Lipid Management in 2020:A Glimpse into the Future
Prof Kausik RayMBChB, MD, MPhil (Cantab), FRCP (Lon), FRCP (Ed),
FESC, FACC, FAHA
School of Public Health,Imperial College London, London, UK
CVD will still be a problem in 2020!
Why ?
• Public Health
• Lifestyle
• Increased life expectancy
• Awareness/ Knowledge
• Treating more advanced disease
• Lack of Screening
• Therapies
• Inadequate use of evidence based treatments
• Side effects of current Tx
• Treatment threshold has been reached
• Cost
59
65
41
49
68
40
61
48
83
31
51
4549 50
53
40
0
10
20
30
40
50
60
70
80
90
*Patients with ≥2 cardiovascular risk factors according to NCEP ATP III guidelines;
CEPHEUS, CEntralized Pan-European survey on tHE Under-treatment of hypercholeSterolaemia,NCEP ATP, National Cholesterol Educational Program Adult Treatment Panel; JETF, Joint European Task Force
1. Hermans MP et al. Curr Med Res Opin 2010;26:445–454; 2. Park JE et al. Eur J Prev Cardiol 2012;19:781–794
Patients on lipid-lowering drugs for >3 months(stable medication >6 weeks)
CEPHEUS: about half of patients achieved LDL-C goals
% o
f p
atie
nts
at
LDL-
Cgo
al
Europe1
JETF guidelines
Asia2
NCEP ATP III guidelines*
What will change?
• Revolution in the management of FH
• Screening and Earlier Treatment to Prevent CVD
• More widespread understanding and use of absolute risk scores to
Familial Hypercholesterolaemia
Estimated millions of individuals worldwide with FH by WHO regions and by income groups
Nordestgaard BG et al. Eur Heart J 2013;34:3478-3490
Estimated % of individuals diagnosedwith FH in different countries/ territories, as a fraction of those theoretically predicted based on a frequency of 1/500 in the general population
Familial Hypercholesterolaemia
Nordestgaard BG et al. Eur Heart J 2013;34:3478-3490
Despite available treatment approaches, we still have a significant percentage of patients not at goal
• Pijlman AH et al. Atherosclerosis 2009;209:189–194
100
80
40
02
Att
ain
me
nt
of
targ
et
(%)
LDL-C target (mmol/l)
60
20
0 43 5 6 7 8 9 10
LDL-C burden in individuals with or without FH as a function of the age of initiation of statin therapy
Familial Hypercholesterolaemia
Nordestgaard BG et al. Eur Heart J 2013;34:3478-3490
Solutions
• Awareness/ Improve Knowledge
• Screening systematically
• Change Policy/ ICD codes
• Additional new therapies
www.eas-society.org
RUTHERFORD-2: LDL-Ca goal achievement <70 mg/dL at Week 12
Evolocumab is an investigational drug under clinical development. Raal et al Abstract No. 400-05, Featured Clinical Research, Oral Presentation, Saturday, March 29, 2:36 – 2:54 p.m. EDT
0
10
20
30
40
50
60
70
80
Pro
po
rtio
n o
f p
ati
en
ts (
%)
2%
68%
2%
63%
61%b
66%b
Placebo Q2W (N = 54)
Placebo QM (N = 55)
Evolocumab 140 mg Q2W (N = 110)
Evolocumab 420 mg QM (N = 110)
aDetermined by the Friedewald formula with reflexive testing via preparative ultracentrifugation when calculated LDL-C was < 40 mg/dL or triglyceride
levels were >400 mg/dL; bp<0.001; analyzed using CMH test, stratified by the stratification factors
Most heFH Patients Receiving Alirocumab on
Background Statin Other LLT Achieved LDL-C Goals
13
72.2%
81.4%
2.4%
11.3%
0
10
20
30
40
50
60
70
80
90
P<0.0001
% p
atie
nts
Placebo
†Very high-risk: <1.81 mmol/L (70 mg/dL); high-risk: <2.59 mmol/L (100 mg/dL). LLT = lipid-lowering therapy.
Proportion of patients reaching LDL-C goal† at Week 24
FH I FH IIAlirocumab
Intent-to-treat (ITT) Analysis
Preserve Health vs Treating Disease
Ference BA et al. J Am Coll Cardiol 2012;60:2631–2639; Baigent C et al. Lancet 2005;366:1267–1278
Screen early, treat early,think about lifetime risk
rs12916
rs4299376
rs599839
rs11206510
rs2228671rs646776 rs6511720
rs4420638
rs11591147
1.00 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 11.010.0 12.013.0 14.015.016.017.0 18.0
10%
20%
30%
Lower LDL-C (mg/dL)
Pro
po
rtio
nal
Ris
k R
edu
ctio
n (
SE)
50%
40%
30%
20%
10%
0%
-10%
0.5 1.0 1.5 2.0
Reduction in LDL cholesterol (mmol/L)
Pro
po
rtio
nal
red
uct
ion
in e
ven
t ra
te (
SE)
Major vascular events
54.5% relative risk reductionper 1 mM/L (38.7mg/dL)
LDL-C lowering
22% relative risk reductionper 1 mmol/L (38.7mg/dL)
LDL-C lowering
Solutions
• Systematic Screening
• Exemplar NHS Vascular Health Checks being offered in the UK to everyone aged 40-70
Problems
• Visualising absolute risk in a n individual is poor
• Reluctance to use higher doses based on unfounded concerns
• Wait and watch approach
The Need for Absolute Risk Prediction for People on Statin
Therapy
0 1 2 3 4 5 6
8%-20% = 1.6% abs RR
-20% = 1.3% abs RR
-20% = 1% abs RR
-20% = 0.8% abs RR3.3%
Log
of
Ris
k
LDL-C mmoles
Relationship of LDL-C lowering and Risk Reduction with a statin~ 20% reduction in RR per mmol LDL-C
As abs risk
NNT
Consistent effect on relative risk; diminishing effect on absolute risk
• Bhatt JAMA REACH REGISTRY
• Bhatt JAMA REACH REGISTRYc
Other Therapies
CETP Inhibition HDL pathways Anti Inflammatory Tx
Other
Anacetrapib Apo A mimetics IL-1B inhibtion Target Lp(a)
Evacetrapib A1 Milano Methotrexate Target Apo C III
TA 8995 RVX 208 PPAR alpha agonists
High Dose fish oils
26 24 2520
9
1720 19 20
14 15 14
4340 42
13 14 1317
915
0
20
40
60
80
100
CHD Stroke CHD or stroke
Antiplatelet Beta-blockers ACEi or ARBs Diuretics BP-lowering Ca-channel blockers Statins
Overall rates of secondary prevention medication use for CVD is low worldwide
PURE study, 17 countries
PURE, Prospective Urban Rural Epidemiology; ACEi, angiotensin-converting-enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure
Yusuf S et al. Lancet 2011;378:1231–1243
% o
f p
atie
nts
wit
h t
reat
men
t
Conclusion
• All these emerging therapies will increase uptake of statins and other current Tx
• FH will be better detected (hope), better treated yes
• Screen and treat early
• Need to be more sophisticated about who we offer additional Tx to