Νεότερα δεδοµένα καρδιαγγειακής ασφάλειας των αναστολέων της DPP4: η Κλινική αξία για τον Καρδιολόγο Χαράλαµπος Βλαχόπουλος

Νεότερα δεδοµένα καρδιαγγειακής ασφάλειας των αναστολέων της DPP4: η Κλινική αξία για τον Καρδιολόγο Χαράλαµπος Βλαχόπουλος Επίκουρος Καθηγητής Καρδιολογίας 1η Πανεπιστηµιακή Κλινική, Ιπποκράτειο ΓΝΑ

Δήλωση Οι παρουσιάσεις στοχεύουν σε εκπαιδευτικούς σκοπούς και µόνο, και δεν αντικαθιστούν την ανεξάρτητη επιστηµονική κρίση. Οι δηλώσεις και οι απόψεις που εκφράζονται προέρχονται αποκλειστικά από τους οµιλητές και, εκτός από την περίπτωση που δηλώνεται ρητά το αντίθετο, δεν αποτελούν άποψη ή θέση της AstraZeneca. Η AstraZeneca δεν υποστηρίζει, δεν εγκρίνει και δεν αναλαµβάνει καµία ευθύνη για το περιεχόµενο, την ακρίβεια ή την πληρότητα των πληροφοριών που παρουσιάζονται.

Αναστολείς της DPP4 και καρδιαγγειακό σύστηµα Σ Διαβήτης και καρδιαγγειακός κίνδυνος Θεραπευτικοί στόχοι Αντιδιαβητικά φάρµακα και καρδιαγγειακό όφελος/ασφάλεια Συµπεράσµατα

Γιατί ενδιαφέρει τους Καρδιολόγους ο Διαβήτης;

Is type 2 diabetes really a coronary heart disease risk equivalent? Saely and Drexel. Vasc Pharmacol 2013

Σακχαρώδης Διαβήτης και Καρδιαγγειακό Σύστηµα

Ο ΣΔ στον πραγµατικό κόσµο Τα καταφέρνουµε αρκετά καλά;

Diabetes Mellitus in real world EUROASPIRE IV

Are we doing enough? EUROASPIRE IV Prevalence of DM: 40% (27% knew, 13% did not) Percentage of DM 3 times higher for the age range Only 50% of diabetics controlled well DM (HbA1c<7)

Treatment targets in patients with DM Glycaemic control Blood pressure control Dyslipidaemia control

Treatment targets in patients with DM Glycaemic control ESC Guidelines 2013

Treatment targets in patients with DM Blood Pressure control Target BP <140/85 Use a RAAS blocker ESC Guidelines 2013

Cardiovascular risk assessment in patients with DM The concept of target organ damage 2013 ESC/EASD guidelines Cardiovascular target organ damage, including low ABI, increased carotid intima-media thickness, artery stiffness or CAC score, cardiac autonomic neuropathy and silent myocardial ischemia may account for a part of the cardiovascular residual risk that remains, even after control of conventional risk factors. The detection of these disorders contributes to a more accurate risk estimate and should lead to a more intensive control of modifiable risk factors.

Aortic PWV as predictor of CV events Vlachopoulos C / Aznaouridis K, et al, J Am Coll Cardiol 2010 15,877 patients / follow up 7.7 years Increased arterial stiffness is linked to a twofold increase in CV events and mortality, as well as all-cause mortality

Treatment targets in patients with DM Dyslipidemia control ESC Guidelines 2013

Είναι όλα τα φάρµακα ίδια;

Antidiabetic agents and their cardiovascular safety N Engl J Med 2007;356:2457-2471 Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with a borderline significant risk of death from cardiovascular causes.

Η εποχή των mega trials Ελάχιστη πιθανότητα δυσάρεστων εκπλήξεων µετά την ευρεία κυκλοφορία του φαρµάκου!!!

