Ueda2015 canagliflozin dr.inass shaltout

Canagliflozin:Background and Evidence Update

Inass Shaltout

Cairo University

Diabetes is a huge and growing problem, and the costs to society are high and escalating

Diabetes is a neglected development issue, affecting all countries

There are cost-effective solutions to reverse the global diabetes epidemic

Diabetes is not only a health issue, its causes are multi-sectoral and it requires a multi-sectoral response

2014

Diabetes is a huge and growing problem…

2035

… and the costs to society are high and escalating

Diabetes is a human and economic burden

4.9 million deaths per year

50% of deaths under 60 years of age

Intersects with all dimensions of development

US$612 billion

11% of worldwide healthcare expenditure

For Egypt the IDF updates Egypt ranking to be the 9th in the the number of people with diabetes (20-79 years), with 7.5 Millions 2014 (Vs. 4.78 Million in 2010) and to be at the 6th position with 13.1 Million in 2030

Is there a need for a new antidiabetic ?

Two thirds of individuals do not achieve target A1c

despite dedicated efforts to achieve glycemic control

1. Liebl A, et al. Diabetologia. 2002;45(7):S23-S28.

EuropeCODE-2 study - HbA1c goal 6.5%

Pathophysiology of Diabetes:

The Ominous Octet

The Triumvirate

Liver hepatic glucose

production

Muscle and

adipose tissue Insulin-dependent

glucose uptake by

adipose tissue and

muscle

PancreasImpaired insulin

secretion by

pancreatic -cells

Ralph DeFronzo: Banting Lecture ADA June 2008.

The Septet

Liver hepatic glucose

production

Muscle and

adipose tissue Insulin-dependent

glucose uptake by

adipose tissue and

muscle

PancreasImpaired insulin

secretion by

pancreatic -cells

Ralph DeFronzo: Banting Lecture ADA June 2008.

Increased

Lipolysis

Decreased

Incretin

EffectPancreatic

alpha cells

KidneyIncreased glucose

reabsorption

The Role of the Kidney in Diabetes

The Kidney and Glucose

•The kidney

–Plays a significant role in glucose homeostasis under both physiological and pathological conditions

–Contributes to, and regulates blood glucose levels via three mechanisms:

• Glucose utilization

• Gluconeogenesis

• Glucose reabsorption following glomerular filtration

Marsenic, O. (2009) Am J Kidney Dis. 53(5):875-83Gerich, J.E. (2010) Diabet Med. 27(2):136-42

Glomerular Filtration and Glucose Reabsorption

Marsenic, O. (2009) Am J Kidney Dis. 53(5):875-83Gerich, J.E. (2010) Diabet Med. 27(2):136-42

SGLT2• Primarily expressed in kidney• Responsible for majority of renal

glucose reabsorption

SGLT1• Responsible for small portion of

renal glucose reabsorption• Prominent role in intestinal glucose

absorption

Major SGLT Glucose Transporters

Modified from Lee YJ. et al. Kidney Int Suppl. 2007;72:S27-S35.

Characteristic SGLT1 SGLT2

Major sites of expression Intestine & kidney Kidney

Sugar specificity Glucose or galactose Glucose

Main role

Dietary absorption of glucose and galactose

Renal glucose reabsorption

Renal glucose reabsorption

Renal locationLate proximal straight tubule

(distal S2/3 segment)Early proximal convoluted tubule

(S1/S2 segment)

Affinity for glucose (Km) High (0.4 μM) Low (2 μM)

Capacity for glucose transport

Low High

% Renal glucose reabsorption

10% 90%

Glucose Transport in Tubular Epithelial Cells

G Glucose

Na+ Sodium

K Potassium

BloodLumen

S1 Proximal Tubule

G

Na+

KGLUT2

ATPase

SGLT2High

CapacityLow

Affinity

BloodLumen

S3 Proximal Tubule

G

2Na+

2KGLUT1

ATPase

SGLT1Low

CapacityHigh

Affinity

Adapted from Bakris GL et al. Kidney Int 2009;75:1272-7Marsenic O. Am J Kidney Dis. 2009;53:875-83

