Il MACE nel Diabete Mellito Tipo 2:ruolo delle associazioni terapeutiche sulla protezione cardiovascolare

Andrea GiaccariCentro per le

Malattie Endocrinee Metaboliche

diabete@policlinicogemelli.it

DIABETE MELLITO TIPO 2 E RISCHIO CARDIOVASCOLARE: UN UPDATE SULLA GESTIONE CLINICA

9 giugno 2018Albano Laziale

insulina

SGLT-2i + GLP-1 RA +pio +DPP-4i +

metformina

acarbosio

pio

SGLT-2i

SU

acarbosio acarbosio acarbosio

SGLT-2i GLP-1 RApioDPP-4i

DPP-4i

SGLT-2i

GLP-1 RA

SU

GLP-1 RA

SU

pio

DPP-4i pio

SGLT-2i

SU GLP-1 RA

pio

DPP-4i

SGLT-2i

metformina +

metformina +

metformina

iperglicemia

NO P.T. SI P.T. no rimborsoStandard italiani per la cura del diabete mellito 2018

A1c = glycosylated hemoglobin; CHD = coronary heart disease. *P<0.01 vs lowest tertile; †P<0.05 vs lowest tertile.Kuusisto J et al. Diabetes 43:960, 1994

A1c Predicts CV Riskprospective study of 229 Finnish type 2 diabetic patients

without previous vascular disease

A1c Tertile:

CHD Mortality All CHD Events

Low<6.0

Middle6.0-7.9

High>7.9

Low<6.0

Middle6.0-7.9

High>7.9

*

†

Inci

denc

e (%

) O

ver

3.5

Year

s

0

5

10

15

20

25

0

5

10

15

20

25

NEJM

micro macro

VA-DT NO NO

ADVANCE ? NO

ACCORD ? ?

3 trials: VA-DT ADVANCE ACCORD

Any diabetes related endpoint RRR: 12% 9%P: 0.029 0.040

Microvascular disease RRR: 25% 24%P: 0.0099 0.001

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

Aggregate Endpoint 1997 2007

UKPDS Group. NEJM 359:1577, 2008

UKPDS: after 8.5 yrs. of post-trial follow-upalmost 20 years to gain primary prevention

%

0 1 3 420

5

10

15

20

5

metformina + insulina: CVDpazienti con DT2 in tp solo con insulina

Kooy A et al. Arch Intern Med 6:616, 2009

40% eventi CV

metformina

placebo

eventi%

0

5

15

0 12 18 366

pioglitazone

mesi

PROACTIVE: MACE

24

10

HR 0.82(0.70-0.97)

p=0.02

Wilcox R. et al AHJ 155:712, 2008

placebo

PROACTIVE: Heart failure risk

Erdmann E et al.: Diabetes Care 30:2773, 2007

events%

0

2

4

6

0 12 18 30 366

pioglitazoneplacebo

months24

la riduzione di HbA1c < 7%previene eventi CV?

NO!target HbA1c più alti (> 8%)

the burdening clinical point

empagliflozin

placebo

181614121086420

HR 0.86(95% CI 0.74, 0.99)

p=0.0382risk reduced by 14%

EMPAREG primary outcome:3-point MACE

1 2 3 40yearsZinman B et al.: NEJM 373:2117, 2015

patie

nts

with

eve

nt (

%)

Zinman B et al.: NEJM 373:2117, 2015

9876543210

empagliflozin

placebo

1 2 3 40

HR 0.62(95% CI 0.49, 0.77)

p<0.0001risk reduced by 38%

patie

nts

with

eve

nt (

%)

years

EMPAREG: CV mortality

FINALLY!happy doctors

Number Needed to Treat (NNT) per prevenireuna morte cardiovascolare in pazienti ad alto rischio

