Opportunities for Improving Attainment of Quality Measures ... · uates the potential financial implications of quality mea-sure attainment in patients with T2DM. ... These faculty

Opportunities for Improving Attainment of Quality Measures in Patients With Type 2 Diabetes Mellitus

Volume 20, Number 1, Supplement – January 2014

Highlights

n Quality Measure Attainment in Patients With Type 2 Diabetes Mellitus

n Attainment of Diabetes-Related Quality Measures With Canaglifl ozin Versus Sitagliptin

Supplement to The American Journal of Managed Care © 2014 Managed Care & Healthcare Communications, LLC

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VOL. 20, NO. 1 n THE AMERICAN JOURNAL OF MANAGED CARE n S1

January 2014 – Vol. 20, No. 1, Sup.


Table of Contents

Participating Faculty S2

Reports

n Quality Measure Attainment in Patients With Type 2 Diabetes Mellitus S5

Marie-Hélène Lafeuille, MA; Amanda M. Grittner, MA; Jonathan Gravel, MSc; Robert A. Bailey, MD; Silas C. Martin, MS; Lawrence Garber, MD; Mei Sheng Duh, MPH, ScD; and Patrick Lefebvre, MA

n Attainment of Diabetes-Related Quality Measures With Canagliflozin Versus Sitagliptin S16

Robert A. Bailey, MD; C. V. Damaraju, PhD; Silas C. Martin, MS; Gary E. Meininger, MD; Marcia F. T. Rupnow, PhD; and Lawrence Blonde, MD

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n PARTICIPATING FACULTY n

Opportunities for Improving Achievement of Quality Measures in Patients With Type 2 Diabetes Mellitus

This supplement to The American Journal of Managed Care reports the results of 2 studies evaluating quality measure attainment in type 2 diabetes mellitus (T2DM). The first study eval-uates the potential financial implications of quality mea-sure attainment in patients with T2DM. The second study reports a post hoc analysis of a randomized controlled clinical trial evaluating the quality measure attainment of patients treated with either canagliflozin 300 mg/day or sitagliptin 100 mg/day in addition to metformin and sulfonylurea. Although further research is necessary, these results may help managed care organizations evaluate the value of improving qual-ity measures associated with T2DM.

n Faculty

Robert A. Bailey, MD DirectorHealth Economics and Outcomes ResearchJanssen Scientific Affairs, LLCRaritan, New Jersey

Lawrence Blonde, MD DirectorOchsner Diabetes Clinical Research UnitDepartment of EndocrinologyOchsner Medical CenterNew Orleans, Louisiana

C. V. Damaraju, PhD DirectorMedical Affairs, BiostatisticsJanssen Research & Development, LLCRaritan, New Jersey

Mei Sheng Duh, MPH, ScD Managing PrincipalAnalysis Group, IncBoston, Massachusetts

Lawrence Garber, MD Medical Director for Informatics Reliant Medical GroupWorcester, Massachusetts

Jonathan Gravel, MScEconomistGroupe d’Analyse, LtéeAnalysis Group, IncMontreal, Quebec, Canada

Amanda M. Grittner, MA EconomistGroupe d’Analyse, LtéeAnalysis Group, IncMontreal, Quebec, Canada

Marie-Hélène Lafeuille, MA Senior EconomistGroupe d’Analyse, LtéeAnalysis Group, IncMontreal, Quebec, Canada



Patrick Lefebvre, MA Vice PresidentGroupe d’Analyse, LtéeAnalysis Group, IncMontreal, Quebec, Canada

Silas C. Martin, MS DirectorHealth Economics and Outcomes ResearchJanssen Scientific Affairs, LLCRaritan, New Jersey

Gary E. Meininger, MD Vice President, Franchise Medical LeaderJanssen Research & Development, LLCRaritan, New Jersey

Marcia F. T. Rupnow, PhD Senior DirectorHealth Economics and Outcomes ResearchJanssen Scientific Affairs, LLCRaritan, New Jersey

n Faculty Disclosures

These faculty report relationships with the following organizations:

Robert A. Bailey, MD Employment: Janssen Scientific Affairs, LLC (a Johnson & Johnson company)Stock ownership: Johnson & Johnson

Lawrence Blonde, MD Grant/research support: Eli Lilly and Company; Novo Nordisk; SanofiConsultant: Amylin Pharmaceuticals, Inc; Eisai; GlaxoSmithKline; Janssen Pharmaceuticals, Inc; Merck & Co, Inc; Novo Nordisk; Pfizer; Sanofi; SantarusLecture fees: Amylin Pharmaceuticals, Inc; Bristol-Myers Squibb/AstraZeneca; Janssen Pharmaceuticals, Inc; Johnson & Johnson Diabetes Institute, LLC; Merck & Co, Inc; Novo Nordisk; Sanofi; Santarus; Vivus, Inc

C. V. Damaraju, PhD Employment/stock ownership: Janssen Research & Development, LLC


Mei Sheng Duh, MPH, ScD Employment: Analysis Group, Inc (recipient of grants from Janssen Pharmaceuticals, Inc)

Jonathan Gravel, MSc Employment: Analysis Group, Inc (recipient of grants from Janssen Pharmaceuticals, Inc)

Amanda M. Grittner, MA Employment: Analysis Group, Inc (recipient of grants from Janssen Pharmaceuticals, Inc)

Marie-Hélène Lafeuille, MA Employment: Analysis Group, Inc (recipient of grants from Janssen Pharmaceuticals, Inc)

Patrick Lefebvre, MA Employment: Analysis Group, Inc (recipient of grants from Janssen Pharmaceuticals, Inc)

Silas C. Martin, MS Employment: Janssen Scientific Affairs, LLC (a Johnson & Johnson company)Stock ownership: Johnson & Johnson

Gary E. Meininger, MD Employment: Janssen Research & Development, LLCStock ownership: Johnson & Johnson, Merck & Co, Inc

Marcia F. T. Rupnow, PhD Employment and meeting/conference attendance: Janssen Scientific Affairs, LLC (a Johnson & Johnson company)Stock ownership: Johnson & Johnson

Lawrence Garber, MD, reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this supplement.


Signed disclosures are on file at the office of The American Journal of Managed Care, Plainsboro, New Jersey.


© Managed Care &Healthcare Communications, LLC

T he total economic burden of diabetes in the United States in 2012 was estimated at $245 bil-lion, a 21% increase from 2007.1 The prevalence of diabetes increases with age and reaches its

peak in the population aged 60 to 74 years.2 Management of diabetes is challenging, especially in an elderly population due to complex comorbid medical issues and a generally lower functional status.3

According to guidelines for diabetes monitoring and treat-ment, glycated hemoglobin (A1C), blood pressure (BP), low-density lipoprotein cholesterol (LDL-C) level, and weight/body mass index (BMI) have been identified as important interrelated quality measures in the treatment and monitoring of type 2 dia-betes mellitus (T2DM).4 The Centers for Medicare & Medicaid Services (CMS) has set specific treatment goals for particular clinical parameters that accountable care organizations partici-pating in its Medicare Shared Savings Program have to achieve when treating patients with diabetes: A1C: 8%, BP: 140/90 mm Hg, LDL-C level: 100 mg/dL.5-7 The Medicare Shared Savings Program is an initiative under the Patient Protection and Affordable Care Act. CMS records a provider’s score for achiev-ing these measures to calculate the part of cost savings that it will share with the provider. A BMI less than 30 kg/m2 is an emerging quality measure for diabetes, because a higher BMI indicates obe-sity, a major risk factor for T2DM.8 This threshold is already being applied by the Clinical Advisory Committee of Better Health Greater Cleveland, a network of primary care practice partners responsible for Cuyahoga County in northeastern Ohio.9

In addition to improving diabetes control to minimize the risk of complications and to potentially improve the well-being of patients with T2DM, achievement of such predefined quality measure goals may also have important economic implications since improved diabetes control leads to fewer disease compli-cations, which can be costly. A study found that the average lifetime medical costs of treating T2DM, including diabetic complications, totaled $85,200, with 53% due to treating dia-betic complications.10 To the authors’ knowledge, despite the importance of these quality measures for diabetes control and treatment and their potential importance for the management

AbstractObjectives: This study examined the demographics, comorbidities, clinical characteristics, and treatments of people with type 2 diabetes mellitus (T2DM) treated with metformin and sulfonylurea as well as an elderly subgroup. Achievement of predefined quality measure goals (glycated hemoglobin [A1C], blood pressure [BP], low-density lipoprotein cho-lesterol [LDL-C], body mass index [BMI]) and their association with diabetes-related healthcare costs were assessed.

Study design: The study applied a retrospective lon-gitudinal cohort design.

Methods: Health insurance claims and electronic medical records from 14,532 adults with T2DM (2007-2011) were used to identify a sample receiving met-formin and sulfonylurea (MET+SU) concomitantly. The index date was the first dispensing of MET+SU after 6 months of eligibility. Clinical characteristics were assessed during baseline. Quality measure attainment (A1C <8%, BP <140/90 mm Hg, LDL-C level <100 mg/dL, BMI <30 kg/m2), was evaluated during the 12 months following the index date. Association between attainment and diabetes-related costs was evaluated using non-parametric bootstrap methods adjusting for imbalance in baseline characteristics between cohorts.

Results: Among 2044 patients, including 1283 patients 65 years and older, hyperlipidemia, hyper-tension, and cardiovascular disease were the most common baseline comorbidities. Quality measure goal attainment was 63.9% for A1C, 33.1% for BP, 68.2% for LDL-C level, and 34.4% for BMI, and was associated with significantly lower diabetes-related costs per patient per year compared with non-attainment (adjusted mean cost differences: –$1445 for A1C; –$1218 for BMI; –$2029 for A1C and BMI; –$2073 for A1C, BMI, and BP; all P <.05).

Conclusion: This study highlights the high incidence of comorbidities and potential financial implications of attaining T2DM quality outcomes.

(Am J Manag Care. 2014;20:S5-S15)

For author information and disclosures, see end of text.

n REPORTS n

Quality Measure Attainment in Patients With Type 2 Diabetes Mellitus

Marie-Hélène Lafeuille, MA; Amanda M. Grittner, MA; Jonathan Gravel, MSc; Robert A. Bailey, MD; Silas Martin, MS;

Lawrence Garber, MD; Mei Sheng Duh, MPH, ScD; and Patrick Lefebvre, MA

Reports


of the economic burden of T2DM, there are no studies that use real-world data from patients with T2DM to assess the achievement of these quality measure goals and its associa-tion with diabetes-related costs.

The objective of this study was to examine the demo-graphic and clinical characteristics and the achievement of predefined quality measure goals in a T2DM popula-tion receiving metformin and sulfonylurea, as well as in an elderly subgroup of this population, and to assess the association of goal attainment with diabetes-related healthcare costs.

Metformin and sulfonylurea are well-established core therapies for controlling hyperglycemia in patients with T2DM.11 Adding a sulfonylurea is one of the treatment options available for metabolic management if metformin and lifestyle changes alone fail to achieve or sustain glyce-mic control. Hence, patients who receive this combination therapy can be considered as having faced challenges in controlling their hyperglycemia. Achieving predefined quality measure goals may therefore have particular effects on clinical outcomes and healthcare cost for this patient population.

Methods

Data SourceThe study used data from health insurance claims

and electronic medical records from the Reliant Medical Group (RMG) database covering the 5-year period from January 1, 2007, through December 31, 2011. RMG is a large nonprofit multispecialty group practice that provides comprehensive care for patients; it has a total of over 1 million patient visits each year to more than 250 physi-

cians practicing across 20 locations throughout central Massachusetts.

The data were de-identified in compliance with the Health Insurance Portability and Accountability Act of 1996 to preserve patient confidentiality. Database ele-ments used for this study included longitudinal, member-linked medical claims, pharmacy claims, enrollment records (including patient demographics), laboratory results (eg, A1C), and clinical measures (eg, weight and BP).

Study Design and Patient SelectionA retrospective longitudinal landmark cohort design

was used (Figure 1). Adult patients with at least 1 diag-nosis of T2DM (International Classification of Diseases, 9th Revision [ICD-9]= 250.x0 or 250.x2) who were being treated concomitantly with metformin and a sulfonyl-urea (eg, chlorpropamide, glimepiride, glipizide, glyburide, tolazamide, and tolbutamide) after at least 6 months of continuous eligibility (baseline period) were included in the study population. The index date was defined as a patient’s first day of a metformin and sulfonylurea pre-scription. Patients had to be continuously eligible for at least 12 months after the index date (landmark period). Patients who were diagnosed with type 1 diabetes mellitus or treated with insulin (with or without other oral antihy-perglycemic agents in combination) during the baseline period were excluded from the study population.

From the real-world sample of 14,532 patients with T2DM, 2666 were being treated with a combination of met-formin and sulfonylurea. Applying subsequent inclusion and exclusion criteria resulted in an overall study population of 2044 patients, including 1283 patients 65 years and older.

n Figure 1. Study Design

Eligibilitystart date

Eligibilityend date

Baseline period:6 monthsbefore

index date

Index date:First day of

metformin + sulfonylurea treatmentafter 6 months of continuous

eligibility

Landmark period:12 months

after index date

Observation period:From end of landmark period

to the end of eligibility

Continuous eligibility



Study OutcomesEvaluation of Quality Measures and Goal AttainmentQuality measures (A1C, BP, LDL-C level, BMI) were

evaluated during the landmark period and reported for the overall population and the elderly subgroup. Quality measure goal attainment was defined as having no values equal to or higher than the predefined threshold during the landmark period. The individual thresholds were:

• A1C: 7%, 8%, and 9%• BP: 140/90 mm Hg

• LDL-C level: 100 mg/dL

• BMI: 30 kg/m2

The combined thresholds were: • A1C: 8%; BP: 140/90 mm Hg; LDL-C level: 100 mg/dL• A1C: 7%; BP: 140/90 mm Hg; LDL-C level: 100 mg/dL• A1C: 8%; BMI: 30 kg/m2

• A1C: 8%; BMI: 30 kg/m2; BP: 140/90 mm Hg

Quality Measure Goal Attainment and Healthcare CostsEvaluated during the observation period, diabetes-related

medical healthcare costs were identified through claims associated with a diagnosis for diabetes (ICD-9 = 250.x0 or 250.x2), whereas diabetes-related pharmacy costs were defined as claims for antihyperglycemic agents. Medical costs were further broken down into emergency department costs, inpatient costs, and outpatient/other visits, according to their recorded medical cost category.

Statistical AnalysesUnivariate descriptive statistics were generated to describe

the baseline demographics, clinical characteristics, and costs of the overall population and an elderly subgroup (>65 years of age), as well as the evaluation of quality measures during the landmark period, including mean ± standard deviation for continuous data and relative frequencies for categorical data.

Costs were reported in US dollars (2011) per patient per year (PPPY) for quality measure goal achievers versus non–goal achievers. Unadjusted and adjusted cost differences were estimated using (a) generalized linear models (GLMs) with a log link and gamma distribution; or (b) 2-part models (for cost components with a portion of zero values greater than 5%), where the first part was a logistic model and the second part was a GLM model with a log link and a gamma distribu-tion. The gamma distribution was chosen, as it is recognized to fit well-skewed healthcare cost data.12 Controlling factors included age, sex, year of index date, race, payer type, and Charlson Comorbidity Index. As baseline diabetes-related comorbidities may contribute to goal achievement, it was

decided not to adjust for them in the multivariate analysis to avoid removing the explanatory effect of the goal achieve-ment variable. Statistical differences between groups (P values) and 95% confidence intervals were calculated using nonparametric bootstrap re-sampling techniques with 499 replications to ensure parameter stability.13 Significance level was set at a 2-sided α value of 0.05.

Results

Baseline Population CharacteristicsDemographics, clinical characteristics, and costs at index

date/baseline are presented in Table 1. Mean (median) age at index date was 66.6 (69.0) years

in the overall study population and 74.6 (74.0) years in the elderly population subgroup. The incidence of macrovas-cular comorbidities, including cardiovascular disease and chronic heart failure, was higher than that of microvascu-lar comorbidities, such as nephropathy, neuropathy, and retinopathy, in both the overall study population and the elderly population subgroup. The most common comor-bidities were hyperlipidemia (overall population, 73.9%; elderly subgroup, 78.1%), hypertension (66.5% and 74.2%, respectively), and cardiovascular disease (25.5% and 33.4%, respectively). Compared with the overall population, the elderly population subgroup had higher incidence of most of the macrovascular and microvascular complications and other comorbidities. Antihypertensives were prescribed to 67.2% of all patients and 75.1% of those 65 years and older. Loop diuretics accounted for 10.5% and 13.6% and non-loop diuretics accounted for 21.1% and 24.5% in the total and elderly populations, respectively.

Evaluation of Quality Measures and Goal Attainment Figures 2A and 2B present the evaluation of quality

measures and goal attainment. Figure 2A shows that in the overall study population, mean A1C was 7.5%, mean BP was 131.8/72.8 mm Hg, mean LDL-C level was 85.2 mg/dL, and mean BMI was 32.7 kg/m2. In the overall study population, 63.9% achieved the A1C goal of less than 8%, 27.2% the A1C goal of less than 7%, 33.1% the BP goal (<140/90 mm Hg), 68.2% the LDL-C level goal (<100 mg/dL), and 34.4% the BMI goal (<30 kg/m2).

Figure 2B illustrates that in the elderly subgroup, mean values were similar to those in the overall population, with 7.4% for A1C, 133.5/70.5 mm Hg for BP, 82.2 mg/dL for LDL-C level, and 31.1 kg/m2 for BMI. In this population, 70.7% achieved the A1C goal of less than 8%, 29.8% the A1C goal of less than 7%, 29.1% the BP goal, 73.3% the LDL-C level goal, and 42.1% the BMI goal.

Reports


n Table 1. Population Baseline Characteristics

Overall Study Population N = 2044

Elderly (>65 y) Population Subgroup

n = 1283

Age at index date, mean ± SD [median] 66.6 ± 12.4 [69.0] 74.6 ± 6.1 [74.0]

Age categories, N (%)

18-44 years 101 (4.9%) 0 (0.0%)

45-64 years 660 (32.3%) 0 (0.0%)

65-74 years 690 (33.8%) 690 (53.8%)

>75 years 593 (29.0%) 593 (46.2%)

Female, N (%) 943 (46.1%) 658 (51.3%)

Ethnicity, N (%)

White 1428 (69.9%) 924 (72.0%)

Black 37 (1.8%) 9 (0.7%)

Nativea 31 (1.5%) 18 (1.4%)

Asian 33 (1.6%) 5 (0.4%)

Other 14 (0.7%) 6 (0.5%)

Unknown 501 (24.5%) 321 (25.0%)

Payer type, N (%)

HMO 622 (30.4%) 82 (6.4%)

Medicare 1156 (56.6%) 1119 (87.2%)

Medicaid 77 (3.8%) 2 (0.2%)

Other 15 (0.7%) 8 (0.6%)

Multiple payers 174 (8.5%) 72 (5.6%)

Year of index date, N (%)

2007 1225 (59.9%) 816 (63.6%)

2008 304 (14.9%) 176 (13.7%)

2009 255 (12.5%) 140 (10.9%)

2010 260 (12.7%) 151 (11.8%)

Baseline medication,b N (%)

Antidepressants 391 (19.1%) 220 (17.1%)

Antihyperlipidemics 1396 (68.3%) 939 (73.2%)

Statins 1236 (60.5%) 858 (66.9%)

Beta-blockers 811 (39.7%) 622 (48.5%)

Antihypertensives 1374 (67.2%) 963 (75.1%)

Loop diuretics 215 (10.5%) 177 (13.8%)

Non-loop diuretics 431 (21.1%) 314 (24.5%)

(Continued)



With respect to achievement of various composite mea-sure goals, 15.9% of the overall population and 16.3% of the elderly subgroup achieved the combined A1C less than 8%, BP, and LDL-C level goal; 7.6% and 8.2% achieved the com-bined A1C less than 7%, BP, and LDL-C level goal; 21.9% and 28.2% achieved the combined A1C and BMI goal; and

7.4% and 8.0% achieved the combined A1C, BMI, and BP goal, respectively.