Glucose Reabsorption in a Nondiabetic Person (Plasma Glucose <10 mmol/L )

Glomerulus Proximal Convoluted Tubule

Glucose reabsorption into tissue

Early Distal

Glucose SGLT1SGLT2

Urine

Adapted with permission from Rothenberg PL et al. SGLT = sodium-glucose linked co-transporter.Rothenberg PL et al. Poster presented at EASD 2010; Stockholm, Sweden

Glucose Reabsorption in a Person With T2DM (Plasma Glucose >10 and <13.3 mmol/L)

Glomerulus Proximal Convoluted Tubule

Increased glucose reabsorption into tissue compared to normal

Early Distal

Urine

Adapted with permission from Rothenberg PL et al. SGLT = sodium-glucose linked co-transporter.Rothenberg PL et al. Poster presented at EASD 2010; Stockholm, Sweden

Glucose SGLT1SGLT2

Urin

ary G

luco

se

Excreti

on

(g/d

)

0

100

50

25

0

Plasma Glucose (mmol/L)

150

75

125

1412108642

Below RTG

Minimal Glucosuria OccursAbove RTG

Glucosuria Occurs

Healthy RTG

~10 mmol/L

The Renal Glucose Threshold (RTG) Concept• Maximum plasma glucose concentration at which kidneys reabsorb

glucose back into the blood

• When glucose levels exceed the RTG, excess glucose is eliminated from the body through urinary glucose excretion

• Usual RTG in healthy subjects reported to be up to 10-11 mmol/L

Polidori D et al.. Poster presented at EASD 2010; Stockholm, Sweden

Urin

ary G

luco

se E

xcreti

on

(g/d

ay)

0

75

100

50

150

Plasma Glucose (mmol/L)

125

25

4 6 8 1610 14

Below RTG minimal glucosuria occurs

12

Healthy RTG

T2DMRTG

Above RTG glucosuria occurs

~13.8 mmol/L~10 mmol/L

The Renal Glucose Threshold (RTG) is Increased in Subjects with Type 2 Diabetes

Polidori D et al. Poster presented at ADA 2010; Orlando, Florida.Polidori D et al. Poster presented at EASD 2010; Stockholm, Sweden.

• Renal glucose reabsorption is increased in diabetes, which could contribute to further increasing plasma glucose levels

SGLT2 and Familial Renal Glucosuria

• Familial renal glucosuria (FRG) characterised by

– Persistent glucosuria

• No hyperglycaemia or renal tubular dysfunction

– Absence of clinical manifestations (aka benign glucosuria)

– Autosomal recessive or dominant inheritance (variable penetrance)

– Wide range of SLC5A2 (SGLT2) mutations identified

– Historically, divided into:

• Type A FRG

– Low renal threshold for glucose, low maximum tubular glucose reabsorption

• Type B FRG– Low renal threshold for glucose, can reach normal maximum glucose reabsorption

• Type O FRG (most severe form)

– Absence of renal glucose reabsorption

Santer, R. et al. (2010). Clin J Am Soc Nephrol 5: 133-41.

Introduction to Canagliflozin

Introducing SGLTs inhibitors — From a Natural Product to an Investigational Drug

• Origin from apple tree bark (also skin and fruit of apples); naturally found in human diet

• In 1886, reported to cause glucosuria

• In 1930s, phlorizin used as a tool to investigate renal physiology

• In 1987, phlorizin used to show that insulin deficiency leads to insulin resistance ‘Phlorizin diabetes’

• Limitations of Phlorizin as a Drug

• Non-specific inhibitor of SLGT1 as well as SGLT2

• Metabolite, phloretin also inhibits GLUT2

• Poor oral bioavailability

27

HO

OH

OH

O

OH

O

O

HO

HO

HO

Phlorizin Structure

Ehrenkranz JR, et al. Diabetes Metab Res Rev 2005;21:31–38.

