Ilaria Malandrucco - SID Italia · Diabetes is associated with significant loss of life years...

Diabete e rischio cardiovascolare: cosa abbiamo

imparato dai recenti CVOTs e novità

dallo studio LEADER

Ilaria MalandruccoUOC Endocrinologia e Diabetologia

Ospedale Fatebenefratelli Isola Tiberina Roma

ACISMOM Latina

Dichiaro di aver ricevuto negli ultimi due anni compensi o finanziamenti per la ricerca o contratti di consulenza dalle seguenti Aziende Farmaceutiche e/o Diagnostiche: MOVI SPA

Diabetes is associated with significant loss of life years

Seshasai et al. N Engl J Med 2011;364:829-41

.

0

7

6

5

4

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1

040 50 60 70 80 90

Age (years)

Year

s o

f lif

e lo

st

Men7

6

5

4

3

2

1

040 50 60 70 80 900

Age (years)

Women

Non-vascular deaths

Vascular deaths

In media una persona di 50 anni con diabete in assenza di storia di malattia cardio-vascolare ha una aspettativa di vita inferiore di 6 anni rispetto alle persone senza diabete

per

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erso

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id

i fo

llow

-up

60

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10

30

50

40

Chicago Framingham Whitehall Paris

Uomini

DonneUomini

Donne

RR 4

RR 6,9

RR 2,5

RR 4,5

RR 3,9

RR 2

Non diabetici Diabetici

Mortalità per CHD nel pz con diabete tipo 2 rispetto alla popolazione generale

After median 8.5 years post-trial follow-up

Aggregate Endpoint 1997 2007

Any diabetes related endpoint RRR: 12% 9%

P: 0.029 0.040

Microvascular disease RRR: 25% 24%

P: 0.0099 0.001

Myocardial infarction RRR: 16% 15%

P: 0.052 0.014

All-cause mortality RRR: 6% 13%

P: 0.44 0.007

RRR = Relative Risk Reduction, P = Log Rank

Early vs late glycaemic intervention

ADVANCEACCORD VADT

N Engl J Med 2009;360: 129N Engl J Med 2008;358:2545 N Engl J Med 2008;358:2562

CV risk in intensive vs standard blood glucose control groups in the ACCORD, ADVANCE and VADT Trials

Dormandy JA et al., Lancet 2005; 366: 1279

5.238 soggetti con pregressa malattia cardiovascolare. Periodo mediano 2.9 anni.NNT per prevenire un MACE :50, NNH 33 per 2.9 anni di trattamento

The PROACTIVE StudyPIOGLITAZIONE and CVD

N Engl J Med. 2012 Jul 26;367(4):319-28

12.537 soggetti in ampia maggioranza con DM2 di recente diagnosi e pregressi eventi. Circa 6 anni di trattamento

The ORIGIN StudyGlargine and CVD

Autorità regolatorie, focus sulla sicurezza cardiovascolare delle nuove

terapie per il diabete

New type 2 diabetes drugs must demonstrate no unacceptable increase in

CV events

“We need to better understand the safetyof new antidiabetic drugs; therefore, companies

should conduct a more thorough examination of their drug’s cardiovascular risks during the

product’s development stage”

Mary Parks, MD Director of the Division of Metabolism and Endocrinology Products,

Center for Drug Evaluation and Research

FDA Guidance for Industry to Evaluate CV Risk in New Antihyperglycemic Medications

Cardiovascular death

Non-fatal myocardial infarction

Non-fatal stroke

Additional components

may be included

MACE

MACE-plus events, e.g.:• Hospitalisation

for acute coronary syndrome

• Urgent revascularisation procedures

• Heart failure

MACE, major adverse cardiovascular eventFDA guidance for industry December 2008 last accessed May 2016, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf; Hirschberg B and Katz A, Diabetes Care 2013;36:S253‒S258

Additional components for MACE-plus

Key components of MACE (hard endpoints of atherosclerotic disease)

What are Major Adverse Cardiovascular Events?

