NEW TREATMENT OPTIONS IN INDIVIDUALIZED TYPE 2 DIABETES MELLITUS MANAGEMENT

TARGETING THE KIDNEY TO REDUCE HYPERGLYCAEMIA

Richard Yazbeck, MD Endocrinologist

Lebanese Hospital (Geitaoui)

11/26/2016

Disclosures: Richard Yazbeck, MD

Advisor or consultant: AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi-aventis, Eli Lilly…

Speaker: AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi-aventis, Janssen,…

Presentation Objectives

Pathogenesis of type 2 diabetes

Understand the role of the kidney in type 2 diabetes

Review the mechanism of action for Canagliflozin

Update about the latest guidelines in treating T2DM

Review the efficacy and safety profile for

Canagliflozin in the treatment of type 2 diabetes

3

*Conceptual representation. Adapted with permission from Ramlo-Halsted et al. Prim Care. 1999;26:771–789.

Development and Progression of Type 2 Diabetes

Almost 50% of ß cells not functioning upon diagnosis

Progression of Disease

Impaired Glucose Tolerance

Insulin level

Insulin resistance

Hepatic glucose

production

Diabetes Diagnosis

Postprandial

glucose

Fasting glucose

β-cell function

Frank Diabetes

4–7 years

0

50

100

Re

lati

ve %

Liver

Pancreas Gut

Muscle

Hyperglycemia

Adipose tissue

Glucose uptake

FFA output

Insulin secretion

carbohydrate

absorption

Hepatic

glucose

output

Glucose uptake

Insulin Resistance

Type 2 Diabetes Pathophysiology

Glucose

reabsorption

Neurotransmitters

dysfunction

Neurons

Kidneys

GLP-1

Pancreas

Glucagon

secretion

Incretin

effect

The“ominous octet“of factors which are responsible for the pathophysiologic

disturbances of type 2 diabetes

(Frightful)

Visceral Fat Distribution: Normal vs Type 2 Diabetes

Normal Type 2 Diabetes

The Adipose tissue as an Endocrine organ

Adipose

tissue

Leptin

Adiponectin PAI-1

HB-EGF

TNFα Resistin

FFA

IL-1b, IL-6, IL-8

IL-18, TGFb TNFα

Adpsin Complement

factors

Agiotensinogen

Energy balance, Reproduction

Hypertension

Lipid

Metabolism

Cardiovascular

diseases

Coagulation Factors

PAI-1, TF

Glucose

Metabolism

LPL, CETP, Apo E Acylation

stimulating factor Immune

function

Unknown factors

Reproduction

Androgen Estrogen

Leptin

Adapted from Nutrition and Health: Nutrition and Metabolism . Christos S.Mantzoros, 2009

Weight loss in diabetes provides multiple clinical benefits

Norris SL, et al. Arch Intern Med. 2004;164(13):1395-1404.

BP reductions as little as 2 mmHg reduce the risk of CV events by up to 10%¹

Steno-2: intensive multifactorial therapy associated with improved outcomes

Multi-target Approach (The Steno Model)

Cumulative Incidence of Any Cardiovascular Event (%)

80

70

60

40

30

10

50

20

0

Conventional therapy

Intensive therapy

Years

0 1 2 3 4 5 6 7 8 9 10 12 13

Cu

mu

lati

ve in

cid

en

ce o

f

an

y C

V e

ven

t (%

)

11

Adapted from Gaede P, et al. N Engl J Med 2008; 358:580–591.

HR 0.41 (95% CI 0.25–0.67); P < 0.001 at 13.3 years

• Brain ~125 g/day

• Rest of the body ~125 g/day

Glucose uptake ~250 g/day:

−

• Dietary intake ~180 g/day

• Glucose production ~70 g/day

• Gluconeogenesis

• Glycogenolysis

Role of the kidneys in T2D Normal glucose homeostasis1,2

1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18; 2. Gerich, JE. Diabetes Obes Metab 2000;2:345–50.

