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EDUCATIONAL SLIDE MODULES - PPT Presentation

Module D Evaluating CV safety and potential for CV risk reduction with newer T2D agents ACROSS T2D educational slide modules 2 3 Ongoing CVOTs DPP4 inhibitors GLP1 receptor agonists SGLT2 inhibitors ID: 809967

placebo mace diabetes met mace placebo met diabetes years 2013 2015 baseline add risk pbo endpoint care fatal data

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Slide1

EDUCATIONAL SLIDE MODULES

Module D:

Evaluating CV safety and potential for CV risk reduction with newer T2D agents

Slide2

ACROSS T2D educational slide modules

2

Slide3

3

Ongoing CVOTs

DPP4 inhibitors

GLP1 receptor agonists

SGLT2 inhibitors

Completed and ongoing CVOTs

Slide4

A closer look at CV effects of 21st century

T2D agents

4

Adapted from 1. Kirby.

Br

J Diabetes

Vasc

Dis

 

2012;12:315–20

.

2. Lantus® SPC. FDA 2015.19501960

1970198019902000

2010

2012

2013

Lente class of insulins produced

SUs first used

Metformin introduced in the UK

Recombinant human insulin produced

2nd generation SUs available

Three new classes introduced:

-glucosidase inhibitors, meglitinides and TZDs

Glimepiride:

3rd generation SU

DPP4 inhibitors

GLP1 receptor agonists

SGLT2 inhibitors

Insulin

degludec

Older T2D agents

Newer T2D agents

Insulin glargine

available

2

Slide5

CV safety trials are being conducted for each compound within the newer classes

5

Timings represent estimated completion dates as per ClinicalTrials.gov.

Adapted from Johansen. World J Diabetes

2015;6:1092–96. (references 1–19

expanded in slide notes

)

CANVAS-R

8

(n = 5700)

Albuminuria

2013

2014

20152016

2017

2018

2019

SAVOR-TIMI 53

1

(n = 16,492)

1,222 3P-MACE

EXAMINE

2

(n = 5380)

621 3P-MACE

TECOS

4

(n = 14,724)

≥ 1300 4P-MACE

LEADER

6

(n = 9340)

≥ 611 3P-MACE

SUSTAIN-6

7

(n = 3297)

3P-MACE

DECLARE-TIMI 58

15

(n = 17,150)

≥ 1390 3P-MACE

EMPA-REG OUTCOME®

5

(n = 7034)

691 3P-MACE

CANVAS

10

(n = 4365)

≥ 420 3P-MACE

CREDENCE

17

(n = 3700)

Renal

+ 5P-MACE

CAROLINA

®

11

(n =

6000)

≥ 631 4P-MACE

ITCA CVOT

9

(n = 4000)

4P-MACE

EXSCEL

14

(n = 14,000)

≥ 1591 3P-MACE

DPP4 inhibitor CVOTs

SGLT2 inhibitor CVOTs

GLP1 CVOTs

Ertugliflozin

CVOT

18

(n = 3900)

3P-MACE

OMNEON

13

(n = 4000)

4P-MACE

CARMELINA

12

(n = 8300)

4P-MACE

+

renal

REWIND

16

(n = 9622)

≥ 1067 3P-MACE

2021

ELIXA

3

(n = 6068)

≥ 844 4P-MACE

HARMONY Outcomes

19

(n = 9400) 3P-MACE

Slide6

6

Slide7

DPP4 inhibitors: Mechanism of action

Adapted

from

Drucker.

Expert

Opin

Invest

Drugs 2003;12:87–100

and

Ahrén Curr Diab Rep. 2003;3:365–372.

Food intake

Glucose-dependent insulin secretion

Increases glucose

utilisation

by muscle and adipose tissue

Decreases hepatic glucose release improving overall glucose control

Glucose-dependent glucagon suppression

β

-cells

α-cells

DPP4

Active

GLP1

(

7-36)

Inactive

GLP1

(9-36)

amide

2

amino acids

cleaved from

amino terminus

Pancreas

DPP4 inhibitors

Intestine

7

Slide8

Selected mechanistic trials indicate potential CV effects of the DPP4 inhibitor class

8

1. Ye et al. Am J

Physiol

Heart

Circ

Physiol 2010;298:H1454–65. 2. Hocher

et al. Int J

Cardiol 2013;167:87–93. 3. van Poppel et al. Diabetes Care 2011;34:2072–77. 4. Kröller-Schön et al. Cardiovasc

Res 2012;96:140–9. 5. Ta et al. J Cardiovasc Pharmacol 2011;58:157–66. 6. Sauvé et al. Diabetes 2010;59:1063–73.

7. Read et al. Circ Cardiovasc Imaging 2010;3:195–201. 8. Matikainen et al. Diabetologia 2006;49:2049–57.

Endothelialfunction3

Atherosclerotic plaque volume5

Left

ventricular

function

6,7

Myocardial

infarct size

1,2

Triglycerides

8

Inflammation and

oxidative stress

4

Slide9

*Ongoing.

1.

Scirica et al. N

Engl

J Med 2013;369:1317–26. 2. White et al. N

Engl

J Med 2013;369:1327–35. 3. Green et al. N Engl J Med 2015; DOI:

10.1056/NEJMoa1501352. 4. Marx et al. Diabetes Vasc Dis Res 2015;12:164–74. 5. NCT01897532. 6.

Scirica et al. Am Heart J 2011;162:818–25.e6. 7. Data on file (BI trial no. 1218.22 trial protocol). 8. NCT01243424.Summary of CV outcomes

trials with DPP4 inhibitors9

SAVOR-TIMI 531 EXAMINE2TECOS

3CAROLINA®4CARMELINA®5Intervention

Saxagliptin/ placeboAlogliptin/ placeboSitagliptin/ placeboLinagliptin/ glimepiride

Linagliptin/ placeboMain inclusion criteriaHistory of or multiple risk factors for CVDACS within 15–90 days before randomisationCVD≥ 2 specified traditional CV risk factors or manifest CVD

High risk of CV events (e.g. albuminuria,

prior CVD)

No. of patients

16,492

5380

14,671

6041

8300

Primary

outcome

3P-MACE

3P-MACE

4P-MACE

4P-MACE

4P-MACE

Key secondary outcome

Expanded MACE

4P-MACE

3P-MACE

3P-MACE

3P-MACE; renal composite

Target no.

of events

1040

6

650

1300

631

625

7

Median follow-up (y)

2.1

1.5

3.0

6–7*

4*

7

Estimated completion

Completed

Completed

Completed

2018

8

2018

Link to study design +

data

Link to study design +

data

Link to study design +

data

Link to study design + baseline data

Link to study design + baseline data

Slide10

DPP4 inhibitor CVOTs: baseline characteristics

10

Data are provided for the DPP4 inhibitor treatment arm. Mean values show unless otherwise indicated.

– indicates that the data are not reported.

*Median.

1.

Scirica

et al. N

Engl J Med 2013;369:1317–26. 2. White et al. N Engl J Med 2013;369:1327–35. 3. Green et al. N Engl J Med 2015;

DOI: 10.1056/NEJMoa1501352. 4. Marx et al. Diabetes Vasc Dis Res 2015;12:164–74. 5. NCT01897532.

SAVOR-TIMI 531 EXAMINE2TECOS

3CAROLINA®4CARMELINA®5

Mean age, years65.161.0*65.464.0

–% with prior MI38.087.542.7

13.8

% with prior HF

12.8

27.8

17.8

% with prior CVD

78.4

73.6

34.5

Diabetes

duration

, y

10.3*

7.3*

11.6

6.2*

HbA

1c

,%

8.0

8.0

7.2

7.2

Statin use, %

78.3

90.6

79.8

64.1

T2D therapy,

%

Naive

Metformin

SU

TZD

Insulin

4.1

69.9

40.5

6.2

41.6

Naive

Metformin

SU

TZD

Insulin

1.1

65.0

46.9

2.5

29.4

Naive

Mono

Dual

TZD

Insulin

47.7

51.4

23.5

Naive

Mono

Dual

TZD

Insulin

9.2

66.0

23.8

Ex.–

Slide11

Summary of completed DPP4 inhibitor CVOTS

11

*Upper boundary of 1-sided repeated CI.

1.

Scirica

et al

. N Engl J Med 2013;369:1317–26.

2. White et al. N Engl

J Med 2013;369:1327–35. 3. Green et al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352.

SAVOR-TIMI 53

1 Primary endpoint Hazard ratioCVD or CRFsHbA1c 6.5–12.0%n = 16,492Saxagliptin

Placebo3P-MACE

1.00(95% CI 0.89–1.12)p = 0.99(superiority)

2.1 year median follow-upEXAMINE2

ACS

HbA

1c

6.5–11.0%

n = 5380

Alogliptin

Placebo

3P-MACE

0.96

(upper CI

*

1.16)

p = 0.32

(superiority

)

1.5 year median follow-up

Randomisation

1

2

3 years of median follow-up

TECOS

3

CVD

HbA

1c

6.5–8.0%

n = 14,735

Sitagliptin

Placebo

4P-MACE

0.98

(95%

CI 0.89–1.08)

p = 0.65

(superiority)

3.0 year median follow-up

Slide12

12

Slide13

GLP1 has various potential effects on the CV system:

Data derived from non-clinical and mechanistic proof-of-concept studies

13

1. Jax. Clin Res Cardiol

2009;98:75–9. 2. Grieve. Br J Pharmacol 2009;157:1340–51 (modified).

