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

] 2015 1
Clinical Therapeutics

complications such as nephropathy, neuropathy, and SGLT2 inhibitors in the treatment of T2DM were
retinopathy and macrovascular complications such as reviewed.
heart disease and stroke. Cardiovascular (CV) risk is
signicant in T2DM, with heart disease or stroke RESULTS
claiming the lives of 2 of 3 patients.2,3 Substantial Clinical Pharmacology
evidence indicates that controlling blood glucose Under normal circumstances, the adult kidney
prevents the risk or reduces progression of micro- lters 180 g of glucose per day.11 Almost all of
vascular complications.4,5 Furthermore, controlling the glucose ltered by the kidney is reabsorbed and
other risk factors such as hypertension and dyslipide- returned to the systemic circulation via the SGLT
mia reduces the risk of both nephropathy and retin- proteins SGLT2 and SGLT1. Even though plasma
opathy and is paramount to decreasing the occurrence glucose levels are elevated in T2DM, the kidneys con-
of CV disease in diabetes. tinue to reabsorb glucose through the SGLT proteins,
First-line therapy for the management of T2DM thereby contributing to hyperglycemia. SGLT2 is a
generally involves lifestyle modications, including low-afnity, high-capacity transporter found exclu-
diet and exercise, along with metformin.6 Other oral sively in the proximal renal tubule. It is responsible for
medications for the treatment of T2DM have tradi- reabsorption of 90% of glucose ltered by the kidney.
tionally included sulfonylureas, meglitinides, thiazoli- SGLT1 is a high-afnity, low-capacity transporter
dinediones (TZDs), dipeptidyl-peptidase-4 inhibitors, located further along the proximal tubule, and it
-glucosidase inhibitors, bromocriptine, and coleseve- reabsorbs the remaining glucose.12 SGLT1 is also
lam. Injectable agents such as various forms of insulin, expressed in the brush border of the small intestine
glucagon-like peptide-1 (GLP-1) receptor agonists, where it plays a signicant role in glucose absorption.
and amylin analogs are also used for the treatment The available SGLT2 inhibitors differ in their relative
of T2DM. Despite the availability of a wide variety of selectivity for SGLT2 versus SGLT1. For instance,
medications, almost one-half of patients with diabetes empagliozin is the most selective for SGLT2
fail to achieve acceptable glycemic control.7 Thus, the (42500:1), followed by dapagliozin (41200:1)
search for effective medications for diabetes continues. and canagliozin (4250:1).13 The clinical signi-
In 2013 a new class of antihyperglycemic medications, cance of SGLT2 selectivity is not fully established.
the sodium-glucose co-transporter 2 (SGLT2) inhib- Agents with lower selectivity for SGLT2 may
itors, entered the market. Canagliozin was the rst of transiently inhibit SGLT1-mediated glucose absorp-
these agents to obtain approval by the US Food and tion in the small intestine, thereby reducing postpran-
Drug Administration (FDA) in March 2013. Subse- dial glucose.14
quently, the FDA approved dapagliozin in January The SGLT2 inhibitors exert their main pharmaco-
2014 and empagliozin in August 2014. Each of these logic action by preferentially inhibiting SGLT2. Inhibi-
agents is approved for the treatment of T2DM in tion of SGLT2 decreases reabsorption of glucose,
adults.810 This article provides an overview of ef- leading to an increase in urinary glucose excretion
cacy and safety data for the SGLT2 inhibitors and (UGE) and a reduction in plasma glucose levels. The
outlines their role in the management of T2DM. increased UGE seen with SGLT2 inhibitors also results
in a loss of 200 to 300 kcal/d, which may contribute
METHODS to modest weight loss observed with these agents.12 In
Relevant articles were identied through searches of addition, modest reductions in systolic blood pressure
PubMed (publication date range: 1966November may occur, likely attributable to the mild osmotic
2014) and International Pharmaceutical Abstracts diuresis produced by this class. Because SGLT2 inhi-
(publication date range: January 1970November bitors depend on sufcient glomerular ltration to be
2014) by using the key terms canagliozin, dapagli- effective, they subsequently work best in patients with
ozin, empagliozin, and sodium-glucose co-trans- normal renal function or mild renal impairment.15
porter 2 inhibitor. A review of bibliographies of Dapagliozin should not be used in patients with an
retrieved articles was also performed to identify addi- estimated glomerular ltration rate (eGFR) of o60
tional references. All identied trials published in mL/min/1.73 m2. Canagliozin and empagliozin should
English and that involved efcacy and safety of not be used if eGFR is o45 mL/min/1.73 m2.810

