Il MACE nel Diabete Mellito Tipo 2: ruolo delle associazioni terapeutiche sulla protezione cardiovascolare Andrea Giaccari Centro per le Malattie Endocrine e Metaboliche [email protected]DIABETE MELLITO TIPO 2 E RISCHIO CARDIOVASCOLARE: UN UPDATE SULLA GESTIONE CLINICA 9 giugno 2018 Albano Laziale
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Il MACE nel Diabete Mellito Tipo 2:ruolo delle associazioni terapeutiche sulla protezione cardiovascolare
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
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
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