Antidiabetic agents and their cardiovascular safety Recent CV outcome trials evaluating DPP-4 inhibitors: saxagliptin and alogliptin SAVOR TIMI-53 16.394 pts with DM II with CVD or high CVD risk Randomized to saxagliptin vs placebo EXAMINE 5380 pts with DM post ACS alogliptin vs placebo Primary outcome: CV death/mi/cva CV death/mi/cva Met the primary safety objective of noninferiority median FU: 2.1 years median FU: 18 months Met the primary safety objective of noninferiority (HR, 1.0; 95% CI, 0.89-1.12) (HR, 0.96; 95% UCL, 1.16) Superiority P value=.99 Superiority P value=.32 NEJM 2013 NEJM 2013

Saxagliptin(CV(Safety:(Pooled(Analysis(From(Phase 2/3(Development(Program((N(=(4607) SaxagliptinYtreated(patients(vs(control(patients(had(a(lower(rate(of CECYadjudicated(MACE((total(#(of(events(=(41) ( P e r c e n t W it h Fi rs t 4 3 2 1 Patients(at(Risk Control All(Saxa(((( E v e n t 5 Time%to%onset%of%first%MACE* HR(=(0.42;(95%(CI((0.23 0.80) Control 0 Baseline 24 37 50 63 76 89 102 115 1251 3356 935 2651 860 2419 774 2209 Time((weeks) 545 1638 Conclusion: No(increased(risk(of(CV death/mi/stroke 288 994 144 498 *Includes(CV(death,(MI,(and(stroke CEC,(clinical(events(committee;(MACE,(major(adverse(CV(event Frederich(R,(et(al.(Postgrad)Med.(2010;122:16Y27. ( 123 436 102 373 All(Saxa 128 57 19 Patient((demographics Median(age((BL): Mean(duration(of(disease((BL): 54(yrs 3.8(yrs Mean(HbA1c: 8.5% Population(with( 1(CV(risk factor Mean(duration(of(exposure 81% 1.15(yrs Hypertension 52% Hypercholesterolemia 44% Smoking(history 39% Familial(risk(factors(for(CVD 20%

Study&Design N 16,500 patients Documented*T2DM and*established*cvd*(secondary*prevention)*or multiple*cv*risk*factors*(primary*prevention) SAXAGLIPTIN 5*mg/d (2.5%mg%for%eGFR% 50%ml/min) RANDOMIZE*1:1*DOUBLE*BLIND Dosing'based'on'eGFR All'other'diabetes'therapy'per treating'doctors PLACEBO Duration Event*driven; 1040*events*required FollowWup visits Q6*months Final*Visit Primary*endpoint CV*death,*nonWfatal*MI, nonwfatal*ischemic* stroke CVD:&cardiovascular&disease;&eGFR:&estimated&glomerular&filtration&rate Scirica&BM,&et&al.&Am#Heart#J.&2011;162:818E825.&(Permission&requested)

SAVOR&TIMI*53:*International,*Multi&Center, Phase*4*Study North&America Canada**** Mexico**** Puerto*Rico****** United*States**** Europe Czech*Republic**** France**** Germany**** Hungary**** Italy**** The*Netherlands**** Poland**** Spain**** Sweden**** United*Kingdom**** Total&of&788&sites&in&26 countries1,2 * Middle2 East Israel**** Asia China**** Hong*Kong**** India**** Russian*Federation Taiwan**** Thailand**** Pacific Australia South&America Argentina**** Brazil**** Chile**** Peru**** Africa South*Africa 1.*Scirica*BM,*et*al.*N"Engl"J"Med."2013.10.1056/NEJMoa1307684;*2.*Mosenzon*O,*et*al.*Diabetes"Metab"Res"Rev.*2013;29:417&426. 3