+

Net balance ~0 g/day

Glucose input ~250 g/day:

The kidney filters

circulating glucose

Glucose filtered

~180 g/day Glucose reabsorbed

~180 g/day

The kidney reabsorbs

and recirculates

glucose

Usual RTG in healthy subjects reported to be approximately 10 mmol/L (180mg/dL)

U

rin

ary G

luco

se

Excreti

on

(g/d

)

0

100

50

25

0

Plasma Glucose (mmol/L)

150

75

125

14 12 10 8 6 4 2

Below RTG Minimal Glucosuria Occurs

Above RTG Glucosuria Occurs

Healthy RTG

~10 mmol/L

THE RENAL GLUCOSE THRESHOLD (RTG) CONCEPT

RTG, renal threshold for glucose excretion. Polidori D et al. 2010. Presented at: European Association for the Study of Diabetes. September 20-24, 2010; Stockholm, Sweden

(180mg/dL)

• Dietary intake >180 g/day

• Glucose production ~100 g/day

• Gluconeogenesis*

• Glycogenolysis

Glucose input >280 g/day:

• Brain ~125 g/day

• Rest of the body >125 g/day

Glucose uptake >250 g/day:

Glucose handling in Type 2 diabetes

− Increased reabsorption

and recirculation of

glucose

Average blood glucose

concentration 150 mg/dL

Kidney filters all

circulating glucose

Above the renal threshold for

glucose (~200 mg/dL), glucose is

excreted in the urine (glucosuria)

+

Glucose filtered

~270 g/day

*Elevated glucose production in patients with Type 2 diabetes attributed to hepatic and renal gluconeogenesis.2

1. Gerich JE. Diabet Med 2010;27:136–42; 2. Abdul-Ghani MA, DeFronzo RA. Endocr Pract 2008;14:782–90.

Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559.

Increased SGLT-2 expression

Glucose directly stimulates hepatocyte nuclear factor-1 alpha

Hepatocyte nuclear factor-1 alpha is a direct promoter of the SGLT-2 gene

This increased SGLT-2 activity results in greater glucose and sodium reabsorption

Upregulation of SGLT-2 activity in Hyperglycaemic state

New Pathophysiologic defect in T2D

Osorio H, et al 2010 J Nephrol;23:541-546 Freitas HS, et al 2008 Endocrinology;149:717-724

Sodium- Glucose Cotransporters

SGLT1 SGLT2

Site Mostly intestine with some kidney

Almost exclusively kidney

Sugar Specificity Glucose or galactose Glucose

Affinity for glucose High Km= 0.4 Mm

Low Km = 2 Mm

Capacity for glucose transport

Low High

Role Dietary glucose absorption Renal glucose reabsorption

Renal glucose reabsorption

Lee YJ, at al. Kidney Int Suppl. 2007;72:S27-S35.

SGLT2 is a sodium glucose cotransporter1,2

SGLTs transfer glucose and sodium from the lumen into the cytoplasm of tubular cells through a secondary active transport mechanism

Na+:glucose coupling ratio for SGLT1 = 2:1 and for SGLT2 = 1:1

ATP, adenosine triphosphate; GLUT, glucose transporter; SGLT, sodium glucose cotransporter. 1. Wright EM, et al. Physiology. 2004;19:370–376. 2. Bakris GI, et al. Kidney Int. 2009;75:1272–1277.

Figure adapted from Mather A, Pollock C. Kidney Int Suppl. 2011;120:S1–S6.

Segment S1–2 Basolateral membrane

GLUT2 SGLT2

Glucose

Na+

Glucose

Na+

Glucose

Na+

K+ K+

Na+/K+ ATPase pump

Lateral intercellular space

Uri

na

ry

Glu

cose

Ex

cre

tio

n

(g/d

ay)

0

75

100

50

150

Plasma Glucose (mmol/L)

125

25

4 6 8 16 10 14

Below RTG minimal glucosuria occurs

12

Healthy RTG

T2DM RTG

Above RTG glucosuria occurs

~13.8 mmol/L (248mg/dL)

~10 mmol/L

The Renal Glucose Threhold (RTG) is

Increased in Subjects with Type 2 Diabetes

RTG, renal threshold for glucose excretion.

Polidori D et al. 2010. Abstract 2186-PO. American Diabetes Association. June 25-29, 2010; Orlando, Florida.

Polidori D et al. 2010. Presented at: European Association for the Study of Diabetes. September 20-24, 2010;

Stockholm, Sweden.

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

(180mg/dL)

Isolated from apple tree bark (1835)

Inhibitor of SGLT1 and SGLT2a

Glycosuric effect (1886)

Renal actions identified in rat (1903) and man (1933)

Antidiabetic effect discovered (1987)

Phlorizin

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

SGLT2 Inhibitors From apple bark to an insulin-independent treatment option

aSGLT2, sodium-glucose cotransporter 2.