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf

2013 2014 2015 2016 2017 2018 2019 2020

SGLT2i

GLP-1

DPP-4

Source: ClinicalTrials.gov (30 June 2015). ‘Completion date’ is the estimated completion date for the primary outcomes measure. *Also known as C-SCADE-8

TECOS(Sitagliptin, DPP-4i)

n=14,671; follow-up ~3 yrsQ1 2015 - RESULTS

CARMELINA(Linagliptin, DPP-4i)n= 8,300; duration ~4 yrs completion Q1 2018

CAROLINA(Linagliptin, DPP-4i vs

SU)n= 6,000; duration~8 yrs completion Q3 2018

SAVOR TIMI-53(Saxagliptin, DPP-4i)

n=16,492; follow-up ~2 yrs Q2 2013 - RESULTS

EXAMINE(Alogliptin, DPP-4i)

n=5,380; follow-up ~1.5 yrsQ3 2013 - RESULTS

ALECARDIO(Aleglitazar, PPAR-αγ)

n=7,226; follow-up 2.0 yrsTermin. Q3 2013 RESULTS

LEADER(Liraglutide, GLP-1)

n=9,340; duration 3.5-5 yrscompletion Q4 2015

ELIXA(Lixisenatide, GLP-1)

n=6,068; follow-up ~2 yrsQ1 2015 –RESULTS

EMPA-REG OUTCOME*(Empagliflozin, SGLT2i)n=7,097; duration up to 5yrs Q2 2015 –RESULTS

SUSTAIN 6(Semaglutide, GLP-1)

n=3,297; duration ~2.8 yrscompletion Q1 2016

EXSCEL(Exenatide QW, QW GLP-1)n=14,000; duration ~7.5 yrs

completion Q1 2018

OMNEON(Omarigliptin, QW DPP-4i)n=4,000; duration ~3 yrs

completion Q4 2017

CANVAS(Canagliflozin, SGLT2i)

n=4,407; duration 4+yrscompletion Q2 2017

CANVAS-R(Canagliflozin, SGLT2i)

n=5,865; duration ~3 yrscompletion Q1 2017

DEVOTE(Insulin degludec, basal insulin)

n=7,637; duration up to 5yrscompletion H2 2016

FREEDOM-CVO(ITCA 650, GLP-1 in DUROS)

n=4,000; duration ~2 yrscompletion Q3 2018

CREDENCE (cardio-renal)(Canagliflozin, SGLT2i)

n= 3,700; duration ~5.5 yrs completion Q1 2019

REWIND(Dulaglutide, QW GLP-1)

n=9,622; duration ~6.5yrscompletion Q2 2019

DECLARE-TIMI-58(Dapagliflozin, SGLT2i)

n=17,150; duration~6 yrscompletion Q2 2019

NCT01986881(Ertugliflozin, SGLT2i)

n=3,900; duration~6.3 yrscompletion Q2 2021

HARMONY OUTCOMES(Albiglutide, GLP-1)

n=9,400; duration ~4yrs completion by Q2 2019

Completed with results Ongoing

Ongoing and recently completed cardiovascular outcomes trials within diabetes enrolling >130,000 patients

Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus

Empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

Lixisenatide in acute coronary syndrome, a long-term cardiovascular end point trial of

lixisenatide vs placebo

Alogliptin after acute coronary syndrome in patients with type 2 diabetes

SUSTAIN 6: cardiovascular and other long-term outcomes with semaglutide

in subjects with type 2 diabetes

Liraglutide and cardiovascular outcomes in type 2 diabetes

Test for heterogeneity for 3 trials:p=0.877, I2=0%

1.Scirica BM et al. N Engl J Med 2013; 369: 1317–13262.White WB et al. N Engl J Med 2013; 369: 1327–13353.Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

SAVOR-TIMI, EXAMINE and TECOSMACE EVENTS

SAVOR-TIMI, EXAMINE and TECOS*

Hospitalization for Heart Failure

Time to first occurrence of CV death, non-fatal MI, non-fatal stroke or hospitalisation for unstable angina

CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.

