Cardiovascular outcomes that will change diabetes practice: … · 2019. 4. 23. · Cardiovascular...

Cardiovascular outcomes that will change

diabetes practice: What are the key findings

from recent trials?

Game changing clinical trials in T2DM & CVD: Novel insights

& implications

Asian Cardio Diabetes ForumMarch 30-31, 2019 - Hanoi, Vietnam

Prof. Mark Cooper, MD Melbourne, Australia

All trial completion and estimated disclosure dates come from ClinicalTrials.gov

3P-MACE, 3-point major adverse cardiovascular events; 4P-MACE, 4-point major adverse cardiovascular events; 5P-MACE, 5-point major adverse cardiovascular events;

CV, cardiovascular; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose co-transporter-2; SU, sulphonylurea

Adapted from: Johansen OE. World J Diabetes 2015;6:1092. See notes for full list of references

Evolving landscape of CVOT

TECOS4

Sitagliptin

N=14,671

1690 4P-MACE

ELIXA3

Lixisenatide

N=6068

805 4P-MACE

EMPA-REG OUTCOME®5

Empagliflozin

N=7020

772 3P-MACE

CARMELINA®12

Linagliptin

N=6980

3P-MACE + renal

EXSCEL10

Exenatide

N=14,752

1744 3P-MACE

DECLARE-TIMI 5816

Dapagliflozin

N=17,276

3P-MACE

CV death or HHF

CANVAS Program11

Canagliflozin

N=10,142

1011 3P-MACE

FREEDOM-CVO6,7

ITCA 650

N=4156

4P-MACE

PIONEER-615

Semaglutide (oral)

N=3176

3P-MACE

CAROLINA®18,19

Linagliptin vs SU

N=6072

≥631 3P-MACE

HARMONY13

Albiglutide

N=9400

3P-MACE

REWIND14

Dulaglutide

N=9622

3P-MACE

LEADER8

Liraglutide

N=9340

1302 3P-MACE

SUSTAIN-69

Semaglutide (inj)

N=3297

254 3P-MACE

CREDENCE20

Canagliflozin

N=4200

Renal + 5P-MACE

VERTIS CV17

Ertugliflozin

N=8000

3P-MACE

DPP-4 inhibitorSGLT2 inhibitorGLP-1 receptor agonist

2

EXAMINE2

Alogliptin

N=5380

621 3P-MACE

SAVOR-TIMI 531

Saxagliptin

N=16,492

1222 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

CVOTs in T2D

• Safety expectations for all new anti-diabetes drugs1

• Specific focus on CV safety in recognition of the excess

burden of CVD in T2D1

• To establish the safety of a new antidiabetic therapy, sponsors

should demonstrate that the therapy will not result in an

unacceptable increase in CV risk2

• Primary aim to demonstrate non-inferiority versus placebo in major

adverse cardiac event (MACE) primary composite end point1

1. Cefalu et al Diabetes Care 2018; 41:14–31. 2. Guidance for Industry. FDA, 2008.

CV, cardiovascular; CVD, CV disease; CVOT, CV outcomes trial; T2D type 2 diabetes.

3P-MACE 3P-MACE 4P-MACE 4P-MACE 3P-MACE 3P-MACE 3P-MACE 3P-MACE 3P-MACE

5P-MACE 4P-MACE 5P-MACE 3P-MACERenal

composite

4P-MACEMicrovascular

composite

All-cause

mortality;

HHF

Expanded

CV

composite

All-cause

mortality;

HHF;

HACS

SAVOR-TIMI

531

(saxagliptin)

N=16,492

EXAMINE2

(alogliptin)

N=5,380

ELIXA3

(lixisenatide)

N=6,068

TECOS4

(sitagliptin)

N=14,671

CARMELINA®5

(linagliptin)

N=6,991

EMPA-REG

OUTCOME®6

(empagliflozin)

N=7,020

CANVAS

Program7

(canagliflozin)

N=10,142

LEADER®8

(liraglutide)

N=9,340

EXSCEL9

(exenatide)

N=14,752

Primary and secondary endpoints in recent CVOTs

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. Pfeffer et al. N Engl J Med 2015;373:2247–57. 4.

Green et al. N Engl J Med 2015;373:232–42. 5. Rosenstock et al. Cardiovasc Diabetol 2018;17:39. 6. Zinman et al. N Engl J Med 2015;373:2117–28. 7.