Selectively inhibiting SGLT2 cotransporters is key for efficacy and safety

Transporter Major site of action

Function Disease Associated with Malfunction

SGLT1

Small intestine, heart, trachea and kidney

Co-transports sodium, glucose and galactose across the brush border of the intestine and proximal tubule of the kidney

Congenital glucose-galactose malabsorption syndrome

SGLT2

Kidney

Co-transports sodium and glucose in the S1 segment of the proximal tubule of the kidney

Familial renal glucosuria

SGLT3

Small intestine, uterus, lungs, thyroid and testis

Transports sodium (not glucose)

Unknown

SGLT4

Small intestine, kidney, liver, stomach and lung

Transports glucose and mannose

Unknown

SGLT5 Kidney Unknown Unknown

SGLT6

Spinal cord, kidney, brain, and small intestine

Transports myo-inosotol and glucose Unknown

Bays H. Curr Med Res Opin. 2009;25:671–681.

SGLT2 inhibitors efficacy requires sufficient kidney function

•The efficacy of SGLT2 inhibitors is dependent on renal function1,2

• Efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment

•SGLT2 inhibitors are not recommended for use in patients with moderate-to-severe renal impairment (eGFR <60 mL/min/1.73 m2) *1

SGLT2 Reduced

glucose

reabsorption

Increased urinary

excretion of

excess glucose

(~70 g/day,

corresponding to

280 kcal/day*)

Proximal tubule

Glucose

filtration

GLIFLOZIN: A NOVEL INSULIN-INDEPENDENT APPROACH TO REMOVE EXCESS GLUCOSE1–3

*Increases urinary volume by only ~1 additional void/day (~375 mL/day) in a 12-week study of healthy subjects

and patients with Type 2 diabetes.4

1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35;

3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14–21; 4. Dapagliflozin. Summary of product

characteristics. Bristol-Myers Squibb/AstraZeneca EEIG, 2012.

SGLT2

Glucose

Gliflozin

Gliflozin

Canagliflozin selectively inhibits SGLT2 in the renal proximal tubule

U

rin

ary

Glu

cose

Ex

cre

tio

n (

g/d

)

0

100

50

25

0

Plasma Glucose (mmol/L)

150

75

125

14 12 10 8 6 4 2

Below RTG minimal glucosuria occurs

Above RTG glucosuria occurs

RTG RTG

Untreated healthy

SGLT2i-treated Untreated T2DM

SGLT2, sodium glucose co-transporter 2; RTG, renal threshold for glucose excretion; UGE, urinary glucose excretion.

Polidori D et al. 2010. Abstract 2186-PO. Presented at: American Diabetes Association. ADA 2010.

Polidori D et al. 2010. Abstract 875. Presented at: European Association for the Study of Diabetes. EASD 2010.

SGLT2 inhibition lowers RTG

Appreciable UGE occurs only when plasma glucose exceeds RTG

Healthy subjects

SGLT2 Inhibition Lowers RTG

5mmol/L (90mg/dl)

NAP1002: CANA treatment lowers plasma glucose concentrations throughout the entire day

Sha S, et al. 2010. Presented at American Diabetes Association. Orlando, Florida; 25-29 June 2010. Janssen Core Slides for the January 10, 2013 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee.

Available from: www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf. Accessed January 2014.

Example: CANA 100 mg treatment in subjects with T2DM

120

140

160

180

200

220

240

260

280

300 P

lasm

a g

luco

se (

mg

/dL

)

0 4 8 12 16 20 24

Time (hours)

Placebo (n = 19)

CANA 100 mg (n = 16)

CANA lowers fasting, postprandial, and 24-hour mean plasma glucose

Day 16

NAP1001: CANA doses > 200 mg reduced postprandial glucose and insulin more than explained by UGE1

Reductions in glucose and insulin observed only in first meal after dosing

Hypothesis: higher doses of CANA transiently inhibit intestinal SGLT1 during drug absorption

UGE, urinary glucose excretion. Sha S, et al. Diabetes Obes Metab. 2011;13:669-72.