Introduction to CanagliflozinMechanism of Action

Nomura S, et al. J Med Chem. 2010;53(17):6355-6360. Rosenstock J, et al. Diabetes Care. 2012;35(6):1232-1238.

Sha S, et al. Diabetes Obes Metab. 2011;13(7):669-672. Liang Y, et al. PLoS One. 2012;7(2):e30555.

Devineni D, et al. Diabetes Obes Metab. 2012;14(6):539-545. Polidori D et al. Diabetes Care. 2013 Feb 14. [Epub ahead of print]

Sha S et al. 2010. Presented at ADA 2010; Orlando, Florida

SGLT2 Inhibitor


• SGLT2 is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen

• Patients with diabetes have elevated renal glucose reabsorption which contributes to persistent elevated blood glucose concentrations

• Canagliflozin is an orally-active inhibitor of SGLT2

• By inhibiting SGLT2, Canagliflozin

– Reduces reabsorption of filtered glucose and lowers the RTG

– Increases urinary glucose excretion (UGE), lowering elevated plasma glucose concentrations

Invokana SmPC (Nov 2013) Available at: http://www.medicines.org.uk/emc/medicine/28400/SPC/Invokana+100+mg+film-coated+tablets/#PRODUCTINFO


• The increased UGE

– Translates to an osmotic diuresis, leading to a reduction in systolic blood pressure

– Results in a loss of calories and therefore a reduction in body weight

• Canagliflozin acts to increase UGE independent of insulin

• Improvement in homeostasis model assessment for β-cell function (HOMA β-cell) and improved β-cell insulin secretion response to a mixed-meal challenge has been observed in clinical studies with Canagliflozin


Canagliflozin Elimination

Plasma Canagliflozin

41% Canagliflozin (unchanged)

3,2% O-glucuronide

7% Hydroxylatedmetabolite

<1% Canagliflozin (unchanged)

30,5 %O-glucuronidemetabolite

LIVER

KIDNEY

Faeces

Urine


The major metabolic elimination

pathway for Canagliflozin is O-

glucuronidation.

CYP3A4-mediated metabolism is

minimal (∼7%)

Canagliflozin Treatment Lowers Plasma Glucose Concentrations Throughout the Entire Day

Example: CANA 100 mg treatment in subjects with T2DM

Data shown are mean values from NAP1002

CANA: Canagliflozin

120

140

160

180

200

220

240

260

280

300

Pla

sm

a g

luco

se (

mg

/d

L)

0 4 8 12 16 20 24

Time (Hours)

Placebo (N=19)

CANA 100 mg (N=16)

Day 16

Sha S et al. 2010. Presented at: American Diabetes Association. June 25-29, 2010; Orlando, FloridaJanssen Core Slides for the January 10, 2013 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf

Overview of Canagliflozin Clinical Development

Phase 3 Clinical Development Programme: 9 Studies Conducted

Canagliflozin Head to Head StudiesAdd-on to MET Study: Canagliflozin vs Glimepiride (DIA3009)

Add on to Metformin vs Glimepiride(DIA3009): Study Design

R, randomisation; AHA, antihyperglycaemic agent.*Protocol-specified = ≥2,000 mg (or ≥1,500 mg, if unable to tolerate higher dose).†To be discontinued before titrating MET.