Neal et al. N Engl J Med 2017;377:644–57. 8. Marso et al. N Engl J Med 2016;375:311–22. 9. Holman et al. N Engl J Med 2017;377:1228–39.

Primary

endpoint

Secondary

endpoints*

3P-MACE is defined as the time to first occurrence of…

CV, cardiovascular. MACE, major adverse coronary events

1. Marx et al. Diabetes Care 2017;40:1144–51.

CV Death Myocardial Infarction Stroke

or or

Major adverse coronary events (MACE) in CVOTs

• .

0

2

4

6

8

10

12

14

16

18

20

3-Point MACE 4-Point MACE 5-Point MACE

Incid

en

ce

(%

)*

Hospitalisation for HF

Hospitalisation for UA

Non-fatal stroke

Non-fatal MI

CV death

12%

14%

18%

Composite outcome:

*Placebo group from EMPA-REG OUTCOME® trial

CV, cardiovascular; CVOT, CV outcomes trial; HF, heart failure; MI, myocardial infarction; UA, unstable angina

1. Zinman et al. N Engl J Med 2015;373:2117–28.

CVOTs in T2D1

• Safety expectations for all new anti-diabetes drugs

• Specific focus on CV safety, in recognition of the excess burden of

CVD in T2D

• Primary aim to demonstrate non-inferiority versus placebo in major

adverse cardiac event (MACE) primary composite endpoint

• Typically conducted in trial populations in which some or all

patients had advanced atherosclerotic CV risk or established

CVD to ensure accrual of sufficient events in a timely manner

CV, cardiovascular; CVD, CV disease; CVOT, CV outcomes trial; T2D type 2 diabetes;

Cefalu et al Diabetes Care 2018;41:14–31.

Trial populations in recent CVOTs — established CVD

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;373:232–42. 4.

Rosenstock et al. Cardiovasc Diabetol 2018;17:39. 5. Zinman et al. N Engl J Med 2015;373:2117–28. 6. Neal et al. N Engl J Med 2017;377:644–57. 7.

Wiviott et al. N Engl J Med 2018;doi: 10.1056/NEJMoa1812389. 8. Pfeffer et al. N Engl J Med 2015;373:2247–57. 9. Marso et al. N Engl J Med

2016;375:311–22. 10. Holman et al. N Engl J Med 2017;377:1228–39.

78,6

100

10090,0

99,2

72,2

40,6

100,0

81,373,1

21,4 2610

27,8

59,4

18,726,9

0

10

20

30

40

50

60

70

80

90

100

Pro

po

rtio

n o

f p

art

icip

an

ts (

%)

Established CVD High CV risk

SAVOR-TIMI

531

(saxagliptin)

N=16,492

EXAMINE2

(alogliptin)

N=5,380

TECOS3

(sitagliptin)

N=14,671

CARMELINA®4

(linagliptin)

N=6,979

EMPA-REG

OUTCOME®5

(empagliflozin)

N=7,020

CANVAS

Program6

(canagliflozin)

N=10,142

DECLARE-

TIMI 537

(dapagliflozin)

N=17,160

ELIXA8

(lixisenatide)

N=6,068

LEADER®9

(liraglutide)

N=9,340

EXSCEL10

(exenatide)

N=14,752

DPP-4 inhibitors SGLT2 inhibitors GLP-1 receptor agonists

Trial populations in recent CVOTs — 3P-MACE 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;373:232–42. 4.

Rosenstock et al. Cardiovasc Diabetol 2018;17:39. 5. Zinman et al. N Engl J Med 2015;373:2117–28. 6. Neal et al. N Engl J Med 2017;377:644–57. 7. Wiviott

et al. N Engl J Med 2018;doi: 10.1056/NEJMoa1812389. 8. Pfeffer et al. N Engl J Med 2015;373:2247–57. 9. Marso et al. N Engl J Med 2016;375:311–22. 10.

Holman et al. N Engl J Med 2017;377:1228–39.