Key$Inclusion$and$Exclusion$Criteria Inclusion$Criteria1 Documented*T2DM*and*HbA1c* 6.5%*and*<12.0%;*AND * * History*of*Established*CVD * 40*yrs * Documented*atherosclerosis *(coronary,*cerebrovascular,*pv) * Exclusion$Criteria1,2 Current'or'previous'(within'6'months)'incretin4based'therapy Acute'vascular'(cardiac'or'stroke)'event'<2'months'before'randomization Uncontrolled'CV'or'metabolic'risk'factors Chronic'dialysis,'renal'transplant,'or'serum'creatinine'>6'mg/dL * * * * Includes*other*DPPL4*inhibitors*and*GLPL1*agonists GLPL1:*glucagonLlike*peptide*1;*PV:*peripheral*vascular*;*HTN*=*hypertension 55*yrs*(male)*or* 60*yrs*(female) OR 1 additional*risk*factor (dyslipidemia,*htn,*smoking) 1.*Scirica*BM,*et*al.*N"Engl"J"Med."2013.10.1056/NEJMoa1307684;*2.*Scirica*BM,*et*al.*Am"Heart"J.*2011;162:818L825. * * Multiple*risk*factors:

Study&Endpoints Primary'safety'and'efficacy'endpoint1,2 Composite)of)non,fatal)MI,)non,fatal)ischemic)stroke,)or)CV)death & Secondary'endpoints )Primary)composite)endpoint)plus)hospitalization)for: Heart)failure Coronary)revascularization Unstable)angina )All,cause)mortality & Safety'endpoints &AEs)and)AEs)of)special)interest)(eg,)pancreatitis) )Hypoglycemic)events & AE:&adverse&event 1.&Scirica&BM,&et&al.&N"Engl"J"Med."2013.10.1056/NEJMoa1307684;&2.&Scirica&BM,&et&al.&Am"Heart"J.&2011;162:818G825.

Baseline(Antidiabetic(and(CV(Medication(Use (((Saxagliptin((((Placebo ((((N(=(8,280)(((((N(=(8,212) Antidiabetic(medications((((!!!! ((((Metformin!!!!5789!(69.9)!!!!5684!(69.2)!!!!!!!!SU!!!!!3352!(40.5)!!!!3281!(40.0)!!!!TZD!!!!!513!(6.2)!!!!465!(5.7)!!!!Insulin!!!!!3448!(41.6)!!!!3384!(41.2)!!!!None!(((!343!(4.1)!!!!392!(4.8) CV(medications((((!!!! ((((Statin!!!!!6482!(78.3)!!!!6435!(78.4)!!!!Aspirin!!!!!6249!(75.5)!!!!6155!(75.0)!!!!ACEi!!!!!4435!(53.6)!!!!4505!(54.9)!!!!ARB(((((2332!(28.2)!!!!2263!(27.6) ((((βjblockers!!!!5101!(61.6)!!!!5061!(61.6) ((((((((( ACEi:!angiotensinJconverting!enzyme!inhibitor;!ARB:!angiotensin!receptor!blocker;!SU:!sulfonylurea;!TZD: thiazolidinedione.!! Scirica!BM,!et!al.!N"Engl"J"Med."2013.10.1056/NEJMoa1307684.

Kaplan&Meier+Rates+of+the+Primary+Composite Endpoint+ +CV+Death,+MI,+or+Stroke *K#M%event%rates%are%presented%after%2%yrs. HR:%hazard%ratio;%K#M:%Kaplan#Meier;%Pbo:%placebo;%Saxa:%saxagliptin Scirica%BM,%et%al.%N"Engl"J"Med."2013.10.1056/NEJMoa1307684. Days 798 3 807 1 776 1 783 6 726 7 731 3 485 5 492 0 851 847 Placebo Saxaglipti n 821 2 828 0 P at ie n ts W it h E n d p oi n ts ( % ) 14 12 10 8 6 4 2 0 0 180 360 540 720 900 HR+1.00;+95%+CI,+0.89 1.12 P<0.001+(NI) P=0.99+(superiority) Saxagliptin:+7.3%* Rate/100+person&yrs+ +3.7 Placebo:'7.2%* Rate/100+person&yrs+ +3.7