3. Robinson et al. BMJ Open 2013;3:pii e001986.

Insulin sensitivity (direct or indirect?)

Insulin secretion

↓ Glucagon secretion↑ Insulin biosynthesis↑

β-cell proliferation↓ β -cell apoptosis↓ Appetite

↑ Neuroprotection

↓ Glucose output

Brain

Pancreas

Liver

Muscle

and

adipose tissue

↑ Endothelial function

↑ Nitric oxide production

↑ ↓ Myocardial

contractility (data conflict)

↑ Systolic function in myocardial infarction

↑ Systolic function in cardiomyopathy

↓ Infarct

size

Ischaemic pre-conditioning

Post-ischaemic

recovery

↑ Myocardial glucose uptake

Heart

Incretin hormone

1,2

Clinical trial data show that GLP1 receptor agonists are associated

with

small increases

in heart rate and modest reductions in body weight and blood

pressure

3

Slide14

Summary of CV outcomes trials with GLP1 receptor agonists

14

*Once weekly.

1. NCT01147250. 2.

Bentley-Lewis

et al. Am Heart J

2015;0:1-8.e7. 3. Marso

et al. Am Heart J 2013;166:823–30.e5. 4. NCT01720446. 5. NCT01144338. 6. NCT01394952. 7.

NCT02465515

 Intervention

Main inclusion criteriaNo. of patientsPrimary outcomeKey 2° outcomeTarget no.of events

Estimated follow-upEstimated completionELIXA1,2Lixisenatide/ placeboHistory of

ACS60684P-MACEExpanded MACE8442.1 years median

CompletedLEADER®3Liraglutide/ placeboVascular disease, or risk factors, or CRF, or CHF9340

3P-MACE

Expanded MACE

> 611

Up to ~5 years

Nov-15

SUSTAIN-6

™4

Semaglutide/ placebo

Evidence of CV disease

3297

3P-MACE

Expanded MACE

Not specified

Up to ~3 years

Jan-16

EXSCEL

5

Exenatide ER*/ placebo

No CV criteria specified

14,000

3P-MACE

All-cause mortality; HHF

Not specified

Up to ~7.5 years

Apr-18

REWIND

6

Dulaglutide

/ placebo

Pre-existing vascular disease or

2 CV risk factors

9622

3P-MACE

Microvascular composite

Not specified

Up to ~6.5 years

Apr-19

HARMONY OUTCOMES

7

Albiglutide/ placebo

Established CVD

9400

3P-MACE

Expanded MACE

Not specified

3–5

years

May-19

Link to study

+

baseline data

Link to study design + data

Slide15

Summary of ELIXA findings

15

1

.

Pfeffer

et al. ADA, 8 Jun 2015, Boston,

USA (oral presentation).

Randomisation

1

2

3 years of median follow-up

ELIXA1ACSHbA1c 5.5–11%n = 6068Placebo

4P-MACE 1.02(95% CI 0.89–1.17)

No difference in 4P-MACE

with lixisenatide vs placebo

HR

1.02

(95%

CI 0.89–1.17)

No

difference in HHF with lixisenatide vs placebo

HR 0.96 (95

%

CI 0.75–1.23)

No

difference in

CV

death + HHF with lixisenatide vs

placebo

HR 0.97 (95

% CI 0.82–1.16)

2.1 year median follow-up

Lixisenatide

Slide16

Summary of completed T2D CVOTS for newer T2D agents

16

*Upper boundary of 1-sided repeated CI.

1

.

Scirica

et al. N

Engl J Med 2013;369:1317–26. 2. White et al. N

Engl J Med 2013;369:1327–35. 3. Green et al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352. 4. Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).

SAVOR-TIMI 53

1 CVD or CRFsHbA1c 6.5–12.0%n = 16,492Saxagliptin

Placebo3P-MACE 1.00

(95% CI 0.89–1.12)p = 0.99

2.1 year median follow-upEXAMINE2

ACS

HbA

1c

6.5–11.0%

n = 5380

Alogliptin

Placebo

3P-MACE

0.96

(upper CI* 1.16)

p = 0.315

1.5 year median follow-up

Randomisation

1

2

3 years of median follow-up

TECOS

3

CVD

HbA

1c

6.5–8.0%

n = 14,735

Sitagliptin

Placebo

4P-MACE

0.98

(95%

CI

0.88–1.09

)

p = 0.645

(superiority)

3.0 year median follow-up

ELIXA

4

ACS

HbA

1c

5.5–11%

n = 6068

Placebo

4P-MACE

1.02

(95%

CI

0.89–1.17

)

2.1 year median follow-up

Primary endpoint

Hazard

ratio

Lixisenatide

Slide17

For the primary outcome, all completed CVOTs fall within the FDA mandated upper 95% CI limit of 1.3

17

*Upper boundary of 1-sided repeated

CI.

†Total event rate, %.

1.

Scirica et al

. N Engl J Med 2013;369:1317–26. 2. White et al. N

Engl J Med 2013;369:1327–35. 3. Green et al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352. 4. Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).

1.0

2.00.80.6HR (95% CI)

1.3FDA mandated upper 95% CI for CV safety

Number of events(event rate, % per 100 person-years)Placebo+ usual care

Comparator + usual care DPP4 inhibitor trials SAVOR-TIMI 531

609 (3.7%)

613 (3.7%)

GLP1 agonist trials

ELIXA

4

406 (13.4

%)

399 (13.2

%)

EXAMINE

2

316 (11.8%

)

305 (11.3%

)

TECOS

3

851 (4.17%)

839 (4.06%)

Favours comparator

Favours placebo

*

Slide18

Hospitalisation for heart failure (HHF) data for all completed CVOTs

18

Analysis 1 = as

component of

expanded MACE.

Analysis 2 =

as component of post-hoc composite

of

CV death and HHF.1. Scirica et al. N Engl

J Med 2013;369:1317–26. 2. White et al. N Engl J Med 2013;369:1327–35. 3. Green et al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352. 4. Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).

1.02.00.80.6

HR (95% CI)Number of events (%)

Placebo+ usual care Comparator + usual care

Favours comparatorFavours placebo

SAVOR-TIMI 53 (

HHF)

1

EXAMINE (HHF analysis 1)

2

EXAMINE (HHF analysis 2)

2

TECOS (HHF)

3

TECOS (HHF + CV death)

3

ELIXA (HHF)

4

ELIXA (HHF + CV

death)

4

228 (2.8)79 (2.9)

89 (3.3)229 (3.1)525 (7.2)

127 (4.2)253 (8.3)

289 (3.5)85 (3.1)106 (3.9)

228 (3.1)538 (7.3)122 (4.0)248 (8.2

)

Slide19

19

Slide20

Urinary glucose excretion via SGLT2 inhibition

1

20

1

.

Bakris

et al. Kidney Int 2009;75;1272–7.

SGLT2

SGLT2

inhibitor

SGLT1

SGLT2 inhibitors reduce glucose

reabsorption

in the proximal tubule, leading to

urinary glucose excretion

*

and osmotic diuresis

Filtered glucose load > 180 g/day

Slide21

Pharmacological properties of available

SGLT2 inhibitors

21

*For the 300 mg dose.

Data from http://www.ema.europa.eu/ (

Jardiance

SPC, Forxiga SPC , Invokana

PI, Invokana

SPC, all accessed June 2015); 1. Sha et al. Diab Obes Metab 2015;17:188–97.

 

EmpagliflozinDapagliflozinCanagliflozinTherapeutic dose (mg/day)Starting dose

10–25105–1010100–300100

AdministrationQDWith or without foodQDWith or without food

QDBefore first meal Peak plasma concentration (hours post-dose)1.5

Within 2

1–2

Absorption

(mean oral bioavailability)

≥ 60%

~ 78%

~ 65%

Metabolism

Primarily

g

lucuronidation - no active metabolite

Elimination

(half-life, hours)

Hepatic:renal

43:57

[12.4]

Hepatic:renal

22:78

[12.9]

Hepatic:renal 67:33

[13.1]*

Selectivity over SGLT1

1:5000

> 1:1400

>

1:160

1

Glucose

excretion

with

higher dose

(g/day)

78

~ 70

119

Link to SGLT2 clinical data

Slide22

 SNS

activity (?)

SGLT2 inhibitors modulate a range of factors

related to CV

risk

Based on clinical and mechanistic studies

22

Inzucchi

et al.

Diab

Vasc Dis Res 2015;12:90‒100.

 Weight Visceral adiposity

 Blood pressure Arterial stiffness

 Glucose Insulin

Albuminuria

Uric Acid

Novel

Pathways (?)

LDL-C

HDL-C

Triglycerides

Oxidative

stress

 SNS

activity (?)

