial infarction, stroke, or hospitalized unstable angina)
did not differ between canagliflozin and its comparators
(hazard ratio [HR] = 0.91, 95% confidence interval [CI] =
0.68-1.22), there was a signal for an increased risk of stroke
(HR = 1.46, 95% CI = 0.83-2.58) although the number of
events was low (6.8% for canagliflozin vs 4.6% for com-
parators).37 It has been proposed that this potential increase
in stroke may be related to an acute osmotic diuretic effect
of canagliflozin. The CANVAS study also showed 13
(0.45%) early cardiac events in the canagliflozin group ver-
sus 1 (0.07%) in the placebo group (HR = 6.50, 95% CI =
0.85-49.66).37 No differences in patient characteristics
between canagliflozin patients who had a cardiac event
before 30 days or after 30 days were appreciated. It was
hypothesized that these early cardiac events may be related
to canagliflozin-induced volume changes that occur shortly
after the drug is initiated.
Additional safety risks have been raised with the SGLT-2
inhibitor class. Dapagliflozin was denied approval by the
FDA in 2011 due to an increased incidence of cancer. Phase
2b and 3 studies of 4310 subjects and 4354 patient-years of
exposure to dapagliflozin showed 7 (0.2%) cases of bladder
cancer versus 0 cases in the 1962 placebo subjects with
1899 patient-years of exposure.39 They also reported 9
(0.2%) patients who developed breast cancer following
dapagliflozin use versus none in the control group. For all
phase 3 clinical trial data for canagliflozin collected through
November 15, 2012, the incidence of breast, bladder, and
renal cancer was low and did not differ compared with the
controls.37
Formulary Considerations
Metformin remains the first-line oral treatment option for
T2DM.4,5 For patients who are intolerant to metformin or
for those who fail to achieve glycemic targets despite dose
optimization, selection of subsequent pharmacotherapy
remains highly individualized. Medication factors such as
adverse effects, targeted blood glucose effects, formulation,
Downloaded from aop.sagepub.com at Library - Periodicals Dept on October 6, 2014
convenience, cost, and HbA1c reduction/durability must be
taken into consideration along with patient specific charac-
teristics. Preference is given to non-metformin oral medica-
tions as second-line options prior to insulin initiation due to
ease of administration and education. Inexpensive sulfonyl-
ureas are frequently selected; however, evidence shows that
sulfonylureas do not sustain glycemic durability over
time.40 TZDs have proven utility in improving insulin resis-
tance and blood lipids; however, significant adverse effects
(such as edema, weight gain, and new-onset heart failure)
combined with FDA restrictions have decreased the use of
TZD. α-Glucosidase inhibitors are associated with signifi-
cant and drug-limiting gastrointestinal adverse effects. For
the past few years, higher cost second-line line options,
such as incretin-based regimens (DPP-4 inhibitors and
GLP-1 agonists), are commonly considered.4,5 Incretin-
based medications have demonstrated improvements in
A1c and potential to positively affect β-cells but are associ-
ated with gastrointestinal adverse effects and increase rates
of pancreatitis.
Canagliflozin offers potential advantages, which may
help define a unique role in the treatment of diabetes. While
the available literature focuses on canagliflozin in the treat-
ment of T2DM, its pathophysiologic target could suggest a
role in the management of type 1 diabetes. A recently pre-
sented phase 2a study of another SGLT-2 inhibitor, dapa-
gliflozin, in patients with type 1 diabetes mellitus showed
dose-dependent increases in UGE and lower daily insulin
requirements (−16% to 19%) versus placebo warranting
further study of this class in type 1 patients.41 Additionally,
canagliflozin’s therapeutic effects are exerted independent
of β-cell function. In fact, canagliflozin has demonstrated
improvement in HOMA-β similar to that of DPP-4 inhibi-
tors making it a suitable option for patients with early onset
or advanced disease.17 Similar to TZDs and DPP-4 inhibi-
tors, canagliflozin is dosed once daily and possesses a low
risk of hypoglycemia when used as monotherapy.3 Direct
comparison studies have demonstrated more favorable
HbA1c, systolic blood pressure, and weight reduction with
canagliflozin versus a DDP-4 inhibitor (sitagliptin) with
similar rates of hypoglycemia and overall adverse effects.17
Although a comparative analysis versus GLP-1 agonists has
not been performed, canagliflozin offers an advantage in
terms of route of administration (oral vs injectable) and a
similar ability to induce weight loss. Although more expen-
sive than generically available products, canagliflozin
should be available at a similar cost or co-pay as incretin-
based options.