K"M$Rates$of$the$Secondary$Endpoint* *K#M%event%rates%are%presented%after%2%yrs.%Composite%of%CV%death,%MI,%stroke,%and%hosp%for%HF,%UA,%or%coronary%revasc. % Scirica%BM,%et%al.%N"Engl"J"Med."2013.10.1056/NEJMoa1307684. Days 784 3 788 0 750 2 753 9 692 6 696 3 460 2 466 0 813 817 Placebo Saxaglipti n 821 2 828 0 14 12 10 8 6 4 2 0 0 180 360 540 720 900 % HR$1.02;$95%$CI$0.94"1.11 P=0.66 Saxagliptin:$12.8%* Rate/100$person"yrs$ $6.6 Placebo:(12.4%* Rate/100$person"yrs$ $6.5 P at ie n ts W it h E n d p oi n ts ( % )

Primary'and'Secondary'Endpoints! Saxagliptin n'(%;'rate)* (N'='8,280) Placebo n'(%; rate)* (N'='8,212) HR (95%'CI) P value NI P'value Superiori ty Primary'endpoint CV'death,'MI,'or stroke! 613 (7.3;!3.7)! 609 (7.2;!3.7)! 1.00 (0.89. 1.12)! <0.001! 0.99 Secondary'endpoint CV'death,'MI, stroke,'hosp'for UA,'HF,'or coronary'revasc! 1059 (12.8;!6.6)! 1034 (12.4;!6.5)! 1.02 (0.94. 1.11)!!! 0.66! AllRcause'mortality 420!(4.9) 378!(4.2) 1.11 (0.96. 1.27)! 0.15 *%!=!K.M!event!rate!at!2!yrs!;!rate!=!rate/100!person.yrs HF:!heart!failure;!hosp:!hospitalization:!revasc:!revascularization;!UA:!unstable!angina Scirica!BM,!et!al.!N"Engl"J"Med."2013.10.1056/NEJMoa1307684.

Individual)Components)of)the)Composite)Endpoints ))))Saxagliptin))))Placebo )))n)(%)*))))n)(%)* Efficacy)endpoint))))(N)=)8,280)))))(N)=)8,212))))))HR)(95%)CI))))))))))P"value CV)death%%%%269%(3.2)%%%%260%(2.9)%%%%%%%%%%%1.03%(0.87 1.22)%%%%%%%%%%0.72 MI%%%%%%%%%%265%(3.2)%%%%%%%%%%278%(3.4)%%%%%%%%%%%0.95%(0.80 1.12)%%%%%%%%%%0.52 Ischemic)stroke%%%%%%%%%%157%(1.9)%%%%%%%%%%141%(1.7)%%%%%%%%%%%%1.11%(0.88 1.39)%%%%%%%%%%0.38 Hosp)for)UA%%%%%%%%%%%%97%(1.2)%%%%%%%%%%%81%(1.0)%%%%%%%%%%%1.19%(0.89 1.60)%%%%%%%%%%0.24 Hosp)for)HF%%%%%%%%%%289%(3.5)%%%%%%%%%%%228%(2.8)%%%%%%%%%%%%1.27%(1.07 1.51)%%%%%%%%%%%0.007 Hosp)for coronary)revasc.%%%%%%%%%%%423%(5.2)%%%%%%%%%%%459%(5.6)%%%%%%%%%%%0.91%(0.80 1.04)%%%%%%%% %0.18%%%%%%%%%%%% *K#M%event%rates%are%presented%after%2%yrs. % Scirica%BM,%et%al.%N"Engl"J"Med."2013.10.1056/NEJMoa1307684.