Link to SGLT2 clinical data

Slide23

EMPA-REG OUTCOME

®

1

CANVAS

2

CANVAS-R

3

CREDENCE

4

DECLARE-

TIMI 585Ertugliflozin CVOT6InterventionsEmpagliflozin/ placeboCanagliflozin/

placeboCanagliflozin/placeboCanagliflozin/placebo

Dapagliflozin/ placeboErtugliflozin/placeboMain inclusion criteriaEst. vascular complications Est. vascular complications or ≥ 2 CV risk factors

Est. vascular complications or ≥ 2 CV risk factorsStage 2 or 3 CKD + macroalbuminuriaHigh risk for CV eventsEst. vascular complicationsNo. of patients70344339

5700

3627

17,150

3900

Primary outcome

3P-MACE

3P-MACE

Progression of albuminuria

ESKD,

S-creatinine doubling, renal/CV death

3P-MACE

3P-MACE

Key secondary outcome

4P-MACE

Fasting insulin secretion, progression of albuminuria

Regression of albuminuria, change in

eGFR

4P-MACE + HHF

4P-MACE + HHF +

revascularisation

4P-MACE

Target no.

of events

691

≥ 420

TBD

TBD

1390

TBD

Estimated median FU

~3 years

6–7 years

3 years

~4 years

4–5 years

5–7

years

Estimated completion

2015

Apr 2017

2017

2019

2019

2021

Summary of CV

outcome

trials with SGLT2

inhibitors

23

Adapted from Inzucchi et al. Diabetes

Vasc

Dis Res 2015;12:90

100. 1

. Zinman et al.

Cardiovasc

Diabetol

2014;13:102.

2. NCT01032629. 3. NCT01989754. 4. NCT02065791. 5. NCT01730534. 6. NCT01986881.

Link to study design

Link to study design

Link to study design

Link to study design

Link to study design

Will report

EASD 2015

Slide24

Patients

7034

Long-term CV safety of empagliflozin is being evaluated in a large, multicentre Phase IV trial (EMPA-REG OUTCOME

®

)

24

*Cumulative percentage for North America, Australia and New Zealand.

1.

Zinman

et al.

Cardiovasc Diabetol 2014;13:102. 2. NCT01131676.Countries

42592

Clinical sites

Countries

with study centres involved in the

EMPA-REG

OUTCOME

®

trial

41%

19%

Asia

Europe

North

America /

Western Pacific

20%

15%

Latin America

4%

Africa

*

Slide25

EMPA-REG OUTCOME

®

: Study design

25

Zinman et al.

Cardiovasc

Diabetol

2014;13:102.

Placebo

run-in

2 weeks

Empagliflozin 10 mg QD + usual care

Empagliflozin 25 mg QD + usual care Placebo + usual care

Screening (n = 11,507)

Background therapy adjustment

allowed after Week 12

12 weeks of stable background glucose-lowering therapy

Visit 1

Week

4

8

12

16

28

40

52

0

-2

-3

Visit 3

Visits

4–7

every

4 weeks

Visits 8–10

every 12

weeks

Visits every

14

weeks

Visit 2

Follow-up

R

End of

study visit

+30

days

Aim Compound-specific

To determine CV safety of empagliflozin

vs placebo + usual care for glycaemic control and

CV risk in

patients with

T2D

and high CV risk

Slide26

EMPA-REG OUTCOME

®

: Inclusion criteria

26

Zinman et al.

Cardiovasc

Diabetol 2014;13:102.

Adults with insufficient glycaemic control

High risk of CV events (≥1 of the following)

Age ≥ 18 years HbA1c

≥ 7% and ≤ 10% if on background glucose-lowering therapy, or≥ 7% and ≤ 9% if drug-naïveBMI ≤ 45 kg/m2 History of MI (> 2 months prior to enrolment)Evidence of single/multi-vessel CAD Unstable angina > 2 months prior to consent with evidence of single- or multi-vessel CADHistory of stroke (ischaemic or haemorrhagic) > 2 months prior to consent

Occlusive peripheral artery disease

Slide27

EMPA-REG OUTCOME

®

: Primary endpoint

Target number of events:

691

Non-inferiority and superiority of empagliflozin vs placebo will be assessed (hierarchical testing)

90% power to demonstrate non-inferiority for the primary (3P-MACE) and key secondary (4P-MACE) outcome

≥ 80% power to detect hazard ratio of 0.785 for primary (3P-MACE) outcome27

Zinman et al. Cardiovasc Diabetol 2014;13:102.

Primary endpoint: time to 1st occurrence of any of the following adjudicated components of the primary composite endpoint (3P-MACE)1. CV death (including fatal stroke and fatal MI)2. Non-fatal MI (excluding silent MI)3. Non-fatal stroke

Slide28

EMPA-REG OUTCOME

®

: Secondary endpoints

28

Zinman

et al.

Cardiovasc Diabetol 2014;13:102.

Key secondary outcome

Additional secondary outcomes

Expanded primary outcome (4P-MACE)3P-MACE + hospitalisation for unstable angina

Occurrence of and time to new onset of:Albuminuria (UACR ≥ 30 mg/g) Macroalbuminuria (UACR ≥ 300 mg/g)Occurrence of and time to a composite microvascular outcome, comprising:Initiation of laser therapy for retinopathy,

vitreous haemorrhage, diabetes-related blindness and new or worsening nephropathy as defined by:New-onset macroalbuminuria

Doubling of serum creatinine accompanied by eGFR ≤ 45 mL/min/1.73 m2

Initiation of renal replacement therapyDeath due to renal diseaseIndividual components of this compositeFurther CV outcomes

Individual components of the 4P-MACE

Individual occurrence of and time to:

Silent MI

Heart failure requiring hospitalisation

All-cause mortality

Transient

ischaemic attack

Coronary revascularisation procedures

Slide29

EMPA-REG OUTCOME

®

: Other outcomes of interest

Efficacy

Change from baseline in:

HbA

1c, fasting plasma glucose, weight, waist circumference and blood pressure

Proportion of patients that obtain the composite endpoint of: HbA

1c reduction ≥ 0.5%, systolic blood pressure reduction > 3 mmHg and body weight reduction > 2%Sub-studiesImpact on renal and CV biomarkers (cystatin C, hs-CRP and

hs-troponin T)Pharmacogenomics (potential genetic variations associated with drug responses) SafetyAEs, clinical laboratory tests, vital signs, 12-lead ECG, physical examination, use of rescue medication, confirmed hypoglycaemia*, volume depletion, bone fracture, hepatic events, malignancies, UTI and GIs

29*Plasma glucose ≤ 70mg/dL (3.9 mmol/L) and/or requiring assistance. Zinman et al. Cardiovasc Diabetol 2014;13:102.

Slide30

EMPA-REG OUTCOME

®

: Demographics

30

Zinman et al.

Cardiovasc

Diabetol 2014;13:102.

Treated set (n = 7034)

A

ge, years, mean (SD)

63.1 (8.6)≥ 75 y, n (%)652 (9)Male, n (%)5026 (72)

Race, n (%) White Asian Black/African American

Other5089 (72)1518 (22)357 (5)70 (1)

Ethnicity, n (%) Hispanic or Latino1268 (18)

Smoking

history, n (%)

Current

Ex-smoker

930 (13)

3216

(46)

Time

since T2D diagnosis, n (%)

≤ 5 years

> 5–10

years

> 10 years

1265

(18)

1754 (25)

4015 (57)

Slide31

EMPA-REG OUTCOME

®

: Baseline metabolic characteristics

31

Data are mean (SD) unless otherwise stated.

Zinman et al.

Cardiovasc

Diabetol 2014;13:102.

Treated set (n = 7034)

HbA1c, %8.1 (0.8)HbA1c < 8.5%, n (%)

4811 (68)FPG, mmol/L8.5 (2.4)

BMI, kg/m2 30.6 (5.3)≥ 35, n (%)1426 (20)

Weight, kg86.4 (18.9)Waist circumference, cm105 (14)

eGFR,

mL/min/1.73 m

2

(MDRD)

74 (21)

≥ 90, n (%)

1534 (22)

60

to

< 90,

n (%)

3671 (52)

30

to

< 60,

n (%)

1796 (26)

Median (Q1, Q3)

ACR

albumin ratio, mg/g

17.7 (7.1,

72.5)

Slide32

EMPA-REG OUTCOME

®

: Baseline CV characteristics

32

Data are mean (SD) unless otherwise stated.

Zinman et al.

Cardiovasc

Diabetol 2014;13:102.

Treated set (n = 7034)

History of CVD (any of the below), n (%)

6978 (99) History of stroke1631 (23) History of MI

3275 (47) Peripheral occlusive arterial disease1449 (21) CABG

1738 (25) Single-vessel CAD743 (11) Multi-vessel CAD

3285 (47)SBP/DBP, mmHg135 (17) / 77 (10)Lipids (mmol/L)

Total cholesterol

4.2 (1.1)

LDL-cholesterol

2.2 (0.9)

HDL-cholesterol

1.2 (0.3)

Triglycerides

1.9 (1.4)

Slide33

EMPA-REG OUTCOME

®

: Background therapies

33

*Data on file.