Time (hours) 0 1 2 3 4

Plasma glucose (mg/dL)

80

90

100

110

120

130

140

150

160 Placebo CANA 100mg and 200mg CANA >200mg

Time (hours)

0 1 2 3 4

Serum insulin (µU/mL)

0

10

20

30

40

50

60

70

UGE0–2h (g)

0

1

2

3

4

5

6

7

100 mg and 200 mg

> 200 mg

Plasma glucose Serum insulin Urinary glucose

excretion

PERCENT CHANGE IN BODY WEIGHT LS m

ean %

change (±SE)

from

baseline

PBO CANA 100 mg CANA 300 mg

99.2 97.5 102.3 Baseline (kg)

–2.7%

(–2.7 kg)

–1.8%

(–1.9 kg)

0.0%

(0.0 kg)

–1.8% (95% CI: –2.7, –0.9)

(–1.9 kg [95% CI: –2.9, –1.0])

–2.7% (95% CI: –3.6, –1.8)

(–2.8 kg [95% CI: –3.7, –1.9])

Time point (wk)

LS mean

% change

Difference

vs PBO

0 18 12 6

1.0

–0.5

0.5

0

–1.0

–1.5

–2.0

–2.5

–3.0

–3.5

Rosenstock J et al. Poster presented at the 73rd Scientific sessions of the American Diabetes Association (ADA), 2013; Jun.

21-25; Chicago, Illinois, (P1084).

86.8 kg 87.2 kg 92.8 kg 94.1 kg 97.0 kg 97.0 kg 89.5 kg

DIA3005 + Diet/Ex

DIA3006 + MET

DIA3002 + MET/SU

DIA3012 + MET/Pio

DIA3008 + insulin

DIA3008 + SU

DIA3010 + Any

BODY WEIGHT RESULTS IN ANALYZED STUDIES*

% LS Mean Change from Baseline

-0.6

-1.0

-0.7

-0.1 -0.1-0.2

-0.1

-2.8

-3.5

-2.1

-2.8

-1.8

-0.6

-2.4

-3.8-3.9

-2.6

-3.8

-2.0

-2

-3.1

-4.5

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

Body w

eig

ht (%

)

PBO

CANA 100 mg

CANA 300 mg

P <0.05 vs

PBO for both CANA doses in all studies

except CANA 100 mg in

DIA3008 + SU

-1.0% -0.4% -0.5% -1.0% -0.6% -1.4% -0.7%

∆ 300 mg vs 100 mg

Baseline body weight

*Only studies enrolling patients with normal/mild chronic renal insufficiency are shown.

Stenlof et al. Diabetes Obes Metab. 2013;15(4):372-82. Lavalle-González FJ et al. Diabetologia. 2013 Sep 13. [Epub ahead of print] Wilding JP et al. Int J Clin Pract. 2013 Oct 13. [Epub ahead of print] Matthews D. et al. Poster presented at the 48th European Association for the Study of Diabetes (EASD);2012;Oct.1-5: Berlin, Germany, (P764). Bode B et al. Hosp Pract. 2013;41(2):72-84. Forst T et al. Poster presented at the 4th World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy), 2012;Nov.8-11; Barcelona, Spain, (P64). Fulcher G et al. Poster presented at the 73rd Scientific sessions of the American Diabetes Association (ADA), 2013; Jun. 21-25; Chicago, Illinois, (P1124).

1.06

-0.89 -1.12

1.02

-2.89 -2.51

-5

-4

-3

-2

-1

0

1

2

3

Ch

an

ge f

rom

ba

se

lin

e (k

g)

-5

-4

-3

-2

-1

0

1

2

CHANGES IN BODY COMPOSITION AND WEIGHT ACTIVE (GLIMEPIRIDE)-CONTROLLED ADD-ON TO METFORMIN STUDY (DIA3009)

Change in Body Composition (DXA Analysis Subgroup)

N=312

CANA 100 mg Glimepiride

CANA 300 mg

Weight Loss Over Time

LS

Mea

n %

Ch

an

ge

from

Base

lin

e ±

SE

Bo

dy

Wei

gh

t

Fat Mass Lean Mass Week BL 4 8 12 18 26 36 44 52

-5.7%*

(-4.7 kg)

BL Mean Body Weight (kg): 86.6

N =1450

* p <0.001 Based on ANCOVA model, data prior to rescue (LOCF)

CANA 300 mg CANA 100 mg Glimepiride

-5.2%*

(-4.4 kg)

Weight changes relative to glimepiride in DXA analysis subgroup (-5.3 kg and -5.0 kg for CANA 100 mg and 300 mg, respectively) were

similar to overall cohort.