Pfeffer MA et al. N Engl J Med 2015;373:2247–2257

Pati

en

ts w

ith

even

t (%

)

0

0 12 24 36

5

10

15

20

Lixisenatide: 406/3034 = 13.4%Placebo: 399/3034 = 13.2%

Hazard Ratio (95% CI) 1.02 (0.89–1.17)

p<0.001 for noninferiorityp=0.81 for superiority

Months

30343034

27592785

15661558

476484

Number at riskPlacebo

Lixisenatide

The ELIXA StudyLIXISENATIDE and CVD

6.068 soggetti con pregressa malattia cardiovascolare. Periodo mediano 2.1 anni.

Primary outcome:

3-point MACE (CV death, non-fatal MI, non fatal stroke)

HR 0.86(95.02% CI 0.74, 0.99)

p=0.0382*

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)

- 14%

Ussher JR et al. Circ Res 114:1788-1803, 2014

Potential indirect cardiovascular effects of GLP-1R agonists

GLP-1: a cardiologic dimension

Ussher and Drucker , Endocr Rev 2012

-11,9

-23,1

-7.6

-25

-20

-15

-10

-5

0

BNP hsCRP PAI-1

P<0.001

P<0.001

LEAD-1–6: meta-analysis

*Change from baseline to week 26 with liraglutide 1.8 mg once daily

Plutzky et al. Diabetologia 52 (Suppl. 1): S299, 2009 Plutzky et al. Circulation 120:S397, 2009

P<0.001

Ch

an

ge

fro

m b

ase

lin

e (

%)

Liraglutide consistently improved biomarkers of CV

risk in subjects with type 2 diabetes

Liraglutide ha dimostrato di migliorare i parametri biochimici implicati nella

valutazione del rischio cardiovascolare

*P <0.05 vs. placebo

Infarct Infarct

Liraglutide

Infa

rct

siz

e

(% o

r a

rea

at

risk

)

*

0

10

20

30

Placebo

Infarct size (21% vs. 29%; P=0.02)

MI, myocardial infarction

Noyan-Ashraf et al. Diabetes 58:975–983, 2009

Infarct size is reduced with liraglutide at 28 days post-MI in mice

liraglutide riduce l’area infartuata e migliora la sopravvivenza dei cardiomiociti

Cantini G, Mannucci E, Luconi M. Trends Endocrinol Metab 2016; 27:427-438

Alternative GLP-1 receptors?

LEADER: Study design

CV, cardiovascular; HbA1c, glycosylated haemoglobin; OAD, oral antidiabetic drug; OD, once daily; T2DM, type 2 diabetes mellitus.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

Liraglutide 0.6–1.8 mg OD + standard of care

Placebo + standard of care

Duration 3.5–5 years

9340 patients

• Double blinded

• 2-week placebo run-in

Randomisation (1:1) End of treatment

Key exclusion criteria

• T1DM

• Use of GLP-1RAs, DPP-4i, pramlintide, or rapid-acting insulin

• Familial or personal history of MEN-2 or MTC

Key inclusion criteria

• T2DM, HbA1c ≥7.0%

• Antidiabetic drug naïve; OADs and/or basal/premix insulin

• Age ≥50 years and established CV disease or chronic renal failure or

• Age ≥60 years and risk factors for CV disease

Placebo run-

in

Safety follow-up

Safety follow-up

30 days2 weeks

Screening

Primary and key secondary outcomes

Primary outcome

Time to first MACE composed of

• CV death

• Non-fatal MI

• Non-fatal stroke

Key secondary outcomes

Time to first occurrence of

• Expanded composite CV outcome (CV death, non-fatal MI, non-fatal stroke, coronary revascularisation, unstable angina pectoris requiring hospitalisation, or hospitalisation for heart failure)

• All-cause death

• Each individual component of expanded composite CV outcome

CV, cardiovascular; MACE, major adverse cardiovascular event; MI, myocardial infarction.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

Study patient disposition

Did not complete study N=139 (3.0%)• Alive N=127 (2.7%)Vital status unknown N=12 (0.3%)• Withdrawal of consent N=4 (0.1%)• Lost to follow-up N=8 (0.2%)