Pretreatment PeriodCore Double-blind Treatment Period

Screening visit

Week –2Run-in start

Day 1Baseline

AHA adjustment period start

• On protocol-specified doses* of MET• HbA1c ≥7.0% and ≤9.5%

Week 104

Continue stable protocol-specified* dose of MET

CANA 300 mg

CANA 100 mg

GLIM (titrated)

Not on protocol-specified doses* of MET

- Low-dose MET: A1C ≥7.5 and ≤10%

- MET + another AHA†: HbA1c ≥6.5 and ≤9%

1. Titrate MET(up to 2 weeks)

2. Stable MET dose (10 weeks)

A1C≥7.0% and ≤9.5%

2-week, single-blind

placebo run-in

R

Extension Double-blind Treatment

Period

Week 52Primary endpoint

Cefalu WT et al. Lancet. 2013; 382(9896):941-50. Cefalu WT et al. Poster presented ADA 2013 Chicago, Illinois, (65-LB).

Add on to Metformin vs Glimepiride (DIA3009): Baseline Demographic and Disease Characteristics

CharacteristicGLIM

(n = 482) CANA 100 mg

(n = 483) CANA 300 mg

(n = 485)

Sex, n (%)Male 263 (54.6) 252 (52.2) 241 (49.7)

Mean (SD) age, years 56.3 (9.0) 56.4 (9.5) 55.8 (9.2)

Race, n (%)*WhiteBlack or African American AsianOther†

322 (66.8) 22 (4.6) 93 (19.3) 45 (9.3)

323 (66.9) 20 (4.1) 99 (20.5) 41 (8.5)

333 (68.7)18 (3.7)93 (19.2)41 (8.5)

Mean (SD) BMI, kg/m2 30.9 (5.5) 31.0 (5.3) 31.2 (5.4)

Mean (SD) HbA1c, % 7.8 (0.8) 7.8 (0.8) 7.8 (0.8)

SD, standard deviation; BMI, body mass index.*Percentages may not total 100.0% due to rounding.†Includes American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, multiple, and other.

Cefalu WT et al. Lancet. 2013; 382(9896):941-50. Cefalu WT et al. Poster presented ADA 2013 Chicago, Illinois, (65-LB).

Add on to Metformin vs Glimepiride (DIA3009): Change in HbA1c (MMRM)*

74

GLIM CANA 100 mg CANA 300 mg

0 8 12 18 26 36 44 52

Time point (wk)

Baseline (%)

64 78 88 104

LS meanchange

–0.68%

–0.58%

–0.38%–0.20%(95% CI: –0.34, –0.06)

–0.30%(95% CI: –0.44, –0.16)

7.8 7.8 7.8

*Mixed-Effect Model Repeated Measure Model

–1.2

–1.0

–0.8

–0.6

–0.4

–0.2

0

LS m

ean c

hange (±

SE)

from

baseline (

%)

104 week data

Cefalu WT et al. Poster presented ADA 2013 Chicago, Illinois, (65-LB).

• Both CANA doses showed a reduction in HbA1c vs GLIM at 104 weeks when

assessed using MMRM

Add on to Metformin vs Glimepiride (DIA3009): Proportion of Subjects With Documented HypoglycaemiaEpisodes Through Weeks 52 and 104

76

40.9

6.8 8.2

0

20

40

60

80

100

Perc

enta

ge o

f subje

cts

104 week data

Cefalu WT et al. Lancet. 2013; 382(9896):941-50. Cefalu WT et al. Poster presented ADA 2013 Chicago, Illinois.

34

6 5

0

20

40

60

80

100

GLIM

CANA 100 mg

CANA 300 mg

Perc

enta

ge o

f subje

cts

52 week data

Add on to Metformin vs Glimepiride (DIA3009): Percent Change in Body Weight (LOCF)*

77

LS m

ean %

change (

±SE)

from

baseline


0 8 12 18 26 36 44 52

Time point (wk)

Baseline (kg)

64 78 88 104

LS mean% change

–4.2%(–3.6 kg)

–4.1%(–3.6 kg)

0.9%(0.8 kg)

–5.1% (95% CI: –5.6, –4.5)(–4.3 kg)([95% CI: –4.8, –3.8])

–5.2% (95% CI: –5.7, –4.6)(–4.4 kg)([95% CI: –4.9, –3.9])

86.6 86.8 86.6

4

*N = 1,450 (Baseline); N = 1,425 (Week 4); N = 1,436 (Week 8); N = 1,438 (Weeks 12, 18, 26, 36, 44, 52, 64, 78, 88, and 104).