1. 4S investigator. Lancet 1994; 344: 1383-89, http://www.trialresultscenter.org/study25904S.htm2. HOPE investigator N Engl J Med 2000;342:145-53, http://www.trialresultscenter.org/study2606-HOPE.htm

statina 1

per 5.4 anni

alto rischio CV 5% diabete 26% ipertensione

1994 2000 2015

era pre-statina

alto rischio CV38% diabete,

46% ipertensione

ACE-I 2per 5 anni

era pre-ACEi/ARB

<29% statina

DMt2 con alto rischio CV92% ipertensione

gliflozinaper 3 anni

>80% ACEi/ARB

>75% statina

years510

placebo liraglutide

2 3 4patie

nts

with

eve

nt (

%)

LEADER: MACE (primary outcome)CV Death, Nonfatal Myocardial Infarction or Nonfatal Stroke

Marso SP et al.: NEJM 375:311, 2016

Hazard ratio, 0.87 (95% CI, 0.78–0.97) P<0.001 for noninferiorityP=0.01 for superiority

20

16

12

8

4

0

months2460

placebo semaglutide

12 18patie

nts

with

eve

nt (

%)

SUSTAIN6: MACE (primary outcome)CV Death, Nonfatal Myocardial Infarction or Nonfatal Stroke

Marso SP et al.: NEJM 375:1834, 2016

Hazard ratio, 0.74 (95% CI, 0.58–0.95) P<0.001 for noninferiorityP=0.02 for superiority

10

8

6

4

1

0

Lifestyle + metformin + two additional agents

Lifestyle management + metformin

Lifestyle + metformin + additional agent

A1c at target after 3 months?

A1c < 9%, consider monotherapy

A1c ≥ 9%, consider dual therapy

A1c ≥ 10%, glucose ≥ 300 mg/dl, symptomsconsider combination injectable therapy

monotherapy

dual therapy

triple therapy

combination injectable therapy

add agent proven to reduce MACE and/or CV mortalityadd second agent after consideration of drug-specificeffects and patients factors

YESNO

ASCVD?

NO YES monitor

ADA Standardof Care 2018

LEADER: group sub-analysis

Chronic heart failure

Renal function<60 ml/min/1.73 m2

≥60 ml/min/1.73 m2

0.85 (0.76–0.96)0.94 (0.72–1.21)

0.94 (0.83–1.07)0.69 (0.57–0.85)

Yesp=0.53

p<0.01

1.0Liraglutide Better

0.6

No

Placebo Better

1.4

Marso SP et al.: NEJM 375:311, 2016

CANVAS, Neal B et al.: NEJM Jun 12, 2017 years5 610

placebo canagliflozin

2 3 4

20181614121086420

patie

nts

with

eve

nt (

%)

CANVAS: MACE (primary outcome)CV Death, Nonfatal Myocardial Infarction or Nonfatal Stroke

commenti

• anche se non conosciamo il vero meccanismodi azione, SGLT-2i e liraglutide prevengonoeventi CV in prevenzione secondaria:devono essere utilizzati

• ma in prevenzione primaria?

years5 610 2 3 4

20181614121086420

patie

nts

with

eve

nt (

%)

empagliflozin

placebo canagliflozin

Neal B et al.: NEJM 377, 2097, 2017Zinman B et al.: NEJM 373:2117, 2015

CANVAS & EMPAREG: MACE (primary outcome)CV Death, Nonfatal Myocardial Infarction or Nonfatal Stroke

SGLT-2i GLP-1 RA DPP-4iTrial EMPA-REG CANVAS DECLARE ELIXA LEADER SUSTAIN SAVOR EXAMINE TECOS

Baseline empa cana dapa lixi lira sema saxa alo sitan 7,020 10,142 17,160 6,068 9,340 3,297 16,492 5,400 14,671Age (yr) 63 63.3 63.8 60 64 65 65 61 66Diabetes (yr) 57%>10 13.5 <5 to > 20 9.3 12.8 13.9 10 7.2 9.4BMI (kg/m2) 30.6 32 32.1 30.1 32.5 32.8 31 29 29Insulin (%) 48 50 40 39 44 58 41 30 23

Prior CV disease (%) 99 65 40 100 81 83 78 100 100

Type of prior CV disease

MI, CHD, CVD, PVD

MI, CHD, CVD, PVD

CVD 40% or ≥1 lipids,

smoke, HTN60%

ACS < 180 days

≥ 50 yr + CVD or CKD; ≥ 60 yr + ≥1

risk factor

≥ 40 yr + CVD or CKD;