2 Volume ] Number ]
K. Whalen et al.

No dosing considerations are required for hepatic use of canagliozin and rifampin was found to de-
impairment. crease the efcacy of canagliozin. Therefore, an
All 3 agents are administered once daily in the increase in the dose of canagliozin may be required
morning. Dapagliozin and empagliozin may be when coadministered with rifampin and other UGT
administered with or without food.9,10 Although inducers, including phenytoin, phenobarbital, and
canagliozin may be taken without regard to food, ritonavir.8,29 Exposure of canagliozin is increased
the product information recommends administration with cyclosporine and probenecid; however, these inter-
before the morning meal, because the SGLT1 activity actions are not clinically relevant.30 No clinically mea-
of this agent may delay intestinal glucose absorption ningful interaction was observed when empagliozin or
and reduce postprandial hyperglycemia.8,14 canagliozin were used with oral contraceptives that
contain ethinyl estradiol and levonorgestrel.8,31
Drug Interactions The mechanism of action of the SGLT2 inhibitors
Drug interaction studies that examined the con- relies heavily on adequate kidney function. Drugs that
current use of the SGLT2 inhibitors with other anti- affect kidney function (eg, angiotensin-converting
hyperglycemics such as metformin and sulfonylureas enzyme inhibitors, angiotensin receptor blockers,
have revealed no clinically signicant pharmacokinetic NSAIDs) should be used cautiously, because a de-
changes.8,1619 When dapagliozin and glimepiride crease in the effect of the SGLT2 inhibitors may be
are used together, there may be a slight increase in expected. Although no signicant pharmacokinetic
the risk of hypoglycemia; therefore, patients should be interaction exists with diuretics and the SGLT2 inhi-
monitored appropriately.17 Dapagliozin was also bitors, pharmacodynamic interactions may occur. Pa-
investigated in combination with pioglitazone and tients who are particularly sensitive to volume changes
sitagliptin.16 Results of these pharmacokinetic stu- should be monitored closely for signs and symptoms
dies found that no dosage adjustment is needed for of dehydration and electrolyte abnormalities when
either medication. The combination of empagliozin SGLT2 inhibitors are combined with diuretics.29 Cana-
with the dipeptidyl-peptidase-4 inhibitors sitagliptin gliozin use may lead to an increase in serum potas-
or linagliptin20,21 was examined. Although sitagliptin sium levels.32 Potassium levels should be monitored in
slightly increases exposure to empagliozin, these patients who take canagliozin in combination with
changes were not considered clinically relevant. other medications that can increase potassium. Despite
The concurrent administration of the SGLT2 in- similar mechanisms of action, no evidence supports
hibitors with simvastatin, warfarin, and digoxin re- alterations in potassium with empagliozin or
vealed no clinically signicant interactions, with the dapagliozin.
exception of the combination of canagliozin and
digoxin.8,2225 If administered together, digoxin levels Clinical Trials
should be closely monitored, because canagliozin Canagliozin, dapagliozin, and empagliozin were
increases the exposure to digoxin.8 The use of the di- each studied as monotherapy for T2DM and as add-on
uretic hydrochlorothiazide in combination with cana- therapy with other oral antihyperglycemic agents and/
gliozin or empagliozin was also studied with no or insulin. A summary of clinical trials performed with
clinically relevant interactions reported.26,27 Likewise, canagliozin, dapagliozin, and empagliozin is pro-
dapagliozin and empagliozin were studied in com- vided in Table I,3339 Table II,4047 and Table III,4855
bination with antihypertensives such as valsartan, respectively. Selected trials for each agent are reviewed
verapamil, and ramipril with no clinically signicant below.
effects noted.22,25
Dapagliozin is mainly metabolized via uridine Canagliflozin Clinical Trials
diphosphate-glucuronosyltransferase 1A9 (UGT1A9). Stenlf et al33 evaluated the efcacy and safety
Rifampin, an inducer of UGT1A9, reduces exposure prole of canagliozin monotherapy in a randomized,
to dapagliozin, and mefenamic acid, a UGT1A9 inhi- double-blind, placebo-controlled phase 3 study. Eligi-
bitor, enhances exposure. However, changes in dapa- ble subjects included patients with T2DM who were
gliozin levels are not clinically meaningful, and no 18 to 80 years of age and had a glycosylated
dosage adjustments are warranted.9,28 The concurrent hemoglobin (HbA1c) between 7% and 10% on no