Quality Measure Goal Attainment and Healthcare Costs

For the overall study population, quality measure goal

n Table 1. Population Baseline Characteristics (Continued)

Overall Study Population N = 2044

Elderly (>65 y) Population Subgroup

n = 1283

Quan-Charlson Comorbidity Index,b mean ± SD [median] 0.69 ± 1.2 [0.0] 0.9 ± (0.1%)

Incidence of comorbidities,b N (%)

Macrovascular comorbidities

Cardiovascular diseasec 522 (25.5%) 429 (33.4%)

Chronic heart failured 120 (5.9%) 104 (8.1%)

Microvascular comorbidities

Neuropathye 328 (16.0%) 259 (20.2%)

Retinopathyf 106 (5.2%) 85 (6.6%)

Nephropathyg 59 (2.9%) 39 (3.0%)

Chronic kidney diseaseh 31 (1.5%) 29 (2.3%)

Proteinuriai 23 (1.1%) 10 (0.8%)

Other comorbidities

Hypertensionj 1359 (66.5%) 952 (74.2%)

Hyperlipidemiak 1510 (73.9%) 1002 (78.1%)

Obesityl 301 (14.7%) 134 (10.4%)

Hypoglycemiam 9 (0.4%) 7 (0.5%)

Healthcare costs (PPPY)b mean ± SD [median]

Pharmacy costs ($) 4925 ± 4942 [4006] 5115 ± 3979 [4493]

Emergency department costs ($) 841 ± 3249 [3916] 938 ± 3574 [0]

Inpatient costs ($) 6600 ± 37,127 [0] 7584 ± 33,760 [0]

Outpatient/other costs ($) 9423 ± 23,610 [3916] 10,676 ± 26,534 [4366]

Total costn ($) 21,788 ± 49,934 [9598] 24,313 ± 49,871 [10,513]

Observation period (days), mean ± SD [median] 1271 ± 416 [1461] 1292 ± 416 [535]

HMO indicates health maintenance organization; ICD-9, International Classification of Diseases, Ninth Revision; PPPY, per person per year; SD, standard deviation. aIncludes “American Indian,” “American Indian or Alaska Native,” and “Whilkut.” bEvaluated during the baseline period defined as 6 months prior to the index date. cIncludes the following ICD-9 codes: 402.9, 410, 411.0, 411.1, 411.81, 411.89, 413, 414.0, 414.1, 414.8, 414.9, 427.0, 427.1, 427.3, 427.4, 427.5, 427.8, 428, 429.3, 430, 431, 432, 433, 434, 435, 436, and 437. dIncludes the following ICD-9 codes: 398.91, 402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, 425.4, 425.5, 425.7, 425.8, 425.9, and 428.eIncludes the following ICD-9 codes: 250.6, 337.0, 337.1, 356, and 357.fICD-9 code: 362.0.gIncludes the following ICD-9 codes: 581.8, 581.9, 583.6, 583.7, 583.8, and 583.9.hICD-9 code: 585.iICD-9 code: 791.0.jIncludes the following ICD-9 codes: 401, 402, 403, 404, and 405.kIncludes the following ICD-9 codes: 272.0, 272.1, 272.2, 272.3, and 272.4.lICD-9 code: 278.0.mIncludes the following ICD-9 codes: 251.0, 251.1, and 251.2.nTotal cost includes all pharmacy and medical costs.

Reports


attainment was associated with significantly lower total diabetes-related healthcare costs PPPY (Table 2 and Figure 3). For the individual goals, the adjusted mean cost difference between achievers and non-achievers was –$992 (P = .060) for A1C less than 7%, –$1445 (P = .016)

for A1C less than 8%, –$749 (P = .112) for BP, –$37 (P = .844) for LDL-C level, and –$1218 (P = .032) for BMI. For the combined quality measure goals, the adjusted mean cost difference was –$595 (P = .460) for A1C less than 8%, BP, and LDL-C level; –$1044 (P = .176) for A1C less than 7%,

n Figure 2A. Evaluation of Quality Measures and Goal Attainment–Overall Study Population

n Figure 2B. Evaluation of Quality Measures and Goal Attainment–Elderly Subgroup

90

80

70

60

50

40

30

20

10

Perc

enta

ge o

f S

tud

y Po

pu

lati

on

Ach

ievi

ng

Go

al

0<7% <8% <9%

A1C

27.2

63.9

BP <140/90 mm Hg

33.1

LDL-C <100 mg/dL

68.2

BMI <30 kg/m2

34.4

A1C <8%, BP <140/90

mm Hg, LDL-C <100 mg/dL

15.9

A1C <7%, BP <140/90


7.6

A1C <8%, BMI <30 kg/m2

21.9

A1C <8%, BMI <30 kg/m2,

BP <140/90 mm Hg

7.4

82.9

N = 1745Mean = 7.5%

N = 1947Mean = 131.8/72.8

mm Hg

N = 1600Mean = 85.2 mg/dL

N = 1890Mean = 32.7 kg/m2

N = 1526

N = 1526

N = 1667

N = 1640

Composite measure achievement

90

80

70

60

50

40

30

20

10

Perc

enta

ge o

f E

lder

ly P

op

ula

tio

n S

ub

gro

up

A

chie

vin

g G

oal

0<7% <8% <9%

A1C

29.8

70.7

BP <140/90 mm Hg

29.1

LDL-C <100 mg/dL

73.3

BMI <30 kg/m2

42.1

A1C <8%, BP <140/90


16.3

A1C <7%, BP <140/90


8.2

A1C <8%, BMI <30 kg/m2

28.2

A1C <8%, BMI <30 kg/m2,

BP <140/90 mm Hg

8.0

88.2

N = 1128Mean = 7.4%

N = 1225Mean = 133.5/70.5

mm Hg

N = 1049Mean = 82.2 mg/dL

N = 1190Mean = 31.1 kg/m2

N = 999

N = 999

N = 1077

N = 1057

Composite measure achievement

A1C indicates glycated hemoglobin; BMI, body mass index; BP, blood pressure; LDL-C, low-density lipoprotein cholesterol.

A1C indicates glycated hemoglobin; BMI, body mass index; BP, blood pressure; LDL-C, low-density lipoprotein cholesterol.



BP, and LDL-C level; –$2029 (P <.001) for A1C less than 8% and BMI; and –$2073 for A1C less than 8%, BMI, and BP (P <.001).

The largest significant contributor to cost savings was outpatient costs for the A1C goal (adjusted mean cost differ-ence: –$969, P <.001), the combined A1C less than 8%, BP, and LDL-C level goal (–$582, P <.001) and the combined A1C less than 7%, BP, and LDL-C level goal (–$580, P = .028). Inpatient costs were the largest significant contributor to cost savings for BMI (–$1319, P <.001), the combined A1C and BMI goal (–$1270, P = .012), and the combined A1C, BMI, and BP goal (–$1370, P = .028).

Discussion

This study examined baseline demographic and clini-cal characteristics as well as the achievement of predefined quality measure goals (A1C <7%, A1C <8%, BP <140/90 mm Hg, LDL-C level <100 mg/dL, and BMI <30 kg/m2) in a population with T2DM and an elderly subgroup treated with metformin and sulfonylurea. Since this patient population can be considered as having faced challenges in controlling their hyperglycemia, achieving predefined quality measure goals may have particular effects on clinical outcomes and health-care costs. The study further assessed how achieving these goals was associated with diabetes-related healthcare costs.

Previously published results support the findings of this study with respect to the cost impact of individual quality measures. Improved glycemic control in patients with type 1 diabetes mellitus and T2DM has been associated with lower direct medical and pharmacy costs in studies using health plan administrative data.14,15 A study using survey data combined with cost data from a large health maintenance organization found that future healthcare costs were higher for persons who are overweight, especially for those with BMI of at least 30 kg/m2.16 Similarly, an observational study in patients with T2DM from Spain found that reductions in BMI were associated with appreciable short-term economic benefits, especially in obese patients.17 A recently published study found that patients with TD2M who achieved the LDL-C level goal of <100 mg/dL incurred significantly lower diabetes-related medical service costs compared with non-goal achievers (–$246, P <.001). However, a statistical difference was not observed with respect to costs for patients who achieved only an A1C goal of less than 7% compared with patients who achieved both the LDL-C and the A1C goal (–$57, P = .404).18 Both the study population (US military veterans, predominantly male) and the definition of diabetes-related costs (medical service costs associated with a diagnosis of diabetes or microvascular or macrovascular

complications) in the cited study differed from the one in the study presented here, potentially explaining the difference in economic and statistical significance while supporting the consistency of the negative sign of the association.

The small difference between the cost savings associated with the combined A1C/BMI goal ($2029, P <.001) and those related to the combined A1C/BMI/BP goal ($2073, P <.001) in the present study should not be interpreted as indi-cating that BP is insignificant for reducing overall healthcare costs. First, there may be a maximum effect; the cost savings that can be realized through achieving additional quality measures may be marginally decreasing. Second, this study only evaluated the impact of quality measure goal achieve-ment on diabetes-related costs. BP control is likely to have an important influence on other healthcare costs, especially cardiovascular-related costs. Since these costs are primarily associated with cardiovascular complications, they may not be linked to a diabetes diagnosis in a claims database, even if the patient has diabetes. Hence, the potential importance of BP control for overall healthcare costs may be underestimated when only diabetes-related costs are considered.

The present study adds to this literature by showing that the achievement of a composite quality measure goal is associated with greater cost savings than the attainment of individual goals alone. Only a few other studies analyze the achievement of multiple goals simultaneously. Eddy and Shah (2012) evaluated the effects of the Medicare Shared Savings Program quality measures and performance targets on Medicare costs in patients with T2DM and reported only minor cost savings, after taking the cost of performance improvement into account.7 However, their study differs from the one described here in several aspects. First, Eddy and Shah simulated the study population and the behavior of healthcare providers, instead of obtaining it from admin-istrative real-world data, as the present study did. Hence, unobservable interactions between treatment, quality mea-sure attainment, and healthcare costs that take place in the real world may not be incorporated in the simulation model. To determine the cost impact of quality measure attain-ment, Eddy and Shah calculated the effect of treatment that brings measures to exactly the thresholds specified, but not beyond. In reality, improved monitoring and control of these quality measures may often lead to patients not only achieving, but exceeding, treatment goals. The cost of per-formance improvement was also estimated based on assump-tions about the number of additional tests and visits required to reach the performance targets. The study presented here did not impose how the improvements in quality measures can be achieved.

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n Table 2. Association Between Diabetes-Related Healthcare Costs and Quality Measure Goal Achievement

(Cost PPPY in US $2011)

Goal

Achievement

Non-Goal

Achievement

Unadjusted Cost

Difference, $

Adjusted Cost Difference, $

[95% CI]a

Pa

A1C Goal (<7%), N 475 1270

Antidiabetic pharmacy costs ($) 1253 2136 –883 –711 [–881 to –555] <.001

Diabetes-related medical costs

Emergency department costs ($) 121 181 –61 –57 [–101 to –8] .024

Inpatient costs ($) 3199 2980 219 –342 [–1216 to – 565] .384

Outpatient/other costs ($) 2256 3031 –774 –744 [–1072 to –460] <.001

Total diabetes-related pharmacy and medical costs ($) 5576 6192 –616 –992 [–2011 to 1] .060

A1C Goal (<8%), N 1115 630

Antidiabetic pharmacy costs ($) 1682 2307 –625 –533 [–703 to 356] <.001


Emergency department costs ($) 136 216 –80 –82 [–144 to 26] .016

Inpatient costs ($) 2974 3137 –162 –435 [–1499 to 367] .319

Outpatient/other costs ($) 2535 3344 –809 –969 [–1455 to 542] <.001


BP Goal (<140/90 mm Hg/mm Hg), N 645 1302

Antidiabetic pharmacy costs ($) 1904 1787 118 55 [–97 to 218] .416




Outpatient/other costs ($) 2530 2933 –403 –225 [–596 to 127] .140


LDL-C Goal (<100 mg/dL), N 1091 509

Antidiabetic pharmacy costs ($) 1932 1804 128 161 [–5 to 332] .056



Inpatient costs ($) 3088 2859 229 –37 [–1071 to 893] .936


Total diabetes-related pharmacy and medical costs ($) 5991 5876 115 –37 [–1230 to 1006] .844

BMI Goal (< 30kg/m2), N 651 1239

Antidiabetic pharmacy costs ($) 1722 1919 –197 –109 [–279 to 35] .184


Emergency department costs ($) 184 159 24 –7 [–60 to 44] .812

Inpatient costs ($) 2332 3098 –766 –1319 [–2052 to 564] <.001

Outpatient/other costs ($) 3124 2700 423 –14 [–492 to 385] .792


A1C (<8%) and BMI (< 30kg/m2) Goal, N 365 1302

Antidiabetic pharmacy costs ($) 1619 2026 –406 –327 [–523 to 163] <.001


Emergency department costs ($) 170 169 2 –11 [–75 to 44] .664


Outpatient/other costs ($) 2543 2986 –443 –697 [–1054 to 315] <.001

Total diabetes-related pharmacy and medical costs ($) 5009 6316 –1307 –2029 [–2922 to 1078] <.001

(Continued)



Apart from analyzing the association between quality measure attainment and healthcare costs, the present study also confirmed the high incidence of comorbidities in a T2DM population, especially in the elderly subgroup. This highlights the need for integrated management of T2DM that considers a variety of quality measures and interven-tions (including lifestyle changes and pharmacologic treat-ments) simultaneously to improve patients’ outcomes and quality of life.19,20

LimitationsThis study has several limitations. It was designed to

investigate quality measure attainment in a study popula-tion of patients with T2DM receiving metformin and sul-

fonylurea, defined as those with at least 1 day of treatment with both metformin and sulfonylurea during the baseline period. Since the study did not intend to attribute quality measure achievement to a particular treatment regimen, it did not require patients to be new users of metformin and sulfonylurea or to continue treatment throughout the land-mark period.

Administrative claims data may also be subject to inaccuracies and miss some specific clinical information. For example, incorrect diagnoses recorded on claims may hamper the correct attribution of healthcare costs to clini-cal conditions. Also, claims do not contain information on other unrecorded factors that may affect healthcare costs, such as smoking habits and over-the-counter drug use (eg,

n Table 2. Association Between Diabetes-Related Healthcare Costs and Quality Measure Goal Achievement (Continued)

(Cost PPPY in US $2011)

Goal

Achievement

Non-Goal

Achievement

Unadjusted Cost

Difference, $

Adjusted Cost Difference, $

[95% CI]a

Pa

A1C (<8%), BP (<140/90 mm Hg/mm Hg), and LDL-C (<100 mg/dL) Goal, N

242 1284





Outpatient/other costs ($) 2207 2919 –712 –582 [–883 to –241] <.001


A1C (<7%), BP (<140/90 mm Hg/mm Hg), and LDL-C (<100 mg/dL) Goal, N

116 1410

Antidiabetic pharmacy costs ($) 1464 1965 –501 –368 [–640 to –33] .044


Emergency department costs ($) 58 172 –115 –80 [–133 to –11] .036


Outpatient/other costs ($) 2106 2863 –757 –580 [–1046 to –73] .028


A1C (<8%), BMI (<30kg/m2), and BP (<140/90 mm Hg/mm Hg) Goal, N

122 1518



Emergency department costs ($) 138 171 –33 32 [–1101 to 221] .826



Total diabetes-related pharmacy and medical costs ($) 3996 6175 –2179 –2073 [–3198 to 932] <.001

A1C indicates glycated hemoglobin; BMI, body mass index; BP, blood pressure; CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; PPPY, per person per year. aAdjusted cost differences, controlling for age, sex, year of index date, race, payer type, and Charlson Comorbidity Index, were estimated using a) generalized linear models (GLMs) with a log link and gamma distribution or b) 2-part models (for cost components with a portion of zero values greater than 5%), where the first part is a logistic model and the second part is a GLM model with a log link and a gamma distribution. Statistical differences between groups (P values) and 95% CIs were calculated using nonparametric bootstrap re-sampling techniques with 499 replications.

Reports


aspirin). Nevertheless, the use of linked, electronic medi-cal record data made it possible to provide unique insights into the association between quality measure attainment and healthcare costs for a real-world population. To assess this association, the study excluded patients without A1C, BP, LDL-C level, or BMI assessment during the landmark period, thus potentially resulting in a subpopulation dif-ferent from the general T2DM population treated with metformin and sulfonylurea. The strict definition of goal achievement in this study (no values above a specific threshold) may have further selected a population that is relatively stable and may have influenced the associated economic burden.

The study assessed the cost impact of quality mea-sure achievement, controlling for demographic and clinical baseline characteristics. It could not, however, account for unobserved factors that may affect healthcare costs, such as

general lifestyle changes or improved adherence to treatment regimens. If these factors are correlated with quality measure achievement, the estimates for the cost impacts of these qual-ity measures may be biased.

Because patients from the RMG are predominantly located in central Massachusetts, the study results may not necessarily be generalizable to other populations. The limited external validity may, however, be overweighed by the high internal validity that stems from the large sample size of the data set used; this is the current trade-off with all data sets.

Conclusion

This study confirms the high incidence of comorbidi-ties in a population with T2DM, particularly in elderly patients. Using real-world data, the study demonstrated that the achievement of quality measure goals in terms of A1C, BP, and BMI is significantly associated with impor-

n Figure 3. Adjusted Cost Difference Associated With Goal Achievement Versus Non–Goal Achievementa

1000

500

0

–500

–1000

–1500

–2000

–2500

–3000

–3500

Ad

just

ed C

ost

Diff

eren

ce o

f G

oal

Ach

ieve

men

t Ver

sus

No

n–G

oal

Ach

ieve

men

t P

PPY

(20

11 U

S d

olla

rs)

A1C <7% A1C <8% BP <140/90 mm Hg

LDL-C <100 mg/dL

BMI <30 kg/m2

A1C <8%, BP <140/90

mm Hg, LDL-C <100

mg/dL

A1C <8%, BMI <30 kg/m2,

BP <140/90 mm Hg

A1C <7%, BP <140/90

mm Hg, LDL-C <100

mg/dL

A1C <8%, BMI <30

kg/m2

–992

–1445

–1218–1044

–2029 –2073

–595–749

–37

A1C indicates glycated hemoglobin; BMI, body mass index; BP, blood pressure; LDL-C, low-density lipoprotein cholesterol; PPPY, per patient per year. aError bars represent 95% confidence intervals.



tant reductions in diabetes-related healthcare costs in a population of patients with T2DM exposed to metformin and sulfonylurea.

Author affiliations: Health Economics and Outcomes Research, Janssen Scientific Affairs, LLC, Raritan, NJ (RAB, SCM); Analysis Group, Inc, Boston, MA (MSD); Reliant Medical Group, Worcester, MA (LG); Groupe d’Analyse, Ltée, Analysis Group, Inc, Montreal, QC, Canada (JG, AMG, MHL, PL).

Funding source: This supplement was supported by Janssen Pharmaceuticals, Inc.

Author disclosures: Dr Bailey reports employment with Janssen Scientific Affairs, LLC (a Johnson & Johnson company), and reports stock ownership with Johnson & Johnson. Dr Duh, Mr Gravel, Ms Grittner, Ms Lafeuille, and Mr Lefebvre report employment with Analysis Group, Inc (recipient of grants from Janssen Pharmaceuticals, Inc). Mr Martin reports employment with Janssen Scientific Affairs, LLC (a Johnson & Johnson company) and stock ownership with Johnson & Johnson. Dr Garber reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this supplement.

Authorship information: Concept and design (RAB, MSD, LG, JG, MHL, PL, SCM); acquisition of data (RAB, LG, MHL, PL, SCM); analysis and interpretation of data (RAB, MSD, JG, AMG, MHL, PL, SCM); draft-ing of the manuscript (RAB, AMG, MHL, PL, SCM); critical revision of the manuscript for important intellectual content (RAB, MSD, AMG, MHL, PL, SCM); statistical analysis (JG, AMG, MHL, PL); obtaining funding (MSD, MHL, PL); administrative, technical, or logistic support (LG); and supervision (RAB).