Completed study N=4529 (97.0%)

Completed study N=4513 (96.6%) Did not complete study N=159 (3.4%)

• Alive N=142 (3.0%)Vital status unknown N=17 (0.4%)• Withdrawal of consent N=8 (0.2%)• Lost to follow-up N=9 (0.2%)

PlaceboN=4672 (100%)

LiraglutideN=4668 (100%)

Randomised (FAS)N=9340 (100%)

ScreenedN=12076

Screening failures N=2002Withdrew before run-in N=456

Run-inN=9618

Run-in failures N=106Withdrew before randomisation N=172

FAS, full analysis set.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

Liraglutide (N=4668) Placebo (N=4672)

Male sex, N (%) 3011 (64.5) 2992 (64.0)

Age, years 64.2 ± 7.2 64.4 ± 7.2

Diabetes duration, years 12.8 ± 8.0 12.9 ± 8.1

Geographic region

Europe 1639 (35.1) 1657 (35.5)

North America 1401 (30.0) 1446 (31.0)

Asia 360 (7.7) 351 (7.5)

Rest of the world 1268 (27.2) 1218 (26.1)

HbA1c, % 8.7 ± 1.6 8.7 ± 1.5

BMI, kg/m2 32.5 ± 6.3 32.5 ± 6.3

Body weight, kg 91.9 ±21.2 91.6 ± 20.8

Systolic blood pressure,

mmHg135.9 ± 17.8 135.9 ± 17.7

Diastolic blood pressure,

mmHg77.2 ± 10.3 77.0 ± 10.1

Heart failure*, N (%) 835 (17.9) 832 (17.8)

Baseline characteristics

Full analysis set. Data are means ± standard deviations or number of patients (percentage of either liraglutide-treated or placebo-treated group). Percentage data refer to proportion of patients. *Heart failure includes NYHA class I, II and III.BMI, body mass index; HbA1c, glycosylated haemoglobin; NYHA, New York Heart Association.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

Baseline cardiovascular risk profile (1/2)

Liraglutide

(N=4668)

Placebo

(N=4672)

Established CVD (age ≥50 years) 3831

(82.1)

3767

(80.6)

Prior myocardial infarction 1464 (31.4) 1400 (30.0)

Prior stroke or prior TIA 730 (15.6) 777 (16.6)

Prior revascularisation 1835 (39.3) 1803 (38.6)

>50% stenosis of coronary, carotid, or

lower extremity arteries1188 (25.4) 1191 (25.5)

Documented symptomatic CHD 412 (8.8) 406 (8.7)

Documented asymptomatic cardiac

ischaemia1241 (26.6) 1231 (26.3)

Chronic heart failure NYHA II – III 653 (14.0) 652 (14.0)

Chronic kidney disease 1185 (25.4) 1122 (24.0)

Full analysis set. Data are number of patients (percentage of either liraglutide-treated or placebo-treated group). Percentage data refer to proportion of patientsCHD, coronary heart disease; CVD, cardiovascular disease; NYHA, New York Heart Association; TIA, transient ischaemic attack.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

Baseline cardiovascular risk profile (2/2)

Liraglutide

(N=4668)

Placebo

(N=4672)

CVD risk factors (age ≥60 years) 837 (17.9) 905 (19.4)

Microalbuminuria or proteinuria 501 (10.7) 558 (11.9)

Hypertension and left ventricular

hypertrophy248 (5.3) 251 (5.4)

Left ventricular systolic or diastolic

dysfunction203 (4.3) 191 (4.1)

Ankle/brachial index <0.9 110 (2.4) 116 (2.5)

Full analysis set. Data are number of patients (percentage of either liraglutide-treated or placebo-treated group). Percentage data refer to proportion of patientsCVD, cardiovascular disease.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

HbA1c

Time from randomisation (months)

Hb

A1

c(%

)

Hb

A1

c(m

mo

l/m

ol)

ETD at month 36: -0.40% 95% CI (-0.45 ; -0.34)