Changes(in(Antidiabetic(and(CV(Medications((((((Over Time ( Baseline Year*1************** Year*2************** End*of*treatment % Saxa Pbo Saxa Pbo Saxa Pbo Saxa Pbo Metformi n SU TZD Insulin Other None Aspirin Statin ACEi ARB βrblockers ( Antidiabetic*medications n(= 8280 8212 7999 7943 5101 5059 8041 8007 69.9 40.5 (6.2 41.6 (0.6 (4.1 69.2 40.0 (5.7 41.2 (0.6 (((4.8* 69.6 39.7 (5.4 42.3 (0.6 (4.4 70.1 40.4 (5.2 43.6 (0.5 (4.3 70.0 39.2 (4.7 42.5 (0.6 (5.0 69.9 39.5 (4.7 (45.8 (0.4 (4.7 69.4 39.8 (4.9 43.8 (0.7 (4.5 70.0 40.2 (4.7 (46.4 (0.6 (4.0 CV*medications n(= 8280 8212 7512 7405 3695 3603 7539 7498 75.5 78.3 53.6 28.2 61.6 ( 75.0 78.4 54.9 27.6 61.6 ( 77.3 80.8 52.8 29.7 62.6 ( ( 77.3 80.8 54.2 29.8 62.5 ( *P"=(0.0496;( P"=(0.0008;(P"=(not(significant(for(all(other(endpoints(shown. Scirica(BM,(et(al.(N"Engl"J"Med."2013.10.1056/NEJMoa1307684. 72.7 77.1 52.9 29.7 58.3 ( 72.4 78.7 53.1 31.3 57.2 ( 77.7 80.5 51.8 30.0 62.8 ( ( 78.0 81.1 52.4 30.3 62.4 (

Ανακεφαλαίωση των αποτελεσµάτων που αφορούν το καρδιαγγειακό H σαξαγλιπτίνη δεν αυξάνει το κίνδυνο για µείζονα συµβάµατα όπως καρδιαγγειακό θάνατο, έµφραγµα του µυοκαρδίου και εγκεφαλικό επεισόδιο Η σαξαγλιπτίνη αυξάνει τον κίνδυνο για νοσηλειών για καρδιακή ανεπάρκεια

Assessing'the'Effects'That'T2DM'Has'on'the Cardiovascular'System'Is'Challenging Disease'vs treatment'effects Short@term'vs'long@term assessments Patient'factors' (ie,'bmi, hypertension, duration'of disease,'severity of'disease) ' Because'there'are'multiple factors'that'affect'risk'of'cvd with't2dm,'detecting significant'cv'differences'with the'addition'of'a'single'new drug'can'be'challenging1 Study'variables Pharmaceutical'impact: 1.'Antihyperglycemic therapy'with'unknown longgterm'cv safety/benefit 2.'Background'therapies for'cv'risk'factors'(ie, HTN,'cholesterol) ' Per$the$FDA$2008$Advisory$Committee:2 Diabetes'is'a'metabolic'disorder'with'multiple'coGmorbidities'increasing'overall'risk'of CVD.'It'will'be'difficult'for'glycemic'control'alone'to'demonstrate'CV'risk'reduction. BMI,'bodyGmass'index;'HTN,'hypertension 1.'Hemmingsen'B.'BMJ.%2011;343:d6898'doi:'10.1136/bmj.d6898'(Published'Nov'24,'2011);' 2.'FDA.'2008.'http://www.fda.gov/downloads/Drugs/NewsEvents/UCM209087.pdf.'Downloaded'Aug'15,'2013.

Συµπεράσµατα Λίγοι αντι-υπεργλυκαιµικοί παράγοντες έχουν µελετηθεί σε τόσο βάθος όπως η σαξαγλιπτίνη H σαξαγλιπτίνη δεν αυξάνει το κίνδυνο για καρδιαγγειακό θάνατο, έµφραγµα του µυοκαρδίου και εγκεφαλικό επεισόδιο Η σαξαγλιπτίνη αυξάνει τον κίνδυνο για νοσηλειών για καρδιακή ανεπάρκεια Τα αποτελέσµατα αυτά ενισχύουν το προφίλ ασφάλειας του φαρµάκου και επιτρέπουν την βασισµένη σε αποδείξειςεξατοµικευµένη χρήση του

Συµπεράσµατα (προσωπικά) Δε µε προβληµατίζει από καρδιολογική άποψη η λήψη της σαξαγλιπτίνης σε καρδιολογικό ασθενή Σε ασθενείς µε καρδιακή ανεπάρκεια: Δε θα τη χορηγούσα σε αποσταθεροποιηµένους ασθενείς. Στους υπόλοιπους ναι, θα πύκνωνα όµως την παρακολούθηση Είναι από τα φάρµακα που θα χορηγούσα ως καρδιολόγος