Zinman

et al. Cardiovasc Diabetol 2014;13:102.

Treated set (n = 7034)

 

Glucose-lowering therapy, n (%)

No therapy128 (1.8)Monotherapy

2055 (29.2)Metformin (% of monotherapy)745 (36.3)Insulin (% of monotherapy)

954 (46.4)Dual combination therapy3188 (45.3)Metformin + sulphonylurea (% of dual combination

therapy)1383 (43.4)Metformin + insulin (% of dual combination therapy)1420 (44.5) Total metformin

5205 (74.0)*

Total insulin

3446 (48.2)*

Anti-hypertensive

therapy, n (%)

6641

(94.4)

Blockers

of the renin–angiotensin system

5651 (80.3)

β-blockers

4537 (64.5)

Any diuretic

3015 (42.9)*

Calcium

channel blockers

2114

(30.1)

Other therapies,

n (%)

Acetylsalicylic

acid

5990 (85.2)

Statins

5387 (76.6)

Fibrates

630

(9.0)

Slide34

Module D: Summary

FDA guidance from 2008 requests CV outcome trials (CVOTs) to demonstrate CV safety of all new glucose-lowering compounds

1

CVOTs designed to assess impact of drugs on CV outcomes (MACE) vs placebo on top of usual care for glucose and CV risk factor management

Not designed to assess impact of differences between treatment arms in, for example, HbA

1c

on CV outcomes

Completed CVOTs in DPP4 inhibitor and GLP1 class report neutral effects on CV outcomes confirming CV safety as defined by FDA2-6

Ongoing CVOTs will provide further clarity on the CV safety of individual glucose-lowering agents34

1. FDA Guidance for Industry. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. 2. Scirica et al. N Engl J Med 2013;369:1317–26. 3. White et al. N Engl

J Med 2013;369:1327–35. 4. Zannad et al. Lancet 2015;385:2067–76. 5. Green et al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352. 6. Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).

Slide35

APPENDIX

Slide36

+

U

sual care

for

Type 2 Diabetes

N = 6068; duration of follow-up 2.1 years

Main inclusion

criteria

1. Age ≥ 30 years old

2. Type 2

Diabetes3. History of acute coronary syndrome

Primary endpoint: time to first occurrence of:Placebo

Lixisenatide 10 g (0.1 mL injection)vsELIXA: Study design

361. NCT01147250. 2. Katz P. Diabetes Vasc Dis Res 2014;11:395–409. 3. Bentley-Lewis et al. Am Heart J 2015;0:1-8.e7.4. Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).

Non-fatal stroke

Non-fatal MI

CV-related death

Unstable angina requiring hospitalisation

Aim Compound-specific

To assess CV morbidity and mortality associated with lixisenatide vs placebo

Back

Next

Slide37

ELIXA: Baseline characteristics

37

Bentley-Lewis

et al. Am Heart J

2015;0:1-8.e7.

Randomised population

(N = 6068)

Age,

years (mean ± SD)

60.3 ± 9.7Male, n (%)4207 (69.3)Race, n (%)

AsianBlackWhite Other768 (12.7)221 (3.6)4563 (75.2)516 (8.5)

Ethnicity, n (%)Hispanic1768 (29.1)BMI, kg/m2 n (%)

Mean ± SD18.5–24.925.0‒29.9≥ 3030.2 ± 5.71017 (16.8)2297 (37.9)2734 (45.1)

Cholesterol, mg/

dL

(mean ± SD)

Total

Triglycerides

HDL-C

LDL-C

153

± 44

164 ± 113

43 ± 11

78 ± 35

Fasting plasma glucose,

mg/

dL

(mean ± SD)

148

± 52

HbA

1c

, %,

(mean ± SD)

7.7 ± 1.3Qualifying ACS event

STEMI

Non-STEMI

UA2667 (44.0)

2346 (38.7)1042 (17.2)

Next

Back

Slide38

ELIXA: Lixisenatide was

non-inferior to

placebo on primary 4P-MACE endpoint

Outcome

Placebo

(n = 3034)

Lixisenatide

(n

= 3034)HR (95% CI)

4-P MACE399 (13.2%)

406 (13.4%)1.02 (0.89–1.17)Individual componentsCV mortality

158 (5.2%)2.4/100 pt-y156 (5.1%)2.3/100 pt-y0.98 (0.78–1.22)MI (fatal/non-fatal)261 (8.6%)4.1/100 pt

-y270 (8.9%)4.2/100 pt-y1.03 (0.87–1.22)Stroke (fatal/non-fatal60 (2.0%)0.9/100 pt-y67 (2.2%)1.0/100 pt-y1.12 (0.79–1.58)Unstable angina

10 (0.3%)0.1/100 pt-y11 (0.4%)0.2/100 pt-y1.11 (0.47–2.62)38Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).

Next

Back

Slide39

ELIXA:

HHF was not significantly increased with

lixisenatide vs placebo

Outcome

Placebo

(n = 3034)

Lixisenatide

(n

= 3034)HR (95% CI)MACE + HHF

469 (15.5%)7.6/100 pt-y456 (15.0%)7.3/100 pt

-y0.97 (0.85–1.10)MACE + HHF + Coronary Revascularisation659 (21.7%)11.2/100 pt-y661 (21.8%)11.1/100 pt-y1.00 (0.90–1.11)HHF127 (4.2%)1.9/100 pt-y122 (4.0%)1.8/100 pt

-y0.96 (0.75–1.23)CV death + HHF253 (8.3%)3.9/100 pt-y248 (8.2%)3.8/100 pt-y0.97 (0.82–1.16)39

Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).Back

Slide40

+ Usual care for T2D

N =

9340

; expected duration of follow-up 3.5–5 years

Main inclusion

criteria

1.

Type

2

Diabetes

2. Patients with prior CVD (e.g., MI, stroke, CHF, CRF) and age ≥ 50 years, or patients without prior CVD and ≥ 60 years old at screening with ≥ 1 CV risk factors

PlaceboLiraglutide 0.6–1.8 mg daily SC

vsLEADER: Study design401. Marso et al. Am Heart J 2013;166:823–30.e5. 2. NCT01179048.

Non-fatal strokeNon-fatal MI

CV-related death

Aim Compound-specific

To

assess the

CV safety

of

liraglutide relative to current usual care

Primary endpoint: time to first occurrence of primary major adverse cardiac events

Non-fatal stroke

CV

death

Non-fatal

MI

Results anticipated 2016

Next

Back

Slide41

LEADER: Baseline characteristics

41

Total population

(N = 9340)

Age,

years (mean ± SD)

64.3 ± 7.2

Male,

n (%)

6003 (64.3)

Race, n (%)

WhiteAsianBlackOther7237 (77.5)922 (9.9)775 (8.3)406 (4.3)Ethnicity, n (%)

Hispanic or Latino1135 (12.2)BMI, kg/m2 (mean ± SD)32.5 ± 6.3

Cholesterol, mg/dL (mean ± SD)TotalTriglyceridesHDL-CLDL-C170.4 ± 45.3182.5 ± 140.0

45.5 ± 12.3

89.5 ± 35.5

HbA

1c

, %,

(mean ± SD)

8.7

± 1.5

Previous CVD, n (%)

7592

(81.3

)

No previous CVD, n (%)

1748 (18.7)

Hypertension, n (%)

8408 (90.0)

Hyperlipidaemia, n (%)

7191 (77.0)

Coronary artery disease, n (%)

5303 (56.8)

Congestive heart failure, n (%)

1599 (17.1)

Peripheral artery disease, n (%)

1644 (17.6)

Diabetes duration, years

12.7 ± 8.0

Marso et al. Am Heart J 2013;166:823–30.e5.

Back

Slide42

SAVOR-TIMI 53: Study design

42

1.

Mosenzon

et al. Diabetes

Metab

Res Rev 2013;29:417–26. 2.

Scirica et al. N Engl

J Med 2013;369:1317–26.

+ Usual care for T2D

N = 16,492; median follow-up, 2.1 years (maximum, 2.9 years)Main inclusion criteria1. Patients with T2D2. HbA

1c > 6.5%, < 12.0%3. High-risk for CV events – established CVD and/or multiple risk factors

Primary endpoint: time to first occurrence of primary composite endpoint:Placebo

Saxagliptin 2.5 or 5 mgvs

Non-fatal stroke

CV

death

Non-fatal

MI

Aim Compound-specific

To determine whether saxagliptin reduces risk of CV events

when used

alone or added to other diabetes medications

Back

Next

Slide43

No.

at

risk

Placebo

8212

7983

7761

7267

4855

851

Saxagliptin

8280

8071

783673134920847

0

180

360

540

720

900

14

12

10

0

2

4

6

8

Saxagliptin

Placebo

HR 1.00

(95

% CI 0.89–1.12

)

p < 0.001

for

non-inferiority

p = 0.99

for superiority

Patients with primary endpoint (%)

SAVOR-TIMI 53: Saxagliptin was non-inferior

to placebo on primary 3P-MACE endpoint

43

Scirica

et al. N

Engl

J Med

2013;369:1317–26.