Number of patients at each visit

3705101809234938103877403441354295435544024668Liraglutide

356187756230336403742390540304235435544134672Placebo

5 .0

6 .0

7 .0

8 .0

9 .0

30

35

40

45

50

55

60

65

70

75

0 6 1 2 2 4 3 6 4 8

L ira g lu t id e

P la ce b o

3 5 41 8 3 0 4 2 E O T

Data are estimated mean values from randomisation to EOT. CI, confidence interval; EOT, end of trial; ETD, estimated treatment difference; HbA1c, glycosylated haemoglobin.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

Body weight


Bo

dy w

eig

ht

(kg

)

Bo

dy w

eig

ht

(lb

)

8 4

8 6

8 8

9 0

9 2

94

96

192

194

196

198

200

202

204

0 1 2 2 4

L ira g lu t id e

P la ce b o

6 3 6 E O T4 8

ETD at month 36: -2.3 kg 95% CI (-2.5 ; -2.0)

370882438354088432444344667

355576636803970428544234671


Liraglutide

Placebo

Data are estimated mean values from randomisation to EOT.CI, confidence interval; EOT, end of trial; ETD, estimated treatment difference.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

Blood pressure

SBP ETD at month 36: -1.2 mmHg

95% CI (-1.9 ; -0.5)

DBP ETD at month 36: 0.6 mmHg

95% CI (0.2 ; 1.0)

Data are estimated mean values from randomisation to EOT; *EOT may be any time from month 42 onwards.CI, confidence interval; DBP, diastolic blood pressure; EOT, end of trial; ETD, estimated treatment difference; SBP, systolic blood pressure.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.


Liraglutide

Placebo

372282338594107433244454668

357076736993975429544354672

7 0

7 5

8 0

0 6 1 2 2 4 3 6 4 8

P l a c e b o

L i r a g l u t i d e

E O T *

1 3 0

1 3 5

1 4 0

P l a c e b o

L i r a g l u t i d e

0 6 12 24 36 48 EOT*

Blo

od

pressu

re (

mm

Hg

)


Heart rate


Heart

rate

(b

pm

)

6 0

6 5

7 0

7 5

8 0

8 5

90

95

10 0

0 1 2 2 4

P la ce b o

L ira g lu t id e

6 3 6 E O T4 8

ETD at month 36: 3.0 bpm 95% CI (2.5 ; 3.4)


Liraglutide

Placebo

372282438534099433044424668

356976736953971429444344672

Data are estimated mean values from randomisation to EOT.Bpm, beats per minute; CI, confidence interval; EOT, end of trial; ETD, estimated treatment difference.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

Rate ratio(95% CI) p-value

Liraglutide Placebo

N % N %

Confirmed hypoglycaemia 0.80

(0.74 ; 0.88) <0.001 2039 43.7 2130 45.6

Severe hypoglycaemia0.69

(0.51 ; 0.93)0.016 114 2.4 153 3.3

Hypoglycaemia

Favours Liraglutide Favours Placebo

10 .5 1 .5

Hazard ratio (95% CI)

Confirmed hypoglycaemia was defined as plasma glucose level of less than 56 mg per decilitre (3.1 mmol per litre) or a severe event. Severe hypoglycaemia was defined as hypoglycaemia for which the patient required assistance from a third party. Analysed using a negative binomial regression model.CI, confidence interval.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

P la ce b o

Pati

en

ts w

ith

an

even

t (%

)


Primary outcomeCV death, non-fatal myocardial infarction, or non-fatal stroke

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

HR=0.8795% CI (0.78 ; 0.97)

p<0.001 for non-inferiority

p=0.01 for superiority

The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke. The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

L ira g lu t id e

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

- 13%

0 6 12 18 24 30 36 42 48 54

0

2

4

6

8

L ira g lu t id e

P la ce b o

CV death

4668

4672

4641

4648

4599

4601

4558

4546

4505

4479

4445

4407

4382

4338

4322

4267

1723

1709

484

465

HR=0.7895% CI (0.66 ; 0.93)

p=0.007

Patients at risk

Liraglutide

Placebo

Pati

en

ts w

ith

an

even

t (%

)