–6

–5

–4

–3

–2

–1

0

1

2

104 week data


Add on to Metformin vs Glimepiride(DIA3009): Change in Systolic BP (LOCF)*

78

LS m

ean c

hange (

±SE)

from

baseline (

mm

Hg)


0 8 12 18 26 36 44 52

Time point (wk)

Baseline (mmHg)

64 78 88 104

LS meanchange

–3.1 mmHg

–2.0 mmHg

1.7 mmHg

–3.7 mmHg(95% CI: –5.2, –2.3)

–4.8 mmHg(95% CI: –6.2, –3.4)

129.5 130.0 130.0

4

Reductions in diastolic BP with CANA 100 and 300 mg and GLIM were –1.3, –2.2, and –0.02 mmHg, respectively, with no notable changes in pulse rate.

*N = 1,450 (Baseline); N = 1,429 (Week 4); N = 1,438 (Week 8); N = 1,440 (Weeks 12, 18, 26, 36, 44, 52, 64, 78, 88, and 104).

–6

–5

–4

–3

–2

–1

0

1

2

3

104 week data


Add on to Metformin vs Glimepiride (DIA3009): Summary of Overall Safety and Selected AEs Over 104 Weeks*

80Cefalu WT et al. Poster presented ADA 2013 Chicago, Illinois, (65-LB).

GLIM (n = 482)

CANA 100 mg (n = 483)

CANA 300 mg (n = 485)

Any AE 378 (78.4) 354 (73.3) 378 (77.9)

AEs leading to discontinuation 35 (7.3) 30 (6.2) 46 (9.5)

AEs related to study drug† 134 (27.8) 138 (28.6) 159 (32.8)

Serious AEs 69 (14.3) 47 (9.7) 47 (9.7)

Deaths 2 (0.4) 3 (0.6) 3 (0.6)

Genital mycotic infectionMale‡,§

Female|,¶

5 (1.9) 6 (2.7)

24 (9.5) 32 (13.9)

22 (9.1)38 (15.6)

Urinary Tract Infection (UTI) 33 (6.8) 51 (10.6) 42 (8.7)

Osmotic diuresis-related AEs# 10 (2.1) 28 (5.8) 32 (6.6)

Volume-related AEs** 11 (2.3) 8 (1.7) 12 (2.5)

*All AEs are reported for regardless of rescue medication.†Possibly, probably, or very likely related to study drug, as assessed by investigators.‡GLIM, n = 263; CANA 100 mg, n = 252; CANA 300 mg, n = 241.§Including balanitis, balanitis candida, balanoposthitis, genital candidiasis, genital infection fungal, and posthitis.|GLIM, n = 219; CANA 100 mg, n = 231; CANA 300 mg, n = 244.¶Including genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, and vulvovaginitis.#Including dry mouth, micturition urgency, nocturia, pollakiuria, polydipsia, polyuria, thirst, and urine output increased.**Including BP decreased, dehydration, dizziness postural, hypotension, orthostatic hypotension, presyncope, and syncope.

Canagliflozin Head to Head StudiesAdd-on to MET Study: Canagliflozin vs Sitagliptin (DIA3006)