3,7

7,9

3,3

5,6

4,4

3,15

2,42

6,3

3,9 4

0

1

2

3

4

5

6

7

8

9

Eve

nts

/10

0P

Y

3P-MACE event rate during trial (in placebo arm)

SAVOR-TIMI

531

(saxagliptin)

N=16,492

EXAMINE2

(alogliptin)

N=5,380

TECOS3

(sitagliptin)

N=14,671

CARMELINA®4

(linagliptin)

N=6,979

EMPA-REG

OUTCOME®5

(empagliflozin)

N=7,020

CANVAS

Program6

(canagliflozin)

N=10,142

DECLARE-

TIMI 537

(dapagliflozin)

N=17,160

ELIXA8

(lixisenatide)

N=6,068

LEADER®9

(liraglutide)

N=9,340

EXSCEL10

(exenatide)

N=14,752

DPP-4 inhibitors SGLT2 inhibitors GLP-1 receptor agonists

New agents are measured against existing standard of care1

CV, cardiovascular; CVOT, CV outcomes trial

EMA, 2012. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf]. Accessed Nov 2018.

A new agent must be compared with a placebo arm that

includes established background therapy, defined as

current standard of care

In CVOTs, all patients receive background standard of care for CV risk

reduction and glucose control to achieve guideline-recommended targets

.

EMPA-REG OUTCOME® study baseline medications1,2

1. Chilton. Am J Cardiol 2017;120:S1–3. 2. Zinman et al. N Engl J Med 2015;373:2117–28

98%Receiving any glucose-

lowering therapy1

74%Receiving metformin

(as monotherapy or

in combination)1

48%Receiving insulin

(as monotherapy or

in combination)1

Glucose-lowering therapy Cardiovascular therapy

95%Receiving antihypertensive

therapy1

89%Receiving antiplatelet

agents or anticoagulants2

82%Receiving lipid lowering

therapy2

1. SAFETYNon-inferiority to placebo for their primary cardiovascular (CV) composite end point

CVOT

What have

we learnt?

TECOS3

Note: data are from different trials and cannot be directly compared.

1. Scirica BM et al. N Engl J Med 2013;369:1317; 2. White WB et al. N Engl J Med 2013;369:1327; 3. Green JB et al. N Engl J Med 2015;373:232; 4, EASD Berlin 2018

Demonstration of CV Safety in DPP-4 inhibitor CVOTs

13

Randomisation 1 2 3Median follow-up (years)

EXAMINE2

T2D + ACS

HbA1c 6.5–11.0%

N=5380

HR 0.96

(upper CI‡ 1.16)

p

2. SUPERIORITY

1. SAFETYCVOT

Superiority to placebo for their primary cardiovascular (CV) composite end pointWhat have

we learnt?

EMPA-REG OUTCOMES – 3P MACE outcome

Cumulative incidence function. MACE, Major Adverse Cardiovascular Event;

HR, hazard ratio. * Two-sided tests for superiority were conducted (statistical significance was indicated if p≤0.0498)

HR= 0.86(95% CI 0.74 -0.99)

P=0.019*

Study name SGLT2 inhibitor Placebo

3P-MACE

HR (95% CI) HR (95% CI) P-value

EMPA-REG

OUTCOME®1,437.4 43.9 0.86 (0.74, 0.99) 0.04

CANVAS

Program2,426.9 31.5 0.86 (0.75, 0.97) 0.02

DECLARE-TIMI

533,422.6 47.2 0.93 (0.84, 1.03) 0.17

Pooled analysis (all SGLT2 inhibitors) 0.89 (0.83, 0.96) 0.0014

SGLT2 inhibitors in CVOT — 3P-MACE outcomes

1. Zinman et al. N Engl J Med 2015;373:2117–28. 2. Neal et al. N Engl J Med. 2017;377:644–57. 3. Wiviott et al. N Engl J Med 2018;

doi:10.1056/NEJMoa1812389. 4. Zelniker et al. Lancet 2018;doi:10.1016/S0140-6736(18)32590-X.

0.5 2.51

Events per 1,000 PY

Favours treatment Favours placebo


3P-MACE


Patients with ASCVD

EMPA-REG OUTCOME®1,4 37.4 43.9 0.86 (0.74, 0.99)

CANVAS Program2,4 34.1 41.3 0.82 (0.72, 0.95)

DECLARE-TIMI 533,4 36.8 41.0 0.90 (0.79, 1.02)


Patients with multiple risk factors

CANVAS Program2,4 15.8 15.5 0.98 (0.74, 1.30)

DECLARE-TIMI 533,4 13.4 13.3 1.01 (0.86, 1.20)


3-P MACE stratified by the presence or absence of ASCVD

1. Zinman et al. N Engl J Med 2015;373:2117–28. 2. Neal et al. N Engl J Med. 2017;377:644–57. 3. Wiviott et al. N Engl J Med 2018DOI: 10.1056/NEJMoa1812389.