Address correspondence to: Marie-Hélène Lafeuille, MA, Groupe d’Analyse, Ltée, 1000 De La Gauchetiere West, Suite 1200, Montreal, QC, Canada H3B 4W5. E-mail: [email protected].

REFERENCES1. American Diabetes Association. Economic costs of diabetes in the U.S. in 2012. Diabetes Care. 2013;36(4):1033-1046.2. Cowie CC, Rust KF, Ford ES, et al. Full accounting of diabetes and pre-diabetes in the U.S. population in 1988-1994 and 2005-2006. Diabetes Care. 2009;32(2):287-294.3. Chau D, Edelman SV. Clinical management of diabetes in the elderly. Clinical Diabetes. 2001;19(4):172-175.4. American Diabetes Association. Standards of medical care in diabetes – 2011. Diabetes Care. 2011;34(suppl 1):S11–S61.5. Centers for Medicare & Medicaid Services. Medicare program; Medicare Shared Savings Program: accountable care organiza-tions: final rule. Fed Regist. 2011;76(212):67802–67990.6. RTI International, Telligen. Accountable care organization 2012 program analysis, quality performance standards narrative measure specifications, final report. Research Triangle Park, NC:

RTI International; December 12, 2011. RTI Project No. 0213195 .000.004.7. Eddy DM, Shah R. A simulation shows limited savings from meeting quality targets under the Medicare Shared Savings pro-gram. Health Aff (Millwood). 2012;31(11):2554-2562.8. Obesity and Overweight. World Health Organization website. www.who.int/dietphysicalactivity/media/en/gsfs_obesity.pdf. Accessed October 8, 2013.9. Cebul RD, Love TE, Jain AK, Hebert CJ. Electronic health records and quality of diabetes care. N Engl J Med. 2011;365(9): 825-833.10. Zhuo X, Zhang P, Hoerger TJ. Lifetime direct medical costs of treating type 2 diabetes and diabetic complications. Am J Prev Med. 2013;45(3):253-261.11. Nathan DM, Buse JB, Davidson MB, et al; American Diabetes Association; European Association for Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1): 193-203.12. Manning WG, Basu A, Mullahy J. Generalized modeling approaches to risk adjustment of skewed outcomes data. J Health Econ. 2005;24(3):465-488.13. Davidson R, MacKinnon JG. Econometric Theory and Methods. New York, NY: Oxford University Press; 2004. 14. Manning WG, Basu A, Mullahy J. Generalized modeling approaches to risk adjustment of skewed outcomes data. J Health Econ. 2005;24(3):465-488.15. Shetty S, Secnik K, Oglesby AK. Relationship of glycemic con-trol to total diabetes-related costs for managed care health plan members with type 2 diabetes. J Manag Care Pharm. 2005;11(7): 559-564.16. Thompson D, Brown JB, Nichols GA, Elmer PJ, Oster G. Body mass index and future healthcare costs: a retrospective cohort study. Obes Res. 2001;9(3):210-218.17. Dilla T, Valladares A, Nicolay C, Salvador J, Reviriego J, Costi M. Healthcare costs associated with change in body mass index in patients with type 2 diabetes mellitus in Spain: the ECOBIM study. Appl Health Econ Health Policy. 2012;10(6):417-430.18. Shi L, Ye X, Lu M, et al. Clinical and economic benefits asso-ciated with the achievement of both HbA1c and LDL cholesterol goals in veterans with type 2 diabetes mellitus. Diabetes Care. 2013;36(10):3297-3304.19. Kalda R, Rätsep A, Lember M. Predictors of quality of life of patients with type 2 diabetes. Patient Prefer Adherence. 2008; 2:21-26.20. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348(5): 383-393.


© Managed Care &Healthcare Communications, LLC

D iabetes is a chronic disease associated with a variety of comorbidities, including retinopathy, nephropa-thy, neuropathy, and cardiovascular (CV) disease. In 2010, diabetes affected approximately 25.8 mil-

lion people in the United States.1 Among diagnosed cases of diabetes in adults, approximately 90% to 95% are type 2 diabetes mellitus (T2DM).1 While a primary goal of T2DM management is improvement of glycemic control, as measured by the lowering of glycated hemoglobin (A1C), reductions in blood pressure (BP) and body weight and improvements in lipid control are also ben-eficial for reducing the risk of comorbidities and diabetes-related complications.1-3 The American Diabetes Association currently recommends attainment of A1C less than 7%, BP less than 140/80 mm Hg, and low-density lipoprotein cholesterol (LDL-C) level less than 100 mg/dL for most adults with T2DM, with poten-tial for individualization of treatment targets based on patient characteristics and medical history.3 Despite a range of available antihyperglycemic agents (AHAs), evidence suggests that nearly half of patients with diabetes in the United States do not meet recommended diabetes treatment goals.4

As the US healthcare system transitions from a fee-for-service model to one in which compensation is based on optimizing patient outcomes, quality measures (ie, standards used to assess achieve-ment of improved patient outcomes) are becoming an increasingly important mechanism for evaluating quality of care that allows for comparisons across treatments, healthcare delivery systems, and patient populations. Diabetes is one of the first diseases for which quality measures have been adopted due to its prevalence and the number of measurable parameters related to diabetes care,4 includ-ing A1C, BP, and LDL-C level. A number of diabetes-related quality measures, including A1C greater than 9.0% (poor control) or less than 8.0% (good control), BP less than 140/90 or 140/80 mm Hg, and LDL-C level less than 100 mg/dL, have been speci-fied for use in the 2013 Health Effectiveness Data and Information Set measures developed by the National Committee on Quality Assurance.5 Quality measures related to body mass index (BMI) and body weight are also relevant, as approximately 80% of patients with T2DM are overweight or obese and weight loss is an important aspect of T2DM management.2 The Health Resources and Services Administration’s Health Disparities Collaboratives measures

AbstractObjective: To evaluate attainment of diabetes-related quality measures with canagliflozin, a sodium glu-cose cotransporter 2 inhibitor, versus sitagliptin in patients with type 2 diabetes mellitus (T2DM).

Study design: This post hoc analysis included data from a 52-week, randomized, double-blind, phase 3 study comparing canagliflozin 300 mg and sitagliptin 100 mg in patients with T2DM on metformin plus sulfonylurea.

Methods: Individual and composite diabetes-related quality measures based on glycated hemoglobin (A1C), blood pressure (BP), low-density lipoprotein cholesterol (LDL-C) level, body mass index (BMI), and body weight were assessed in the overall population and a sub-group with a baseline BMI of at least 25 kg/m2.

Results: At baseline, the proportion of patients meet-ing criteria for quality measures was similar between groups. At week 52, more canagliflozin-treated patients achieved quality measures of an A1C less than 8% or less than 7%, and fewer canagliflozin-treated patients had an A1C greater than 9%, com-pared with sitagliptin. More patients achieved BP measurement less than 140/90 mm Hg, less than 140/80 mm Hg, or less than 130/80 mm Hg with canagliflozin versus sitagliptin. The proportion of patients with an LDL-C level less than 100 mg/dL was similar between groups. More patients had a BMI of at least 25 kg/m2 and a greater than 10 lb (4.5 kg) weight loss from baseline, and a BMI less than 30 kg/m2 at week 52, with canagliflozin versus sitagliptin. A greater proportion of patients achieved composite end points based on A1C, BP, and LDL-C level with canagliflozin versus sitagliptin. Similar results were observed in the subgroup of patients with a baseline BMI of at least 25 kg/m2.

Conclusion: In this study involving patients with T2DM on metformin plus sulfonylurea, after 52 weeks, patients treated with canagliflozin 300 mg demonstrated better attainment of individual and composite diabetes-related quality measures com-pared with patients treated with sitagliptin 100 mg.

(Am J Manag Care. 2014;20:S16-S24)

For author information and disclosures, see end of text.

n REPORTS n

Attainment of Diabetes-Related Quality Measures With Canagliflozin Versus Sitagliptin

Robert A. Bailey, MD; C. V. Damaraju, PhD; Silas C. Martin, MS; Gary E. Meininger, MD; Marcia F. T. Rupnow, PhD; and Lawrence Blonde, MD



include a measure of the proportion of patients with a BMI of at least 25 kg/m2 who have lost 10 lb (4.5 kg) at any time in the last 12 months6; BMI less than 30 kg/m2 is also a qual-ity measure for diabetes approved by Better Health’s Clinical Advisory Committee.7 In addition to these quality measures, diabetes-related composite quality measures that combine individual quality measures to provide an overall assessment of patient outcomes have also been used.8-11 HealthPartners, the largest consumer-governed health plan in the United States, has established a set of composite measures for diabetes known as the D5 that includes: A1C less than 7%, BP less than 130/80 mm Hg, LDL-C level less than 100 mg/dL, no use of tobacco, and daily use of aspirin (for patients aged 41-75 years).10 Another set of composite measures developed by the Centers for Medicare & Medicaid Services includes A1C less than 8%, BP less than 140/90 mm Hg, LDL-C level less than 100 mg/dL, no use of tobacco, and use of aspirin.11

Canagliflozin is a sodium glucose cotransporter 2 inhibi-tor approved in the United States for the treatment of patients with T2DM.12-20 In phase 3 studies, canagliflozin treatment provided improved glycemic control, clinically meaningful weight loss, and BP reductions in patients with T2DM as monotherapy or added on to a variety of back-ground AHAs.12-17,20 In a 52-week, phase 3 study in patients with T2DM on background metformin plus sulfonylurea,15 canagliflozin 300 mg demonstrated noninferiority, and, in a subsequent pre-specified assessment, superiority to sitagliptin 100 mg in reducing A1C. Canagliflozin reduced mean A1C from a baseline value of 8.1% to 7.1% at week 52, whereas sitagliptin was associated with a reduction from 8.1% to 7.5%. Canagliflozin 300 mg provided significant reductions in body weight and systolic BP compared with sitagliptin 100 mg (P <.001 for both comparisons). Canagliflozin 300 mg was also associated with a greater decrease from baseline in diastolic BP, and a greater increase from baseline in LDL-C level, compared with sitagliptin 100 mg. Canagliflozin was generally well tolerated in this patient population, with no notable increase in the incidence of hypoglycemia compared with sitagliptin (43.2% and 40.7%, respectively).

This paper reports findings from a post hoc analysis of data from this 52-week study and evaluates the attainment of indi-vidual and composite diabetes-related quality measures with canagliflozin 300 mg compared with sitagliptin 100 mg in the overall patient population. Quality measures assessed in this analysis have been endorsed by the National Quality Forum and have also been used in studies of other AHAs.21-24 Results are also reported from assessments of quality measures attain-ment in a subgroup of patients with a baseline BMI of at least 25 kg/m2 (classified as overweight or obese based on National

Institutes of Health criteria25), as this patient population represents the majority of patients with T2DM2 and has been reported to have a greater contribution to healthcare costs.25

Methods

Study Design and Patient Population This 52-week, randomized, double-blind, active-con-

trolled, phase 3 study compared canagliflozin 300 mg with sitagliptin 100 mg as add-on therapy to metformin plus sulfonylurea in patients with T2DM. Details of the study design, including patient inclusion and exclusion criteria, have previously been reported.15 Briefly, eligible patients were men or women with T2DM at least 18 years old who had an A1C between 7.0% and 10.5% and taking metformin plus sulfonylurea at maximally or near-maximally effective doses (metformin: >2000 mg/day or >1500 mg/day if unable to tolerate a higher dose; sulfonylurea: at least half-maximal labeled dose). Those who had a repeated fasting plasma glucose (FPG) of at least 300 mg/dL; a history of type 1 dia-betes mellitus, CV disease, or uncontrolled hypertension; or estimated glomerular filtration rate less than 55 mL/min/1.73 m2 (or <60 mL/min/1.73 m2 if based on restriction in the metformin local label) were excluded. No glycemic rescue therapy was provided in this study, and patients meeting protocol-specified glycemic withdrawal criteria were discon-tinued from the study.

The study was conducted in accordance with the ethi-cal principles that have their origin in the Declaration of Helsinki and are consistent with Good Clinical Practice and applicable regulatory requirements. Approval of the study protocol and amendments was obtained from institutional review boards and independent ethics committees for par-ticipating centers. All patients provided informed, written consent prior to participation.

Assessments and Statistical Analyses

The pre-specified primary efficacy end point of the clini-cal study was the change in A1C from baseline to week 52; these data have previously been reported.15 Efficacy data at week 52 were used in post hoc analyses evaluating the propor-tion of patients achieving diabetes-related quality measures. Individual quality measures (based on A1C, BP, LDL-C level, BMI, and body weight) and composite quality measures evalu-ated in this analysis are shown in Table 1. The use of tobacco or aspirin was not included in quality measures evaluated in this analysis because neither canagliflozin nor sitagliptin was expected to affect aspirin or tobacco use measures.

Analyses were performed using the modified intent-to-treat (mITT) population consisting of randomized patients

Reports


who received at least 1 dose of study drug, and a subgroup of these patients with baseline BMI of at least 25 kg/m2. For all analyses, the last observation carried forward approach was used to impute missing data for consistency with the primary analysis method for pre-specified end points in the clinical study. Statistical comparisons of canagliflozin 300 mg versus sitagliptin 100 mg were not performed for these post hoc analyses because they were not pre-specified; therefore, no P values are reported. However, 95% confidence intervals (CIs) for the between-group differences are reported; odds ratios (ORs) (based on a logistic regression model with treat-ment and study as factors and baseline value as a covariate) and associated 95% CIs for the comparison of canagliflozin versus sitagliptin are also presented.

Results

PatientsDetails regarding patient disposition and baseline char-

acteristics for the overall population of this study have previously been reported.15 Briefly, 755 of the 756 patients randomized in the clinical study were included in the mITT analysis set, and 464 (61%) completed the 52-week treat-ment period. The most common reason for discontinuation was meeting glycemic withdrawal criteria (10.6% and 22.5% with canagliflozin and sitagliptin, respectively15), as rescue therapy was not provided in this study. Baseline demographic and disease characteristics were generally similar between the canagliflozin 300 mg and sitagliptin 100 mg groups. Patients had mild to moderate hyperglycemia at baseline, with a mean A1C of 8.1% and a mean duration of T2DM of 9.6 years. At baseline, mean systolic BP was 130.7 mm Hg, mean diastolic

BP was 78.9 mm Hg, and mean LDL-C level was 98.7 mg/dL. Patients had a mean baseline body weight of 88.3 kg and mean baseline BMI of 31.6 kg/m2, with 53% of patients being obese (BMI >30 kg/m2 based on National Institutes of Health criterion25). Many patients were on background antihyper-tensive medications, with 65% taking agents that act on the renin-angiotensin system, 21% on beta-blocking agents, 21% on calcium channel blockers, and 32% on diuretics; 54% of patients were taking lipid-modifying medications, including statins. There were no meaningful differences between treat-ment groups in the use of antihypertensive and lipid-modify-ing medications at baseline; adjustments to these medication regimens were to have been made during the pretreatment phase to limit the need for adjustments during the double-blind treatment phase. Baseline demographic and disease characteristics were also generally similar between treatment groups in the BMI of at least 25 kg/m2 subgroup (n = 642; see eAppendix Table available online at www.ajmc.com).

Quality Measures in the Overall PopulationIndividual quality measuresAt baseline, there were no notable differences between

canagliflozin 300 mg and sitagliptin 100 mg in the propor-tion of patients who met individual quality measures criteria related to A1C, BP, LDL-C level, and BMI (Table 2). At week 52, more patients treated with canagliflozin 300 mg com-pared with sitagliptin 100 mg achieved an A1C less than 8% (85.0% vs 66.0%) and less than 7% (47.6% vs 35.3%); fewer canagliflozin-treated patients had an A1C greater than 9% compared with those who received sitagliptin (1.9% vs 8.5%). A higher proportion of patients in the canagliflozin 300 mg

n Table 1. Summary of Individual and Composite Quality Measures Assessed

Individual Measures Composite Measures

A1C A1C <7%, BP <130/80 mm Hg, LDL-C <100 mg/dL

>9% (poor control)a A1C <7%, BP <140/80 mm Hg, LDL-C <100 mg/dL

<8% (good control)a A1C <8%, BP <140/80 mm Hg, LDL-C <100 mg/dL

<7% A1C <8%, BP <140/90 mm Hg, LDL-C <100 mg/dL

BP

<140/90 mm Hg

<140/80 mm Hg

<130/80 mm Hg

LDL-C

<100 mg/dL

BMI and body weight

>25 kg/m2 and >10 lb (4.5 kg) weight loss from baseline

>30 kg/m2

A1C indicates glycated hemoglobin; BMI, body mass index; BP, blood pressure; HEDIS, Health Effectiveness Data and Information Set; LDL-C, low-density lipoprotein cholesterol. aPoor and good control are as defined in HEDIS quality measures.5



group achieved a BP less than 140/90 mm Hg, less than 140/80 mm Hg, and less than 130/80 mm Hg at week 52 (84.5%, 62.4%, and 53.3%, respectively) compared with the sitagliptin 100 mg group (71.9%, 48.2%, and 38.4%, respectively). For all comparisons of canagliflozin versus sitagliptin in A1C- and BP-related quality measures, the 95% CIs for between-group differences excluded 0 and the 95% CIs for ORs excluded 1 (Table 2). The proportion of patients who achieved an LDL-C level less than 100 mg/dL was similar with canagliflozin 300 mg (47.9%) and sitagliptin 100 mg (54.4%) at week 52 (the 95% CIs for between-group differences included 0 and the 95% CIs for ORs included 1). Among patients who had an LDL-C level less than 100 mg/dL at baseline, 76.5% and 80.1% still had an LDL-C level less than 100 mg/dL at week 52 with canagliflozin 300 mg and sitagliptin 100 mg, respec-tively. At week 52, more patients treated with canagliflozin 300 mg compared with sitagliptin 100 mg had a BMI of at

least 25 kg/m2 and a greater than 10 lb (4.5 kg) weight loss from baseline (16.3% vs 6.5%), and had a BMI less than 30 kg/m2 (54.1% vs 44.4%). For comparisons of canagliflozin versus sitagliptin in BMI- and body weight–related quality measures, the 95% CIs for between-group differences excluded 0 and the 95% CIs for ORs excluded 1 (Table 2).