52 week data

et al. Efficacy Sodium Glucose Co-Transporter 2 Inhibitor, Compared With Glimepiride in Patients With Type 2 Diabetes on Background Metformin presented at the 72nd American Diabetes Association (ADA) Scientific Sessions, which took place in Philadelphia, USA, from 8-12 June 2012

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

intermediate low risk

loss

GU, dehydration

high

SU

TZD

Insulin§

GLP-1 receptor agonist

+

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)

+

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

Phase III Canagliflozin Clinical Development Program: 9 Studies conducted in more than 10.000 patients

Monotherapy Dual Combination Triple Combination Insulin +/- oral(s)

Combo with MET vs GLIM (DIA3009)

52 / 52 wks N=1452

Combo with MET/SU vs SITA

(DIA3015) 52 wks N=756

Combo with INSULIN

(Substudy DIA3008) 18 wks N=1718

Combo with SU (Substudy DIA3008)

18 wks N=127

Monotherapy

(DIA3005)

26 / 26 wks N=587

Combo with MET/PIO (DIA3012)

26 / 26 wks N=344

Combo with MET/SU (DIA3002)

26 / 26 wks N=469

Pbo-control

Active-control

Studies in Special T2DM Populations Placebo-controlled studies / add-on to current diabetes treatment

Older Subjects - Bone Safety and Body Comp

(DIA3010) 26 / 78 wks N=716

Renal Impairment (DIA3004)

26 / 26 wks N=272

CV Safety Study (DIA3008: CANVAS)

Event-driven N=4330

Combo with MET vs SITA (DIA3006)

26 / 26 wks N=1284

HBA1C RESULTS IN PLACEBO-CONTROLLED STUDIES*

Change from Baseline

0.14

-0.17-0.13

-0.26

0.010.04

-0.03

-0.77 -0.79

-0.85-0.89

-0.63

-0.7

-0.6

-1.03

-0.95

-1.06-1.03

-0.72

-0.79

-0.73

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

A1c (

%)

PBO

CANA 100 mg

CANA 300 mg

-0.26% -0.16% -0.21% -0.14% -0.09% -0.09% -0.13% ∆ 300 mg vs 100 mg

8.01% 7.94% 8.13% 7.9%

8.27% 8.35% 7.7% Baseline A1C

DIA3005 + Diet/Ex

DIA3006 + MET

DIA3002 + MET/SU

DIA3012 + MET/Pio

DIA3008 + insulin

DIA3008 + SU

DIA3010 + Any

P <0.05 vs PBO for both CANA doses in all studies

*excluding the study in patients with chronic renal impairment

Stenlof et al. Diabetes Obes Metab. 2013;15(4):372-82. Lavalle-González FJ et al. Diabetologia. 2013 Sep 13. [Epub ahead of print] Wilding JP et al. Int J Clin Pract. 2013 Oct 13. [Epub ahead of print] Matthews D. et al. Poster presented at the 48th European Association for the Study of Diabetes (EASD);2012;Oct.1-5: Berlin, Germany, (P764). Bode B et al. Hosp Pract. 2013;41(2):72-84. Forst T et al. Poster presented at the 4th World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy), 2012;Nov.8-11; Barcelona, Spain, (P64). Fulcher G et al. Poster presented at the 73rd Scientific sessions of the American Diabetes Association (ADA), 2013; Jun. 21-25; Chicago, Illinois, (P1124).

HBA1C CHANGE FROM BASELINE OVER TIME ACTIVE (GLIMEPIRIDE)-CONTROLLED ADD-ON TO METFORMIN STUDY (DIA3009)

LS

Mea

n C

ha

ng

e fr

om

Base

lin

e ±

SE

Hb

A1c

(%)

BL 8 12 18 26 36 44 52

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

Weeks

52 week data

-0.12%

(95% CI: -0.217; -0.023)

-0.01%

(95% CI: -0.109; 0.085)

Glimepiride dose:

• Mean (median) of highest dose reached - 5.6 mg (6.0 mg)

• 82% of subjects on ≥4 mg/day

CANA 300 mg CANA 100 mg Glimepiride

Based on ANCOVA model, data prior to rescue (LOCF)

Baseline Mean HbA1c (%): 7.8 N = 1450

and Safety Sodium Glucose Co-Transporter 2 Inhibitor, Compared With Glimepiride in Patients With Type 2 Diabetes on Background Metformin presented at the 72nd American Diabetes Association (ADA) Scientific Sessions, which took place in Philadelphia, USA, from 8-12 June 2012

ADD-ON TO MET: CANAGLIFLOZIN VS GLIMEPIRIDE

Hypoglycaemic episodes were defined as biochemically documented with a glucose test reported of ≤3.9 mmol/L (70 mg/dL), or

severe hypoglycaemic events (requiring the assistance of another person, or with loss of consciousness or a seizure regardless of

whether biochemically documented).