4. Zelniker et al. Lancet 2016;10.1016/S0140-6736(18)32590-X

Events per 1,000 PY

0.5 2.5

3P-MACE, 3-point major adverse cardiovascular event; ASCVD, atherosclerotic CV disease, CI, confidence interval; CV, cardiovascular; HR, hazard ratio; PY, patient-year; SGLT2, sodium–glucose transporter 2.


1

P-value for subgroup differences: 0.05

GLP-1 receptor agonists — 3P-MACE outcomes1–5

1. Pfeffer et al. N Engl J Med 2015;373:2247–57. 2. Marso et al. N Engl J Med 2016;375:311–22. 3. Marso et al. N Engl J Med. 2016 Nov 10;375:1834–1844. 4.

Holman et al. N Engl J Med 2017;377:1228–39. 5. Hernandez et al. Lancet 2018;392:1519–29.

338 /4731 (7.1%) 428/4732 (9.0%) 0.78 0.68 0.90 0.001

0.5 21

3P-MACE, 3-point major adverse cardiovascular event; CI, confidence interval; GLP-1, glucagon-like peptide-1.

HARMONY investigated an agent that has now been discontinued (albiglutide)

1. SAFETY

2. SUPERIORITY

3. NEW SIGNALS

CVOT

What have

we gained?

New positive signals emerging from CVOTs

1. Scirica et al. N Engl J Med 2013;369:1317–26. 2. Green et al. N Engl J Med 2015;373:232–42. 3. Schaffer et al Dermatology 2017;233:401–403 4. Marso et al. N Engl J Med 2016 Nov

10;375:1834–44. 5. Marso et al. N Engl J Med 2016;375:311–22. 6. Holman et al. N Engl J Med 2017;377:1228–39. 6. Neal et al. N Engl J Med 2017;377:644–57. 7. Zinman et al. N Engl J Med

2015;373:2117–28. 8. Sung et al. J Clin & Transl Endocrinol 2018;13:46–7. 9. Cefalu et al. Lancet 2013;382:941–50. 10. Akuta et al. Hepatology Communications 2017;1:46–52.

Heart failure?1,2

Pancreatitis1,2

Pemphigoid3

Fracture?6–8

Amputation?6–8

Retinopathy?4,5 CV Death6,7

Heart Failure6,7

Renal6,7

Fatty Liver9,10 CV Death?4,5

CV, cardiovascular; CVOT, CV outcomes trial; DPP-4, dipeptidyl peptidase-4; GLP-1,RA glucagon-like peptide-1 receptor agonists; SGLT2, sodium–glucose transporter 2.

SGLT2 inhibitors

GLP-1 RA

DON’T LIKE LIKE

EMPA-REG OUTCOMES – CV Death


CV death


Patients with ASCVD

EMPA-REG OUTCOME®1,4 12.4 20.2 0.62 (0.49, 0.77)

CANVAS Program2,4 14.8 16.8 0.86 (0.70, 1.06)

DECLARE-TIMI 533,4 10.9 11.6 0.94 (0.76, 1.18)


Patients with multiple risk factors

CANVAS Program2,4 6.5 6.2 0.93 (0.60, 1.43)

DECLARE-TIMI 533,4 4.4 4.1 1.06 (0.79, 1.42)


CV death – a clear difference between SGLT2 inhibitors

1. Zinman et al. N Engl J Med 2015;373:2117–28. 2. Neal et al. N Engl J Med. 2017;377:644–57. 3. Wiviott et al. N Engl J Med 2018;doi:10.1056/NEJMoa1812389.

4. Zelniker et al. Lancet 2018;doi:10.1016/S0140-6736(18)32590-X.

0.5 2.5

ASCVD, atherosclerotic CVD, CI, confidence interval; CV, cardiovascular, CVD, CV disease; HR, hazard ratio; PY, patient-year; SGLT2, sodium–glucose transporter 2.


1

Events per 1,000 PY

P-value for subgroup differences: 0.31

122/4731 (2.6%) 130/4732 (2.7%) 0.93 0.73 1.19 0.578

1. Pfeffer et al. N Engl J Med 2015;373:2247–57. 2. Marso et al. N Engl J Med 2016;375:311–22. 3. Marso et al. N Engl J Med. 2016 Nov 10;375:1834–1844. 4.