Days

Back

Next

Slide44

SAVOR-TIMI 53: Increased risk of

hospitalisation for heart failure in saxagliptin arm

Scirica

et

al.

Circulation 2014;130:1579–88.

HR 1.27 (05% CI 1.07–1.51); p

=

0.007

0

8212

8280

180

8036

8064

Days

0

1

2

3

Hospitalisation for heart failure (%)

4

360

7856

7867

720

4959

4978

540

7389

7375

Placebo

Saxagliptin

2.8%

3.5%

Placebo

Saxagliptin

Back

44

Slide45

EXAMINE: Study design

45

*Depending on renal function.

1. White et al

.

Am Heart J 2011;162:620–26.e1. 2. White et al. N

Engl

J Med 2013;369:1327–35.

+

Usual care for T2D

N = 5380; median follow-up = 18 months (maximum 40 months) Main inclusion criteria1. Patients with T2D2. HbA

1c ≥ 6.5%, ≤ 11.0% (if on oral or combination); HbA1c ≥ 7.0%, ≤ 11.0% (if treatment includes insulin) 3. History of acute coronary syndrome within 15–90 days pre-randomisation

Primary endpoint: time to first occurrence of primary major adverse cardiac events Placebo

Alogliptin 6.25–25 mg daily*vs

Non-fatal stroke

CV

death

Non-fatal

MI

Aim Compound-specific

To demonstrate non-inferiority of

alogliptin

vs

placebo with respect to

CV

events in patients at high CV risk

Next

Back

Slide46

Risk of

HHF occurring

as

the first

event

in pre-specified exploratory extended MACE endpoint did

not differ significantly between

groups

Risk

of events assessed as component of post-hoc composite endpoint

of CV death and HHF was not significantly different between groupsEXAMINE: HHF was not significantly increased with alogliptin vs placebo46Zannad

et al. Lancet 2015;385:2067–76.Alogliptin (n = 2701)Placebo (n = 2679)HR (95% CI)

p valueHospital admission for heart failure85 (3.1%)79 (2.9%)1.07 (0.79–1.46)0.657Alogliptin (n = 2701)

Placebo (n = 2679)HR (95% CI)p valueHospital admission for heart failure106 (3.9%)89 (3.3%)1.19 (0.90–1.58)0.220Next

Back

Slide47

No. at risk

Placebo

2679

2299

1891

1375

805

286

Alogliptin

2701

2316

1899

1394

821

296

Placebo

24

6

12

18

100

80

60

40

20

0

24

18

12

0

30

Months

Cumulative incidence of primary endpoint events (%)

6

0

0

6

12

18

24

30

Alogliptin

HR 0.96

(upper boundary of

the 1-sided repeated CI 1.16)

p < 0.001 for non-inferiority; p = 0.32 for superiority

EXAMINE: Alogliptin was non-inferior to placebo on primary 3P-MACE endpoint

47

1. White et al. N

Engl

J Med

2013;369:1327–35,

Back

Slide48

TECOS: Study design

48

*

50

mg daily if the baseline eGFR

was

≥ 30

and < 50 mL per

minute per 1.73 m2.Green et al. N Engl J Med 2015; DOI 10.1056/NEJMoa1501352

+ Usual care for T2D

N = 14,671; median follow-up 3.0 years

Main inclusion criteriaPatients aged ≥ 50 years with T2DHbA1c 6.5–8.0% receiving stable oral glucose-lowering therapy and/or

insulin*3. Pre-existing vascular diseasePrimary endpoint: time to first occurrence of:

PlaceboSitagliptin 100 mg daily*

vs

Non-fatal stroke

Non-fatal MI

CV-related death

Unstable angina requiring hospitalisation

Aim Compound-specific

To determine CV outcomes associated with long-term

sitagliptin

Next

Back

Slide49

TECOS: Baseline characteristics

49

Values

mean

±

SD if not specified n (%).

Green et al. N Engl J Med 2015; DOI 10.1056/NEJMoa1501352

Characteristic

Sitagliptin

n = 7332

Placebon = 7339Age, years65.4 ± 7.965.5 ± 8.0Women, n (%)

2134 (29.1)2163 (29.5)Race, n (%) White

Black Asian Other4955 (67.6)206 (2.8)

1654 (22.6)517 (7.1)5002 (68.2)241 (3.3)

1611 (22.0)

485 (6.6)

Hispanic or Latino

886 (12.1)

912 (12.4)

BMI (kg/m

2

)

(mean ± SD)

30.2

± 5.6

30.2

± 5.7

eGFR

(mL/min/1.73 m

2

)

74.9 ± 21.3

74.9 ± 20.9

HbA1c

7.2

± 0.5

7.2

± 0.5

CV risk management

Systolic blood pressure (mmHg)

135

± 16.9

135

± 17.1

Diastolic blood pressure (mmHg)

77.1 ± 10.3

77.2

± 10.6

Total cholesterol (mg/

dL

)

166.1

± 44.8

165.4

± 45.9

LDL-C (mg/

dL

)

91.2

± 63.8

90.7

± 51.2

HDL-C (mg/

dL

)

43.5

± 12.0

43.4

± 13.0

Triglycerides (mg/

dL

)

166.0

± 101.0

164.8

± 98.8

Aspirin use, n (%)

5764 (78.6)

5754 (78.4)

Statin use, n (%)

5851 (79.8)

5868 (80.0)

Next

Back

Slide50

TECOS: Baseline CV risk factors

50

*Enrolled participants could have one or more prior

CV event.

Green

et al. N

Engl J Med 2015; DOI 10.1056/NEJMoa1501352.

Characteristic, n (%)

Sitagliptin

n = 7332

Placebon = 7339Prior CV disease*5397 (73.6)5466 (74.5)

Myocardial infarction3133 (42.7)3122 (42.5) PCI

2814 (38.9)2900 (40.1)CABG

1845 (25.2)1819 (24.8)≥ 50% stenosis in a coronary artery3804 (51.9)

3883 (52.9)

Prior cerebrovascular disease

1806 (24.6)

1782 (24.3)

Stroke

1297 (17.7)

1258 (17.1)

TIA

280 (3.8)

286 (3.9)

≥ 50% stenosis in a carotid artery

431 (5.9)

429 (5.8)

Peripheral arterial disease

1217 (16.6)

1216 (16.6)

History of heart failure

1303 (17.8)

1340 (18.3)

Next

Back

Slide51

TECOS: Diabetes characteristics at baseline

51

Values are mean ±SD or median (IQR) for continuous variables

or

n (%)

for categorical variables.

Green et al. N Engl J Med 2015; DOI 10.1056/NEJMoa1501352.

Characteristic

Sitagliptin

n = 7332

Placebon = 7339

Duration of diabetes, years

11.6 ± 8.1

11.6 ± 8.1

HbA

1c

,

%

7.2 ± 0.5

7.2 ± 0.5

Medication taken alone or in combination

Metformin

5936 (81.0)

6030 (82.2)

Sulphonylurea

3346 (45.6)

3299 (45.0)

Thiazolidinedione

196 (2.7)

200 (2.7)

Insulin

1724 (23.5)

1684 (22.9)

Median daily dose (units)

50 (33, 80)

50 (32, 80)

Monotherapy

3496 (47.7)

3498 (47.7)

Dual combination therapy

3766 (51.4)

3768 (51.3)

Next

Back

Slide52

TECOS:

Sitagliptin was non-inferior

to placebo on primary 4P-MACE

endpoint

*CV

death,

non-fatal MI, non-fatal stroke, hospitalisation

for unstable angina.Green et

al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352.

Sitagliptin

72576857

65196275

59315616

39192896

1748

1028

Placebo

7266

6846

6449

6165

5803

5421

3780

2743

1690

1005

100

8

0

60

4

0

20

0

0

4

8

12

18

24

30

36

42

48

Months in the trial

Patients with an event (%)

Patients at risk:

0

0

4

8

12

18

24

30

36

42

48

5

10

15

Sitagliptin

Placebo

HR (95% CI): 0.98 (0.88–1.09)

p < 0.001

Next

Back

52

Slide53

TECOS:

No significant difference in rate of

hospitalisation for heart failure (ITT analysis)

Outcome

Placebo

Sitagliptin

HR (95% CI)

HHF

*

228 (3.1%)1.07/100 pt-y

228 (3.1%)1.09/100 pt-y1.00 (0.83–1.20)p = 0.98CV Death + HHF*525 (7.2%)2.50/100 pt-y

538 (7.3%)2.54/100 pt-y1.02 (0.90–1.15)p = 0.7453

ITT population. Adjusted for history of heart failure at baseline

*Pre-specified analyses Green et al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352Back

Slide54

CAROLINA

®

will evaluate CV safety of linagliptin compared with glimepiride in patients with T2D

54

1.

Rosenstock

et al. Diab

Vasc Dis Res 2013;10:289–301. 2. Marx et al. Diabetes

Vasc Dis Res 2015;12:164–74.