When INVOKANA™ is used as add-on with insulin or an insulin secretagogue, a lower dose of insulin or the insulin secretagogue

may be considered to reduce the risk of hypoglycaemia

Incidence of Hypoglycemia with Canagliflozin vs Glimepiride at 104 Weeks

Canagliflozin Canagliflozin

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

42

LS m

ean %

change (±SE)

from

baseline

GLIM CANA 100 mg CANA 300 mg

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

Leiter L.A., et al. (2014). Diabetes Care. Sep 9. pii: DC_132762. [Epub ahead of print]

Canagliflozin

ADD-ON TO MET: CANAGLIFLOZIN VS SITAGLIPTIN

HbA1c Reductions with Canagliflozin

vs Sitagliptin at 52 Weeks

1. Lavalle-González FJ, Januszewicz A, et al. (2013). Diabetologia 2013; 56(12): 2582-2592.

Canagliflozin Canagliflozin

CANA 100 mg CANA 100 mg

CHANGE IN HBA1C (LOCF)

Time point (wk)

SITA 100 mg CANA 300 mg

0 6 12 18 26 34 42 52

LS mean

change

–1.03%

–0.66%

–0.37%

(95% CI: –0.50, –0.25)

Baseline (%) 8.1 8.1

–0.2

–0.4

–0.6

–0.8

–1.0

–1.2

–1.4

0

0.2

LS

mea

n c

han

ge

(±S

E)

fro

m b

asel

ine

(%)

LOCF, last observation carried forward ; SITA, sitagliptin; CANA, canagliflozin; LS, least squares; SE, standard error; CI, confidence

interval.

Schernthaner G. et al. Poster presented at the 4th World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy), 2012;Nov.8-11; Barcelona, Spain, (P70). Schernthaner G et al. Diabetes Care. 2013 Apr 5. [Epub ahead of print]

CANTATA D2 (DIA3015) Add-on to MET + SU vs Sitagliptin

SITA 100 mg CANA 300 mg

PERCENT CHANGE IN BODY WEIGHT (LOCF)

Baseline (kg) LS mean

% change 89.6 87.6

–2.5%

(–2.3 kg)

0.3%

(0.1 kg)

–2.8%

(–2.4 kg)

P <0.001

0 6 12 18 26 34 52

Time point (wk)

42 –4.0

–3.0

–2.0

–1.0

0

1.0

LS

mea

n %

ch

ang

e (±

SE

) fr

om

bas

elin

e

46

LOCF, last observation carried forward; SITA, sitagliptin; CANA, canagliflozin; LS, least

squares; SE, standard error.

Schernthaner G. et al. Poster presented at the 4th World Congress on Controversies to Consensus in Diabetes,

Obesity and Hypertension (CODHy), 2012;Nov.8-11; Barcelona, Spain,

(P70).Schernthaner G et al. Diabetes Care. 2013 Apr 5. [Epub ahead of print]

CANTATA D2 (DIA3015) Add-on to MET + SU vs Sitagliptin

CANVAS: ADD-ON TO BASAL INSULIN

Change in insulin dose defined as an increase or decrease of >15% from baseline for ≥7 consecutive days

Post-baseline mean daily insulin dose (prior to glycemic rescue) was unchanged for

93% of PBO-treated subjects 85% of subjects treated with CANA 100 mg 86% of subjects treated with CANA 300 mg

Majority of those receiving CANA had a decrease in insulin dose, whereas all of those receiving PBO had an increase.

Change in Insulin Dose

Daily insulin dose from baseline

Mean daily insulin dose at Week 18

CANA 100 mg -3.2 IU 53.3 IU

CANA 300 mg -2.4 IU 58.4 IU

Placebo +1.1 IU 60.4 IU

CHANGE IN HBA1C

LS, least squares; SE, standard error.