Composite quality measuresNo differences related to composite quality measures were

observed at baseline between patients who received cana-gliflozin 300 mg compared with sitagliptin 100 mg (Table 3). At week 52, the proportion of patients who achieved the composite quality measure of an A1C less than 7%, BP less than 130/80 mm Hg, and LDL-C level less than 100 mg/dL was higher with canagliflozin 300 mg than with sitagliptin 100 mg (15.7% vs 8.8%; 95% CI for the between-group difference excluded 0 and 95% CI for the OR excluded 1). The propor-

n Table 2. Proportion of Patients Who Met Individual Quality Measures at Baseline and Achieved Individual Quality Measures at Week 52 (Overall Population)

Baseline Week 52 (LOCF)

Measure

Canagliflozin 300 mg,

% (n)

Sitagliptin 100 mg,

% (n)

Difference,

%


% (n)

Sitagliptin 100 mg % (n)

Difference, %

(95% CI)

Odds Ratio (95% CI)

A1C, n 377 378 374 365

>9% (poor control)a 16.4% 18.5% –2.1% 1.9% 8.5% –6.6%b 0.18b

(62) (70) (–7.8, 3.6) (7) (31) (–10.0 to –3.2)b (0.08 to 0.43)b

<8% (good control)a 49.1% 46.0% 3.0% 85.0% 66.0% 19.0%b 3.31b

(185) (174) (–4.3, 10.4) (318) (241) (12.7 to 25.3)b (2.26 to 4.86)b

<7% 7.4% 9.5% –2.1% 47.6% 35.3% 12.3%b 1.79b

(28) (36) (–6.3, 2.1) (178) (129) (4.9 to 19.6)b (1.30 to 2.47)b

BP, n 377 378 375 367

<140/90 mm Hg 70.3% 72.0% –1.7% 84.5% 71.9% 12.6%b 2.59b

(265) (272) (–8.4, 5.1) (317) (264) (6.5 to 18.7)b (1.74 to 3.86)b

<140/80 mm Hg 42.2% 44.7% –2.5% 62.4% 48.2% 14.2%b 2.12b

(159) (169) (–9.9, 4.8) (234) (177) (6.8 to 21.5)b (1.54 to 2.93)b

<130/80 mm Hg 32.9% 35.4% –2.6% 53.3% 38.4% 14.9%b 2.24b

(124) (134) (–9.6, 4.5) (200) (141) (7.6 to 22.3)b (1.62 to 3.09)b

LDL–C, n 377 377 363 353

<100 mg/dL 50.4% 56.8% –6.4% 47.9% 54.4% –6.5% 0.86

(190) (214) (–14, 1.0) (174) (192) (–14.0 to 1.1) (0.59 to 1.25)

BMI and body weight, n 377 378 375 367

>25 kg/m2 and >10 lb (4.5 kg) weight loss from baseline

NA NA NA 16.30% (61)

6.50% (24)

9.7%b

(4.9 to 14.5)b3.23b

(1.90 to 5.49)b

<30 kg/m2 48.3% 45.8% 2.5 54.1% 44.4% 9.7%b 5.56b

(182) (173) (–4.9, 9.9) (203) (163) (2.3 to 17.1)b (2.44 to 12.50)b

A1C indicates glycated hemoglobin; BMI, body mass index; BP, blood pressure; CI, confidence interval; HEDIS, Health Effectiveness Data and Information Set; LDL-C, low-density lipoprotein cholesterol; LOCF, last observation carried forward; NA, not applicable. aPoor and good control are as defined in HEDIS quality measures.5 bComparisons for which the 95% CI for the between-group difference excluded 0, or the 95% CI for the odds ratio of canagliflozin versus sitagliptin excluded 1.

Reports


tion of patients who achieved this composite quality measure, as well as several individual quality measures, is shown in Figure 1. The proportion of patients who achieved a similar composite quality measure with a less stringent BP criterion (A1C <7%, BP <140/80 mm Hg, and LDL-C level <100 mg/dL) was numerically higher with canagliflozin 300 mg than with sitagliptin 100 mg (16.5% vs 11.6%); the 95% CI for the between-group difference included 0, but the 95% CI for the OR excluded 1 (Table 3). For 2 other composite quality measures that both had criteria of an A1C less than 8% and an LDL-C level less than 100 mg/dL with a BP criterion of less than 140/80 or less than 140/90 mm Hg, attainment was higher with canagliflozin 300 mg (27.8% and 35.5%, respectively) versus sitagliptin 100 mg (20.4% and 27.8%, respectively; 95% CIs for the between-group differences excluded 0 and 95% CIs for the ORs excluded 1). Differences (95% CIs) between canagliflozin 300 mg and sitagliptin 100 mg in the proportion of patients who met quality measures at baseline and achieved quality measures at week 52 are shown in Figure 2.

Quality Measures in the BMI of at Least 25 kg/m2 Subgroup

Findings on attainment of individual and composite quali-ty measures in the subgroup of patients with a baseline BMI of at least 25 kg/m2 were generally similar to those in the overall population (Tables 4 and 5). A higher proportion of patients achieved quality measures related to A1C with canagliflozin 300 mg compared with sitagliptin 100 mg (<8%, 85.2% vs 64.0%; <7%, 48.7% vs 31.8%); the proportion of patients

with A1C greater than 9% was 1.9% and 8.9% with cana-gliflozin and sitagliptin, respectively. Similarly, more patients treated with canagliflozin than those treated with sitagliptin achieved quality measures related to BP, BMI, and body weight. Achievement of an LDL-C level less than 100 mg/dL was similar with canagliflozin 300 mg and sitagliptin 100 mg. For all comparisons of canagliflozin versus sitagliptin, with the exception of that for LDL-C level less than 100 mg/dL, 95% CIs for the between-group differences excluded 0 and 95% CIs for the ORs excluded 1 (Table 4). Better attainment was observed with canagliflozin 300 mg compared with sitagliptin 100 mg for all 4 composite quality measures assessed (Table 5), with 95% CIs for the between-group differences excluding 0 and 95% CIs for the ORs excluding 1 for all comparisons.

Discussion

This post hoc analysis evaluated the attainment of indi-vidual and composite diabetes-related quality measures with canagliflozin 300 mg compared with sitagliptin 100 mg using data from a randomized, double-blind, active-controlled, phase 3 trial. The quality measures assessed in this analysis were endorsed by the National Quality Forum and have also been used in studies of other AHAs.21-24 The use of data from a head-to-head, active comparator study allowed for direct comparison of efficacy between canagliflozin and sitagliptin.

Canagliflozin 300 mg provided better attainment of individual quality measures related to A1C, BP, BMI, and body weight compared with sitagliptin 100 mg in patients with T2DM inadequately controlled on metformin plus

n Table 3. Proportion of Patients Who Met Composite Quality Measures at Baseline and Achieved Composite Qual-ity Measures at Week 52 (Overall Population)


Composite Measure


% (n) (n = 377)

Sitagliptin 100 mg,

% (n) (n = 377)

Difference, % (95% CI)


% (n) (n = 363)

Sitagliptin 100 mg,

% (n) (n = 353)


Odds Ratio (95% CI)

A1C <7%, BP <130/80 mm Hg, LDL-C <100 mg/dL

0.8%(3)

1.6%(6)

–0.8%(–2.6 to 1.0)

15.7%(57)

8.8%(31)

6.9%a

(1.9 to 12.0)a2.46a

(1.49 to 4.07)a


0.8%(3)

2.4%(9)

–1.6%(–3.6 to 0.5)

16.5%(60)

11.6%(41)

4.9%(–0.4 to 10.3)

1.83a

(1.15 to 2.92)a


10.9%(41)

13.3%(50)

–2.4%(–7.3 to 2.5)

27.8%(101)

20.4%(72)

7.4%a

(0.9 to 13.9)a1.95a

(1.32 to 2.89)a


17.8%(67)

21.0%(79)

–3.2%(–9.1 to 2.7)

35.5%(129)

27.8%(98)

7.8%a

(0.7 to 14.8)a1.84a

(1.28 to 2.63)a

A1C indicates glycated hemoglobin; BP, blood pressure; CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; LOCF, last observation carried forward. aComparisons for which the 95% CI for the between-group difference excluded 0, or the 95% CI for the odds ratio of canagliflozin vs sitagliptin excluded 1.



sulfonylurea. In addition, a greater proportion of patients achieved composite quality measures based on A1C, BP, and LDL-C level in the canagliflozin group compared with the sitagliptin group. These findings are consistent with previ-ously reported results from this study demonstrating greater improvements in glycemic control and greater reductions in body weight and systolic BP with canagliflozin 300 mg com-pared with sitagliptin 100 mg.15 Notably, the greater reduction in A1C observed with canagliflozin compared with sitagliptin in this study was not associated with an increased risk of hypoglycemia.

Canagliflozin has been associated with increases from base-line in LDL-C level across phase 3 studies.12-16,20 In the study on which the present analysis was based, a greater increase from baseline in LDL-C level was observed with canagliflozin 300 mg compared with sitagliptin 100 mg.15 However, attain-ment of LDL-C level less than 100 mg/dL was generally similar with canagliflozin and sitagliptin in this analysis. Thus, the proportion of patients achieving the LDL-C target was compa-rable with canagliflozin and sitagliptin, despite the increase in LDL-C levels observed with canagliflozin versus sitagliptin. In addition to increases in LDL-C level, increases in HDL-C level were also seen with canagliflozin compared with sitagliptin; both treatment groups were associated with modest increases in triglycerides, as well as increases in non–HDL-C that were smaller than the LDL-C increases, with no notable difference between groups in the change in LDL-C/HDL-C ratio.15 There were no notable differences between treatment groups in the use of lipid-modifying medications (including statins).

Patients treated with canagliflozin 300 mg demonstrated better attainment of composite quality measures (across various definitions) compared with patients treated with

sitagliptin 100 mg in this analysis. In a previously published, cross-sectional population survey (the National Health and Nutrition Examination Survey [NHANES] from 2007 to 2010), 18.8% of participants achieved the most restric-tive composite measure of A1C less than 7%, BP less than 130/80 mm Hg, and LDL-C level less than 100 mg/dL.26

An important consideration regarding these findings is that NHANES participants included patients with T2DM across the spectrum of disease and AHA use, including those with more recent onset of T2DM and those who had A1C less than 7% at baseline. Thus, the proportion achieving quality measures may be expected to be higher among NHANES participants compared with patients enrolled in this clini-cal trial, who were selected for having inadequate glycemic control on metformin plus sulfonylurea. In this population, the proportion of patients who met A1C less than 7%, BP less than 130/80 mm Hg, and LDL-C level less than 100 mg/dL at baseline was 0.8% and 1.6% in the canagliflozin 300 mg and sitagliptin 100 mg groups, respectively, and increased to 15.7% and 8.8%, respectively, at week 52. Similarly, the proportion of patients who met A1C less than 8%, BP less than 140/90 mm Hg, and LDL-C level less than100 mg/dL with canagliflozin and sitagliptin increased from 17.8% and 21.0%, respectively, at baseline to 35.5% and 27.8%, respectively, at week 52. Although the proportion of patients achieving composite quality measures with canagliflozin was numerically low, when applied to the total number of individuals living with T2DM, this would still translate to an improvement in treatment outcome for a large number of patients. Additionally, as treatment with canagliflozin 300 mg provided clinically meaningful improvements from base-line in efficacy parameters including A1C, FPG, body weight,

n Figure 1. Proportion of Patients Who Met Quality Measures at Baseline and Achieved Quality Measures at Week 52 (LOCF)

A1C indicates glycated hemoglobin; BP, blood pressure; LDL-C, low-density lipoprotein cholesterol; LOCF, last observation carried forward.

Canagliflozin 300 mg (baseline)

Canagliflozin 300 mg (week 52)

Sitagliptin 100 mg (baseline)

Sitagliptin 100 mg (week 52)

100

90

80

70

60

50

40

30

20

10

Quality Measures

Pro

po

rtio

n o

f Pa

tien

ts (

%)

0A1C <7% A1C <8% BP <130/80 mm Hg BP <140/90 mm Hg LDL-C <100 mg/dL A1C <7%,

BP <130/80 mm Hg,LDL-C <100 mg/dL

Reports


n Table 4. Proportion of Patients Who Met Individual Quality Measures at Baseline and Achieved Individual Quality Measures at Week 52 (BMI >25 kg/m2 subgroup)


Measure


% (n)

Sitagliptin 100 mg,

% (n)



% (n)

Sitagliptin 100 mg,

% (n)

Difference, %

(95% CI)

Odds Ratio (95% CI)

A1C, n 318 324 318 314

>9% (poor control)a 16.7% 17.6% –0.9% 1.9% 8.9% –7.0%b 0.18b

(53) (57) (–7.1, 5.2) (6) (28) (–11.0 to –3.2)b (0.07 to 0.44)b

<8% (good control)a 49.1% 46.3% 2.8% 85.2% 64.0% 21.2%b 3.79b

(156) (150) (–5.3, 10.8) (271) (201) (14.3 to 28.1)b (2.50 to 5.74)b

<7% 7.5% 9.3% –1.7% 48.7% 31.8% 16.9%b 2.30b

(24) (30) (–6.3, 2.9) (155) (100) (9.0 to 24.7)b (1.61 to 3.27)b

BP, n 318 324 318 316 <140/90 mm Hg 67.9% 70.1% –2.1% 82.7% 69.6% 13.1%b 2.48b

(216) (227) (–9.6, 5.3) (263) (220) (6.2 to 20.0)b (1.64 to 3.76)b

<140/80 mm Hg 41.5% 43.5% –2.0% 60.1% 44.9% 15.1%b 2.11b

(132) (141) (–10, 5.9) (191) (142) (7.1 to 23.1)b (1.49 to 2.98)b

<130/80 mm Hg 31.8% 33.6% –1.9% 50.9% 34.8% 16.1%b 2.28b

(101) (109) (–9.4, 5.7) (162) (110) (8.2 to 24.0)b (1.61 to 3.23)b

LDL-C, n 318 323 307 302 <100 mg/dL 50.9% 57.9% –7.0% 50.2% 55.1% –4.8% 0.91

(162) (187) (–15, 1.1) (154) (166) (–13.0 to 3.4) (0.61 to 1.37)BMI and body weight, n 318 316 318 316 >25 kg/m2 and >10 lb (4.5 kg) weight loss from baseline

19.2% 7.6% 11.6%b 3.22b

NA NA NA (61) (24) (6.1 to 17.1)b (1.90 to 5.44)b

<30 kg/m2 38.7% 35.8% 2.9 45.9% 35.4% 10.5%b 5.56b

(123) (113) (–4.9, 10.8) (146) (112) (2.5 to 18.4)b (2.44 to 12.50)b

A1C indicates glycated hemoglobin; BMI, body mass index; BP, blood pressure; CI, confidence interval; HEDIS, Health Effectiveness Data and Information Set; LDL-C, low-density lipoprotein cholesterol; LOCF, last observation carried forward; NA, not applicable. aPoor and good control are as defined in HEDIS quality measures.5 bComparisons for which the 95% CI for the between-group difference excluded 0, or the 95% CI for the odds ratio of canagliflozin vs sitagliptin excluded 1.

n Figure 2. Differences (95% CIs) Between Canagliflozin and Sitagliptin in the Proportion of Patients Who Met Quality Measures at Baseline and Achieved Quality Measures at Week 52 (LOCF)

–30 –25 –20 –15 –10 –5 0 5 10 15 20 25 30

Favors Sitagliptin Favors Canagliflozin

–30 –25 –20 –15 –10 –5 0 5 10 15 20 25 30

Favors Sitagliptin Favors Canagliflozin


A1C <8%

A1C <7%

BP <140/80 mm Hg

BP <140/90 mm Hg

BP <130/80 mm Hg

LDL-C <100 mg/dL

BMI >25 kg/m2 and >10 lb (4.5 kg) weight loss

BMI <30 kg/m2


A1C indicates glycated hemoglobin; BMI, body mass index; BP, blood pressure; CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; LOCF, last observation carried forward.



and systolic BP in the clinical study,15 patients who did not achieve the thresholds defined by quality measures with canagliflozin treatment may still have had improvements in these parameters.

Assessment of quality measures attainment was also per-formed in a subgroup of patients with a baseline BMI of at least 25 kg/m2, who constituted approximately 85% of the overall population. Patients with a BMI of at least 25 kg/m2 are of interest because overweight and obese individuals are at an increased risk of developing comorbidities and may have higher healthcare costs,25 and because of the prevalence of obesity among patients with T2DM.2 Findings in this subgroup of patients were generally similar to those in the overall popu-lation, suggesting that canagliflozin treatment is also effective in patients with T2DM who are overweight or obese.

A limitation of this analysis was the overall rate of dis-continuation in the clinical study (38.5%), which was higher than that seen in other phase 3 studies of canagliflozin.12-17,20 This was related to the study design, which did not provide glycemic rescue therapy and discontinued patients who met pre-specified glycemic criteria.15 The discontinuation rate observed with sitagliptin in this study was generally consistent with that observed in another 52-week study of sitagliptin that also did not provide glycemic rescue therapy.27 Additionally, this analysis was based on data from a single study that included only the 300-mg dose of canagliflozin. Further analysis including the canagliflozin 100-mg dose, in patients on different background AHAs, in special patient populations (eg, older patients or those with renal impair-

ment), in studies of longer duration, and in studies with other active comparators, would be helpful for further understand-ing of the treatment effects of canagliflozin and how they compare with those of other AHAs. Additional studies in a real-world clinical setting will also be useful for further evalu-ation of the attainment of quality measures with canagliflozin and its comparative effectiveness versus other AHAs.

Conclusion

Canagliflozin 300 mg demonstrated better attainment of individual and composite diabetes-related quality measures compared with sitagliptin 100 mg, suggesting that cana-gliflozin may provide improved health outcomes relative to sitagliptin in the treatment of patients with T2DM. These findings may help inform the decisions of physicians, patients, and payers in the selection of treatment options for the man-agement of T2DM.

AcknowledgmentsThis analysis was funded by Janssen Scientific Affairs, LLC, and was

based on data from a study supported by Janssen Research & Development, LLC. Editorial support was provided by Kimberly Dittmar, PhD, of MedErgy and was funded by Janssen Scientific Affairs, LLC. Canagliflozin has been developed by Janssen Research & Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation.

Author affiliations: Health Economics and Outcomes Research, Janssen Scientific Affairs, LLC, Raritan, NJ (RAB, SCM, MFTR); Ochsner Diabetes Clinical Research Unit, Department of Endocrinology, Ochsner Medical Center, New Orleans, LA (LB); Medical Affairs, Biostatistics, Janssen Research & Development, LLC, Raritan, NJ (CVD); Janssen Research & Development, LLC (GEM).

Funding source: This supplement was supported by Janssen Pharmaceuticals, Inc.

n Table 5. Proportion of Patients Who Met Composite Quality Measures at Baseline and Achieved Composite Quality Measures at Week 52 (BMI >25 kg/m2 subgroup)


Composite Measure


% (n) (n = 318)

Sitagliptin 100 mg,

% (n) (n = 323)



% (n) (n = 307)

Sitagliptin 100 mg,

% (n) (n = 302)


Odds Ratio (95% CI)


0.9%(3)

1.2%(4)

–0.3%(–2.2, 1.6)

16.6%(51)

8.6%(26)

8.0%a

(2.4 to 13.6)a2.65a

(1.53 to 4.57)a


0.9%(3)

2.2%(7)

–1.2%(–3.4, 1.0)

17.6%(54)

11.3%(34)

6.3%a

(0.4 to 12.2)a2.01a

(1.22 to 3.33)a


11.0%(35)

13.9%(45)

–2.9%(–8.3, 2.5)

28.0%(86)

19.3%(58)

8.8%a

(1.8 to 15.8)a2.02a

(1.32 to 3.09)a


17.3%(55)

21.7%(70)

–4.4%(–11, 2.1)

36.2%(111)

27.2%(82)

9.0%a

(1.3 to 16.7)a1.88a

(1.28 to 2.64)a

A1C indicates glycated hemoglobin; BMI, body mass index; BP, blood pressure; CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; LOCF, last observation carried forward. aComparisons for which the 95% CI for the between-group difference excluded 0, or the 95% CI for the odds ratio of canagliflozin vs sitagliptin excluded 1.

Reports


Author disclosures: Dr Bailey reports employment with Janssen Scientific Affairs, LLC (a Johnson & Johnson company), and reports stock ownership with Johnson & Johnson. Dr Blonde reports receipt of grants and research support from Eli Lilly and Company, Novo Nordisk, and Sanofi, and reports serving as a consultant for Amylin Pharmaceuticals, Inc; Eisai; GlaxoSmithKline; Janssen Pharmaceuticals, Inc; Merck & Co, Inc; Novo Nordisk; Pfizer; Sanofi; and Santarus. Dr Blonde also reports receipt of lecture fees from Amylin Pharmaceuticals, Inc; Bristol-Myers Squibb/AstraZeneca; Janssen Pharmaceuticals, Inc; Johnson & Johnson Diabetes Institute, LLC; Merck & Co, Inc; Novo Nordisk; Sanofi; Santarus; and Vivus, Inc. Dr Damaraju reports employment and stock ownership with Janssen Research & Development, LLC. Mr Martin reports employment with Janssen Scientific Affairs, LLC (a Johnson & Johnson company), and stock ownership with Johnson & Johnson. Dr Meininger reports employment with Janssen Research & Development, LLC, and stock ownership with Johnson & Johnson and Merck & Co, Inc. Ms Rupnow reports employment and meeting/conference attendance on behalf of Janssen Scientific Affairs, LLC (a Johnson & Johnson company), and reports stock ownership with Johnson & Johnson.