] 2015 3
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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
8

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 with 3 self-reported readings. The primary end point
0.89% with dapagliozin treatment compared with was change in HbA1c from baseline. Secondary out-
0.23% with placebo. The dose-ordered reductions in comes included change in mean insulin dose, weight,
HbA1c afforded by dapagliozin were statistically and FPG.
signicant for the 5- and 10-mg groups (P 0.005, A statistically signicant reduction in HbA1c from
P o 0.001, respectively). Patients in the high HbA1c baseline was observed (0.32%, 0.49%, 0.54%;
exploratory cohort (10.1%12%) saw the greatest P o 0.001 all groups) in the 2.5-, 5-, and 10-mg
reduction in HbA1c (1.90% to 1.98%); the P value groups, respectively. The most rapid decrease in
was not reported. HbA1c occurred within the rst 8 weeks and was
Dapagliozin was tolerated well and was not maintained at 48 weeks. Total weight decreased in all
discontinued in the study secondary to hypoglycemia. groups (0.96 to 1.61 kg), compared with an
Reductions were statistically signicant for FPG in the increase in the placebo arm (0.82 kg). FPG was
5- and 10-mg arms. Reductions in weight and both reduced in all treatment arms. Patients in the dapagli-
systolic and diastolic blood pressures were observed ozin treatment arms did not necessitate an increase in
but did not reach statistical signicance. Signicant insulin requirement throughout the trial; however, the
changes in serum electrolytes or renal function were placebo group requirements did increase progressively
not observed in the active treatment. Consistent with (with an up titration mean of 10.54 units/d). Reduc-
other SGLT2 inhibitors, patients in the treatment arm tions of systolic blood pressure (3.8 to 5.4 mm Hg)
experienced more events suggestive of genital infec- along with diastolic reductions (2.3 to 3.1 mm Hg)
tions and UTIs (7.7%12.9% vs 1.3% placebo and were noted in the dapagliozin treatment groups.
4.6%12.5% vs 4% placebo, respectively). Of note, Orthostatic hypotension was not observed in the
weight reductions did not plateau by the end of the treatment arms.
study. Long-term studies may identify a greater weight Similar to other clinical trials, dapagliozin was
reduction. Results of other monotherapy trials found well tolerated, and the overall adverse event rate was
similar reductions in HbA1c, weight, and FPG and are similar between the treatment arms. A larger number
summarized in Table II.4042 of patients experienced hypoglycemia in the dapagli-
The safety prole and efcacy of dapagliozin was ozin arms (56.6%) compared with placebo (51.8%).
evaluated in a 48-week placebo-controlled, multicen- In addition, more patients in the treatment arms
ter trial in patients inadequately controlled on insulin experienced UTIs and genital infections. Data suggest
(with or without other oral antidiabetic agents).47 A treatment with dapagliozin improves glycemic con-
total of 808 patients with T2DM inadequately trol, produces sustained weight loss, and appears to be
controlled on at least 30 units of insulin daily were insulin sparing.
randomly assigned to treatment with dapagliozin 2.5 Consistently, dapagliozin 5 and 10 mg daily, im-
mg, 5 mg, 10 mg or placebo. Enrolled patients were proved glycemic control in patients with inadequately
between 18 and 80 years of age, had a BMI r45, and controlled T2DM as monotherapy and as add-on com-
an HbA1c between 7.5% and 10.5%. During the 8 bination therapy with metformin,44 glimepiride,17 pio-
weeks before enrollment, patients must have been on glitazone,45 sitagliptin,46 and insulin47 (Table II). In
at least 1500 mg of metformin daily or at least one- each trial, signicant reductions were noted in HbA1c
half the maximum dose of other oral antidiabetic and FPG. Combination trials saw greater reductions in
agents. Exclusion criteria included T1DM, eGFR weight compared with placebo, with similar trends ob-
o50 mL/min/1.73 m2, serum creatinine (SCr) 42 served in monotherapy trials. In addition, dapagliozin
mg/dL, or SCr Z1.5 mg/dL for men or Z1.4 mg/dL established noninferiority compared with glipizide in
for women if on metformin. Study medications and patients inadequately controlled on 1500 to 2500 mg/d
oral antidiabetic drugs were not modied except when metformin.43 Results of this 1-year study found no
hypoglycemia was a concern, and the dose of the oral treatment differences for markers of glycemic control
antidiabetic drugs were subsequently decreased. Up and found a more favorable effect on weight in the
titration of insulin was allowed if FPG was 4240 mg/dL dapagliozin arm. Consistent with the above-mentioned
between weeks 0 and 12, 4220 mg/dL between weeks trials, reductions in both systolic and blood pressure
12 and 24, or 4180 mg/dL between weeks 25 and 48 were observed.