Inclusion if ≥ 1 of the following is fulfilled:

Previous vascular complications Evidence of end-organ damage, e.g., albuminuriaAge ≥ 70 years≥ 2 specified traditional CV risk factors

With or without metformin background therapy (including patients with contraindication to metformin use in renal impairment)N = 6041; approximate 6–7 year follow-up

Primary endpoint: time to first occurrence of primary composite endpoint:Glimepiride 1–4 mg

Linagliptin 5 mgvs

Active comparator trial

CV death (including fatal stroke and fatal

MI)

Non-fatal MI

Non-fatal stroke

Hospitalisation for UA

Next

Back

Slide55

 

Total

(n =

6041*)

Group A:

Previous CV

events

(

n = 2084, 34.5% of total)

Group B: Retinopathy/ albuminuria(n = 513, 8.5% of total)Group C:Age > 70 years (n = 1163,

19.3% of total)Group D:≥ 2 CV risk factors (n = 2252,37.3% of total)

Age, years (mean ± SD)64.0 ± 9.564.6 ± 8.965.6 ± 9.7

74.0 ± 3.458.0 ± 7.2≥ 75 y, %

14.0

14.3

21.2

37.9

0.0

Sex, male, n (%)

3622 (

60.0)

1511 (

72.5)

284 (

55.4)

593 (

51.0)

1219 (

54.1)

Race, n (%)

 

 

 

 

 

White

4408 (

73.0)

1489 (

71.4)

367 (

71.5)

911 (

78.3)

1634 (

72.6)

Asian

1061 (

17.6)

427 (20.5)

85 (

16.6)

145 (

12.5)

402 (

17.9)

Black/African

American

331 (

5.5)

101 (

4.8)

32 (

6.2)

40 (

3.4)

157 (

7.0)

Other

241 (

4.0)

67 (

3.2)

29 (

5.7)

67 (

5.8)

59 (

2.6)

Ethnicity, n (%)

 

    

Hispanic or Latino1033 (17.1)309 (14.8)

96 (18.7)260 (22.4)368 (16.3)

Smoking: Current/ex-smoker, %

19.5/33.716.3/46.2

14.4/30.2

6.6/32.8

30.7/23.6Time since T2D

diagnosis, years (median, IQR)6.2 (2.9, 11.0)5.8(2.7, 10.4)

6.6(3.6, 11.3)7.7(4.3, 12.0)

5.8(2.6, 10.7)Time since T2D diagnosis, %

≤ 5 years40.643.736.1

30.5

44.2> 5–10 years28.2

29.1

30.4

30.5

25.9

> 10

years

30.9

27.2

33.5

39.0

29.9

CAROLINA

®

: Baseline characteristics

55

*A few patients had no reliable CV risk categorisation.

Myocardial infarction 13.8%, coronary artery disease 17.1%,

stroke 7.8%, peripheral arterial occlusive disease 5.5%.

American Indian/Native, Alaskan/Native, Hawaiian/Pacific Islander.

Marx et al. Diabetes

Vasc

Dis Res 2015;12:164–74.

Back

Slide56

CARMELINA

®

will evaluate CV and renal safety of linagliptin in patients with T2D at high CV and renal risk

56

NCT01897532.

N = 8300; ~ 4-year follow-up

I

nclusion criteria

T2D

with HbA

1c ≥ 6.5% and ≤ 10.0%Stable background anti-diabetes medication, excluding GLP1, DPP4 inhibitors, SGLT2 inhibitorsHigh risk of CV,

defined by: 1) albuminuria (micro or macro) and previous macrovascular disease 2) and/or impaired renal function with predefined UACRPrimary CV endpoint: time to first occurrence of primary composite endpoint:

PlaceboLinagliptin 5 mg

vsCV death (including fatal stroke and fatal MI)

Non-fatal MI

Renal endpoint: time to first occurrence of the composite

endpoint:

Renal death, ESRD, and sustained decrease of ≥ 50%

eGFR

This study addresses the CV safety requirements from the FDA,

as well as investigates the potential renal effects of the drug

Non-fatal stroke

Hospitalisation for UA

Back

Slide57

CANVAS: Study design

57

1. Neal et al. Am Heart J 2013;166:217–223.e11. 2

.

NCT01032629.

In addition to usual care for T2D, patients

randomised

1:1:1 to

Stable dose of background

antihyperglycaemic

agents administered for 8 weeks prior to screeningN = 43652; expected duration of follow-up 6-7 yearsMain inclusion criteria1

1. Patients with T2D2. Age ≥ 30 years with history of symptomatic atherosclerotic vascular disease or ≥ 50 years with 2 or more risk factors for CVD

Primary endpoint: time to first occurrence of1:Placebo

Canagliflozin (100 mg)Non-fatal MI

CV-related death

Non-fatal stroke

Aim Compound-specific

To determine CV risk associated with

canagliflozin

Canagliflozin

(300

mg)

Back

Slide58

CANVAS-R: Study design

58

NCT01989754.

N = 5700; expected duration of follow-up 3 years

Main inclusion

criteria

Established

CV disease or multiple risk factors

Age ≥ 30 years

T2D

Primary endpoint:

Number of participants with progression of albuminuria Aim Compound-specificEffects of canagliflozin on renal endpoints in adults with T2D and at high CV risk

+ Usual care for T2DPlacebo

Canagliflozin (100 or 300 mg)vs

Other endpoints:

CV

safety data will be evaluated as

3P-MACE

Although primarily a renal study, CANVAS-R will prospectively collect adjudicated CV outcomes, as required by the FDA mandate

Back

Slide59

CREDENCE: Study design

59

*CV

death, non-fatal

MI,

non-fatal stroke,

hospitalised congestive heart failure and hospitalised

unstable angina.NCT02065791.

N = 3700; expected duration of follow-up ~4 years

Main inclusion

criteriaStage 2 or 3 CKD and macroalbuminuriaOn ACE inhibitor or ARBAge ≥ 30 yearsPrimary endpoint: time to first occurrence of:

End-stage kidney diseaseSerum creatinine doubling

Aim Compound-specificTo determine whether canagliflozin has a renal/vascular protective effect vs placebo + Usual care for T2D

PlaceboCanagliflozin (100 mg)

vs

Renal

or CV death

Other endpoints:

Composite CV safety endpoint*

Although primarily a renal study, CREDENCE will prospectively collect adjudicated CV outcomes, as required by the FDA mandate

Back

Slide60

DECLARE-TIMI 58: Study design

60

1. http://www.timi.org/index.php?page=declare-timi-58. Accessed March 2015. 2

.

NCT01730534.

N = 17,150; expected duration of follow-up ~4.5 years

Main inclusion

criteria

High risk for CV events

Age ≥ 40 years

T2DPrimary endpoint: time to first occurrence of:

CV deathMyocardial infarction

Aim Compound-specificTo determine whether dapagliflozin reduces CV events vs placebo + Usual care for T2DPlacebo

Dapagliflozin (10 mg)vs

Ischaemic

stroke

Back

Slide61

Ertugliflozin CVOT: Study design

61

NCT01986881.

N = 3900; expected duration of follow-up up to 6.3 years

Main inclusion

criteria

Evidence or a history of atherosclerosis (coronary, cerebral or peripheral)

Age ≥ 40 years

T2D

Primary endpoint: time to first occurrence of:

CV

deathNon-fatal MIAim Compound-specificTo determine whether ertugliflozin reduces CV events

vs placebo + Background therapy for T2DPlacebo

Ertugliflozin (5 or 15 mg)vs

Non-fatal

stroke

Back

Slide62

Clinical profile of SGLT2 inhibitors

62

Back

Slide63

Pooled data

Empagliflozin pooled Phase III placebo-corrected change from

baseline

in

HbA

1c

*

63

*

All statistically significant.

†Error bar represents 95% CI.1. Hach et al. Diabetes 2013;62(suppl 1A):A21(P69-LB). 2. Roden et al. Lancet Diabetes Endocrinol 2013;1:208‒19. 3. Häring et al. Diabetes Care 2014;37:1650–9. 4. Kovacs et al. Diabetes Obes

Met 2014;16:147‒58. 5. Häring et al. Diabetes Care 2013;36:3396‒3404. 6. Rosenstock et al. Diabetes 2013;(suppl 1):(1102-P). 7. Barnett et al. Lancet Diabetes Endocrinol 2014;2:369‒84

Pooled1Monotherapy2MET

3PIO4MET + SU5

Insulin

78-week

6

Mild RI

7

Patients, n

831

821

224

224

217

213

165

168

225

216

169

155

98

97

BL HbA

1c

(%)

7.98

7.96

7.87

7.86

7.94

7.86

8.07

8.068.07

8.10

8.278.278.027.96

Adjusted mean (SE) difference

vs placebo

in

change from baseline in HbA

1c

(%)

Empagliflozin 10 mg QD

Empagliflozin 25 mg QD

Back

Slide64

Empagliflozin pooled Phase III placebo-corrected change from

baseline

in body weight*

64

Pooled data

Pooled

1

Monotherapy

2

MET

3

PIO4MET + SU5Insulin

78-weekMild RI6N/AN/A

Adjusted mean (SE) difference vs placebo in change from baseline in body weight (kg)Patients, n

831

821

224

224

217

213

165

168

225

216

N/A

N/A

98

97

BL BW

(kg)

78.8

79.1

78.4

77.8

81.6

82.2

78.0

78.9

77.1

77.5

91.6

94.7

92.1

88.1

*All statistically significant.