≥ 55 yr + ≥1 risk factor

ACS < 90 days

CHD, CVD, PVD

Hypertension (%) 94 90 89 76 92 93 81 83 86Follow-up (yr) 3.1 3.6 4.5 2.1 3.8 2.1 2.1 1.5 2.8

agent or placebo tested as add-on to usual care, aiming for glycemic equipoise

CVOT: different populations

years5 610 2 3 4

24

20

16

12

8

4

0

patie

nts

with

eve

nt (

%)

empagliflozin

placebo canagliflozin

CANVAS:only patients withprevious CV event

Neal B et al.: NEJM 377, 2097, 2017; Zinman B et al.: NEJM 373:2117, 2015Wanner K et al.: NEJM 375:323, 2016; Mahaffey KW et al.: Circulation 137:323, 2018

CANVAS & EMPAREG: MACE (primary outcome)CV Death, Nonfatal Myocardial Infarction or Nonfatal Stroke

years5 610 2 3 4

24

20

16

12

8

4

0

patie

nts

with

eve

nt (

%)

placebocanagliflozin

no previous CV event

previous CV event

Mahaffey KW et al.: Circulation 137:323, 2018

(P for interaction = 0.18)

CANVAS: MACE in primary or secondary preventionCV Death, Nonfatal Myocardial Infarction or Nonfatal Stroke

years

cum

ulat

ive

inci

denc

eTOSCA.IT: primary outcome

all-cause death, non-fatal MI (including silent), non-fatal stroke, or urgent coronary revascularisation

metformin + pioglitazone metformin + sulfonylureas

HR 0.96, 95% CI 0.74–1.26, p=0.79

Vaccaro O et al for the Thiazolidinediones Or Sulfonylureas Cardiovascular Accidents Intervention Trial (TOSCA.IT) study group and Italian Diabetes Society. Lancet DE 5:887, 2017

5100 2 3 4

0.05

0.10

0.15

0.20

0.25

Any diabetes related endpoint RRR: 12% 9%P: 0.029 0.040

Microvascular disease RRR: 25% 24%P: 0.0099 0.001

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

Aggregate Endpoint 1997 2007

UKPDS Group. NEJM 359:1577, 2008

UKPDS: after 8.5 yrs. of post-trial follow-upalmost 20 years to gain primary prevention

commenti

• anche se non conosciamo il vero meccanismodi azione, SGLT-2i e liraglutide prevengonoeventi CV in prevenzione secondaria:devono essere utilizzati

• un trial in prevenzione primaria non è fattibile!• possiamo avere evidenze da Real World Data?

FDA promotes Real World Evidence

N Engl J Med 375:2293, 2016 DOI: 10.1056/NEJMsb1609216

SGLT-2i

other glucose lowering drugsother glucose

lowering drugs

compared 1:1

Search a patient similar for 42 different criteria

Stuart EA. Stat Sci. 25:1, 2010 doi: 10.1214/09-STS313

propensity match

database N events HR (95%CI)

US 143,264 250 0.38 (0.29, 0.50)

Norway 25,050 364 0.55 (0.44, 0.68)

Denmark 18,468 323 0.46 (0.37, 0.57)

Sweden 18,378 317 0.47 (0.37, 0.60)

UK 10,462 80 0.73 (0.47, 1,15)

Total 215,622 1334 0.49 (0.41, 0.57)

0.25 0.5 2

favor SGLT-2i favor other medicines

Hazard Ratio 1

Kosiborod M. et al.: Circulation 18:249, 2017

CVDReal all cause deathprimary analysis (N=215,622)

HR 0.53 (95% CI 0.40–0.71) HR 0.78 (95% CI 0.69–0.87)

Other glucose-lowering drugs SGLT2 inhibitors

cardiovascular mortality

00

1

2

3

4

5

6

0.5

1.0

1.5

2.0

0 1 2 0 1 2

MACE

years years

% %

Birkeland KI et al.: Lancet DE 5:709 2017

CVD Real Nordic: SGLT-2i vs. othersCV mortality and MACE

Heart Failure CV disease All cause

mortalityNo treat. 1.00 1.00 1.00

Metformin 0.68 *(0.65 to 0.71)