10 Volume ] Number ]
K. Whalen et al.

Empagliflozin Clinical Trials Baseline characteristics were similar between


In a 12-week trial, 408 patients with T2DM were groups, and the mean nal dose of metformin was
randomized to receive empagliozin, placebo, or 1668 mg/d. Compared with placebo, the mean HbA1c
metformin.49 The multicenter trial was conducted at decrease after 12 weeks was greater in all empagli-
75 centers in 13 countries. After a 4-week washout ozin groups (P o 0.0001). In patients with a baseline
period, patients were randomized to receive one of the HbA1c Z8%, the change in HbA1c was 0.6%,
following: empagliozin 5 mg, empagliozin 10 mg, 0.7%, and 1.1% in the empagliozin 5-mg, 10-
empagliozin 25 mg, placebo, or open-label metfor- mg, and 25-mg groups, respectively. For patients with
min at a maximum dose of 1000 mg twice daily. a baseline HbA1c of o8%, HbA1c changes of 0.5%,
The following patients were included in the study: 0.4%, and 0.5% were seen in the empagliozin
men and women aged 18 to 79 years with T2DM, 5-mg, 10-mg, and 25-mg groups, respectively. In
treatment-naive for Z10 weeks or on 1 diabetes addition, more patients in the empagliozin groups
medication (except TZDs, GLP-1 receptor agonists, achieved an HbA1c r7% and a decrease in HbA1c of
or insulin) at a stable dose for Z10 weeks, HbA1c Z0.5% compared with placebo. FPG and mean
6.5% to 9% for patients on 1 medication or HbA1c weight decreased in all empagliozin groups com-
7% to 10% for treatment-naive patients, and BMI pared with placebo. The incidence of adverse events
r40. Patients were excluded from the study for the was similar between all groups, including placebo.
following reasons: acute myocardial infarction, stroke, The most common adverse events reported with
or transient ischemic attack within the past 6 months; empagliozin were pollakiuria, thirst, and nasophar-
impaired hepatic function; impaired renal function yngitis. Seven patients reported adverse events consis-
(SCr 41.5 mg/dL for men and 41.4 mg/dL for tent with UTIs, and 5 patients reported adverse events
women); unstable or acute heart failure; acute or consistent with genital infections. No cases of hypo-
chronic acidosis; diseases of the central nervous glycemia occurred in patients who took empagliozin.
system, psychiatric disorders, or clinically relevant No clinically signicant changes in physical examina-
neurologic disorders; chronic or acute infection; cur- tion, vital signs, electrocardiogram, or laboratory
rent or chronic urogenital infection; dehydration; values were noted.
history of clinically relevant allergy/hypersensitivity; A 12-week study examined the safety prole and
intolerance to metformin; hereditary galactose intol- efcacy of empagliozin in 495 patients inadequately
erance; treatment with TZDs, GLP-1 receptor ago- controlled on metformin.51 Patients were randomized
nists, or insulin within the past 3 months; use of to receive one of the following regimens in addition to
antiobesity medications; current treatment with sys- metformin: empagliozin 1 mg, 5 mg, 10 mg, 25 mg,
temic steroids; alcohol abuse; treatment with an or 50 mg daily; or placebo; or open-label sitagliptin
investigational drug within the past 2 months; and 100 mg daily. Patients meeting the following criteria
pregnancy, breast-feeding, or not using acceptable were included in the study: age of 18 to 80 years, BMI
birth control methods (women). The primary efcacy r40, previous treatment with metformin alone or in
end point was the change in HbA1c from baseline to combination with 1 additional agent, unchanged
week 12. Secondary end points included change in diabetes therapy for at least the past 10 weeks, HbA1c
FPG from baseline to week 12, change in HbA1c from 6.5% to 9% for patients on metformin plus 1 addi-
baseline over time, proportion of patients who tional agent (additional agent was stopped at study
achieved HbA1c r7% after 12 weeks, proportion of entry), or HbA1c 7% to 10% for patients on metfor-
patients who achieved a decrease in HbA1c Z0.5% min monotherapy. The exclusion criteria for this study
after 12 weeks, change in weight from baseline to 12 included history of acute myocardial infarction,
weeks, and pharmacokinetic parameters of empagli- stroke, or transient ischemic attack in the past 6
ozin. Safety and tolerability were assessed from the months; impaired hepatic or renal function; diseases
following data: incidence and intensity of adverse of the central nervous system; chronic or acute
events, withdrawal from treatment due to adverse infection; history of allergy/hypersensitivity; and treat-
events, clinically relevant changes in physical exami- ment with TZDs, GLP-1 receptor agonists, or insulin
nation, vital signs, electrocardiogram, or laboratory within the past 3 months. The primary end point was
results. change in HbA1c from baseline to week 12.