Error bar represents 95% CI.

N/A, published data not available.

1.

Hach

et

al.

Diabetes

2013;62(

suppl

1A):A21(P69-LB

).

2.

Roden

et al. Lancet Diabetes

Endocrinol

2013;1:208‒19

.

3.

Häring

et

al. Diabetes

Care 2014;37:1650–9

.

4

.

Kovacs

et al. Diabetes

Obes

Met 2014;16:147‒58. 5. Häring et al. Diabetes Care 2013;36:3396‒3404. 6. Barnett et al. Lancet Diabetes Endocrinol 2014;2:369‒84.

Empagliflozin 10 mg QDEmpagliflozin 25 mg QD

BackEmpagliflozin is not indicated for

weight loss. Weight change was a secondary endpoint in clinical trials

Slide65

Empagliflozin pooled Phase III placebo-corrected change from baseline in SBP*

65

Pooled data

Pooled

1

Monotherapy

2

MET

3

PIO

4

MET + SU5Insulin78-week

Mild RI6N/AN/A

Adjusted mean (SE) difference vs placebo in change from baseline in SBP (mmHg)Patients, n831

821

224

224

217

213

165

168

225

216

N/A

N/A

98

97

BL SBP (mmHg)

129.6

129.0

133.0

129.9

129.6

130.0

126.5

125.9

128.7

129.3

132.4

132.8

137.4

133.7

Empagliflozin 10 mg QD

Empagliflozin 25 mg QD

*All statistically significant.

Error bar represents 95% CI.

N/A, published data not available.

1.

Hach

et

al.

Diabetes

2013;62(

suppl

1A):A21(P69-LB

).

2.

Roden

et al. Lancet Diabetes

Endocrinol

2013;1:208‒19

.

3.

Häring

et

al. Diabetes

Care 2014;37:1650–9

.

4

.

Kovacs

et al. Diabetes

Obes

Met 2014;16:147‒58. 5. Häring et al. Diabetes Care

2013;36:3396‒3404. 6. Barnett et al. Lancet Diabetes Endocrinol 2014;2:369‒84. . BackEmpagliflozin

is not indicated for blood pressure reduction. Change in blood pressure was a secondary

endpoint in clinical trials

Slide66

12-week ABPM study with

empagliflozin

in patients with T2D and hypertension: hourly mean SBP (mmHg)

66

FAS

(LOCF-H

). 1.

Tikkanen

et al. Diabetes Care 2015;38:420–8.

Mean (SE) SBP (mmHg)

Week 12Baseline0

12345

HourBackReductions in BP were not associated with increases in pulse rate

Empagliflozin is not indicated for blood pressure reduction. Change in blood pressure

was a

secondary

endpoint

in

clinical

trials

Slide67

12-week ABPM study with

empagliflozin

in patients with T2D and hypertension: hourly mean DBP at Week 12

67

Tikkanen

et

al. Diabetes

Care 2015;38:420–8.

Hour

Mean (SE) DBP (mmHg)

0123

45BackReductions in BP were not associated with increases in pulse rate

Empagliflozin is not indicated for blood pressure reduction. Change in blood

pressure was a secondary endpoint in clinical trials

Slide68

Empagliflozin pooled Phase III

data:

Change

in lipids (mg/

dL

) from baseline at Week

24

68

*

p <

0.05; **p < 0.001; ***p = 0.008 vs placeboHach et al. Diabetes 2013;62(Suppl 1A):A21 (P69-LB).*****

***

**LDL-C

HDL-CTriglyceridesLDL/HDL-C ratioTotal cholesterol

Mean baseline

101.2

99.2

99.2

48.6

48.6

49.0

164.7

172.7

173.6

2.18

2.11

2.11

181.7

180.6

181.7

Back

Slide69

n (%)

Placebo

(n = 3695)

Empagliflozin

10 mg QD

(n = 3806)

25 mg QD

(n = 4782)

Patients with any AE

2621 (70.9)

2686 (70.6)

3499 (73.2)

Patients with AE(s) leading to discontinuationof trial drug

208 (5.6)191 (5.0)255 (5.3)Patients with serious AE(s)494 (13.4)

393 (10.3)

573 (12.0)

One or more severe AE(s)

324 (8.8)

258 (6.8)

373 (7.8)

Deaths

29

(0.8)

19 (0.5)

26 (0.5)

Empagliflozin pooled safety and tolerability data:

Summary of adverse events

Kohler et al. ADA 2015 (poster 1173-P).

Rate per 100 patient-years

69

Back

Slide70

Pooled empagliflozin data:

Important

identified safety topics

1. Kohler

et al. ADA

2015 (poster 1173-P). 2.

Data on file.

n

(%)

Placebo(n = 3695)

Empagliflozin 10 mg QD

(n = 3806)25 mg QD(n = 4782)

Urinary tract infection2344 (9.3)374 (9.8)

497 (10.4)Female2Male2

269 (19.3)

75 (3.3)

281 (20.2)

93 (3.8)

360 (20.1)

137 (4.6)

Pyelonephritis

2

4 (0.1)

1 (< 0.1)

3 (0.1)

Pyelonephritis acute

2

3 (0.1)

1 (< 0.1)

2 (< 0.1)

Urosepsis

2

3 (0.1)

2 (0.1)

1 (< 0.1)

Genital

infection

2

41 (1.1)

177 (4.7)

268 (5.6)

Female

2

Male

2

23 (1.6)

18 (0.8)

94 (6.8)

83 (3.4)

156 (8.7)

112 (3.7)

Volume depletion

2

51 (1.4)

57 (1.5)

74 (1.5)

No.

of patients with confirmed

hypoglycaemic AEs

1

567 (15.3)

562 (14.8)

627 (13.1)

Episode requiring assistance (‘severe hypoglycaemic episode’)

1

19 (0.5)

18 (0.5)

18 (0.4)

70

Back

Slide71

Pooled empagliflozin data:

Important

potential safety topics

*Based

on 2

MedDRA

preferred terms. †Based on 1 standardized MedDRA query. ‡Based

on 4 standardized MedDRA queries.

§Based on 60 MedDRA preferred terms. 1. Kohler et al. ADA 2015 (poster 1173-P). 2. Data on file.

n

(%)Placebo(n = 3695)Empagliflozin

10 mg QD(n = 3806)

25 mg QD(n = 4782)Events consistent with malignancies*1

36 (1.0)46 (1.2)67 (1.4)Events consistent with malignancies with

an onset after 6 months

of therapy

or later

1

22 (0.9)

30 (1.0)

39 (1.0)

Patients with renal or bladder

cancer

with an onset after 6 months

of therapy

or later

2

2 (<0.1)

2 (<0.1)

1 (<0.1)

Decreased renal function

†1

36 (1.0)

46 (1.2)

64 (1.3)

Serum

creatinine increase ≥ 2x BL and ≥ ULN

2

10 (0.3)

11 (0.3)

14 (0.3)

Hepatic injury

‡1

66 (1.8)

52 (1.4)

82 (1.7)

Events consistent with bone fracture

§1

67 (1.8)

66 (1.7)

63 (1.3)

Events consistent with DKA

1

5 (0.1)

2 (0.1)

1 (< 0.1)

Diabetic

ketoacidosis

2

4 (0.1)

2 (0.1)

1 (< 0.1)

Ketoacidosis

2

1 (< 0.1)

0

0

Acetoanaemia

2

0

0

0

71

Back

Slide72

Dapagliflozin: Short-term (Week 24) HbA

1c

change from baseline in Phase III trials

72

*p ≤ 0.0001 vs placebo.

Least-squares mean adjusted for baseline value

.

1.

Forxiga 5-mg and 10-mg film-coated tablets [SPC]. Bristol-Myers Squibb/AstraZeneca EEIG, 18 December 2013.

2. Rosenstock et al. Diabetes Care 2012;35:1473–8.7570137 135

401 400145 151108 108

224 223139 140193194

7.798.018.11 7.927.74 7.698.15

8.07

8.24

8.08

7.97

7.90

8.34

8.37

8.46

8.58

HbA

1c

mean change

from baseline (%)

*

*

*

*

(Week 52 data)

*

*

*

Add-on

INS

1

Mono-

therapy

1

Add-on

MET

1

Add-on

MET

vs

GLP

1

Add-on

GLM

1

Add-on

PIO

2

Add-on

SU + MET

1

Add-on

SITA ± MET

1

PBO+

SITA ± MET

PBO

PBO

+

MET

GLP + MET

PBO +

GLM

PBO +

PIO

PBO +

INS

PBO+

SU + MET

Comparator

n

BL HbA

1c

(%)

Study

Back

Slide73

Dapagliflozin: Short-term (Week

24) body

weight change from baseline in Phase III trials

73

*p < 0.0001 vs

placebo

.

Least-squares mean adjusted for baseline value.

