AGGIORNAMENTI IN TEMA DI
TERAPIE DI DISLIPIDEMIE
Mauro Vannucci
V° CONGRESSO NAZIONALE, Riccione 15-17 Maggio 2015
Studi con statine in prevenzione primaria:
riduzione eventi ed LDL-col “on trial”
10
y = 0.0599x – 3.3952
R2 = 0.9305
p = 0.0019
Eventi coronarici (%)
9
WOSCOPS-P
8
7
WOSCOPS-S
6
AFCAPS-P
5
AFCAPS-S
4
3
Gli eventi sembrano
azzerarsi per un
C-LDL di 55 mg/dL
ASCOT-P
2
ASCOT-S
1
0
-1
55
75
95
115
135
155
175
195
C-LDL (mg/dL)
O’Keefe et al. JACC, 2004
Studi con statine in prevenzione secondaria:
riduzione eventi ed LDL-col “on trial”
Eventi coronarici (%)
30
y = 0.1629x – 4.6776
R2 = 0.9029
p = 0.0001
25
4S-P
20
HPS-P
LIPID-P
4S-S
15
HPS-S
CARE-P
LIPID-S
10
Gli eventi sembrano
azzerarsi per un
C-LDL di 30 mg/dL
CARE-S
PROVET-IT-AT
PROVET-IT-PR
5
0
30
50
70
90
110
130
C-LDL (mg/dL)
O’Keefe et al. JACC, 2004
150
170
190
210
THE LOWER
THE BETTER
30
25
4S - Placebo
Rx - Statin therapy
PRA – pravastatin
ATV - atorvastatin
Secondary Prevention
4S - Rx
20
LIPID - Placebo
15
CARE - Placebo
LIPID - Rx
CARE - Rx
HPS - Rx
TNT – ATV10
PROVE-IT
- PRA
TNT – ATV80
10
PROVE-IT – ATV
5
HPS - Placebo
WOSCOPS – Placebo
AFCAPS - Placebo
6
AFCAPS - Rx
WOSCOPS - Rx
ASCOT - Placebo
0
40
(1.0)
Primary Prevention
ASCOT - Rx
Jupiter Ros
60
(1.6)
80
(2.1)
100
(2.6)
120
(3.1)
140
(3.6)
160
(4.1)
180
(4.7)
200
(5.2)
LDL-C achieved mg/dL (mmol/L)
Adattata e modificata da :
LaRosa JC et al. N Engl J Med 2005;352:e-version
Aderenza terapeutica: il fattore di rischio occulto
Furio Colivicchi, Maurizio G. Abrignani, Massimo Santini
In uno studio condotto nell’ASL di Treviso dal 1994 al 2003 su oltre 20 000 soggetti
che avevano ricevuto una prescrizione di statina, il tasso di interruzione è stato del
50% nel primo anno.
Nel Lazio abbiamo osservato un elevato tasso di interruzione del trattamento con
statine che va dal 25% nei primi 3 mesi dalla dimissione dopo una sindrome
coronarica acuta, al 40% dopo 1 anno da un ictus27, al 50% entro 1 anno dalla prima
prescrizione in una popolazione di diabetici afferenti a strutture ambulatoriali.
G Ital Cardiol 2010
Riduzione progressiva della persistenza dei trattamenti
farmacologici raccomandati dalle linee guida durante
il follow-up in pazienti con pregresso IMA
Dati del registro SIMG - Health Search – J Cardiovasc Med 2009
Cause di interruzione della terapia con statine
riferite dai pazienti
“Troppe pastiglie”
Assenza di
evidenti
motivi
clinici
72%




Lievi effetti
collaterali
28%


0%
20%
40%
60%
80%

Effetti collaterali riferiti
Dispepsia (52%)
Astenia (18%)
Cefalea (17%)
Mialgie (11%)
Incremento asintomatico
delle transaminasi (1%)
Incremento asintomatico
del CK totale (1%)
Assenza di reazioni
avverse maggiori
Colivicchi F, et al. Stroke 2007; 38:2652-2657
L’aderenza alla terapia con statine tende a ridursi
nel tempo: dati della ASL di Ravenna
Poluzzi E et al. Br J Clin Pharm 2007; 63: 346-355
Association between switching and MACEs
Colivicchi F, et al. Int J Cardiology 2011; 152:56-60
Recent Coronary IVUS Progression Trials
1.8
CAMELOT
placebo
1.2
Median
Change 0.6
In Percent
Atheroma
0