The risk of genital mycotic infections is higher with cana-
gliflozin versus other oral options, including DPP-4 inhibi-
tors.29 Symptomatic infections can be treated according to the
standard of care, but the risk of these infections should be
accounted for on a patient-by-patient basis. Canagliflozin is
limited to patients with a GFR >45 mL/min/1.73 m2, but
1310 Annals of Pharmacotherapy 47(10)
DPP-4 inhibitors can be used in patients with significantly
impaired renal function depending on dose adjustments. The
risk of hypoglycemia does increase with both canagliflozin
and DPP-4 inhibitors as renal function deteriorates.
Despite sufficient evidence supporting use in combina-
tion with metformin, insulin, TZD, and sulfonylureas,3,28-33
canagliflozin has not been adequately studied in combina-
tion with a DPP-4 inhibitor, GLP-1 agonist, or α-glucosidase
inhibitor. There is also no currently available combination
product with metformin, which may lead to increased pill
burden versus other oral options. There is also lack of data
to recommend use in certain populations, including patients
with advanced age (>80 years old) and poorly controlled
diabetes (HbA1c >10%). At the time of this review, cost-
effectiveness was not possible to ascertain.
Three clinical trials with canagliflozin are ongoing in the
United States. One trial (NCT01809327) is evaluating the
co-administration of canagliflozin and metformin extended-
release compared with either medication alone in patients
with T2DM inadequately controlled on diet and exercise.
As of June 2013, this 26-week study has yet to begin recruit-
ment, but will be completed by December 2014. Another
study (NCT00968812) comparing canagliflozin to
glimepiride in patients with T2DM not adequately con-
trolled on metformin has been completed, but fully pub-
lished results are not currently available. As previously
mentioned, the CANVAS study (NCT01032629), which is
evaluating the cardiovascular safety of canagliflozin, has
completed recruitment and is expected to report results by
2018.38 In addition to a cardiovascular safety trial, the FDA
is requiring 4 other postmarketing studies, including (a) an
enhanced pharmacovigilance program to monitor for malig-
nancies, serious cases of pancreatitis, severe hypersensitiv-
ity reactions, photosensitivity reactions, liver abnormalities,
and adverse pregnancy outcomes; (b) a bone safety study;
(c) and (d) 2 pediatric studies under the Pediatric Research
Equity Act (PREA), including a pharmacokinetic and phar-
macodynamic study and a safety and efficacy study.
Summary
The approval of canagliflozin adds to the oral armamentar-
ium of medications to treat the growing diabetes epidemic.
Canagliflozin demonstrates significant improvements in
A1C, systolic blood pressure, and weight; but introduces
new genitourinary adverse effects in diabetes medication
classes. Among FDA-approved products, canagliflozin is
comparable to second-line oral medications in terms of
effectiveness but has limitations in affordability and long-
term safety data. Considering the lack of outcome data with
any diabetes treatment regimens, certain subset of patients
(particularly those resistant to injectable medications or
intolerant to other oral options) may be ideal targets for the
unique mechanism of canagliflozin.
Downloaded from aop.sagepub.com at Library - Periodicals Dept on October 6, 2014
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: Dr Riche serves on the Speaker’s Bureau for Janssen,
Boehringer Ingelhiem, and Merck.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
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