1. Forxiga

5-mg and 10-mg film-coated tablets [SPC]. Bristol-Myers Squibb/AstraZeneca EEIG, 18 December 2013. 2. Whaley et al. Diabetes Metab Syndr Obes 2012;5:135–48. 3. Rosenstock et al. Diabetes

Care 2012;35:1473–8 . 7570 137135

401400 145151108108

224223 139140 193194

88.8

94.2

87.7

86.3

87.6

88.4

80.9

80.6

90.1

88.6

89.2

91.0

86.4

84.8

94.5

94.5

Body weight mean change

from baseline (kg)

*

*

*

*

*

*

*

(Week 52 data)

n

BL BW

(kg)

Study

PBO +

SITA ± MET

PBO

PBO

+ MET

GLP + MET

PBO +

GLM

PBO +

PIO

PBO +

INS

PBO +

SU + MET

Add-on

INS

1,2

Mono-

therapy

1,2

Add-on

MET

1,2

Add-on

MET

vs

GLP

1

Add-on

GLM

1,2

Add-on

PIO

3

Add-on

SU + MET

1

Add-on

SITA ± MET

1

Comparator

Back

Slide74

Dapagliflozin: Short-term

(

Week 24) SBP

change from baseline in Phase III trials

*

Least-squares mean adjusted for baseline value.

1

.

Ferrannini

et al. Diabetes Care 2010;33:2217–24. 2. Bailey et al. Lancet 2010;375:2223–33. 3. Nauck et al. Diabetes Care 2011;34:2015–22. 4. Strojek

et al. Diabetes Obes Metab 2011;13:928–38. 5. Jabbour et al. Diabetes Care 2014;37:740–50. 6. Rosenstock et al. Diabetes Care 2012;35:1473–8. 7. Wilding et al. Ann Intern Med 2012;156:405–15.SBP mean change

from baseline (mmHg)*n75 70

119122401400145151

108108 111101139140

193

194

NA

NA

128

126

134

133

133

132

NA

NA

139

141

NA

NA

136

141

Week 8

in patients

with SBP

≥ 130 mmHg at baseline

NA

NA

n

BL SBP

(mmHg)

Study

PBO +

SITA ± MET

PBO

PBO

+ MET

GLP + MET

PBO +

GLM

PBO +

PIO

PBO +

INS

PBO +

SU + MET

Add-on

INS

7

Mono-

therapy

1

Add-on

MET

2

Add-on

MET

vs

GLP

3

Add-on

GLM

4

Add-on

PIO

6

Add-on

SU + MET

Add-on

SITA ± MET

5

Comparator

74

Back

Slide75

Dapagliflozin lipid profile (24-week data, SPC)

75

Forxiga

®

10-mg

film-coated tablets [SPC

]. AstraZeneca UK Limited. 2015.

LDL-C

HDL-C

Triglycerides

Total cholesterolBack

Slide76

Dapagliflozin: Pooled safety analysis from

12 placebo-controlled trials (12–24 weeks)

1,2

Overall incidence of AEs with dapagliflozin 10 mg was similar to placebo

Few AEs led to treatment discontinuation and were balanced across groups

Most commonly reported events leading to discontinuation with dapagliflozin 10 mg: increased blood creatinine (0.4%), UTIs (0.3%), nausea (0.2%), dizziness (0.2%) and rash (0.2%)

1

76

See notes for Footnotes.1. Forxiga 5-mg and 10-mg film-coated tablets [SPC]. Bristol-Myers Squibb/AstraZeneca EEIG, 18 December 2013. https://www.medicines.org.uk/emc/medicine/27188/SPC/Forxiga+5+mg++%26+10+mg+film+coated+tablets/. Accessed: February 2014.

2. Forxiga (dapagliflozin) tablets. US Prescribing Information; BMS/AstraZeneca, January 2014.

Common AEs2Placebo (n = 1393)Dapagliflozin 5 mg (n = 1145)Dapagliflozin 10 mg

(n = 1193)Genital mycotic infectionsFemale*

1.58.46.9Male†0.32.8

2.7Nasopharyngitis6.26.66.3UTI‡3.75.7

4.3

Back pain

3.2

3.1

4.2

Increased urination

§

1.7

2.9

3.8

Nausea

2.4

2.8

2.5

Influenza

2.3

2.7

2.3

Dyslipidaemia

1.5

2.1

2.5

Constipation

1.5

2.2

1.9

Discomfort with urination

0.71.6

2.1Pain in extremity

1.42.0

1.7Volume depletion¶

0.40.6

0.8Back

Slide77

Canagliflozin: HbA

1c

change from baseline in Phase III trials

77

*p < 0.001 vs comparator.

Least-squares

mean adjusted for baseline

value

.

Invokana (canagliflozin) tablets Prescribing Information. Janssen Pharmaceuticals, Inc., March 2013.HbA1c mean change from baseline (%)†

****

**nBL HbA1c (%)*

****

*

*

*

Weeks

Add-on

MET + SU vs SITA

52

Mono-

therapy

26

Add-on

MET

26

Add-on

SU

18

Add-on

MET + SU

26

Add-on

MET vs GLM

52

Add-on

MET + PIO

26

Add-on

INS

1

1

8

Placebo-controlled

PBO +

INS

PBO

PBO

+ MET

PBO +

SU

PBO +

SU + MET

GLM + MET

SITA +

MET + SU

PBO +

MET + PIO

Comparator

Active-controlled

192

195

197

183

368

367

45

42

40

156

157

156

115

113

114

565

566

587

482

483

485

378

377

7.97

8.06

8.01

7.96

7.94

7.95

8.49

8.29

8.28

8.12

8.13

8.13

8.007.997.848.20

8.338.277.837.78

7.79

8.138.12

Back

Slide78

Canagliflozin: Body weight change from baseline

in Phase III trials

78

*p

< 0.001

vs

comparator.

Least-squares

mean adjusted for baseline value.Invokana (canagliflozin) tablets

Prescribing Information. Janssen Pharmaceuticals, Inc., March 2013.Body weight mean change from baseline (kg)†

192195197183368

367156157156

115113114565566

587

482

483

485

378

377

87.5

85.9

86.9

86.7

88.7

85.4

90.8

93.5

93.5

94.0

94.2

94.4

97.7

96.9

96.7

86.6

86.8

86.6

89.6

87.6

*

*

*

*

*

*

*

*

*

*

*

*

*

Weeks

Placebo-controlled

Add-on

INS

1

8

PBO +

INS

Mono-

therapy

26

PBO

Add-on

MET

26

PBO

+MET

Add-on

MET + SU

26

PBO +

SU + MET

Add-on

MET + PIO

26

PBO +

MET + PIO

Add-on

MET vs GLM

52

GLM + MET

Add-on

MET + SU vs SITA

52

SITA +

MET + SU

Comparator

Active-controlled

n

BL BW

(kg)

Back

Slide79

Canagliflozin: SBP change from baseline vs comparator in Phase III trials

79

*p < 0.05, **p < 0.001 vs

comparator.

Least-squares

mean adjusted for baseline

value

.

1. Stenlof et al. Diabetes

Obes Metab 2013;15:372–82. 2. Invokana (canagliflozin) tablets Prescribing Information. Janssen Pharmaceuticals, Inc., March 2013. 3. Schernthaner et al. Diabetes Care 2013;36:2508–15.SBP mean difference from comparator (mmHg)

†nBL SBP (mmHg)

192195368367

113114

566

587

375

127

129

NA

NA

NA

NA

NA

NA

131

**

**

**

**

**

**

*

*

**

NA

NA

Weeks

Placebo-controlled

Add-on

INS

2

1

8

PBO +

INS

Mono-

therapy

1

26

PBO

Add-on

MET

2

26

PBO

+MET

Add-on

MET + SU

26

PBO +

SU + MET

Add-on

MET + PIO

2

26

PBO +

MET + PIO

Add-on

MET vs GLM

52

GLM + MET

Add-on

MET + SU vs SITA

3

52

SITA +

MET + SU

Comparator

Active-controlled

Back

Slide80

LDL-C

HDL-C

Triglycerides

Total

c

holesterol

Canagliflozin lipid profile (pivotal studies, SPC)

80

Invokana

®

100-mg and 300-mg film-coated tablets [SPC]. Janssen-Cilag Ltd. 2015.

Back

Slide81

Canagliflozin: General safety profile

Pooled analysis from 4 placebo-controlled trials* at 26 weeks

81

See notes for Footnotes.

Invokana

(canagliflozin) tablets

Prescribing Information.

Janssen Pharmaceuticals, Inc. , March 2013.

Abdominal pain also more commonly reported in patients taking

canagliflozin 100 mg (1.8%) and

300 mg (1.7%) than in patients taking placebo (0.8%)Adverse reactions occurring in ≥ 2% of canagliflozin-treated patients (%)

Placebo (n = 646)Canagliflozin100 mg (n = 833)Canagliflozin300 mg (n = 834)

Genital infections Male†0.64.23.7

Female‡3.210.411.4Urinary tract infection§4.05.9

4.3

Volume depletion

1.5

2.3

3.4

Thirst

#

0.2

2.8

2.3

Constipation

0.9

1.8

2.3

Vulvovaginal

pruritis

0.0

1.6

3.0

Increased

urination

**

0.8

5.34.6

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