Volume
(%)
REVERSAL
atorvastatin
-0.6
REVERSAL
pravastatin
ACTIVATE
placebo
A-Plus
placebo
r2= 0.95
p<0.001
ASTEROID
rosuvastatin
-1.2
50
60
70
80
90
100
110
120
Mean Low-Density Lipoprotein Cholesterol (mg/dL)
Nissen S. JAMA 2006
Efficacy and safety of statin treatment for cardiovascular disease:
a network meta-analysis of 170 255 patients
from 76 randomized trials
Statin therapy reduced:
 All-cause mortality (RR 0.90)
 Cardiovascular disease mortality (RR 0.80)
 Fatal myocardial infarction (RR 0.82)
 Non-fatal MI (RR 0.74)
 Revascularization (RR 0.76)
 Fatal and non-fatal strokes (RR 0.86)
E.J. MILLS et al, Q J Med 2011
Efficacy and safety of statin treatment for cardiovascular disease:
a network meta-analysis of 170 255 patients from 76 randomized trials
E.J. MILLS et al, Q J Med 2011
Linee Guida ESC 2012
Target della terapia con statine
Target LDL-C
Rischio molto alto
< 70 mg/dL(1.8 mmol/L) oppure,
se il target non si riesce a raggiungere,
riduzione ≥ 50% del LDL-C rispetto al basale
Rischio alto
< 100 mg/dL (2.5 mmol/L)
Rischio moderato
< 115 mg/dL (3.0 mmol/L)
Presenza di almeno un fattore di rischio rilevante (per esempio dislipidemie familiari severe)
Diabete mellito (tipo 1 o tipo 2) ma senza fattori di rischio CV concomitante o danno
d’organo
IRC moderata (GFRe 30–59 mL/min/1.73 m2)
Calcolo del rischio a 10-anni SCORE ≥ 5% e < 10% per patologia cardiaca fatale
ACS - CAD documentata – MCV documentata
SCORE > 10%
Recommendations for treatment targets for LDL-C
RECOMMENDATIONS
Class
Level
I
A
In patients at HIGH CV risk (markedly elevated single risk factors, a SCORE level ≥ 5 to
< 10%) an LDL-C goal < 2.5 mmol/L (less than ~ 100 mg/dL) should be considered.
IIa
A
In subjects at MODERATE risk (SCORE level > 1 to ≤ 5%) an LDL-C goal < 3.0 mmol/L (less
than ~ 115 mg/dL) should be considered.
IIa
C
In patients at VERY HIGH CV risk (established CVD, type 2 diabetes, type 1 diabetes with
target organ damage, moderate to severe CKD or a SCORE level ≥ 10%) the LDL-C goal is <
1.8 mmol/L (less than ~ 70 mg/dL) and/or ≥ 50% LDL-C reduction when target level cannot
be reached.
La riduzione di LDL-C necessaria per il raggiungimento del
target spesso in questa categoria di pazienti è ≥ 50 %
European Heart Journal (2011) 32, 1769–1818
Preventive cardiology efforts begin with assessment of
cardiovascular disease risk
Recommendation to begin with a global risk assessment using
the Pooled Cohort Equations to estimate 10-year ASCVD Risk
(other risk assessment algorithms include the European SCORE,
PROCAM, or Framingham scores)
What’s New in the Cholesterol Guideline?
1)Focus on ASCVD reduction: 4 Statin Benefit Groups
2)New Perspective on LDL-C and/or Non-HDL-C Treatment Goals
3)Emphasis on the Clinician-Patient Risk Discussion
4)Global Risk Assessment for Primary Prevention
5)Safety Recommendations
Critical questions addressed the evidence for LDL-C and non-HDL-C goals
primary and secondary prevention and the evidence for reduction in
ASCVD events in relation to cholesterol lowering drugs available
WHAT’S SIMILAR TO ATP III?