A higher proportion of subjects achieved A1C <7.0% with CANA 100 and 300 mg versus PBO (16%, 29%, and

6%, respectively) while required per protocol to remain on stable basal insulin therapy.

LS m

ean c

hange (±SE)

from

baseline (

%)

PBO CANA 100 mg CANA 300 mg

Baseline (%) 8.2 8.4 8.3 Baseline (%)

–0.79%

–0.76%

0.10%

–0.86%

(95% CI: –1.07, –0.65)

–0.89%

(95% CI: –1.09, –0.69)

Time point (wk)

LS mean

change

Difference

vs PBO

0 18 12

0.2

0

–0.2

–0.4

–0.6

–0.8

–1.0

Rosenstock J et al. Poster presented at the 73rd Scientific sessions of the American Diabetes Association (ADA), 2013;

Jun. 21-25; Chicago, Illinois, (P1084).

PERCENT CHANGE IN BODY WEIGHT LS m

ean %

change (±SE)

from

baseline

PBO CANA 100 mg CANA 300 mg

99.2 97.5 102.3 Baseline (kg)

–2.7%

(–2.7 kg)

–1.8%

(–1.9 kg)

0.0%

(0.0 kg)

–1.8% (95% CI: –2.7, –0.9)

(–1.9 kg [95% CI: –2.9, –1.0])

–2.7% (95% CI: –3.6, –1.8)

(–2.8 kg [95% CI: –3.7, –1.9])

Time point (wk)

LS mean

% change

Difference

vs PBO

0 18 12 6

1.0

–0.5

0.5

0

–1.0

–1.5

–2.0

–2.5

–3.0

–3.5

Rosenstock J et al. Poster presented at the 73rd Scientific sessions of the American Diabetes Association (ADA), 2013; Jun.

21-25; Chicago, Illinois, (P1084).

Additional benefits of weight loss and blood pressure reduction

Glycaemic control

Insulin-independent Approach to Treat hyperglycemia

low incidence for hypoglycaemia

Weight loss Blood pressure

reduction

F. Zaccardi, D. R. Webb, Z. Z. Htike, D. Youssef, K. Khunti& M. J. Davies Diabetes, Obesity and metabolism May 2016 doi:10.1111/dom.12670

Efficacy outcomes • HbA1c(%) reduction compared to placebo (38 RCTs)

-0,6% -0,6% -0,7% -0,7%

-0,8% -0,9%

-1,0%

-0,9%

-0,8%

-0,7%

-0,6%

-0,5%

-0,4%

-0,3%

-0,2%

-0,1%

0,0%

Dapa 5mg

Empa 10mg

Dapa 10mg

Empa 25mg

Cana 100mg

Cana 300mg

Mean baseline A1c 8.1%

F. Zaccardi, D. R. Webb, Z. Z. Htike, D. Youssef, K. Khunti& M. J. Davies Diabetes, Obesity and metabolism May 2016 doi:10.1111/dom.12670

Compared to placebo, all SGLT2 inhibitors : The highest dose of CANA reduced HbA1c, FPG, and SBP to a greater extent compared to DAPA and EMPA at any dose

Cardiovascular outcomes of gliflozin

The multicentre trial to evaluate the effect of Dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI 58) April 2019 / 17276

Canagliflozin cardiovascular assessment study (CANVAS) June 2017 / 4411

are the two large scale studies which are currently ongoing and assessing the impact of SGLT 2 inhibitors on the CV risk for MACE

Canagliflozin CANVAS Study

• Aim: To assess CV safety of canagliflozin in adult patients with T2DM and elevated CV risk

• 1:1:1 randomization to Cana 100 mg, Cana 300 mg or PBO

• Due to report in 2017

Study design

• 4330 T2DM patients

• History of prior CV event or ≥2 risk factors for a CV event Patient population

• Primary: Major adverse cardiovascular events, including CV death, nonfatal myocardial infarction (MI), and nonfatal stroke

• Secondary: Progression of albumin in the urine, standard measure of fasting insulin secretion

• The data from this study will be combined with the data from CANVAS-R study in a pre-specified meta-analysis of CV safety outcomes to satisfy US FDA post-marketing requirements for canagliflozin