Holman et al. N Engl J Med 2017;377:1228–39. 5. Hernandez et al. Lancet 2018;392:1519–29.

0.5 21

3P-MACE, 3-point major adverse cardiovascular event; CI, confidence interval; GLP-1, glucagon-like peptide-1.

HARMONY investigated an agent that has now been discontinued (albiglutide)

CV death – a difference between GLP-1 receptor agonists?1–5


All-cause mortality


EMPA-REG

OUTCOME®1,419.4 28.6 0.68 (0.57, 0.82)

Number needed to treat to prevent one patient death

Simvastatin 40mgfor 5 years

T2DM + CV RISK

T2DM + CVD

OR HIGH RISK

Ramipril 10mgfor 4.5 years

Empagliflozin for 2.6 years

HOPE1 HPS2 EMPA-REG3 LEADER4

1. Lancet. 2000 Jan 22;355(9200):253-9.2. Collins et al Lancet. 2003 Jun 14;361(9374):2005-16.

3. Marso SP et al. N Engl J Med 2016;375:311 4. Zinman et al. N Engl J Med. 2015 Nov 26;373(22):2117-28.

T2DM with CVD

Liraglutide for 3.8 years

T2DM + CVD

OR HIGH RISK

Differences in mean survival by age with empagliflozin vs placebo

A sixty year old may expect to live

2.5 years longer on average

Long-Term Benefit of Empagliflozin on Life Expectancy in Patients With Type 2 Diabetes Mellitus and Established Cardiovascular Disease, Volume: 138, Issue: 15, Pages: 1599-1601, DOI: (10.1161/CIRCULATIONAHA.118.033810)


HHF


Patients with ASCVD

EMPA-REG OUTCOME®1,4 9.4 14.5 0.65 (0.50, 0.85)

CANVAS Program2,4 7.3 11.3 0.68 (0.51, 0.90)

DECLARE-TIMI 533,4 11.1 14.1 0.78 (0.63, 0.97)

Pooled analysis (all SGLT2 inhibitors) 0.71 (0.62, 0.82)


All-cause mortality


EMPA-REG

OUTCOME®1,46.3 11.5 0.54 (0.40, 0.75)

CV Death?4,5

New negative signals emerging from CVOTs

1. Scirica et al. N Engl J Med 2013;369:1317–26. 2. Green et al. N Engl J Med 2015;373:232–42. 3. Schaffer et al Dermatology 2017;233:401–403 4. Marso et al. N Engl J Med 2016 Nov 10;375:1834–44. 5. Marso et al. N Engl J Med

2016;375:311–22. 6. Holman et al. N Engl J Med 2017;377:1228–39. 6. Neal et al. N Engl J Med 2017;377:644–57. 7. Zinman et al. N Engl J Med 2015;373:2117–28. 8. Sung et al. J Clin & Transl Endocrinol 2018;13:46–7. 9. Cefalu et

al. Lancet 2013;382:941–50. 10. Akuta et al. Hepatology Communications 2017;1:46–52.

Heart failure?1,2

Pancreatitis1,2

Pemphigoid3

Fracture?6–8

Amputation?6–8

Retinopathy?4,5 CV Death6,7

Heart Failure6,7

Renal6,7

Fatty Liver9,10

DPP-4 inhibitors

CV, cardiovascular; CVOT, CV outcomes trial; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT2, sodium–glucose transporter 2.

SGLT2 inhibitors

GLP-1 RA

DON’T LIKE LIKE

Trial

n event/N analyzed (%)

HR (95% CI) p-valueTrial drug Placebo

SAVOR-TIMI 53*1

(Saxagliptin)289/8280 (3.5) 228/8212 (2.8) 1.27 (1.07, 1.51) 0.007

EXAMINE*2

(Alogliptin)106/2701 (3.9) 89/2679 (3.3) 1.19 (0.90, 1.58) 0.22

TECOS†3

(Sitagliptin)228/7332 (3.1) 229/7339 (3.1) 1.00 (0.83, 1.20) 0.98

CARMELINA4

(Linagliptin) 209/3494 226/3485 0.90 (0.74, 1.08) 0.26

Hospitalisation for Heart Failure

0,5 1 2

Favours trial drug Favours placebo

Trial

n event/N analysed (%)