– Emphasis on lifestyle measures as crucial
– Focus on treatment of LDL cholesterol (LDL-C)
– Greatest intensity of treatment for patients at
highest risk
– Preference for statins over other medications
lowering LDL-C (although this is greater in the
new ACC/AHA Guideline)
4 STATIN BENEFIT GROUPS
• Clinical ASCVD
• LDL–C >190 mg/dL, Age >21 years
• Primary prevention – Diabetes: Age 40-75 years, LDL–C
70-189 mg/dL
• Primary prevention - No Diabetes ≥ 7,5% 10-year
• ASCVD risk, Age 40-75 years, LDL–C 70-189 mg/dL,
These identified statin benefit groups to not imply that
other groups (e.g., those outside the specified age ranges)
will not benefit and should not be treated
INDIVIDUALS NOT IN A STATIN BENEFIT GROUP
 In those for whom a risk decision is uncertain:
 These factors may inform clinical decision making:
•
•
•
•
•
Family history of premature ASCVD
Elevated lifetime risk of ASCVD
LDL–C ≥160 mg/dL
hs-CRP ≥2.0 mg/L
Coronary artery calcium (CAC) score ≥300
Agaston units
• Ankle brachial index (ABI)<0.9
Their use still requires discussion between clinician and patient
Summary of Statin Initiation Recommendations to
Reduce ASCVD Risk (Revised Figure)
Summary of Statin Initiation Recommendations to
Reduce ASCVD Risk (Revised Figure)
Ray KK et al. Eur Heart J 2014
L’impatto della strategia ACC/AHA dovrebbe essere considerato alla
luce del gran numero di soggetti nella popolazione che sarebbero
destinati al trattamento con statine per tutta la vita a partire dall’età di
40 anni
Per la popolazione europea si continua a raccomandare
l’utilizzo delle tabelle SCORE o di tabelle nazionali calibrate sullo
SCORE.
La riduzione del rischio in generale deve essere personalizzata per ogni
paziente, e questa pratica può essere più specifica se vengono definiti
degli obiettivi.
FIRE and Forget….. the patient !!
The results of the EUROASPIRE III survey show that despite
the clear evidence of the benefits of lipid-lowering treatment
in secondary prevention, many coronary patients with
dyslipidaemia are still inadequately treated and a significant
number of patients on lipid-lowering therapy is still not
reaching the treatment goals.
Almost half of all coronary patients did not reach the LDL-C
goal of 2.5 mmol/L and about the same percentage did not
reach the total cholesterol goal of 4.5 mmol/L
Atherosclerosis 2013
Conoscendo la
riduzione percentuale
necessaria per
raggiungere il target
terapeutico, è possibile
individuare quale
opzione terapeutica
consente di ottenerla.
29
30
31
32
33
34
CONCLUSIONS
IMPROVE-IT: First
trial demonstrating incremental
clinical benefit when adding a non-statin agent
(ezetimibe) to statin therapy:
YES:
YES:
YES:
Non-statin lowering LDL-C with ezetimibe
reduces cardiovascular events
Even Lower is Even Better
(achieved mean LDL-C 53 vs. 70 mg/dL at 1 year)
Confirms ezetimibe safety profile
 Reaffirms the LDL hypothesis, that reducing
LDL-C prevents cardiovascular events
 Results could be considered for future guidelines
Inerzia
Terapeutica
Stili di vita
Tipo e
dose di
statina
Aderenza
Continuità
Assistenziale
Target
Appropriatezza
Prescrittiva
G Ital Cardiol 2015;16(1):44-51
DEFINE
Determining the EFficacy and Tolerability of CEPT
INhibition with AnacEtrapib
Safety of Anacetrapib in Patients with
or at Risk for Coronary Heart Disease
Christopher P. Cannon, MD, Sukrut Shah, PhD, RPh, Hayes
M. Dansky, MD, Michael Davidson, MD, Eliot A. Brinton,
MD, Antonio M. Gotto, Jr., MD, DPhil, Michael
Stepanavage, MS, Sherry Xueyu Liu, MS, Patrice Gibbons,
MS, Tanya B. Ashraf, BA, Jennifer Zafarino, MS, Yale
Mitchel, MD, Philip Barter, MD, PhD, for the DEFINE
Investigators
DEFINE
Effects on LDL-C
and HDL-C
Determining the EFficacy and Tolerability
of CEPT INhibition with AnacEtrapib
LDL-C
100
120
100
HDL-C (mg/dL) (SE)
LDL-C (mg/dL) (SE)
80
-39.8% (p<0.001)
60
40
20
0
HDL-C
Anacetrapib
Placebo
BaselineWk 6Wk 12Wk 18Wk 24Wk 30
80
60
40
20
Wk 46
Wk 62
Wk 76
Anacetrapib n = 804 771 716 687 646
604
568
540
Placebo n = 803 759 741 743 735
711
691
666
Study Week
+138.1% (p<0.001)
0
Anacetrapib
Placebo
BaselineWk 6Wk 12Wk 18Wk 24Wk 30
Wk 46
Wk 62
Wk 76
Anacetrapib n = 776 757 718 687 647
607
572
543
Placebo n = 766 761 741 744 736
711
691
666
Study Week
 Anacetrapib treatment had robust effects on HDL-C,
LDL-C, non HDL-C and Lp(a) with sustained effects over
18 months.
 Anacetrapib had an acceptable side-effect profile
with no effects on blood pressure, electrolytes or
aldosterone.