] 2015 11
Clinical Therapeutics

Secondary end points included change in HbA1c over osmotic diuresis. Symptomatic hypotension may
time, change in FPG and weight from baseline to week occur in patients with an eGFR o60 mL/min/
12, and proportion of patients achieving HbA1c 1.73 m2, patients on diuretics or medications that
r7% or HbA1c lowering of Z0.5% at week 12. interfere with the renin-angiotensin-aldosterone sys-
Assessments for safety and tolerability involved labo- tem, the elderly, or patients with low systolic blood
ratory parameters, vital signs, and adverse event pressure.810 Small changes in fasting lipid proles
reporting. were reported with the SGLT2 inhibitors, including an
Of 495 patients randomly assigned, 63% were increase in high-density and low-density lipoproteins
taking metformin alone and 37% were taking met- and a decrease in triglycerides.15,59 Whether this
formin plus 1 additional antidiabetic drug. The represents a clinically signicant effect remains un-
placebo-adjusted mean decrease in HbA1c was known. Weight loss of  1 to 5 kg was observed in all
0.24%, 0.39%, 0.71%, 0.7%, and 0.64% studies with SGLT2 inhibitors and appears to be
for the empagliozin 1-mg, 5-mg, 10-mg, 25-mg, and sustained at 48 to 52 weeks of follow-up.45 Weight
50-mg groups, respectively. The changes in HbA1c loss is predominately because of loss of fat, parti-
were statistically signicant for all doses except cularly visceral adipose tissue, rather than lean
empagliozin 1 mg daily. More patients in the mass.58,61 Both monotherapy and combination ther-
empagliozin 10-mg, 25-mg, and 50-mg groups apy trials have reported weight reduction that may
achieved an HbA1c r7% than placebo. FPG and mitigate weight gain associated with insulin and/or
weight were also signicantly decreased in patients TZDs.45
taking empagliozin compared with placebo, except CANVAS (CANagliozin cardioVascular Assess-
in the 1-mg group. The most commonly reported ment Study) is an ongoing CV safety study of cana-
adverse events in patients taking empagliozin were gliozin in 4330 persons with CV disease or at high
UTI and pollakiuria. Fourteen patients taking empa- risk. Preliminary results suggest that canagliozin is
gliozin reported symptoms consistent with UTI and not associated with an increased risk of CV events.62
genital infections. Hypoglycemia was reported in 4 However, an elevated stroke risk was found within the
patients taking empagliozin; however, no patients rst 30 days of canagliozin therapy. Final results of