Authorship information: Concept and design (RAB, SCM, MFTR); acquisition of data (RAB, SCM, GEM); analysis and interpretation of data (RAB, LB, CVD, SCM, GEM, MFTR); drafting of the manuscript (RAB, LB, SCM, GEM, MFTR); critical revision of the manuscript for important intel-lectual content (RAB, LB, CVD, SCM, GEM, MFTR); statistical analysis (CVD, MFTR); provision of study materials or patients (GEM); obtaining funding (MFTR); and supervision (RAB, MFTR).

Address correspondence to: Robert A. Bailey, MD, 1000 US Route 202 South, Raritan, NJ 08869. E-mail: [email protected].

REFERENCES 1. 2011 National Diabetes Fact Sheet. Centers for Disease Control and Prevention website. http://www.cdc.gov/diabetes/pubs/ factsheet11.htm. Accessed February 7, 2012.2. Inzucchi SE, Bergenstal RM, Buse JB, et al; American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364-1379.3. American Diabetes Association. Standards of medical care in diabetes--2013. Diabetes Care. 2013;36 (suppl 1):S11-S66.4. Ali MK, Bullard KM, Saaddine JB, Cowie CC, Imperatore G, Gregg EW. Achievement of goals in U.S. diabetes care, 1999-2010. N Engl J Med. 2013;368(17):1613-1624.5. National Committee on Quality Assurance. The Healthcare Effectiveness Data and Information Set (HEDIS) measures 2013. http://www.fchp.org/providers/resources/hedis-measures.aspx. 6. National Quality Measures Clearinghouse. Diabetes mellitus: percent of patients with a body mass index (BMI) greater than 25 who have lost 10 pounds at any time in the last 12 months. Agency for Healthcare Research and Quality website. http://www .qualitymeasures.ahrq.gov/content.aspx?id=27634#Section583. 7. Cebul RD, Love TE, Jain AK, Hebert CJ. Electronic health records and quality of diabetes care. N Engl J Med. 2011;365(9): 825-833.8. The Physician Consortium for Performance Improvement. Measures development, methodology, and oversight advisory committee: recommendations to PCPI work groups on composite measures. http://www.ama-assn.org/resources/doc/cqi/compos-ite-measures-framework.pdf. Accessed October 28, 2013.9. O’Connor PJ, Bodkin NL, Fradkin J, et al. Diabetes perfor-mance measures: current status and future directions. Diabetes Care. 2011;34(7):1651-1659.10. Butcher L. Multifaceted diabetes program pays off for HealthPartners. Manag Care. 2009;18(1):36-40.11. Centers for Medicare & Medicaid Services. Accountable care organization 2012 program analysis: quality performance stan-

dards: narrative measure specifications: final report. http://www .cms.gov/medicare/medicare-fee-for-service-payment/shared-savingsprogram/downloads/aco_qualitymeasures.pdf. Accessed October 28, 2013.

12. Bode B, Stenlöf K, Sullivan D, Fung A, Usiskin K. Efficacy and safety of canagliflozin treatment in older subjects with type 2 dia-betes: a randomized trial. Hosp Pract (1995). 2013;41(2):72-84.

13. Cefalu WT, Leiter LA, Yoon K-H, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013;382(9896):941-950.

14. Lavalle-González F, Januszewicz A, Davidson J, et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin mono-therapy: a randomised trial [published online ahead of print, 2013]. Diabetologia.

15. Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week, randomized trial. Diabetes Care. 2013; 36(9):2508-2515.

16. Stenlöf K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes melli-tus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15(4):372-382.

17. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of cana-gliflozin in subjects with type 2 diabetes and chronic kidney dis-ease. Diabetes Obes Metab. 2013;15(5):463-473.

18. Rosenstock J, Aggarwal N, Polidori D, et al; Canagliflozin DIA 2001 Study Group. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in sub-jects with type 2 diabetes. Diabetes Care. 2012;35(6):1232-1238.

19. INVOKANA (canagliflozin) tablets, for oral use [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2013.

20. Wilding JP, Charpentier G, Hollander P, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequate-ly controlled with metformin and sulphonylurea: a randomised trial [published online ahead of print, 2013]. Int J Clin Pract.

21. Davies MJ, Kela R, Khunti K. Liraglutide - overview of the preclinical and clinical data and its role in the treatment of type 2 diabetes. Diabetes Obes Metab. 2011;13(3):207-220.

22. Zinman B, Gough S, Pratley R, Brett J, Lund N, Buse J. Effect of liraglutide, exenatide, and sitagliptin on the composite out-come of glycemic control and weight loss. Diabetes. 2011;60: A289-A290. Abstract 1055-P.

23. Diamant M, Van Gaal L, Stranks S, et al. DURATION-3: chang-es in cardiovascular risk factors observed in patients with type 2 diabetes after 84-week therapy with exenatide once weekly or insulin glargine. Diabetologia. 2011;54:S313. Abstract 778.

24. Boardman MK, Hanefeld M, Kumar A, et al. DURATION-4: improvements in glucose contorl and cardiovascular risk factors in patients with type 2 diabetes treated with exenatide once week-ly, metformin, pioglitazone, or sitagliptin. Diabetologia. 2011; 54:S314. Abstract 779.

25. National Institutes of Health. Clinical guidelines on the identi-fication, evaluation, and treatment of overweight and obesity in adults—the evidence report. Obes Res. 1998;6(suppl 2):51S-209S.

26. Stark Casagrande S, Fradkin JE, Saydah SH, Rust KF, Cowie CC. The prevalence of meeting A1C, blood pressure, and LDL goals among people with diabetes, 1988-2010. Diabetes Care. 2013;36(8):2271-2279.

27. Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP; Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9(2):194-205.

Notes


Notes


FULL PRESCRIBING INFORMATION1 INdICATIONS ANd USAGEINVOKANA™ (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14)].Limitation of UseINVOKANA is not recommended in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.2 dOSAGE ANd AdMINISTRATION2.1 Recommended dosageThe recommended starting dose of INVOKANA (canagliflozin) is 100 mg once daily, taken before the first meal of the day. In patients tolerating INVOKANA 100 mg once daily who have an eGFR of 60 mL/min/1.73 m2 or

greater and require additional glycemic control, the dose can be increased to 300 mg once daily [see Warnings and Precautions (5.2), Clinical Pharma cology (12.2), and Patient Counseling Information (17)].In patients with volume depletion, correcting this condition prior to initiation of INVOKANA is recommended [see Warnings and Precautions (5.1), Use in Specific Populations (8.5 and 8.6), and Patient Counseling Information (17)].2.2 Patients with Renal ImpairmentNo dose adjustment is needed in patients with mild renal impairment (eGFR of 60 mL/min/1.73 m2 or greater).The dose of INVOKANA is limited to 100 mg once daily in patients with moderate renal impairment with an eGFR of 45 to less than 60 mL/min/1.73 m2.INVOKANA should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2.

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INdICATIONS ANd USAGE2 dOSAGE ANd AdMINISTRATION

2.1 Recommended Dosage2.2 Patients with Renal Impairment2.3 Concomitant Use with UDP-Glucuronosyl Transferase (UGT)

Enzyme Inducers3 dOSAGE FORMS ANd STRENGThS4 CONTRAINdICATIONS5 WARNINGS ANd PRECAUTIONS

5.1 Hypotension5.2 Impairment in Renal Function5.3 Hyperkalemia5.4 Hypoglycemia with Concomitant Use with Insulin and Insulin

Secretagogues5.5 Genital Mycotic Infections5.6 Hypersensitivity Reactions5.7 Increases in Low-Density Lipoprotein (LDL-C)5.8 Macrovascular Outcomes

6 AdvERSE REACTIONS6.1 Clinical Studies Experience

7 dRUG INTERACTIONS7.1 UGT Enzyme Inducers7.2 Digoxin

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Renal Impairment8.7 Hepatic Impairment

10 OvERdOSAGE11 dESCRIPTION12 CLINICAL PhARMACOLOGY

12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUdIES14.1 Monotherapy14.2 Combination Therapy14.3 Studies in Special Populations

16 hOW SUPPLIEd/STORAGE ANd hANdLING17 PATIENT COUNSELING INFORMATION* Sections or subsections omitted from the full prescribing information are not listed

INVOKANA™ (canagliflozin) tabletsINVOKANA™(canagliflozin) tablets, for oral use

hIGhLIGhTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use INvOKANA™ safely and effectively. See full prescribing information for INvOKANA.INvOKANA (canagliflozin) tablets, for oral useInitial U.S. Approval: 2013

----------------------------- INdICATIONS ANd USAGE ---------------------------INVOKANA is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1)Limitation of Use:• Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis (1)

--------------------------dOSAGE ANd AdMINISTRATION -----------------------• The recommended starting dose is 100 mg once daily, taken before the

first meal of the day (2.1) • Dose can be increased to 300 mg once daily in patients tolerating

INVOKANA 100 mg once daily who have an eGFR of 60 mL/min/1.73 m2 or greater and require additional glycemic control (2.1)

• INVOKANA is limited to 100 mg once daily in patients who have an eGFR of 45 to less than 60 mL/min/1.73 m2 (2.2)

• Assess renal function before initiating INVOKANA. Do not initiate INVOKANA if eGFR is below 45 mL/min/1.73 m2 (2.2)

• Discontinue INVOKANA if eGFR falls below 45 mL/min/1.73 m2 (2.2)

------------------------ dOSAGE FORMS ANd STRENGThS ----------------------Tablets: 100 mg, 300 mg (3)

-------------------------------- CONTRAINdICATIONS ------------------------------• History of serious hypersensitivity reaction to INVOKANA (4)• Severe renal impairment, ESRD, or on dialysis (4)

-------------------------- WARNINGS ANd PRECAUTIONS ------------------------• Hypotension: Before initiating INVOKANA, assess volume status and

correct hypovolemia in patients with renal impairment, the elderly, in patients with low systolic blood pressure, or if on diuretics, ACEi, or ARB. Monitor for signs and symptoms during therapy (5.1)

• Impairment in Renal Function: Monitor renal function during therapy. More frequent monitoring is recommended in patients with eGFR below 60 mL/min/1.73 m2 (5.2)

• Hyperkalemia: Monitor potassium levels in patients with impaired renal function and in patients predisposed to hyperkalemia (5.3)

• Hypoglycemia: Consider a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia when used in combination with INVOKANA (5.4)

• Genital mycotic infections: Monitor and treat if indicated (5.5)• Hypersensitivity reactions: Discontinue INVOKANA and monitor until signs

and symptoms resolve (5.6)• Increased LDL-C: Monitor LDL-C and treat per standard of care (5.7)

--------------------------------AdvERSE REACTIONS ------------------------------• Most common adverse reactions associated with INVOKANA (5% or

greater incidence): female genital mycotic infections, urinary tract infection, and increased urination (6.1)

To report SUSPECTEd AdvERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 or FdA at 1-800-FdA-1088 or www.fda.gov/medwatch--------------------------------- dRUG INTERACTIONS -----------------------------• UGT inducers (e.g., rifampin): Canagliflozin exposure is reduced. Consider

increasing dose from 100 mg to 300 mg (2.3, 7.1)• Digoxin: Monitor digoxin levels (7.2)

-------------------------- USE IN SPECIFIC POPULATIONS ------------------------• Pregnancy: No adequate and well-controlled studies in pregnant women.

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus (8.1)

• Nursing mothers: Discontinue drug or nursing (8.3)• Geriatrics: Higher incidence of adverse reactions related to reduced

intravascular volume (5.1, 8.5)• Renal impairment: Higher incidence of adverse reactions related to

reduced intravascular volume and renal function (2.2, 5.2, 8.6)• Hepatic impairment: Not recommended with severe hepatic impairment (8.7)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 11/2013

Assessment of renal function is recommended prior to initiation of INVOKANA therapy and periodically thereafter. INVOKANA should be discontinued when eGFR is persistently less than 45 mL/min/1.73 m2 [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].2.3 Concomitant Use with UdP-Glucuronosyl Transferase (UGT) Enzyme

InducersIf an inducer of UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) is co-administered with INVOKANA, consider increasing the dosage to 300 mg once daily in patients currently tolerating INVOKANA 100 mg once daily who have an eGFR of 60 mL/min/1.73 m2 or greater and require additional glycemic control [see Drug Interactions (7.1)]. Consider another anti hyperglycemic agent in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer.3 dOSAGE FORMS ANd STRENGThS• INVOKANA 100 mg tablets are yellow, capsule-shaped, film-coated tablets

with “CFZ” on one side and “100” on the other side.• INVOKANA 300 mg tablets are white, capsule-shaped, film-coated tablets

with “CFZ” on one side and “300” on the other side.4 CONTRAINdICATIONS• History of a serious hypersensitivity reaction to INVOKANA [see Warnings

and Precautions (5.6)].• Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end stage

renal disease or patients on dialysis [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].

5 WARNINGS ANd PRECAUTIONS5.1 hypotensionINVOKANA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKANA [see Adverse Reactions (6.1)] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy.5.2 Impairment in Renal FunctionINVOKANA increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA [see Adverse Reactions (6.1)]. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2.5.3 hyperkalemiaINVOKANA can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia [see Adverse Reactions (6.1)]. Monitor serum potassium levels periodically after initiating INVOKANA in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions. 5.4 hypoglycemia with Concomitant Use with Insulin and Insulin

SecretagoguesInsulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6.1)]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA.5.5 Genital Mycotic InfectionsINVOKANA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions (6.1)]. Monitor and treat appropriately.5.6 hypersensitivity ReactionsHypersensitivity reactions (e.g., generalized urticaria), some serious, were reported with INVOKANA treatment; these reactions generally occurred within hours to days after initiating INVOKANA. If hypersensitivity reactions occur, discontinue use of INVOKANA; treat per standard of care and monitor until signs and symptoms resolve [see Contraindications (4) and Adverse Reactions (6.1)].5.7 Increases in Low-density Lipoprotein (LdL-C)Dose-related increases in LDL-C occur with INVOKANA [see Adverse Reactions (6.1)]. Monitor LDL-C and treat per standard of care after initiating INVOKANA.

5.8 Macrovascular OutcomesThere have been no clinical studies establishing conclusive evidence of macro vascular risk reduction with INVOKANA or any other antidiabetic drug.6 AdvERSE REACTIONSThe following important adverse reactions are described below and elsewhere in the labeling:• Hypotension [see Warnings and Precautions (5.1)]• Impairment in Renal Function [see Warnings and Precautions (5.2)]• Hyperkalemia [see Warnings and Precautions (5.3)]• Hypoglycemia with Concomitant Use with Insulin and Insulin

Secretagogues [see Warnings and Precautions (5.4)]• Genital Mycotic Infections [see Warnings and Precautions (5.5)]• Hypersensitivity Reactions [see Warnings and Precautions (5.6)]• Increases in Low-Density Lipoprotein (LDL-C) [see Warnings and

Precautions (5.7)]

6.1 Clinical Studies ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Pool of Placebo-Controlled TrialsThe data in Table 1 is derived from four 26-week placebo-controlled trials. In one trial INVOKANA was used as monotherapy and in three trials INVOKANA was used as add-on therapy [see Clinical Studies (14)]. These data reflect exposure of 1667 patients to INVOKANA and a mean duration of exposure to INVOKANA of 24 weeks. Patients received INVOKANA 100 mg (N=833), INVOKANA 300 mg (N=834) or placebo (N=646) once daily. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were Caucasian, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m2). Table 1 shows common adverse reactions associated with the use of INVOKANA. These adverse reactions were not present at baseline, occurred more commonly on INVOKANA than on placebo, and occurred in at least 2% of patients treated with either INVOKANA 100 mg or INVOKANA 300 mg.

Table 1: Adverse Reactions From Pool of Four 26−Week Placebo-Controlled Studies Reported in ≥ 2% of INvOKANA-Treated Patients*

Adverse ReactionPlaceboN=646

INvOKANA100 mgN=833

INvOKANA300 mgN=834

Female genital mycotic infections†

3.2% 10.4% 11.4%

Urinary tract infections‡ 4.0% 5.9% 4.3%Increased urination§ 0.8% 5.3% 4.6%Male genital mycotic infections¶

0.6% 4.2% 3.7%

Vulvovaginal pruritus 0.0% 1.6% 3.0%Thirst# 0.2% 2.8% 2.3%Constipation 0.9% 1.8% 2.3%Nausea 1.5% 2.2% 2.3%

* The four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin, metformin and sulfonylurea, or metformin and pioglitazone.

† Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. Percentages calculated with the number of female subjects in each group as denominator: placebo (N=312), INVOKANA 100 mg (N=425), and INVOKANA 300 mg (N=430).

‡ Urinary tract infections include the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis.

§ Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia.

¶ Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. Percentages calculated with the number of male subjects in each group as denominator: placebo (N=334), INVOKANA 100 mg (N=408), and INVOKANA 300 mg (N=404).

# Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia.

INVOKANA™ (canagliflozin) tablets INVOKANA™ (canagliflozin) tablets

Abdominal pain was also more commonly reported in patients taking INVOKANA 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%). Pool of Placebo- and Active-Controlled TrialsThe occurrence of adverse reactions was also evaluated in a larger pool of patients participating in placebo- and active-controlled trials.The data combined eight clinical trials [see Clinical Studies (14)] and reflect exposure of 6177 patients to INVOKANA. The mean duration of exposure to INVOKANA was 38 weeks with 1832 individuals exposed to INVOKANA for greater than 50 weeks. Patients received INVOKANA 100 mg (N=3092), INVOKANA 300 mg (N=3085) or comparator (N=3262) once daily. The mean age of the population was 60 years and 5% were older than 75 years of age. Fifty-eight percent (58%) of the population was male and 73% were Caucasian, 16% were Asian, and 4% were Black or African American. At baseline, the population had diabetes for an average of 11 years, had a mean HbA1C of 8.0% and 33% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 81 mL/min/1.73 m2).The types and frequency of common adverse reactions observed in the pool of eight clinical trials were consistent with those listed in Table 1. In this pool, INVOKANA was also associated with the adverse reactions of fatigue (1.7% with comparator, 2.2% with INVOKANA 100 mg, and 2.0% with INVOKANA 300 mg) and loss of strength or energy (i.e., asthenia) (0.6% with comparator, 0.7% with INVOKANA 100 mg, and 1.1% with INVOKANA 300 mg).In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.9, 2.7, and 0.9 per 1000 patient-years of exposure to comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.In the pool of eight clinical trials with a longer mean duration of exposure to INVOKANA (68 weeks), the incidence rate of bone fracture was 14.2, 18.7, and 17.6 per 1000 patient years of exposure to comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Upper extremity fractures occurred more commonly on INVOKANA than comparator.In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) occurred in 3.0%, 3.8%, and 4.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Five patients experienced serious adverse reactions of hypersensitivity with INVOKANA, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to INVOKANA. Among these patients, 2 patients discontinued INVOKANA. One patient with urticaria had recurrence when INVOKANA was re-initiated.Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.Other adverse reactions occurring more frequently on INVOKANA than on comparator were:Volume Depletion-Related Adverse ReactionsINVOKANA results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical studies, treatment with INVOKANA was associated with a dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2), and age 75 years and older (Table 2) [see Dosage and Administration (2.2), Warnings and Precautions (5.1), and Use in Specific Populations (8.5 and 8.6)].Table 2: Proportion of Patients With at Least One volume depletion-Related

Adverse Reaction (Pooled Results from 8 Clinical Trials)

Baseline Characteristic

Comparator Group*

%

INvOKANA 100 mg

%

INvOKANA 300 mg

%Overall population 1.5% 2.3% 3.4%75 years of age and older† 2.6% 4.9% 8.7%eGFR less than 60 mL/min/1.73 m2† 2.5% 4.7% 8.1%Use of loop diuretic† 4.7% 3.2% 8.8%

* Includes placebo and active-comparator groups† Patients could have more than 1 of the listed risk factorsImpairment in Renal FunctionINVOKANA is associated with a dose-dependent increase in serum creatinine and a concomitant fall in estimated GFR (Table 3). Patients with moderate renal impairment at baseline had larger mean changes.