The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI, confidence interval; CV, cardiovascular; HR, hazard ratio.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

- 22%

Non-fatal myocardial infarction

4668

4672

4609

4613

4531

4513

4454

4407

4359

4301

4263

4202

4181

4103

4102

4020

1619

1594

440

424

0 6 12 18 24 30 36 42 48 54

0

2

4

6

8

L ira g lu t id e

P la ce b o

HR=0.8895% CI (0.75 ; 1.03)

p=0.11

Patients at risk

Liraglutide

Placebo

Pati

en

ts w

ith

an

even

t (%

)


The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI, confidence interval; HR, hazard ratio.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

0 6 12 18 24 30 36 42 48 54

0

1

2

3

4

5

L ira g lu t id e

P la ce b o

Non-fatal stroke

4668

4672

4624

4622

4564

4558

4504

4484

4426

4405

4351

4314

4269

4228

4194

4141

1662

1648

465

445

HR=0.8995% CI (0.72 ; 1.11)

p=0.30

Patients at risk

Liraglutide

Placebo

Pati

en

ts w

ith

an

even

t (%

)



All-cause death

4668

4672

4641

4648

4599

4601

4558

4546

4505

4479

4445

4407

4382

4338

4322

4268

1723

1709

484

465

0 6 12 18 24 30 36 42 48 54

0

5

1 0

1 5

2 0

P la ce b o

Patients at risk

Liraglutide

Placebo

Pati

en

ts w

ith

an

even

t (%

)



HR=0.8595% CI (0.74 ; 0.97)

p=0.02

0 6 12 18 24 30 36 42 48 54

0

5

1 0

1 5

2 0

L ira g lu t id e

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

- 15%

Hazard ratio(95%

CI)p-

value

Liraglutide Placebo

N % R N % R

Number of patients 4668 100.0 4672 100.0

All-cause death0.85

(0.74;0.97)0.02 381 8.2 2.1 447 9.6 2.5

CV death0.78

(0.66;0.93)0.007 219 4.7 1.2 278 6.0 1.6

Non-CV death0.95

(0.76;1.18)0.66 162 3.5 0.9 169 3.6 1.0

Time to all-cause, CV and non-CV death

Hazard ratio (95% CI)

Favours PlaceboFavours Liraglutide

10 .5 1 .5

Hazard ratios and p-values were estimated with the use of a Cox proportional-hazards model with treatment as a covariate.%, percentage of group; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; N, number of patients; R, incidence rate per 100 patient-years of exposure.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

Number needed to treat to prevent one…

MACE All-cause death

for 3 years

66 98

MACE, major adverse cardiovascular event. Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

0 6 12 18 24 30 36 42 48 54

0

5

1 0

1 5

2 0

2 5

L ira g lu t id e

P la ce b o

Expanded MACECV death, non-fatal MI, non-fatal stroke, coronary revascularisation, or hospitalisation for unstable angina pectoris or heart failure

Patients at risk

Liraglutide

Placebo

4668

4672

4515

4506

4356

4336

4221

4157

4063

4002

3914

3857

3793

3697

3682

3581

1452

1410

395

366

HR=0.8895% CI (0.81 ; 0.96)

p=0.005

Pati

en

ts w

ith

an

even

t (%

)


The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI, confidence interval; HR, hazard ratio; MACE, major adverse cardiovascular event.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

- 12%

Hospitalisation for heart failure

4668

4672

4612

4612

4550

4540

4483

4464

4414

4372

4337

4288

4258

4187

4185

4107

1662

1647

467

442

HR=0.8795% CI (0.73 ; 1.05)

p=0.14

0 6 12 18 24 30 36 42 48 54

0

5

1 0

1 5

2 0

L ira g lu t id e

P la ce b o

Patients at risk

Liraglutide

Placebo

Pati

en

ts w

ith

an

even

t (%

)



Selected adverse events

Serious adverse events and nonserious medical events of special interest were identified by search in the Medical Dictionary for Regulatory Activities, version 18.0, or by “action to trial product: trial product permanently discontinued due to adverse event.” P values were calculated by means of Pearson’s chi-square test.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