 Within the power of the study, anacetrapib did not
exhibit adverse cardiovascular effects seen with a prior
CETP inhibitor
 The long term safety and efficacy of anacetrapib will
now be tested in a large clinical outcomes trial.
Cannon CP et al. N Engl J Med 2010;363 (19) online 11/17/2010
• 30,000 patients with occlusive arterial disease
in North America, Europe and Asia
• Background LDL-lowering with atorvastatin
• Randomized to anacetrapib 100 mg vs. placebo
• Scheduled follow-up: 4 years
• Primary outcome: Coronary death, myocardial
infarction or coronary revascularization
www.revealtrial.org
Lipid effects with dalcetrapib
35
*p<0.0001
30
%change from baseline
25
*p<0.01
20
15
10
D 24 weeks
D 48 weeks
Placebo
*p=0.002
5
0
Dalcetrapib
900 mg/day
-5
HDL-C
LDL-C
* D 48 weeks vs. placebo
ApoA-I
Stein EA et al. Eur Heart J 2010;31(4):480-8
Dalcetrapib Phase IIb Trial
HDL-C Increase at Week 12
*
*P < 0.0001 vs placebo
Change From Baseline (%)
*
*
placebo
n = 73
dalcetrapib
300 mg
n = 75
dalcetrapib
600 mg
n = 67
dalcetrapib
900 mg
n = 72
NOTE: Dalcetrapib 600 mg is the dose used in phase III
Stein EA. Am J Cardiol. 2009;104:82-91
CEPT
• Residual CV risk remains problematic despite statinmediated LDL-C reduction
• Low HDL-C is an independent risk factor for CHD
• Most clinical trial and observational data suggest that
raising HDL-C may reduce CVD
• HDL particles are very heterogeneous in composition and
function, not all HDL may be anti-atherogenic
• Many new HDL-C raising treatments are in development
• CETP inhibitors greatly raise HDL-C levels, but their effect
on HDL function and clinical outcomes remains in question
Revisiting the HDL Hypothesis
Residual CVD risk exists despite intense statin
monotherapy
• Low HDL-C predicts high CVD risk; high HDL-C is
protective
• Existing HDL raising therapies have inconsistent effects
• Investigational drugs to raise HDL-C and reduce CVD
risk
– CETP inhibitors
– PPAR agonists, APO A1 agonists, delipidating agents, etc.
• But clinical trials have not yet proven that:
– HDL is a causal factor vs biomarker of risk
– Raising HDL-C reduces CVD risk
Don’t give up on HDL,
researchers plead
At a session on the subject, Dr Alan Tall
(Columbia University, New York)
summarized the situation:
"The HDL hypothesis is certainly under attack.
And there have been a lot of setbacks.
But we mustn't throw the baby out with the bathwater.
I think we need a new, modified HDL hypothesis."
Hughs S, Jun, 2012
Increased risk of diabetes with statin treatment is associated
with impaired insulin sensitivity and insulin secretion:
a 6 year follow-up study of the METSIM cohort
Cederberg H(1), Stančáková A, Yaluri N, Modi S, Kuusisto J, Laakso M.
Diabetologia - 2015 May; 58(5): 1109-17
STATINS AND DIABETES RISK
1) Meta-analysis of 170,255 patients from 76 randomized clinical trials
show overall a 9% increased risk for development of incident diabetes
among statin users (Sattar, Lancet 2010)
2) Increased risk of diabetes only seen in those with multiple risk factors;
obesity, elevated triglycerides, glucose, and hypertension are more
strongly related than statins to development of diabetes
3) Many persons on statins have pre-diabetes to begin with; statins may
accelerate the progression to diabetes, but on average diabetes occurs 5
weeks later in those on placebo.
4) For every case of diabetes associated with statin use, approximately 59 cardiovascular events are prevented
5) Most experts contend the benefits outweigh the risks regarding
increases in glucose / A1c.
Statins and diabetes risk:
how real is it and what are the mechanisms?
Jennifer G. Robinson
• Statins are associated with a modest excess risk of type 2 diabetes
mellitus in individuals at risk for diabetes.
• Multiple mechanisms have been proposed for statin-associated
diabetes, primarily related to increased insulin resistance and
decreased insulin secretion.
• Diabetes is diagnosed on average 2–4 months earlier in statin-treated
patients compared with untreated patients, and is therefore unlikely
to have any more adverse consequences in the long term than
diabetes occurring in patients who did not receive statins.
• The cardiovascular risk reduction benefits far outweigh the potential
for adverse effects in all but the very lowest risk individuals.
Curr Opin Lipidol. 2015 Jun;26(3):228-35