Table 3: Changes in Serum Creatinine and eGFR Associated with INvOKANA in the Pool of Four Placebo-Controlled Trials and Moderate Renal Impairment Trial

PlaceboN=646

INvOKANA 100 mgN=833

INvOKANA 300 mgN=834

Pool of Four Placebo-Controlled Trials

BaselineCreatinine (mg/dL) 0.84 0.82 0.82eGFR (mL/min/1.73 m2) 87.0 88.3 88.8

Week 6 Change

Creatinine (mg/dL) 0.01 0.03 0.05eGFR (mL/min/1.73 m2) -1.6 -3.8 -5.0

End of Treatment Change*

Creatinine (mg/dL) 0.01 0.02 0.03

eGFR (mL/min/1.73 m2) -1.6 -2.3 -3.4

PlaceboN=90

INvOKANA 100 mgN=90

INvOKANA 300 mgN=89

Moderate Renal Impairment Trial

Baseline Creatinine (mg/dL) 1.61 1.62 1.63eGFR (mL/min/1.73 m2) 40.1 39.7 38.5

Week 3 Change

Creatinine (mg/dL) 0.03 0.18 0.28eGFR (mL/min/1.73 m2) -0.7 -4.6 -6.2

End of Treatment Change*

Creatinine (mg/dL) 0.07 0.16 0.18

eGFR (mL/min/1.73 m2) -1.5 -3.6 -4.0

* Week 26 in mITT LOCF populationIn the pool of four placebo-controlled trials where patients had normal or mildly impaired baseline renal function, the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR below 80 mL/min/1.73 m2 and 30% lower than baseline, was 2.1% with placebo, 2.0% with INVOKANA 100 mg, and 4.1% with INVOKANA 300 mg. At the end of treatment, 0.5% with placebo, 0.7% with INVOKANA 100 mg, and 1.4% with INVOKANA 300 mg had a significant renal function decline.In a trial carried out in patients with moderate renal impairment with a baseline eGFR of 30 to less than 50 mL/min/1.73 m2 (mean baseline eGFR 39 mL/min/1.73 m2) [see Clinical Studies (14.3)], the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR 30% lower than baseline, was 6.9% with placebo, 18% with INVOKANA 100 mg, and 22.5% with INVOKANA 300 mg. At the end of treatment, 4.6% with placebo, 3.4% with INVOKANA 100 mg, and 3.4% with INVOKANA 300 mg had a significant renal function decline. In a pooled population of patients with moderate renal impairment (N=1085) with baseline eGFR of 30 to less than 60 mL/min/1.73 m2 (mean baseline eGFR 48 mL/min/1.73 m2), the overall incidence of these events was lower than in the dedicated trial but a dose-dependent increase in incident episodes of significant renal function decline compared to placebo was still observed.Use of INVOKANA was associated with an increased incidence of renal-related adverse reactions (e.g., increased blood creatinine, decreased glomerular filtration rate, renal impairment, and acute renal failure), particularly in patients with moderate renal impairment.In the pooled analysis of patients with moderate renal impairment, the incidence of renal-related adverse reactions was 3.7% with placebo, 8.9% with INVOKANA 100 mg, and 9.3% with INVOKANA 300 mg. Discontinuations due to renal-related adverse events occurred in 1.0% with placebo, 1.2% with INVOKANA 100 mg, and 1.6% with INVOKANA 300 mg [see Warnings and Precautions (5.2)].Genital Mycotic InfectionsIn the pool of four placebo-controlled clinical trials, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 3.2%, 10.4%, and 11.4% of females treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on INVOKANA. Female patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrence and require treatment with oral or topical antifungal agents and anti-microbial agents [see Warnings and Precautions (5.5)].In the pool of four placebo-controlled clinical trials, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.6%, 4.2%, and 3.7% of males treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrent infections (22% on INVOKANA versus none on placebo), and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In the pooled analysis of 8 controlled trials, phimosis was reported in 0.3% of uncircumcised male patients treated with INVOKANA and 0.2% required circumcision to treat the phimosis [see Warnings and Precautions (5.5)].


HypoglycemiaIn all clinical trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials [see Clinical Studies (14)], episodes of hypoglycemia occurred at a higher rate when INVOKANA was co-administered with insulin or sulfonylureas (Table 4) [see Warnings and Precautions (5.4)].

Table 4: Incidence of hypoglycemia* in Controlled Clinical StudiesMonotherapy(26 weeks)

Placebo(N=192)

INvOKANA 100 mg(N=195)


Overall [N (%)] 5 (2.6) 7 (3.6) 6 (3.0)In Combination with Metformin(26 weeks)

Placebo + Metformin

(N=183)

INvOKANA 100 mg + Metformin

(N=368)


(N=367)

Overall [N (%)] 3 (1.6) 16 (4.3) 17 (4.6)Severe [N (%)]† 0 (0) 1 (0.3) 1 (0.3)In Combination with Metformin(52 weeks)

Glimepiride + Metformin

(N=482)


(N=483)


(N=485)

Overall [N (%)] 165 (34.2) 27 (5.6) 24 (4.9)Severe [N (%)]† 15 (3.1) 2 (0.4) 3 (0.6)In Combination with Sulfonylurea(18 weeks)

Placebo + Sulfonylurea

(N=69)

INvOKANA 100 mg+ Sulfonylurea

(N=74)

INvOKANA 300 mg+ Sulfonylurea

(N=72)

Overall [N (%)] 4 (5.8) 3 (4.1) 9 (12.5)In Combination with Metformin + Sulfonylurea(26 weeks)

Placebo + Metformin + Sulfonylurea

(N=156)

INvOKANA 100 mg + Metformin + Sulfonylurea

(N=157)


(N=156)

Overall [N (%)] 24 (15.4) 43 (27.4) 47 (30.1)Severe [N (%)]† 1 (0.6) 1 (0.6) 0In Combination with Metformin + Sulfonylurea(52 weeks)

Sitagliptin + Metformin + Sulfonylurea

(N=378)


(N=377)

Overall [N (%)] 154 (40.7) 163 (43.2)Severe [N (%)]† 13 (3.4) 15 (4.0)In Combination with Metformin + Pioglitazone(26 weeks)

Placebo + Metformin + Pioglitazone

(N=115)

INvOKANA 100 mg + Metformin + Pioglitazone

(N=113)

INvOKANA 300 mg + Metformin + Pioglitazone

(N=114)

Overall [N (%)] 3 (2.6) 3 (2.7) 6 (5.3)In Combination with Insulin(18 weeks)

Placebo(N=565)



Overall [N (%)] 208 (36.8) 279 (49.3) 285 (48.6)Severe [N (%)]† 14 (2.5) 10 (1.8) 16 (2.7)

* Number of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population

† Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained)

Laboratory TestsIncreases in Serum PotassiumDose-related, transient mean increases in serum potassium were observed early after initiation of INVOKANA (i.e., within 3 weeks) in a trial of patients with moderate renal impairment [see Clinical Studies (14.3)]. In this trial, increases in serum potassium of greater than 5.4 mEq/L and 15% above baseline occurred in 16.1%, 12.4%, and 27.0% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. More severe elevations (i.e., equal or greater than 6.5 mEq/L) occurred in 1.1%, 2.2%, and 2.2% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. In patients with moderate renal impairment, increases in potassium were more commonly seen in those with elevated potassium at baseline and in those using medications that reduce potassium excretion, such as potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers [see Warnings and Precautions (5.2 and 5.3)].Increases in Serum MagnesiumDose-related increases in serum magnesium were observed early after initiation of INVOKANA (within 6 weeks) and remained elevated throughout treatment. In the pool of four placebo-controlled trials, the mean change in

serum magnesium levels was 8.1% and 9.3% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to -0.6% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3)], serum magnesium levels increased by 0.2%, 9.2%, and 14.8% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.Increases in Serum PhosphateDose-related increases in serum phosphate levels were observed with INVOKANA. In the pool of four placebo controlled trials, the mean change in serum phosphate levels were 3.6% and 5.1% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to 1.5% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3)], the mean serum phosphate levels increased by 1.2%, 5.0%, and 9.3% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-High-Density Lipoprotein Cholesterol (non-HDL-C)In the pool of four placebo-controlled trials, dose-related increases in LDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with INVOKANA 100 mg and INVOKANA 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups [see Warnings and Precautions (5.7)].Dose-related increases in non-HDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with INVOKANA 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups.Increases in HemoglobinIn the pool of four placebo-controlled trials, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with INVOKANA 100 mg, and 0.51 g/dL (3.8%) with INVOKANA 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively, had hemoglobin above the upper limit of normal.

7 dRUG INTERACTIONS7.1 UGT Enzyme InducersRifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) must be co-administered with INVOKANA (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA 100 mg once daily, have an eGFR greater than 60 mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer and require additional glycemic control [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].7.2 digoxinThere was an increase in the AUC and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA 300 mg [see Clinical Pharmacology (12.3)]. Patients taking INVOKANA with concomitant digoxin should be monitored appropriately.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyTeratogenic EffectsPregnancy Category CThere are no adequate and well-controlled studies of INVOKANA in pregnant women. Based on results from rat studies, canagliflozin may affect renal development and maturation. In a juvenile rat study, increased kidney weights and renal pelvic and tubular dilatation were evident at greater than or equal to 0.5 times clinical exposure from a 300 mg dose [see Nonclinical Toxicology (13.2)].These outcomes occurred with drug exposure during periods of animal development that correspond to the late second and third trimester of human development. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. INVOKANA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.8.3 Nursing MothersIt is not known if INVOKANA is excreted in human milk. INVOKANA is secreted in the milk of lactating rats reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly exposed to INVOKANA showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because many drugs are excreted in human milk and because of the potential for serious adverse


reactions in nursing infants from INVOKANA, a decision should be made whether to discontinue nursing or to discontinue INVOKANA, taking into account the importance of the drug to the mother [see Nonclinical Toxicology (13.2)].8.4 Pediatric UseSafety and effectiveness of INVOKANA in pediatric patients under 18 years of age have not been established.8.5 Geriatric UseTwo thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to INVOKANA in nine clinical studies of INVOKANA [see Clinical Studies (14.3)]. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA (such as hypotension, postural dizziness, ortho static hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1) and Adverse Reactions (6.1)]. Smaller reductions in HbA1C with INVOKANA relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA 100 mg and -0.74% with INVOKANA 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA 100 mg and -0.87% with INVOKANA 300 mg relative to placebo).8.6 Renal ImpairmentThe efficacy and safety of INVOKANA were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m2) [see Clinical Studies (14.3)]. These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR greater than or equal to 60 mL/min/1.73 m2); patients treated with INVOKANA 300 mg were more likely to experience increases in potassium [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.2, and 5.3), and Adverse Reactions (6.1)].The efficacy and safety of INVOKANA have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), with ESRD, or receiving dialysis. INVOKANA is not expected to be effective in these patient populations [see Contraindications (4) and Clinical Pharmacology (12.3)].8.7 hepatic ImpairmentNo dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA has not been studied in patients with severe hepatic impairment and is therefore not recommended [see Clinical Pharmacology (12.3)].10 OvERdOSAGEThere were no reports of overdose during the clinical development program of INVOKANA (canagliflozin).In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis.11 dESCRIPTIONINVOKANA (canagliflozin) contains canagliflozin, an inhibitor of sodium-glucose co-transporter 2 (SGLT2), the transporter responsible for reabsorbing the majority of glucose filtered by the kidney. Canagliflozin, the active ingredient of INVOKANA, is chemically known as (1S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate and its molecular formula and weight are C24H25FO5S•1/2 H2O and 453.53, respectively. The structural formula for canagliflozin is:

Canagliflozin is practically insoluble in aqueous media from pH 1.1 to 12.9.INVOKANA is supplied as film-coated tablets for oral administration, containing 102 and 306 mg of canagliflozin in each tablet strength, corresponding to 100 mg and 300 mg of canagliflozin (anhydrous), respectively.

Inactive ingredients of the core tablet are croscarmellose sodium, hydroxypropyl cellulose, lactose anhydrous, magnesium stearate, and microcrystalline cellulose. The magnesium stearate is vegetable-sourced. The tablets are finished with a commercially available film-coating consisting of the following excipients: polyvinyl alcohol (partially hydrolyzed), titanium dioxide, macrogol/PEG, talc, and iron oxide yellow, E172 (100 mg tablet only).12 CLINICAL PhARMACOLOGY12.1 Mechanism of ActionSodium-glucose co-transporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion. 12.2 PharmacodynamicsFollowing single and multiple oral doses of canagliflozin to patients with type 2 diabetes, dose-dependent decreases in the renal threshold for glucose (RTG) and increases in urinary glucose excretion were observed. From a starting value of RTG of approximately 240 mg/dL, canagliflozin at 100 mg and 300 mg once daily suppressed RTG throughout the 24-hour period. Maximal suppression of mean RTG over the 24-hour period was seen with the 300 mg daily dose to approximately 70 to 90 mg/dL in patients with type 2 diabetes in Phase 1 studies. In patients with type 2 diabetes given 100 mg to 300 mg once daily over a 16-day dosing period, reductions in RTG and increases in urinary glucose excretion were observed over the dosing period. In this study, plasma glucose declined in a dose-dependent fashion within the first day of dosing. In single-dose studies in healthy and type 2 diabetic subjects, treatment with canagliflozin 300 mg before a mixed-meal delayed intestinal glucose absorption and reduced postprandial glucose.Cardiac ElectrophysiologyIn a randomized, double-blind, placebo-controlled, active-comparator, 4-way crossover study, 60 healthy subjects were administered a single oral dose of canagliflozin 300 mg, canagliflozin 1,200 mg (4 times the maximum recommended dose), moxifloxacin, and placebo. No meaningful changes in QTc interval were observed with either the recommended dose of 300 mg or the 1,200 mg dose.12.3 PharmacokineticsThe pharmacokinetics of canagliflozin is similar in healthy subjects and patients with type 2 diabetes. Following single-dose oral administration of 100 mg and 300 mg of INVOKANA, peak plasma concentrations (median Tmax) of canagliflozin occurs within 1 to 2 hours post-dose. Plasma Cmax and AUC of canagliflozin increased in a dose-proportional manner from 50 mg to 300 mg. The apparent terminal half-life (t1/2) was 10.6 hours and 13.1 hours for the 100 mg and 300 mg doses, respectively. Steady-state was reached after 4 to 5 days of once-daily dosing with canagliflozin 100 mg to 300 mg. Canagliflozin does not exhibit time-dependent pharmacokinetics and accumulated in plasma up to 36% following multiple doses of 100 mg and 300 mg.AbsorptionThe mean absolute oral bioavailability of canagliflozin is approximately 65%. Co-administration of a high-fat meal with canagliflozin had no effect on the pharmacokinetics of canagliflozin; therefore, INVOKANA may be taken with or without food. However, based on the potential to reduce postprandial plasma glucose excursions due to delayed intestinal glucose absorption, it is recommended that INVOKANA be taken before the first meal of the day [see Dosage and Administration (2.1)].DistributionThe mean steady-state volume of distribution of canagliflozin following a single intravenous infusion in healthy subjects was 119 L, suggesting extensive tissue distribution. Canagliflozin is extensively bound to proteins in plasma (99%), mainly to albumin. Protein binding is independent of canagliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.MetabolismO-glucuronidation is the major metabolic elimination pathway for canagliflozin, which is mainly glucuronidated by UGT1A9 and UGT2B4 to two inactive O-glucuronide metabolites. CYP3A4-mediated (oxidative) metabolism of canagliflozin is minimal (approximately 7%) in humans. ExcretionFollowing administration of a single oral [14C]canagliflozin dose to healthy subjects, 41.5%, 7.0%, and 3.2% of the administered radioactive dose was recovered in feces as canagliflozin, a hydroxylated metabolite, and an O-glucuronide metabolite, respectively. Enterohepatic circulation of canagliflozin was negligible.Approximately 33% of the administered radioactive dose was excreted in urine, mainly as O-glucuronide metabolites (30.5%). Less than 1% of the dose was excreted as unchanged canagliflozin in urine. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 1.30 to 1.55 mL/min.


Mean systemic clearance of canagliflozin was approximately 192 mL/min in healthy subjects following intravenous administration.Specific PopulationsRenal ImpairmentA single-dose, open-label study evaluated the pharmacokinetics of canagliflozin 200 mg in subjects with varying degrees of renal impairment (classified using the MDRD-eGFR formula) compared to healthy subjects.Renal impairment did not affect the Cmax of canagliflozin. Compared to healthy subjects (N=3; eGFR greater than or equal to 90 mL/min/1.73 m2), plasma AUC of canagliflozin was increased by approximately 15%, 29%, and 53% in subjects with mild (N=10), moderate (N=9), and severe (N=10) renal impairment, respectively, (eGFR 60 to less than 90, 30 to less than 60 and 15 to less than 30 mL/min/1.73 m2, respectively), but was similar for ESRD (N=8) subjects and healthy subjects. Increases in canagliflozin AUC of this magnitude are not considered clinically relevant. The pharmacodynamic response to canagliflozin declines with increasing severity of renal impairment [see Contraindications (4) and Warnings and Precautions (5.2)].Canagliflozin was negligibly removed by hemodialysis.Hepatic ImpairmentRelative to subjects with normal hepatic function, the geometric mean ratios for Cmax and AUC∞ of canagliflozin were 107% and 110%, respectively, in subjects with Child-Pugh class A (mild hepatic impairment) and 96% and 111%, respectively, in subjects with Child-Pugh class B (moderate hepatic impairment) following administration of a single 300 mg dose of canagliflozin.These differences are not considered to be clinically meaningful. There is no clinical experience in patients with Child-Pugh class C (severe) hepatic impairment [see Use in Specific Populations (8.7)].Pharmacokinetics Effects of Age, Body Mass Index (BMI)/Weight, Gender and RaceBased on the population PK analysis with data collected from 1526 subjects, age, body mass index (BMI)/weight, gender, and race do not have a clinically meaningful effect on pharmacokinetics of canagliflozin [see Use in Specific Populations (8.5)].PediatricStudies characterizing the pharmacokinetics of canagliflozin in pediatric patients have not been conducted.Drug Interaction StudiesIn Vitro Assessment of Drug InteractionsCanagliflozin did not induce CYP450 enzyme expression (3A4, 2C9, 2C19, 2B6, and 1A2) in cultured human hepatocytes. Canagliflozin did not inhibit the CYP450 isoenzymes (1A2, 2A6, 2C19, 2D6, or 2E1) and weakly inhibited CYP2B6, CYP2C8, CYP2C9, and CYP3A4 based on in vitro studies with human hepatic microsomes. Canagliflozin is a weak inhibitor of P-gp.Canagliflozin is also a substrate of drug transporters P-glycoprotein (P-gp) and MRP2.In Vivo Assessment of Drug InteractionsTable 5: Effect of Co−Administered drugs on Systemic Exposures of

Canagliflozin

Co-Administered drug

dose of Co-Administered

drug*

dose of Canagliflozin*

Geometric Mean Ratio(Ratio With/Without

Co-Administered drug)No Effect=1.0

AUC†

(90% CI)Cmax

(90% CI)See Drug Interactions (7.1) for the clinical relevance of the following:

Rifampin 600 mg QDfor 8 days 300 mg 0.49

(0.44; 0.54)0.72

(0.61; 0.84)No dose adjustments of INvOKANA required for the following:

Cyclosporine 400 mg 300 mg QD for 8 days

1.23(1.19; 1.27)

1.01(0.91; 1.11)

Ethinyl estradiol and levonorgestrel

0.03 mg ethinyl estradiol and

0.15 mg levonorgestrel

200 mg QD for 6 days

0.91(0.88; 0.94)

0.92(0.84; 0.99)

Hydrochlorothiazide 25 mg QDfor 35 days


1.12(1.08; 1.17)

1.15(1.06; 1.25)

Metformin 2,000 mg 300 mg QD for 8 days

1.10(1.05; 1.15)

1.05(0.96; 1.16)