82

Screening Visit

Week–2

Day 1Baseline

AHA Adjustment Period Start

• On protocol-specified doses of MET• A1C ≥7% and ≤10.5%

Week52

CANA 300 mg

SITA 100 mg

PBO

A1C≥7% and ≤10.5%

R

SITA 100 mg

SITA 100 mg

CANA 300 mg

Week26

CANA 100 mg CANA 100 mg

• On below protocol-specified doses of MET• A1C ≥7.5% and ≤11%

1. Titrate MET (up to 2 weeks)

2. Stable MET dose (8 weeks)

• On MET/SU• A1C ≥6.5% and ≤9.5%

Add-on to MET vs Sitagliptin (DIA3006): Study Design

Pretreatment PeriodPBO/Active-

controlled, Double-blind Treatment Period

Active-controlled, Double-blind

Treatment Period

PBO

Continue stable protocol-specified dose of MET

2-week, single-blind PBO

run-in

Discontinue SU

83

Lavalle González, et al. Poster presented at ADA 2013 Chicago, Illinois,

Lavalle-González FJ et al. Diabetologia. 2013 Sep 13. [Epub ahead of print]

Add-on to MET vs Sitagliptin (DIA3006): Baseline Characteristics

Lavalle González, et al. Poster presented at ADA 2013 Chicago, Illinois,

Lavalle-González FJ et al. Diabetologia. 2013 Sep 13. [Epub ahead of print]

Characteristic PBO/SITA(n=183)

SITA 100 mg(n=366)

CANA 100 mg (n=368)

CANA 300 mg

(n=367)

Sex, n (%)MaleFemale

94 (51.4)89 (48.6)

172 (47.0)194 (53.0)

174 *47.3)194 (52.7)

165 (45.0)202 (55.0)

Age (years) 55.3 ± 9.8 55.5 ± 9.6 55.5 ± 9.4 55.3 ± 9.2

Race, n (%) †WhiteBlack or African

AmericanAsianOther ‡

129 (70.5)3 (1.6)

30 (16.4)21 (11.5)

264 (72.1)13 (3.6)41 (11.2)48 (13.1)

252 (68.5)16 (4.3)51 (13.9)49 (13.3)

256 (69.8)13 (3.5)60 (16.3)38 (10.4)

HbA1c (%) 8.0 (0.9) 7.9 (0.9) 7.9 (0.9) 7.9 (0.9)

FPG (mmol/L) 9.1 (2.1) 9.4 (2.3) 9.3 (2.3) 9.6 (2.5)

Body weight (kg) 86.6 (22.4) 87.7 (21.6) 88.8 (22.2) 85.4 (20.9)

BMI (kg/m2) 31.1 (6.1) 32.0 (6.1) 32.4 (6.4) 31.4 (6.3)

Duration of diabetes (years)

6.8 (5.3) 6.8 (5.2) 6.7 (5.4) 7.1 (5.4)

BMI, body mass index; CANA, Canagliflozin; SITA, sitagliptin; FPG, fasting plasma glucose; HbA1c, haemoglobin A1c; PBO, placebo; s.d., standard deviation.∗Data are mean (s.d.) unless otherwise indicated..

‡Including American Indian or Alaska Native, other, unknown and not reported for the main stud

Add-on to MET vs Sitagliptin (DIA3006):

Change in HbA1c

SITA 100 mg CANA 100 mg CANA 300 mg

Time point (wk)

LS m

ean c

hange (±

SE)

from

baseline (

%)

Baseline (%) 7.9 7.9 8.0

LS meanchange

0%(95% Cl: –0.12, 0.12)

–0.73%

–0.73%

–0.88%–0.15%(95% Cl: –0.27, –0.03)

0 6 12 18 26 34 42 52

0.2

0

–0.2

–0.4

–0.6

–0.8

–1.0

–1.2mITT, LOCF

Lavalle González FJ et al. Data presented ADA 2013; Chicago, Illinois.Lavalle-González FJ et al. Diabetologia. 2013 Sep 13. [Epub ahead of print]

• CANA 100 and CANA 300 mg demonstrated non-inferiority to SITA 100 mg in HbA1c-lowering;

• CANA 300 mg showed statistical superiority to SITA 100 mg in HbA1c-lowering


Change in FPG


LS m

ean c

hange (±

SE)

from

baseline (

mm

ol/

L)