0.76 *(0.74 to 0.79)

0.64 *(0.63 to 0.66)

SUs 1.00(0.94 to 1.07)

1.00(0.95 to 1.05)

1.24 †(1.20 to 1.28)

Insulin 1.26 †(1.10 to 1.44)

1.22 †(1.08 to 1.37)

1.64 †(1.55 to 1.74)

Glitazones 0.50 *(0.26 to 0.97)

0.79(0.53 to 1.18)

0.89(0.67 to 1.18)

Gliptins 0.87(0.58 to 1.31)

1.14(0.85 to 1.54)

1.20(1.00 to 1.44)

Hippisley-Cox J et al.: BMJ 354:i3477, 2016

diabetes treatments and CV riska cohort (469,688) study in primary care in UK

commenti su CVD Real

• scarsi dati clinici

• possibile bias di selezione (perfettamentecontrollato ma NON randomizzato)

• effetto troppo precoce (come EMPAREG)

Primary Endpoints• 3 MACE: CV death + non fatal MI or stroke• CV death or Hospitalization for Heart Failure

Screening

placebo

dapagliflozin 10 mg

~6 yrsfollow-up ~4.5 yrsevent driven trial: 1,390

1:1

Dou

ble

-blin

dinclusion criteria:• t2DM, ≥ 40 yrs.•previous CV eventor≥ 2 CV risk factors

N = 17,160 standard therapy

40%

60%

Wiviott SD et al.: Am Heart Journal inpress, doi: 10.1016/j.ahj.2018.01.012clinicaltrials.gov/ct2/show/NCT01730534http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM379659.pdf

DECLARE: Dapagliflozin Effects on CardiovascuLAR Eventsthe only trial studying the entire diabetic population

conclusioni• il nostro dovere non è “solo” trattare la

glicemia, ma prevenire eventi CV• SGLT-2is e liraglutide (pio?) li prevengono

almeno in secondaria• non avremo mai dati in primaria• anche se non ne capiamo il MoA, nell’attesa,

inseriamo questi farmaci almeno a tutti ipazienti con evento CV

placebo

Inci

denc

era

te(p

er10

00pa

tient

sov

er5

year

s)

16 fewer patients

15 more patients17 fewer

patients

MACE hosp. for HF amputation

23 fewer patients

5 above ankle10 toes and metatarsals

renalcomposite

canagliflozin

CANVAS, Neal B et al.: NEJM Jun 12, 2017

CANVAS: overall benefits and risk

0

20

40

120

140

160

180

100

80

60

*CANVAS endpoints comparable with EMPAREG

Neal B et al.: NEJM 377, 2097, 2017Zinman B et al.: NEJM 373:2117, 2015Wanner K et al.: NEJM 375:323, 2016

2.0Favors Placebo

0.5 1.00.25Favors SGLT2i

CANVASEMPAREGMACE-3

CV deathNonfatal myocardial infarctionNonfatal stroke

Hospitalization for heart failureCV death or hospitalization for HFAll-cause mortalityProgression to macroalbuminuria*Renal composite*

CANVAS & EMPAREG: key outcomes compared

• vasoconstriction glomerular afferent arteriole• other transporters• hemoglobin• hematocrit increase / fluid loss• increased β OH oxidation• increased glucose oxidation• many others!

possible mechanisms for CV protection

Favors Conventional

0.5 1 20.880.900.94

0.841.110.75

0.0290.340.44

0.0520.520.0099

Diabetes-related end pointsDiabetes-related deathsAll-cause mortality

Myocardial infarctionStrokeMicrovascular

RR P

FavorsIntensive

Relative Riskand 95% CI

UKPDS Group. Lancet 352:837, 1998

UKPDS: primary prevention with intensive therapy

commenti su DECLARE

• disegnato per esaminare popolazionegenerale (tipica dei nostri centri)

• non ha potenza per prevenzioneprimaria

• importante co-primary endpoint(CV death + HF Hospitalization)