experienced a blood glucose level o54 mg/dL. CANVAS are not expected until sometime in 2015.63
Empagliozin was also studied in combination with An updated meta-analysis of dapagliozin, consistent
a sulfonylurea,52 pioglitazone (with or without met- with previous meta-analyses, found no unacceptable
formin),53 and insulin.54 The results of these studies increase in CV risk.64,65 A CV outcome trial with
consistently revealed signicant reductions in HbA1c, empagliozin is also currently under way.66
FPG, and weight. A long-term, active control trial that
involved empagliozin 10 mg or 25 mg as monothe- Adverse Events
rapy or add-on to metformin found empagliozin pro- SGLT2 inhibitors did not lead to signicant changes
vides sustained glycemic control and continued weight in renal function in phase 2 and 3 studies.810 Although
loss over 90 weeks with a low risk of hypoglycemia in no signicant changes were observed, elevations in SCr
patients with T2DM.55 and blood urea nitrogen may occur. Patients with
hypovolemia are more susceptible and may require
CV Safety Profile more frequent monitoring of renal function.810 This
SGLT2 inhibitors are associated with a reduction in class of drugs is primarily renally eliminated, and
systolic and diastolic blood pressures when used as exposure to these agents is increased in renal impair-
both monotherapy or in combination with other ment. Paradoxically, however, glucose lowering is
glucose-lowering agents.5860 A meta-analysis of 21 decreased in severe renal impairment.810,58 Because
placebo-controlled trials indicated a mean drop in the ability to enhance UGE is diminished with severe
systolic blood pressure of 3.77 mm Hg. The same renal impairment, the SGLT2 inhibitors are expected to
analysis reported a drop of 1.75 mm Hg in diastolic be ineffective in patients with an eGFR o30 mL/min/
blood pressure across 16 placebo-controlled trials.59 1.73 m2.
Although the mechanism is not completely understood, Promotion of glucosuria with the SGLT2 inhibitors
these effects are likely attributed to a glucose-induced may be anticipated to increase the incidence of

12 Volume ] Number ]
K. Whalen et al.

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

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68. Meta-analysis in post-marketing Address correspondence to: Karen Whalen, PharmD, BCPS, CDE, Department
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mellitus. ClinicalTrials.gov website. FL 32610. E-mail: whalen@cop.u.edu

] 2015 17