Baseline (mmol.L) 168.9 168.6 172.7

LS mean change

–0.5 mmol/LP <0.001

–1.0 mmol/LP <0.001

–1.0 mmol/L

–1.5 mmol/L

–2.0 mmol/L

Time point (wk)

0 6 12 18 26 34 42 52

0

–0.5

–1.0

–1.5

–2.0

–2.5

mITT, LOCF



Percent Change in Body WeightLS m

ean %

change (±

SE)

from

baseline

Baseline (kg) 87.6 88.7 85.4

LS mean % change

–2.4% (–2.1 kg)P <0.001

–2.9% (–2.5 kg)P <0.001

–1.3%(–1.2 kg)

–3.8%(–3.3 kg)

–4.2%(–3.7 kg)

Time point (wk)

-5

-4

-3

-2

-1

0


0 6 12 18 26 34 42 52

–4

–5

–3

–2

–1

mITT, LOCF



Change in Systolic BP

• With CANA 100 and 300 mg and SITA 100 mg, LS mean changes from baseline in diastolic BP were −1.8, –1.8, and –0.3 mmHg, respectively

• No notable changes in pulse rate were observed across groups

LS m

ean c

hange (±

SE)

from

baseline (

mm

Hg)


–2

–4

–6

2

0

–8

Baseline (mmHg) 128.0 128.0 128.7

LS mean change

–2.9 mmHgP <0.001

–4.0 mmHgP <0.001

–0.7 mmHg

–3.5 mmHg

–4.7 mmHg

Time point (wk)

0 6 12 18 26 34 42 52

mITT, LOCF


Add-on to MET vs Sitagliptin (DIA3006): Summary of Overall Safety at 26 Weeks

Januszewicz A et al. Poster presented at DDG Congress; 2013; Leipzig, Germany.

Subjects, n (%)

PBO (n = 183)

CANA 100 mg(n = 368)

CANA 300 mg(n = 367)

SITA 100 mg(n = 366)

Any AE 107 (58.5) 225 (61.1) 204 (55.6) 202 (55.2)

AEs leading to discontinuation 7 (3.8) 18 (4.9) 12 (3.3) 7 (1.9)

Serious AEs 4 (2.2) 12 (3.3) 10 (2.7) 8 (2.2)

Genital mycotic infectionMale*.†

Female‡,§

1 (1.1)0

7 (4.0)17 (8.8)

4 (2.4)19 (9.4)

2 (1.2)2 (1.0)

Urinary tract infection 4 (2.2) 20 (5.4) 13 (3.5) 13 (3.6)

Osmotic diuresis-related AEsPollakiuria (increased frequency)Polyuria (increased volume)

1 (0.5)0

21 (5.7)2 (0.5)

10 (2.7)2 (0.5)

2 (0.5)0

Volume-related AEsPostural dizzinessOrthostatic hypotension

1 (0.5)0

1 (0.3)0

01 (0.3)

00

Hypoglycaemia episodesǀ 3 (1.6) 16 (4.3) 17 (4.6) 5 (1.4)

*PBO, n = 94; CANA 100 mg, n = 174; CANA 300 mg, n = 165; SITA 100 mg, n = 172.†Including balanitis, balanitis candida, balanoposthitis, and genital infection fungal (based on a pre-specified list of terms).‡PBO, n = 89; CANA 100 mg, n = 194; CANA 300 mg, n = 202; SITA 100 mg, n = 194.§Including vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, and vulvovaginitis (based on a pre-specified list of terms).ǀIncludes episodes that were either biochemically documented (≤3.9 mmol/L) or reported as severe by the investigator.