Probenecid 500 mg BIDfor 3 days


1.21(1.16; 1.25)

1.13(1.00; 1.28)

* Single dose unless otherwise noted† AUCinf for drugs given as a single dose and AUC24h for drugs given as

multiple dosesQD = once daily; BID = twice daily

Table 6: Effect of Canagliflozin on Systemic Exposure of Co-Administered drugs

Co-Administered drug

dose of Co-Administered

drug*

dose of Canagliflozin*

Geometric Mean Ratio(Ratio With/Without

Co-Administered drug)No Effect = 1.0

AUC†

(90% CI)Cmax

(90% CI)

See Drug Interactions (7.2) for the clinical relevance of the following:

Digoxin

0.5 mg QD first day followed by 0.25 mg QD for

6 days

300 mg QDfor 7 days digoxin

1.20(1.12; 1.28)

1.36(1.21; 1.53)

No dose adjustments of co-administered drug required for the following:

Acetaminophen 1,000 mg 300 mg BID for 25 days acetaminophen

1.06‡

(0.98; 1.14)

1.00(0.92; 1.09)

Ethinyl estradiol and levonorgestrel

0.03 mg ethinyl estradiol and

0.15 mg levonorgestrel

200 mg QDfor 6 days

ethinyl estradiol1.07

(0.99; 1.15)

1.22(1.10; 1.35)

levonorgestrel1.06

(1.00; 1.13)

1.22(1.11; 1.35)

Glyburide 1.25 mg 200 mg QDfor 6 days

glyburide1.02

(0.98; 1.07)

0.93(0.85; 1.01)

3-cis-hydroxy- glyburide

1.01(0.96; 1.07)

0.99(0.91; 1.08)

4-trans-hydroxy- glyburide

1.03(0.97; 1.09)

0.96(0.88; 1.04)

Hydro-chlorothiazide

25 mg QDfor 35 days

300 mg QDfor 7 days

hydro-chlorothiazide

0.99(0.95; 1.04)

0.94(0.87; 1.01)

Metformin 2,000 mg 300 mg QDfor 8 days metformin

1.20(1.08; 1.34)

1.06(0.93; 1.20)

Simvastatin 40 mg 300 mg QDfor 7 days

simvastatin1.12

(0.94; 1.33)

1.09(0.91; 1.31)

simvastatin acid1.18

(1.03; 1.35)

1.26(1.10; 1.45)

Warfarin 30 mg 300 mg QDfor 12 days

(R)-warfarin1.01

(0.96; 1.06)

1.03(0.94; 1.13)

(S)-warfarin1.06

(1.00; 1.12)

1.01(0.90; 1.13)

INR1.00

(0.98; 1.03)

1.05(0.99; 1.12)

* Single dose unless otherwise noted† AUCinf for drugs given as a single dose and AUC24h for drugs given as

multiple doses‡ AUC0-12hQD = once daily; BID = twice daily; INR = International Normalized Ratio

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesisCarcinogenicity was evaluated in 2-year studies conducted in CD1 mice and Sprague-Dawley rats. Canagliflozin did not increase the incidence of tumors in mice dosed at 10, 30, or 100 mg/kg (less than or equal to 14 times exposure from a 300 mg clinical dose).Testicular Leydig cell tumors, considered secondary to increased luteinizing hormone (LH), increased significantly in male rats at all doses tested (10, 30, and 100 mg/kg). In a 12-week clinical study, LH did not increase in males treated with canagliflozin.Renal tubular adenoma and carcinoma increased significantly in male and female rats dosed 100 mg/kg, or approximately 12-times exposure from a 300 mg clinical dose. Also, adrenal pheochromocytoma increased significantly in males and numerically in females dosed 100 mg/kg. Carbohydrate malabsorption associated with high doses of canagliflozin was considered a necessary proximal event in the emergence of renal and adrenal tumors in rats. Clinical studies have not demonstrated carbohydrate malabsorption in humans at canagliflozin doses of up to 2-times the recommended clinical dose of 300 mg.


MutagenesisCanagliflozin was not mutagenic with or without metabolic activation in the Ames assay. Canagliflozin was mutagenic in the in vitro mouse lymphoma assay with but not without metabolic activation. Canagliflozin was not mutagenic or clastogenic in an in vivo oral micronucleus assay in rats and an in vivo oral Comet assay in rats.Impairment of FertilityCanagliflozin had no effects on the ability of rats to mate and sire or maintain a litter up to the high dose of 100 mg/kg (approximately 14 times and 18 times the 300 mg clinical dose in males and females, respectively), although there were minor alterations in a number of reproductive parameters (decreased sperm velocity, increased number of abnormal sperm, slightly fewer corpora lutea, fewer implantation sites, and smaller litter sizes) at the highest dosage administered.13.2 Animal Toxicology and/or PharmacologyIn a juvenile toxicity study in which canagliflozin was dosed directly to young rats from postnatal day (PND) 21 until PND 90 at doses of 4, 20, 65, or 100 mg/kg, increased kidney weights and a dose-related increase in the incidence and severity renal pelvic and renal tubular dilatation were reported at all dose levels. Exposure at the lowest dose tested was greater than or equal to 0.5 times the maximum clinical dose of 300 mg. The renal pelvic dilatations observed in juvenile animals did not fully reverse within the 1-month recovery period. Similar effects on the developing kidney were not seen when canagliflozin was administered to pregnant rats or rabbits during the period of organogenesis or during a study in which maternal rats were dosed from gestation day (GD) 6 through PND 21 and pups were indirectly exposed in utero and throughout lactation.In embryo-fetal development studies in rats and rabbits, canagliflozin was administered for intervals coinciding with the first trimester period of non-renal organogenesis in humans. No developmental toxicities were observed at any dose tested other than a slight increase in the number of fetuses with reduced ossification at a dose that was associated with maternal toxicity and that is approximately 19 times the human exposure to canagliflozin at the 300 mg clinical dose.14 CLINICAL STUdIESINVOKANA (canagliflozin) has been studied as monotherapy, in combination with metformin, sulfonylurea, metformin and sulfonylurea, metformin and a thiazolidinedione (i.e., pioglitazone), and in combination with insulin (with or without other antihyperglycemic agents). The efficacy of INVOKANA was compared to a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin) and a sulfonylurea (glimepiride). INVOKANA was also evaluated in adults 55 to 80 years of age and patients with moderate renal impairment.In patients with type 2 diabetes, treatment with INVOKANA produced clinically and statistically significant improvements in HbA1C compared to placebo. Reductions in HbA1C were observed across subgroups including age, gender, race, and baseline body mass index (BMI).14.1 MonotherapyA total of 584 patients with type 2 diabetes inadequately controlled on diet and exercise participated in a 26-week, double-blind, placebo-controlled study to evaluate the efficacy and safety of INVOKANA. The mean age was 55 years, 44% of patients were men, and the mean baseline eGFR was 87 mL/min/1.73 m2. Patients taking other anti hyperglycemic agents (N=281) discontinued the agent and underwent an 8-week washout followed by a 2-week, single-blind, placebo run-in period. Patients not taking oral antihyperglycemic agents (N=303) entered the 2-week, single-blind, placebo run-in period directly. After the placebo run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily for 26 weeks.At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p-value <0.001 for both doses) compared to placebo. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG), in improved postprandial glucose (PPG), and in percent body weight reduction compared to placebo (see Table 7). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -3.7 mmHg and -5.4 mmHg with INVOKANA 100 mg and 300 mg, respectively.Table 7: Results from 26-Week Placebo-Controlled Clinical Study with

INvOKANA as Monotherapy*

Efficacy ParameterPlacebo(N=192)

INvOKANA100 mg(N=195)


hbA1C (%)Baseline (mean) 7.97 8.06 8.01Change from baseline (adjusted mean) 0.14 -0.77 -1.03Difference from placebo (adjusted mean) (95% CI) †

-0.91‡

(-1.09, -0.73)-1.16‡

(-1.34, -0.99)

Table 7: Results from 26-Week Placebo-Controlled Clinical Study with INvOKANA as Monotherapy* (continued)

Efficacy ParameterPlacebo(N=192)



Percent of Patients Achieving hbA1C < 7% 21 45‡ 62‡

Fasting Plasma Glucose (mg/dL)Baseline (mean) 166 172 173Change from baseline (adjusted mean) 8 -27 -35Difference from placebo (adjusted mean) (95% CI) †

-36‡

(-42, -29)-43‡

(-50, -37)2-hour Postprandial Glucose (mg/dL)

Baseline (mean) 229 250 254Change from baseline (adjusted mean) 5 -43 -59Difference from placebo (adjusted mean) (95% CI) †

-48‡

(-59.1, -37.0)-64‡

(-75.0, -52.9)Body Weight

Baseline (mean) in kg 87.5 85.9 86.9% change from baseline (adjusted mean) -0.6 -2.8 -3.9Difference from placebo (adjusted mean) (95% CI) †

-2.2‡

(-2.9, -1.6)-3.3‡

(-4.0, -2.6)

* Intent-to-treat population using last observation in study prior to glycemic rescue therapy

† Least squares mean adjusted for baseline value and stratification factors‡ p<0.001

14.2 Combination TherapyAdd-on Combination Therapy With MetforminA total of 1284 patients with type 2 diabetes inadequately controlled on metformin monotherapy (greater than or equal to 2,000 mg/day, or at least 1,500 mg/day if higher dose not tolerated) participated in a 26-week, double-blind, placebo- and active-controlled study to evaluate the efficacy and safety of INVOKANA in combination with metformin. The mean age was 55 years, 47% of patients were men, and the mean baseline eGFR was 89 mL/min/1.73 m2. Patients already on the required metformin dose (N=1009) were randomized after completing a 2-week, single-blind, placebo run-in period. Patients taking less than the required metformin dose or patients on metformin in combination with another antihyperglycemic agent (N=275) were switched to metformin monotherapy (at doses described above) for at least 8 weeks before entering the 2-week, single-blind, placebo run-in. After the placebo run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, sitagliptin 100 mg, or placebo, administered once daily as add-on therapy to metformin.At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p-value <0.001 for both doses) compared to placebo when added to metformin. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG), in improved postprandial glucose (PPG), and in percent body weight reduction compared to placebo when added to metformin (see Table 8). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -5.4 mmHg and -6.6 mmHg with INVOKANA 100 mg and 300 mg, respectively.

Table 8: Results from 26-Week Placebo-Controlled Clinical Study of INvOKANA in Combination with Metformin*

Efficacy Parameter

Placebo + Metformin

(N=183)

INvOKANA 100 mg +

Metformin(N=368)

INvOKANA 300 mg +

Metformin(N=367)

hbA1C (%)Baseline (mean) 7.96 7.94 7.95Change from baseline (adjusted mean) -0.17 -0.79 -0.94Difference from placebo (adjusted mean) (95% CI) †

-0.62‡

(-0.76, -0.48)-0.77‡

(-0.91, -0.64)Percent of patients achieving hbA1C < 7% 30 46‡ 58‡


Table 8: Results from 26-Week Placebo-Controlled Clinical Study of INvOKANA in Combination with Metformin* (continued)

Efficacy Parameter

Placebo + Metformin

(N=183)

INvOKANA 100 mg +

Metformin(N=368)

INvOKANA 300 mg +

Metformin(N=367)


-30‡

(-36, -24)-40‡

(-46, -34)2-hour Postprandial Glucose (mg/dL)

Baseline (mean) 249 258 262Change from baseline (adjusted mean) -10 -48 -57Difference from placebo (adjusted mean) (95% CI) †

-38‡

(-49, -27)-47‡

(-58, -36)Body Weight


-2.5‡

(-3.1, -1.9)-2.9‡

(-3.5, -2.3)



INVOKANA Compared to Glimepiride, Both as Add-on Combination With MetforminA total of 1450 patients with type 2 diabetes inadequately controlled on metformin monotherapy (greater than or equal to 2,000 mg/day, or at least 1,500 mg/day if higher dose not tolerated) participated in a 52-week, double-blind, active-controlled study to evaluate the efficacy and safety of INVOKANA in combination with metformin. The mean age was 56 years, 52% of patients were men, and the mean baseline eGFR was 90 mL/min/1.73 m2. Patients tolerating maximally required metformin dose (N=928) were randomized after completing a 2-week, single-blind, placebo run-in period. Other patients (N=522) were switched to metformin monotherapy (at doses described above) for at least 10 weeks, then completed a 2-week single-blind run-in period. After the 2-week run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or glimepiride (titration allowed throughout the 52-week study to 6 or 8 mg), administered once daily as add-on therapy to metformin.As shown in Table 9 and Figure 1, at the end of treatment, INVOKANA 100 mg provided similar reductions in HbA1C from baseline compared to glimepiride when added to metformin therapy. INVOKANA 300 mg provided a greater reduction from baseline in HbA1C compared to glimepiride, and the relative treatment difference was -0.12% (95% CI: −0.22; −0.02). As shown in Table 9, treatment with INVOKANA 100 mg and 300 mg daily provided greater improvements in percent body weight change, relative to glimepiride.Table 9: Results from 52−Week Clinical Study Comparing INvOKANA to

Glimepiride in Combination with Metformin*

Efficacy Parameter

INvOKANA 100 mg +

Metformin(N=483)

INvOKANA 300 mg +

Metformin(N=485)

Glimepiride (titrated) + Metformin

(N=482)hbA1C (%)

Baseline (mean) 7.78 7.79 7.83Change from baseline (adjusted mean) -0.82 -0.93 -0.81Difference from glimepiride (adjusted mean) (95% CI) †

-0.01‡

(-0.11; 0.09)-0.12‡

(-0.22; -0.02)Percent of patients achieving hbA1C < 7% 54 60 56Fasting Plasma Glucose (mg/dL)

Baseline (mean) 165 164 166Change from baseline (adjusted mean) -24 -28 -18Difference from glimepiride (adjusted mean) (95% CI) †

-6(-10; -2)

-9(-13; -5)

Table 9: Results from 52−Week Clinical Study Comparing INvOKANA to Glimepiride in Combination with Metformin* (continued)

Efficacy Parameter

INvOKANA 100 mg +

Metformin(N=483)

INvOKANA 300 mg +

Metformin(N=485)

Glimepiride (titrated) + Metformin

(N=482)Body Weight

Baseline (mean) in kg 86.8 86.6 86.6% change from baseline (adjusted mean) -4.2 -4.7 1.0Difference from glimepiride (adjusted mean) (95% CI) †

-5.2§

(-5.7; -4.7)-5.7§

(-6.2; -5.1)


† Least squares mean adjusted for baseline value and stratification factors‡ INVOKANA + metformin is considered non-inferior to glimepiride +

metformin because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%.

§ p<0.001

Figure 1: Mean hbA1C Change at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population)

Add-on Combination Therapy With SulfonylureaA total of 127 patients with type 2 diabetes inadequately controlled on sulfonylurea monotherapy participated in an 18-week, double-blind, placebo-controlled sub-study to evaluate the efficacy and safety of INVOKANA in combination with sulfonyl urea. The mean age was 65 years, 57% of patients were men, and the mean baseline eGFR was 69 mL/min/1.73 m2. Patients treated with sulfonylurea monotherapy on a stable protocol-specified dose (greater than or equal to 50% maximal dose) for at least 10 weeks completed a 2-week, single-blind, placebo run-in period. After the run-in period, patients with inadequate glycemic control were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to sulfonylurea.As shown in Table 10, at the end of treatment, INVOKANA 100 mg and 300 mg daily provided statistically significant (p<0.001 for both doses) improvements in HbA1C relative to placebo when added to sulfonylurea. INVOKANA 300 mg once daily compared to placebo resulted in a greater proportion of patients achieving an HbA1C less than 7%, (33% vs 5%), greater reductions in fasting plasma glucose (-36 mg/dL vs +12 mg/dL), and greater percent body weight reduction (-2.0% vs -0.2%).Table 10: Results from 18-Week Placebo−Controlled Clinical Study of

INvOKANA in Combination with Sulfonylurea*

Efficacy Parameter

Placebo + Sulfonylurea

(N=45)

INvOKANA 100 mg +

Sulfonylurea(N=42)

INvOKANA 300 mg +

Sulfonylurea(N=40)


-0.74‡

(-1.15, -0.33)-0.83‡

(-1.24, -0.41)


† Least squares mean adjusted for baseline value‡ p<0.001


Add-on Combination Therapy With Metformin and SulfonylureaA total of 469 patients with type 2 diabetes inadequately controlled on the combination of metformin (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (maximal or near-maximal effective dose) participated in a 26-week, double-blind, placebo-controlled study to evaluate the efficacy and safety of INVOKANA in combination with metformin and sulfonylurea. The mean age was 57 years, 51% of patients were men, and the mean baseline eGFR was 89 mL/min/1.73 m2. Patients already on the protocol-specified doses of metformin and sulfonylurea (N=372) entered a 2-week, single-blind, placebo run-in period. Other patients (N=97) were required to be on a stable protocol-specified dose of metformin and sulfonylurea for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to metformin and sulfonylurea.At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin and sulfonylurea. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in a significant reduction in fasting plasma glucose (FPG), and in percent body weight reduction compared to placebo when added to metformin and sulfonylurea (see Table 11).

Table 11: Results from 26−Week Placebo-Controlled Clinical Study of INvOKANA in Combination with Metformin and Sulfonylurea*

Efficacy Parameter

Placebo + Metformin and Sulfonylurea

(N=156)

INvOKANA 100 mg +

Metforminand

Sulfonylurea (N=157)

INvOKANA 300 mg +

Metforminand

Sulfonylurea(N=156)

A1C (%)Baseline (mean) 8.12 8.13 8.13Change from baseline (adjusted mean) -0.13 -0.85 -1.06Difference from placebo (adjusted mean) (95% CI) †

-0.71‡

(-0.90; -0.52)-0.92‡

(-1.11; -0.73)Percent of patients achieving A1C < 7% 18 43‡ 57‡


-22‡

(-31, -13)-35‡



-1.4‡

(-2.1; -0.7)-2.0‡

(-2.7; -1.3)



INVOKANA Compared to Sitagliptin, Both as Add-on Combination Therapy With Metformin and SulfonylureaA total of 755 patients with type 2 diabetes inadequately controlled on the combination of metformin (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (near-maximal or maximal effective dose) participated in a 52-week, double-blind, active-controlled study to compare the efficacy and safety of INVOKANA 300 mg versus sitagliptin 100 mg in combination with metformin and sulfonylurea. The mean age was 57 years, 56% of patients were men, and the mean baseline eGFR was 88 mL/min/1.73 m2. Patients already on protocol-specified doses of metformin and sulfonylurea (N=716) entered a 2-week single-blind, placebo run-in period. Other patients (N=39) were required to be on a stable protocol-specified dose of metformin and sulfonylurea for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to INVOKANA 300 mg or sitagliptin 100 mg as add-on to metformin and sulfonylurea.

As shown in Table 12 and Figure 2, at the end of treatment, INVOKANA 300 mg provided greater HbA1C reduction compared to sitagliptin 100 mg when added to metformin and sulfonylurea (p<0.05). INVOKANA 300 mg resulted in a mean percent change in body weight from baseline of -2.5% compared to +0.3% with sitagliptin 100 mg. A mean change in systolic blood pressure from baseline of -5.06 mmHg was observed with INVOKANA 300 mg compared to +0.85 mmHg with sitagliptin 100 mg.Table 12: Results from 52−Week Clinical Study Comparing INvOKANA to

Sitagliptin in Combination with Metformin and Sulfonylurea*

Efficacy Parameter

INvOKANA 300 mg + Metformin and Sulfonylurea

(N=377)

Sitagliptin 100 mg + Metformin and Sulfonylurea

(N=378)hbA1C (%)

Baseline (mean) 8.12 8.13Change from baseline (adjusted mean) -1.03 -0.66Difference from sitagliptin (adjusted mean) (95% CI) †

-0.37‡

(-0.50; -0.25)Percent of patients achieving hbA1C < 7% 48 35Fasting Plasma Glucose (mg/dL)

Baseline (mean) 170 164Change from baseline (adjusted mean) -30 -6Difference from sitagliptin (adjusted mean) (95% CI) †

-24 (-30; -18)

Body WeightBaseline (mean) in kg 87.6 89.6% change from baseline (adjusted mean) -2.5 0.3Difference from sitagliptin (adjusted mean) (95% CI) †

-2.8§

(-3.3; -2.2)


† Least squares mean adjusted for baseline value and stratification factors‡ INVOKANA + metformin + sulfonylurea is considered non-inferior to

sitagliptin + metformin + sulfonylurea because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%.