Study endpoints

Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value

3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382

CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001

Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189

Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638

4-point MACE 599/4687 333/2333 0.89 (0.78, 1.01)* 0.0795

0,25 0,50 1,00 2,00

3-point MACE and 4-point MACE

Favours empagliflozin Favours placebo

Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction

*95.02% CI

This article was published on September 17, 2015, at NEJM.org

CV RISK FACTOR CHANGES WITH CANAGLIFLOZIN

Changes in fasting lipids Increases in HDL-C

No change in LDL-C/HDL-C ratio

Decreases in TG

Increases in LDL-C Smaller increases in non-HDL-C, Apo B, LDL particle number

Decreases in systolic and diastolic blood pressure

Improved glycemic control

Decrease in body weight

KAPLAN-MEIER PLOT OF TIME TO FIRST FEMALE GENITAL MYCOTIC INFECTION

02468

101214161820222426

Estim

ate

d %

of subje

cts

with a

n e

vent

Time (weeks)0 6 12 18 26 52 78

All non-CANA

CANA 100 mg

CANA 300 mg

1,338 1,312 1,250 1,209 1,135 993 443

1,289 1,217 1,143 1,087 1,034 908 421

1,319 1,243 1,153 1,101 1,036 945 440

All non-CANA CANA 100 mg CANA 300 mg

Population 2: 8 placebo and active controlled trials (mean treatment duration>64 weeks)

-No detrimental effect on renal function over 2 years

- Improvement in the albuminuria category

Safety and Tolerability Profile

Effect of canagliflozin and glimepiride on eGFR

-12

-10

-8

-6

-4

-2

0

0 26 52 78 104

Ch

ang

e in

eG

FR

(mL

/min

/1.7

3m2)

Time (weeks)

Glimepiride

Canagliflozin 100 mg

Canagliflozin 300 mg

2.7 ml/min

(1.5 – 3.9)

Least

square

mean

1.5 ml/min

(0.3 – 2.7)

Heerspink et.al. J Am Soc Nephrol 28: 2016

Effect of canagliflozin and glimepiride on albuminuria

Overall population UACR ≥ 30 mg/g

-15

-10

-5

0

5

10

15

20

0 26 52 78 104

Ch

ang

e in

UA

CR

(%

)

Time (weeks)

Glimepiride

Canagliflozin 100 mg

Canagliflozin 300 mg

Least

square

mean

-70

-60

-50

-40

-30

-20

-10

0

10

0 26 52 78 104

Ch

ang

e in

UA

CR

(%

)

Time (weeks)

Glimepiride

Canagliflozin 100 mg

Canagliflozin 300 mg

Least

square

mean

Heerspink et.al. J Am Soc Nephrol 28: 2016

- When SGLT2 inhibitors are combined with insulin, it is often necessary to decrease the insulin dose to avoid hypoglycemia

The lower dose of insulin may be insufficient to suppress lipolysis and ketogenesis

- SGLT2 is expressed in pancreatic α-cells, and SGLT2 inhibitors promote glucagon secretion

-Phlorizin, a nonselective inhibitor of SGLT family transporters decreases urinary excretion of ketone bodies. A decrease in the renal clearance of ketone bodies could also increase the plasma ketone body levels.

- Volume depletion

SGLT2 inhibitors trigger multiple mechanisms that could predispose to diabetic ketoacidosis

S I Taylor , JCEM , Published Online: June 18, 2015

Bone Fractures:

No meaningful changes in mineral homeostasis (phosphate, Ca, Vit D, Mg)

No SGLT2 receptors in bone

CANVAS (CANA 4.0% vs PBO 2.6%)

In pooled non-CANVAS studies (CANA 1.7% vs non- CANA 1.5%)

May be mediated by falls related to volume depletion Caution in high risk patients

- older

- history/risk of CVD

- moderate renal impairment

- higher baseline diuretic use

Alba M et al. Curr Med Res Opin. 2016 May 6:1-11

Important Safety Information

INVOKANA™ (canagliflozin) Tablets, International Package Insert (US Indication), 24 JAN 2014, Version 04, Based on CCDS dated 09 JAN 2014

CANAGLIFLOZIN DOSE RECOMMENDATIONS

SGLT 2 Inhibition: Meeting Unmet Needs in Diabetes Care

Lowers TRIG Increases HDL

Reduces HbA1c

Promotes Weight Loss

Complements Action of Other

Antidiabetic Agents

Reduces Blood

Pressure No

Hypoglycemia

Improves Glycemic Control

and CVRFs

Reversal of Glucotoxicity

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