Management of Hyperglycemia in

Type 2 Diabetes - 2015

A Patient-Centered Approach

Update to a Position Statement of the American Diabetes

Association (ADA) and the European Association for the Study of

Diabetes (EASD)

Diabetes Care 2015;38:140–149

Diabetologia 2015;10.1077/s00125-014-3460-0

Inzucchi SE, Bergenstal RB, Buse JB, Diamant M, Ferrannini E,

Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR

Healthy eating, weight control, increased physical activity & diabetes education

Metformin high low risk

neutral/loss

GI / lactic acidosis

low

If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione

intermediate low risk

neutral

rare

high

DPP-4 inhibitor

highest high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+ SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

or

or

or

GLP-1-RA

high low risk

loss

GI

high

GLP-1 receptor agonist

Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor


loss

GU, dehydration

high

SU

TZD

Insulin§


+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:

Metformin +

Combination injectable therapy‡

GLP-1-RA Mealtime Insulin

Insulin (basal)

+

Figure 2. Anti-hyperglycemic therapy in T2DM: General recommendations

Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0



neutral/loss


low


Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione


neutral

rare

high

DPP-4 inhibitor

highest high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+ SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

or

or

or

GLP-1-RA

high low risk

loss

GI

high


Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor


loss

GU, dehydration

high

SU

TZD

Insulin§


+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i



Metformin +



Insulin (basal)

+





neutral/loss


low


Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione


neutral

rare

high

DPP-4 inhibitor

highest high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+ SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

or

or

or

GLP-1-RA

high low risk

loss

GI

high


Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor


loss

GU, dehydration

high

SU

TZD

Insulin§


+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i



Metformin +



Insulin (basal)

+





neutral/loss


low


Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione


neutral

rare

high

DPP-4 inhibitor

highest high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+ SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

or

or

or

GLP-1-RA

high low risk

loss

GI

high


Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor


loss

GU, dehydration

high

SU

TZD

Insulin§


+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i



Metformin +



Insulin (basal)

+




neutral/loss


low


Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione


neutral

rare

high

DPP-4 inhibitor

highest high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+ SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

GLP-1-RA

high low risk

loss

GI

high


Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor


loss

GU, dehydration

high

SU

TZD

Insulin§


+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i



Metformin +



HbA1c≥9%

Me orminintoleranceorcontraindica on

Uncontrolledhyperglycemia

(catabolicfeatures,BG≥300-350mg/dl,HbA1c≥10-12%)

Insulin (basal)

+

or

or

or


103

•BACK UP on Safety and Tolerability

105

Summary of Safety and Tolerability

• Large Phase 3 program with >10,000 subjects randomized

– Substantial proportion of vulnerable individuals studied

• Overall well tolerated at both doses of canagliflozin

– Low rate of discontinuations due to adverse events (AEs)

– Incidence of serious AEs and deaths comparable to control

– Safety and tolerability profile similar across range of eGFR

(>30 mL/min/1.73 m2)

• Genital mycotic infections

• Urinary tract infections

• Other Adverse events of interest

Summary of Adverse Drug Reactions≥2% and >Placebo in the Placebo-controlled Studies Dataset

PlaceboN=646n (%)

CANA 100 mgN=833n (%)

CANA 300 mgN=834n (%)

Gastrointestinal Disorders

Constipation 6 (0.9) 15 (1.8) 19 (2.3)

Thirst 1 (0.2) 23 (2.8) 19 (2.3)

Renal and Urinary Disorders

Polyuria or pollakiuria 5 (0.8) 44 (5.3) 38 (4.6)

Urinary tract infection 26 (4.0) 48 (5.8) 36 (4.3)

Reproductive System and Breast Disorders

Balanitis or balanoposthitis 2 (0.6) 17 (4.2) 15 (3.7)

Vulvovaginal candidiasis 10 (3.2) 44 (10.4) 49 (11.4)

Other ADR’s: Hypotension, Impaired renal function, Hypoglycemia with concomitant insulin or insulin secretatgoues, Hypersensitivty reactions, Increased LDL-C, Pancreatitis, Bone fractures Increases in: Potassium, Magnesium, Phosphate, and Hemoglobin

Documents

Ueda2015 canagliflozin dr.inass shaltout