Liraglutide Placebo

N % N % p-value

Any adverse event 2909 62.3 2839 60.8 0.12

Acute gallstone disease 145 3.1 90 1.9 <0.001

Cholelithiasis 68 1.5 50 1.1 0.09

Acute cholecystitis 36 0.8 21 0.4 0.046

Hypothyroidism 44 0.9 33 0.7 0.21

Hyperthyroidism 13 0.3 8 0.2 0.27

Diabetic foot ulcer 181 3.9 198 4.2 0.38

Allergic reactions 59 1.3 44 0.9 0.14

Injection site reactions 32 0.7 12 0.3 0.002

0 2 4 6 8 10

Liraglutide Placebo

Proportion of patients (%)

Pancreatic enzymes


Lip

ase (

U/

L)

0

2 0

4 0

6 0

8 0

0 12 24

P la ce b o

L ira g lu t id e

6 36 483 18 30 42

80838004016427343354578

75236213891423043404568


Liraglutide

Placebo

0

2 0

4 0

6 0

8 0

0 12 24

P la ce b o

L ira g lu t id e

6 36 483 18 30 42


Am

yla

se (

U/L)


Liraglutide

Placebo

81438174038428943614600

75836423921424243634590

Lipase Amylase

Data are observed geometric mean values from randomisation to the last scheduled visit for lipase and amylase measurements (month 48). Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

Liraglutide Placebo

p-value

N % N %

Acute pancreatitis 18 0.4 23 0.5 0.44

Chronic

pancreatitis0 0.0 2 0.0 0.16

Pancreatitis (confirmed by adjudication)

Full analysis set. The occurrence of pancreatitis was adjudicated by the event adjudication committee. P-values were calculated by means of Pearson’s chi-square test %, proportion of patients; N, number of patients.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

Pancreatitis and neoplasms (adjudicated)

Liraglutide Placebo

N % N % p-value

Acute pancreatitis 18 0.4 23 0.5 0.44

Chronic pancreatitis 0 0 2 <0.1 0.16

Any benign neoplasm 168 3.6 145 3.1 0.18

Any malignant neoplasm

296 6.3 279 6.0 0.46

Pancreatic carcinoma 13 0.3 5 0.1 0.06

Medullary thyroid carcinoma

0 0 1 <0.1 0.32

0 2 4 6 8 10

Proportion of patients (%)

Full analysis set. Serious adverse events and non-serious medical events of special interest were identified by MedDRA search (version 18.0) or by ‘action to trial product: trial product permanently discontinued due to adverse event’. AE, adverse event.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

Liraglutide Placebo

Cardiovascular medication introduced during trial

Liraglutide

(N=4668)

Placebo

(N=4672)p-value

Antihypertensive therapy 160 (3.4) 163 (3.5) 0.87

Beta blockers 69 (1.5) 66 (1.4) 0.79

Calcium channel blockers 34 (0.7) 29 (0.6) 0.53

ACE inhibitors 81 (1.7) 93 (2.0) 0.36

ARBs 51 (1.1) 65 (1.4) 0.19

Others 11 (0.2) 13 (0.3) 0.68

Diuretics 516 (11.1) 647 (13.8) <0.001

Loop diuretics 304 (6.5) 382 (8.2) <0.01

Thiazides 170 (3.6) 236 (5.1) <0.001

Thiazide-like diuretics 73 (1.6) 93 (2.0) 0.12

Aldosterone antagonists 117 (2.5) 95 (2.0) 0.13

Lipid-lowering drugs 417 (8.9) 481 (10.3) 0.026

Statins 379 (8.1) 450 (9.6) 0.010

Ezetimibe 17 (0.4) 16 (0.3) 0.86

Others 62 (1.3) 64 (1.4) 0.86

Platelet aggregation inhibitors 375 (8.0) 427 (9.1) 0.06

Acetylsalicylic acid 335 (7.2) 369 (7.9) 0.19

Clopidogrel, ticlopidine, prasugrel, ticagrelor

104 (2.2) 124 (2.7) 0.18

Other anti-thrombotic drugs 235 (5.0) 275 (5.9) 0.07Data are number of patients (percent of group). ACE: angiotensin-converting-enzyme; ARB: angiotensin II receptor blockers.Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1603827.