OR (95% CI) p-valueTrial drug Placebo

SAVOR-TIMI 53

(Saxagliptin)17/8280 (0.2) 9/8212 (0.1) 1.88 (0.84, 4.21) 0.128

EXAMINE

(Alogliptin)12/2701 (0.4) 8/2679 (0.3) 1.49 (0.61, 3.65) 0.383

TECOS

(Sitagliptin)23/7257 (0.3) 12/7266 (0.2) 1.92 (0.96, 3.87) 0.067

CARMELINA4

(Linagliptin) 17/3494 9/3485 1.88 (0.84, 4.22) 0.12

0,25 1 4

CVOT, cardiovascular outcomes trial; DPP-4, dipeptidyl peptidase-4; OR, odds ratio

Tkáč I & Raz I. Diabetes Care 2017;40:284

Acute Pancreatitis

Decreased risk Increased risk

1. SAFETY

2. SUPERIORITY

3. NEW SIGNALS

4. NEW HYPOTHESES FOR

NEW TARGETED TRIALS

CVOT

What have

we gained?

EMPEROR-Preserved1 EMPEROR-Reduced2 Dapa-HF3 DELIVER4 SOLOIST-WHF5,6

Intervention Empagliflozin Empagliflozin Dapagliflozin Dapagliflozin Sotagliflozin

Sample size 4126* 2850* 4695* 4700 4000*4 (~6667)5

Heart

failure

criteria

HFpEF (LVEF >40%) HFrEF (LVEF ≤40%) HFrEF (LVEF ≤40%) HFpEF (LVEF >40%) and

structural heart disease) and

NYHA II−IV

–

Primary

endpoint

• Time to first event of adjudicated CV death

or adjudicated HHF

• Time to first occurrence of

CV death, HHF or urgent

HF visit

• Time to first occurrence of

CV death, HHF or urgent

HF visit

• Time to first event of

CV death or HHF (both

EF

SGLT2 inhibitor trials primarily focused on CKD/DKD

*The IDMC of the trial has recommended to stop the trial early based on the achievement of pre-specified efficacy criteria at the time of a planned interim analysis3

1. Jardine MJ et al. Am J Nephrol 2017;46:462; 2. ClinicalTrials.gov. NCT02065791; 3. Janssen Pharmaceuticals, Inc. Press release. 2018. www.jnj.com/phase-3-credence-renal-outcomes-trial-of-invokana-

canagliflozin-is-being-stopped-early-for-positive-efficacy-findings; 4. ClinicalTrials.gov. NCT03036150; 5. ClinicalTrials.gov. NCT03594110 (all accessed September 2018)

CREDENCE1−3 Dapa-CKD4 EMPA-KIDNEY5

Study drug Canagliflozin vs placebo Dapagliflozin vs placebo Empagliflozin vs placebo

Population

DKD including

✓ T2D

x Non-DM

x T1D

CKD including

✓ T2D

✓ Non-DM

x T1D

CKD including

✓ T2D

✓ Non-DM

✓ T1D

Sample size 4401 4000 ~5000

Key inclusion criteriaeGFR ≥30 to 300 mg/g

eGFR ≥25 to ≤75 ml/min/1.73 m2

and UACR ≥200–≤5000 mg/g

eGFR ≥20 to

1. SAFETY

2. SUPERIORITY

3. NEW SIGNALS

4. NEW TRIALS

5. APPLICABILITY & RWE

CVOT

What have

we gained?

Randomised controlled trials vs real-world data

1. The Association of the British Pharmaceutical Industry (ABPI), 2011. [http://www.abpi.org.uk/media/1378/vision-for-real-world-data.pdf]. Accessed Oct 2018. 2. Peperell et al.

Value Health 2012;15:A460–1. 3. Luce et al. Milbank Q 2010;88:256–76.

Ever-increasing role in decisions that affect

patients’ access to therapies2

Can it work?3

Randomised controlled trials Real-world data

Does it work?3

Real-world data are collected outside the controlled constraints of

conventional randomised clinical trials to evaluate what is happening in

normal clinical practice.1

RWE can support CVOT data

1. Zinman et al. N Engl J Med 2015;373:2117–28. 2. Neal et al. N Engl J Med 2017;377:644–57. 3. Kosiborod et al. Circulation. 2017;136:249–59.