§ p<0.001

Figure 2: Mean hbA1C Change at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population)

Add-on Combination Therapy With Metformin and PioglitazoneA total of 342 patients with type 2 diabetes inadequately controlled on the combination of metformin (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and pioglitazone (30 or 45 mg/day) participated in a 26-week, double-blind, placebo-controlled study to evaluate the efficacy and safety of INVOKANA in combination with metformin and pioglitazone. Patients already on protocol-specified doses of metformin and pioglitazone (N=163) entered a 2-week, single-blind, placebo run-in period. Other patients (N=181) were required to be on stable protocol-specified doses of metformin and pioglitazone for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to metformin and pioglitazone.


At the of end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin and pioglitazone. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG) and in percent body weight reduction compared to placebo when added to metformin and pioglitazone (see Table 13). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -4.1 mmHg and -3.5 mmHg with INVOKANA 100 mg and 300 mg, respectively.

Table 13: Results from 26−Week Placebo-Controlled Clinical Study of INvOKANA in Combination with Metformin and Pioglitazone*

Efficacy Parameter

Placebo + Metformin

and Pioglitazone

(N=115)

INvOKANA 100 mg +

Metformin and

Pioglitazone(N=113)

INvOKANA 300 mg +

Metformin and

Pioglitazone(N=114)

hbA1C (%)

Baseline (mean) 8.00 7.99 7.84

Change from baseline (adjusted mean) -0.26 -0.89 -1.03

Difference from placebo (adjusted mean) (95% CI) †

-0.62‡

(-0.81; -0.44)-0.76‡

(-0.95; -0.58)

Percent of patients achieving hbA1C < 7% 33 47‡ 64‡

Fasting Plasma Glucose (mg/dL)

Baseline (mean) 164 169 164

Change from baseline (adjusted mean) 3 -27 -33


-29‡

(-37; -22)-36‡

(-43; -28)

Body Weight

Baseline (mean) in kg 94.0 94.2 94.4

% change from baseline (adjusted mean) -0.1 -2.8 -3.8


-2.7‡

(-3.6; -1.8)-3.7‡

(-4.6; -2.8)



Add-On Combination Therapy With Insulin (With or Without Other Antihyper-glycemic Agents)A total of 1718 patients with type 2 diabetes inadequately controlled on insulin greater than or equal to 30 units/day or insulin in combination with other antihyperglycemic agents participated in an 18-week, double-blind, placebo-controlled substudy of a cardiovascular study to evaluate the efficacy and safety of INVOKANA in combination with insulin. The mean age was 63 years, 66% of patients were men, and the mean baseline eGFR was 75 mL/min/1.73 m2. Patients on basal, bolus, or basal/bolus insulin for at least 10 weeks entered a 2-week, single-blind, placebo run-in period. Approximately 70% of patients were on a background basal/bolus insulin regimen. After the run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to insulin. The mean daily insulin dose at baseline was 83 units, which was similar across treatment groups.At the of end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to insulin. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reductions in fasting plasma glucose (FPG), and in percent body weight reductions compared to placebo (see Table 14). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -2.6 mmHg and -4.4 mmHg with INVOKANA 100 mg and 300 mg, respectively.

Table 14: Results from 18−Week Placebo-Controlled Clinical Study of INvOKANA in Combination with Insulin ≥ 30 Units/day (With or Without Other Oral Antihyperglycemic Agents)*

Efficacy Parameter

Placebo + Insulin(N=565)

INvOKANA 100 mg + Insulin(N=566)

INvOKANA 300 mg + Insulin(N=587)


-0.65‡

(-0.73, -0.56)-0.73‡

(-0.82, -0.65)Percent of patients achieving hbA1C < 7% 8 20‡ 25‡

Fasting Plasma Glucose (mg/dL)Baseline 169 170 168Change from baseline (adjusted mean) 4 -19 -25Difference from placebo (adjusted mean) (97.5% CI) †

-23‡

(-29, -16)-29‡


Baseline (mean) in kg 97.7 96.9 96.7% change from baseline (adjusted mean) 0.1 -1.8 -2.3Difference from placebo (adjusted mean) (97.5% CI) †

-1.9‡

(-2.2, -1.5)-2.4‡

(-2.8, -2.0)


† Least squares mean adjusted for baseline value and stratification factors‡ p<0.00114.3 Studies in Special PopulationsAdults 55 to 80 Years of AgeA total of 714 older patients with type 2 diabetes inadequately controlled on current diabetes therapy (either diet and exercise alone or in combination with oral or parenteral agents) participated in a 26-week, double-blind, placebo-controlled study to evaluate the efficacy and safety of INVOKANA in combination with current diabetes treatment. The mean age was 64 years, 55% of patients were men, and the mean baseline eGFR was 77 mL/min/1.73 m2. Patients were randomized to the addition of INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily. At the end of treatment, INVOKANA provided statistically significant improvements from baseline relative to placebo in HbA1C (p<0.001 for both doses) of -0.57% (95% CI: -0.71; -0.44) for INVOKANA 100 mg and -0.70% (95% CI: -0.84; -0.57) for INVOKANA 300 mg. Statistically significant (p<0.001 for both doses) reductions from baseline in fasting plasma glucose (FPG) and body weight were also observed in this study relative to placebo [see Use in Specific Populations (8.5)].Moderate Renal ImpairmentA total of 269 patients with type 2 diabetes and a baseline eGFR of 30 mL/min/1.73 m2 to less than 50 mL/min/1.73 m2 inadequately controlled on current diabetes therapy participated in a 26-week, double-blind, placebo-controlled clinical study to evaluate the efficacy and safety of INVOKANA in combination with current diabetes treatment (diet or anti hyperglycemic agent therapy, with 95% of patients on insulin and/or sulfonylurea). The mean age was 68 years, 61% of patients were men, and the mean baseline eGFR was 39 mL/min/1.73 m2. Patients were randomized to the addition of INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily.At the end of treatment, INVOKANA 100 mg and INVOKANA 300 mg daily provided greater reductions in HbA1C relative to placebo (-0.30% [95% CI: -0.53; -0.07] and -0.40%, [95% CI: -0.64; -0.17], respectively) [see Warnings and Precautions (5.2), Adverse Reactions (6.1), and Use in Specific Populations (8.6)].16 hOW SUPPLIEd/STORAGE ANd hANdLINGINVOKANA (canagliflozin) tablets are available in the strengths and packages listed below:100 mg tablets are yellow, capsule-shaped, film-coated tablets with “CFZ” on one side and “100” on the other side.NDC 50458-140-30 Bottle of 30NDC 50458-140-90 Bottle of 90NDC 50458-140-50 Bottle of 500NDC 50458-140-10 Blister package containing 100 tablets (10 blister

cards containing 10 tablets each)

300 mg tablets are white, capsule-shaped, film-coated tablets with “CFZ” on one side and “300” on the other side. NDC 50458-141-30 Bottle of 30NDC 50458-141-90 Bottle of 90NDC 50458-141-50 Bottle of 500NDC 50458-141-10 Blister package containing 100 tablets (10 blister

cards containing 10 tablets each)


Storage and HandlingStore at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F).

17 PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Medication Guide).InstructionsInstruct patients to read the Medication Guide before starting INVOKANA (canagliflozin) therapy and to reread it each time the prescription is renewed.Inform patients of the potential risks and benefits of INVOKANA and of alternative modes of therapy. Also inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change.Instruct patients to take INVOKANA only as prescribed. If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of INVOKANA at the same time.Inform patients that the most common adverse reactions associated with INVOKANA are genital mycotic infection, urinary tract infection, and increased urination.Inform female patients of child bearing age that the use of INVOKANA during pregnancy has not been studied in humans, and that INVOKANA should only be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Instruct patients to report pregnancies to their physicians as soon as possible.Inform nursing mothers to discontinue INVOKANA or nursing, taking into account the importance of drug to the mother.Laboratory TestsDue to its mechanism of action, patients taking INVOKANA will test positive for glucose in their urine.HypotensionInform patients that symptomatic hypotension may occur with INVOKANA and advise them to contact their doctor if they experience such symptoms [see Warnings and Precautions (5.1)]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.Genital Mycotic Infections in Females (e.g., Vulvovaginitis)Inform female patients that vaginal yeast infection may occur and provide them with information on the signs and symptoms of vaginal yeast infection. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.5)].Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis)Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.5)].Hypersensitivity ReactionsInform patients that serious hypersensitivity reactions such as urticaria and rash have been reported with INVOKANA. Advise patients to report immediately any signs or symptoms suggesting allergic reaction or angioedema, and to take no more drug until they have consulted prescribing physicians.Urinary Tract InfectionsInform patients of the potential for urinary tract infections. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur.

Active ingredient made in BelgiumManufactured for:Janssen Pharmaceuticals, Inc.Titusville, NJ 08560Finished product manufactured by:Janssen Ortho, LLCGurabo, PR 00778Licensed from Mitsubishi Tanabe Pharma Corporation© 2013 Janssen Pharmaceuticals, Inc.10282402

MEdICATION GUIdEINvOKANA™ (in-vo-KAhN-uh)

(canagliflozin)Tablets

What is the most important information I should know about INvOKANA?INVOKANA can cause important side effects, including:• Dehydration.INVOKANAcancausesomepeopletohave

dehydration (the loss of body water and salt). dehydra-tion may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic hypotension).You may be at higher risk of dehydration if you:o have low blood pressureo take medicines to lower your blood pressure, including

diuretics (water pill)o are on low sodium (salt) dieto have kidney problemso are 65 years of age or older

• Vaginal yeast infection. Women who take INVOKANA may get vaginal yeast infections. Symptoms of a vaginal yeast infection include:o vaginal odoro white or yellowish vaginal discharge (discharge may

be lumpy or look like cottage cheese)o vaginal itching

• Yeastinfectionofthepenis(balanitisorbalanoposthitis). Men who take INVOKANA may get a yeast infection of the skin around the penis. Certain men who are not circumcised may have swelling of the penis that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include:o redness, itching, or swelling of the peniso rash of the peniso foul smelling discharge from the peniso pain in the skin around penis

Talk to your doctor about what to do if you get symptoms of a yeast infection of the vagina or penis. Your doctor may suggest you use an over-the-counter antifungal medicine. Talk to your doctor right away if you use an over-the-counter antifungal medication and your symptoms do not go away.What is INvOKANA?• INVOKANA is a prescription medicine used along with

diet and exercise to lower blood sugar in adults with type 2 diabetes.

• INVOKANA is not for people with type 1 diabetes.• INVOKANA is not for people with diabetic ketoacidosis

(increased ketones in blood or urine).• It is not known if INVOKANA is safe and effective in

children under 18 years of age.Who should not take INvOKANA?do not take INvOKANA if you:• are allergic to canagliflozin or any of the ingredients in

INVOKANA. See the end of this Medication Guide for a list of ingredients in INVOKANA. Symptoms of allergic reaction to INVOKANA may include:o rasho raised red patches on your skin (hives)o swelling of the face, lips, tongue, and throat that may

cause difficulty in breathing or swallowing• have severe kidney problems or are on dialysis.


What should I tell my doctor before taking INvOKANA?Before you take INVOKANA, tell your doctor if you:• have kidney problems• have liver problems• are on a low sodium (salt) diet. Your doctor may change

your diet or your dose of INVOKANA.• have ever had an allergic reaction to INVOKANA• have other medical conditions• are pregnant or plan to become pregnant. It is not known

if INVOKANA will harm your unborn baby. If you are pregnant, talk with your doctor about the best way to control your blood sugar while you are pregnant.

• are breastfeeding or plan to breastfeed. It is not known if INVOKANA passes into your breast milk. Talk with your doctor about the best way to feed your baby if you are taking INVOKANA.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.INVOKANA may affect the way other medicines work, and other medicines may affect how INVOKANA works. Especially tell your doctor if you take:• diuretics (water pills)• rifampin (used to treat or prevent tuberculosis)

• phenytoin or phenobarbital (used to control seizures)

• ritonavir (Norvir®, Kaletra®, Lopinavir ®)* (used to treat HIV infection)

• digoxin (Lanoxin®)* (used to treat heart problems)

Ask your doctor or pharmacist for a list of these medicines if you are not sure if your medicine is listed above.

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.

how should I take INvOKANA?• Take INVOKANA by mouth 1 time each day exactly as

your doctor tells you to take it.

• Your doctor will tell you how much INVOKANA to take and when to take it. Your doctor may change your dose if needed.

• It is best to take INVOKANA before the first meal of the day.

• Your doctor may tell you to take INVOKANA along with other diabetes medicines. Low blood sugar can happen more often when INVOKANA is taken with certain other diabetes medicines. See “What are the possible side effects of INvOKANA?”

• If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take two doses of INVOKANA at the same time. Talk to your doctor if you have questions about a missed dose.

• If you take too much INVOKANA, call your doctor or go to the nearest hospital emergency room right away.

• When your body is under some types of stress, such as fever, trauma (such as a car accident), infection, or surgery, the amount of diabetes medicine you need may change. Tell your doctor right away if you have any of these conditions and follow your doctor’s instructions.

• Stay on your prescribed diet and exercise program while taking INVOKANA.

• Check your blood sugar as your doctor tells you to.

• INVOKANA will cause your urine to test positive for glucose.

• Your doctor may do certain blood tests before you start INVOKANA and during treatment as needed. Your doctor may change your dose of INVOKANA based on the results of your blood tests.

• Your doctor will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C.

What are the possible side effects of INvOKANA?INvOKANA may cause serious side effects including:See “What is the most important information I should know about INvOKANA?”

• kidneyproblems

• ahighamountofpotassiuminyourblood(hyperkalemia)

• lowbloodsugar (hypoglycemia). If you take INVOKANA with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take INVOKANA.Signs and symptoms of low blood sugar may include:o headache o irritabilityo drowsiness o hungero weakness o fast heart-beato dizziness o sweatingo confusion o shaking or feeling jittery

• serious allergic reaction. If you have any symptoms of a serious allergic reaction, stop taking INVOKANA and call your doctor right away or go to the nearest hospital emergency room. See “Who should not take INvOKANA?”. Your doctor may give you a medicine for your allergic reaction and prescribe a different medicine for your diabetes.

The most common side effects of INVOKANA include:• vaginal yeast infections and yeast infections of the penis

(See “What is the most important information I should know about INvOKANA?”)

• urinary tract infection• changes in urination, including urgent need to urinate

more often, in larger amounts, or at nightTell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of INVOKANA. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.


You may also report side effects to Janssen Pharmaceuticals, Inc. at 1-800-526-7736.how should I store INvOKANA?• Store INVOKANA at room temperature between 68°F to

77°F (20°C to 25°C).• Keep INVOKANAandallmedicines out of the reachof

children.

General information about the safe and effective use of INvOKANA.Medicines are sometimes prescribed for purposes other than those listed in the Medication Guide. Do not use INVOKANA for a condition for which it was not prescribed. Do not give INVOKANA to other people, even if they have the same symptoms you have. It may harm them.This Medication Guide summarizes the most important information about INVOKANA. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about INVOKANA that is written for healthcare professionals.For more information about INVOKANA, call 1-800-526-7736 or visit our website at www.invokana.com.

What are the ingredients of INvOKANA?Active ingredient: canagliflozinInactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose anhydrous, magnesium stearate, and micro crystalline cellulose. In addition, the tablet coating contains iron oxide yellow E172 (100 mg tablet only), macrogol/PEG, polyvinyl alcohol, talc, and titanium dioxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.* The brands listed are trademarks of their respective owners and are not trademarks of Janssen Pharmaceuticals, Inc.

Active ingredient made in Belgium.

Manufactured for:Janssen Pharmaceuticals, Inc.Titusville, NJ 08560Manufactured by:Janssen Ortho, LLCGurabo, PR 00778

Licensed from Mitsubishi Tanabe Pharma CorporationDate of approval: March 2013© 2013 Janssen Pharmaceuticals, Inc.

10282402

007319-131206

INVOKANA™ (canagliflozin) tablets


VOL. 20, NO. 1 n THE AMERICAN JOURNAL OF MANAGED CARE n eS41

n eAppendix Table. Baseline Demographics and Disease Characteristics (BMI >25 kg/m2 subgroup)a

Characteristic

Canagliflozin 300 mg (n = 318)

Sitagliptin 100 mg (n = 324)

Total (n = 642)

Age, years 56.7 ± 9.7 56.3 ± 9.3 56.5 ± 9.5

Sex, n (%)

Male 176 (55.3) 183 (56.5) 359 (55.9)

Female 142 (44.7) 141 (43.5) 283 (44.1)

Race, n (%)b

White 222 (69.8) 220 (67.9) 442 (68.8)

Black or African American 36 (11.3) 40 (12.3) 76 (11.8)

Asian 39 (12.3) 39 (12.0) 78 (12.1)

Otherc 21 (6.6) 25 (7.7) 46 (7.2)

A1C, % 8.1 ± 0.9 8.1 ± 0.9 8.1 ± 0.9

FPG, mg/dL 170.8 ± 47.3 166.3 ± 45.4 168.5 ± 46.4

Body weight, kg 92.4 ± 21.7 93.8 ± 21.4 93.1 ± 21.6

BMI, kg/m2 33.1 ± 6.4 33.2 ± 6.3 33.1 ± 6.4

Systolic BP, mm Hg 131.8 ± 13.4 131.1 ± 13.8 131.4 ± 13.6

Diastolic BP, mm Hg 79.4 ± 8.0 79.3 ± 8.6 79.3 ± 8.3

LDL-C, mg/dL 100.0 ± 36.8 97.5 ± 37.1 98.7 ± 36.9

eGFR, mL/min/1.73 m2 87.1 ± 18.2 87.5 ± 20.5 87.3 ± 19.4

Duration of type 2 diabetes mel-litus, years

9.4 ± 5.9 9.2 ± 5.9 9.3 ± 5.9

A1C indicates glycated hemoglobin; BMI, body mass index; BP, blood pressure; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; LDL-C, low-density lipoprotein cholesterol. aData are mean ± standard deviation unless otherwise indicated. bPercentages may not total 100.0% due to rounding. cIncludes American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, multiple, other, unknown, or not reported.

n Supplement Policy Statement n

Standards for Supplements to The American Journal of Managed Care

All supplements to The American Journal of Managed Care are designed to facilitate and enhance ongoing medical education in various therapeutic disciplines. All Journal supplements adhere to standards of fairness and objectivity, as outlined below. Supplements to The American Journal of Managed Care will:

I. Be reviewed by at least one independent expert from a recognized academic medical institution. II. Disclose the source of funding in at least one prominent place. III. Disclose any existence of financial interests of supplement contributors to the funding organization. IV. Use generic drug names only, except as needed to differentiate between therapies of similar class and indication. V. Be up-to-date, reflecting the current (as of date of publication) standard of care. VI. Be visually distinct from The American Journal of Managed Care. VII. Publish information that is substantially different in form and content from that of the accompanying edition of The American Journal of Managed Care. VIII. Prohibit excessive remuneration for contributors and reviewers. IX. Carry no advertising.

Publisher’s Note: The opinions expressed in this supplement are those of the authors, presenters, and/or panel-ists and are not attributable to the sponsor or the publisher, editor, or editorial board of The American Journal of Managed Care. Clinical judgment must guide each professional in weighing the benefits of treatment against the risk of toxicity. Dosages, indications, and methods of use for products referred to in this supple-ment are not necessarily the same as indicated in the package insert for the product and may reflect the clini-cal experience of the authors, presenters, and/or panelists or may be derived from the professional literature or other clinical sources. Consult complete prescribing information before administering.

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