Popolazione studiata 9340 pazienti:• con precedente evento cardiovascolare o insufficienza renale cronica (81%) • alto rischio cardiovascolare

L’aggiunta di Liraglutide rispetto al placedo alla terapia background:

ha ridotto del 13% l’endpoint primario (3-point MACE: mortalità cardiovascolare, infarto non fatale e stroke non fatale)

ha ridotto del 22% la mortalità cardiovascolare e del 12% la mortalità per tutte le cause

ha ridotto il peso corporeo e gli episodidi ipoglicemia.

Liraglutide, in linea con i precedenti tials, è stato associato ad incremento degli enzimipancreatici e della frequenza cardiaca, ad un lieve aumento degli episodi di colelitiasi e colecistite acuta

Non si è osservato aumento degli episodi di pancreatite

Non ci è osservato aumento dell’ospedalizzazione per scompenso cardiaco

LEADER: Summary

Empagliflozin and Liraglutide

CV: cardiovascular; HR: hazard ratio; MI: myocardial infarction.1. Zinman B et al. N Engl J Med 2015;373:2117-2128; 2. Marso SP et al. N Eng J Med 2016; DOI: 10.1056/NEJMoa1603827

0 6 12 18 3024 4236 48

20

10

5

0

15

Pati

en

ts w

ith

an

even

t (%

)


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR: 0.8695.02% CI (0.74 – 0.99)

Pati

en

ts w

ith

an

even

t (%

)Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 540

5

10

15

20

Placebo

Liraglutide

HR: 0.8795% CI (0.78 – 0.97)

EMPA-REG OUTCOME1 LEADER2

CV death, non-fatal MI, or non-fatal stroke CV death, non-fatal MI, or non-fatal stroke

p<0.001 for non-inferiorityp=0.01 for superiority

p<0.001 for non-inferiorityp=0.04 for superiority


Presentation title Date 62

Saxagliptin and cardiovascular outcomes in patients with type 2

diabetes mellitus

Empagliflozin, cardiovascular outcomes and mortality in type 2

diabetes

Effect of sitagliptin on cardiovascular outcomes in type 2

diabetes

Lixisenatide in acute coronary syndrome, a long-term

cardiovascular end point trial of lixisenatide vs placebo

Alogliptin after acute coronary syndrome in patients with type 2

diabetes

SUSTAIN 6: cardiovascular and other long-term

outcomes with semaglutide in subjects with type 2

diabetes

Liraglutide and cardiovascular outcomes in

type 2 diabetes

2016 Settembre 15 DOI: 10,1056/NEJMoa1607141

Considerazioni finali

LA PROTEZIONE DEL PZ CON DIABETE TIPO 2 DAL RISCHIO CARDIO-VASCOLARE DIPENDE DA:

quale target glicemico per quel paziente

come viene raggiunto

con quale farmaco viene raggiunto

Liraglutide e empagliflozin hanno dimostrato di essere in grado di modificare la storia naturale del diabete tipo 2 in presenza di pregressa malattia cardiovascolare.

Si tratta di un risultato molto rilevante con notevoli ricadute clinico-assistenziali.

In pazienti con pregressa malattia cardiovascolare la terapia ipoglicemizzante dovrebbe includere empagliflozin o liraglutide anche in persone in buon controllo glicemico con la terapia in corso

Sembrano assai solide le evidenze che dovrebbero condurre ad una specifica indicazione dell’uso di empagliflozin e liraglutide nei soggetti con pregressa malattia cardiovascolare

Alcune delle indicazioni di uso di empagliflozin e di liraglutide dovrebbero essere aggiornate secondo quanto emerso dagli studi EMPA-REG e LEADER

Grazie per l’attenzione

Ilaria Malandrucco - SID Italia · Diabetes is associated with significant loss of life years...

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Transcript of Ilaria Malandrucco - SID Italia · Diabetes is associated with significant loss of life years...