0.5 21

Trial N Number of events HR (95% CI)

HHF

EMPA-REG OUTCOME®* 7,020 221 0.65 (0.50–0.85)

CANVAS Program* 10,142 243 0.67 (0.52–0.87)

CVD-REAL† 196,802 423 0.61 (0.51–0.73)

HHF or death

EMPA-REG OUTCOME®* 7,020 463 0.66 (0.55–0.79)

CANVAS Program* 10,142 652 0.78 (0.67–0.91)

CVD-REAL† 215,622 1,983 0.54 (0.48–0.60)

Favours SGLT2 inhibitors

EMPRISE® study design

1. ClinicalTrials.gov [NCT03363464]. 2. Boehringer Ingelheim. Data on file, 2018.

1:1 Propensity score

matching between

patients on empagliflozin

and DPP-4i

Patients with T2D

New users of empagliflozin

New users of DPP-4i

=

DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT2, sodium–glucose transporter 2 inhibitor; T2D, type 2 diabetes.

Key inclusion criteria*1

• Adults aged ≥18 years

• Initiation of empagliflozin or a DPP-4i between

August 2014 and August 2019

• Patients with T2D (claims in the 12 months prior to entry)

Key exclusion criteria*1,2

• Concomitant SGLT2i and DPP-4i at treatment initiation

• Use of either SGLT2i or DPP-4i class in the 12 months

preceding cohort entry (switchers)

• Patients with

Beneficial HHF outcomes with empagliflozin in RWE from EMPRISE®

1. Zinman et al. N Engl J Med 2015;373:2117–28. 2. Patorno et al. AHA 2018;poster 1112.

Study

Empagliflozin Comparator

HR (95% CI)

n event/N

analysed

(%)

Rate/

1000 PY

n event/N

analysed

(%)

Rate/

1000 PY

EMPA-REG OUTCOME®1

(empagliflozin vs placebo)

126/4,687

(2.7)9.4

95/2,333

(4.1)14.5

0.65

(0.50, 0.85)

EMPRISE®2

(empagliflozin vs DPP-4 inhibitors)

Broad HHF83/17,539

(0.5)10.5

150/17,539

(0.9)19.9

0.56

(0.43, 0.73)

Without CVD 17/13,243 2.8 47/13,243 8.30.35

(0.20, 0.61)

With CVD 63/4,217 35.2 120/4,217 68.00.53

(0.39, 0.72)

Direct comparison of studies should be interpreted with caution due to differences in study design, populations and methodology; definitions of HHF vary between studies.

CI, confidence interval; CVD, cardiovascular disease; DPP-4, dipeptidyl peptidase-4; HHF, hospitalisation for heart failure; HR, hazard ratio; PY, patient-years.

0,125 0,25 0,5 1 2

Favours

empagliflozin

Favours

comparator

1. SAFETY

2. SUPERIORITY

3. NEW SIGNALS

4. NEW TRIALS


6. CHANGED PRACTICE

CVOT

What has

changed?

ADA–EASD

Guidelines

(2018)

CONSENSUS RECOMMENDATION

Davies et al. Diabetologia 2018;doi:10.1007/s00125-018-4729-5.

Davies et al. Diabetologia 2018;doi:10.1007/s00125-018-4729-5.

ADA–EASD

Guidelines

(2018)

CONSENSUS RECOMMENDATION

Since the publication of CVOT data, how has the approach to

T2D treatment changed? Have we shifted our focus?

What was the approach for T2D treatment

before the availability of CVOT results?

How have CVOT results influenced the treatment of patients with T2D?

1. Scheen. Nat Rev Cardiol 2016;13:509–10. 2. Schernthaner et al. Ther Clin Risk Manag 2017;13:69–79. 3. Perseghin & Solini. Cardiovasc Diabetol

2016;15:85. 4. Schernthaner et al. Cardiovasc Diabetol 2017;16:137.

A historical lack of

evidence for CV

outcomes with different

therapies meant that

treatment focused mainly

on glucose lowering1The CVOT results have demonstrated

the potential to reduce CV risk

- and highlighted its importance2

The new data has enabled a shift to

evidence-based prescribing, where

glucose lowering is still important, but

sits alongside CV outcomes1,2

CV, cardiovascular; CVOT; CV outcomes trial; T2D, type 2 diabetes.

1. SAFETY/ NON-INFERIORITY

2. SUPERIORITY

3. NEW SIGNALS

4. NEW HYPOTHESES & TRIALS


6. CHANGED PRACTICE

CVOT

legacy

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