1. Cardiovascular risk management: What are the strategic changes?
Prof. John Deanfield
University College London
London, United Kingdom

2. 40% Death Rates from All Circulatory Disease in England 1993-2011
180
A fall of 55% since baseline
160
140
Target:
40%
minimum reduction
from
120
100
Death / 100,000 population 80 60 40
Immortality
Guaranteed by 2026 20
1993/5
1995/7
1997/9
2001/3
2003/5
2005/7
2007/9
2009/11
2009/11
1999/2001
B/L
Progress
target
Source: ONS (ICD ; ICD10 I00-I99)

3. Treatment of CVD: Residual Risk
100
Statins
40%
% CV events
Residual Risk
60%

4. CHD Impact of Early vs Late LDL Lowering
Mendelian Randomisation Studies of 9 Polymorphisms in 6 Genes
Ference J Am Coll Cardiol 2012; 60: 2631–9

5. Lifetime Risk of Death from CV Disease
Berry NEJM 2012; 366:

6. Early intervention pays long term dividends

7. A reasonable next step for ATP IV?
….Consider statins for younger persons, perhaps starting at 30 in those with risk factors that convey high lifetime risk (as opposed to 10 yr risk) for CHD
Pletcher JACC 2010; 56:

8. Benefits of further lowering of causal factors?

9. Coronary Heart Disease (%)
LDL Cholesterol and Coronary Heart Disease among Black Subjects by PCSK9142X or PCSK9679X Allele
No Nonsense
Mutation
(n=3278) 12
50th Percentile 30
P=0.008 20 8
88% 10
Frequency (%)
Coronary Heart Disease (%) 50
100
150
200
250
300
PCSK9142X
or PCSK9679X
(N=85) 4
28% 30 20 10
No Yes
PCSK9142X or PCSK9679X 50
100
150
200
250
300
Cohen NEJM 2006; 354:
LDL Cholesterol in Black Subjects (mg/dl)

10. PCSK9 Monoclonal AB in heFH Patients % Change in LDL-C from BaselineTC
Non-HDL-C
ApoB
Lp(a)
-10
-20
% Change in LDL-C from Baseline
-30
-40
-50
-60
Stein Lancet 2012; 380: 29-36

11. Life Course Blood Pressure and Mortality Harvard Alumni Health Study10 8
Survival from CVD 6 4
Normal
Stage 1 hypertension
Pre-hypertension
Stage 2 hypertension 2 20 40 60 80
Follow up time (years)
Gray JACC 2011; 58:

12. 4733 age 62.2 years intensive vs standard BP treatment over 4.7 years
BP Treatment in Type 2 DM
4733 age 62.2 years intensive vs standard BP treatment over 4.7 years
ACCORD Study Group NEJM 2010;362:

13. Lifetime Risk from Blood Pressure: NICE
Short-term (10-year) risk underestimates lifetime CV risk of young people with hypertension... Lifetime risk with untreated stage 1 hypertension in this age group could be substantial. Lifetime risk assessments may be a better way to inform treatment decisions and evaluate cost effectiveness of earlier drug therapy.

14. Need Treatments for New Targets
Evidence for residual risk from other risk factors and pathways
Need Treatments for New Targets

15. Coronary Heart Disease and HDL-C
3.5
3.0
2.5
N = 302,430
Hazard Ratio
2.0
1.5
1.0
0.8 30 40 50 60 70 80
HDL-C (mg/dL)
The Emerging Risk Factors Collaboration. JAMA 2009;302:

16. Effect of ERN/LRPT on Major Vascular Events

17. Dalcetrapib in Patients With Recent ACS
Schwartz NEJM 2012; 367:

18. HDL Trials:Reasons for Failure
Failure of molecule -Toxicity
-Potency
Failure of biology
-HDL not on causal pathway
-Wrong pathway for drug
-HDL properties may change
-Wrong stage of disease

19. HDL : Effects on endothelial NO production in patients with CAD
Healthy
P<0.025
sCAD 30
ACS 20
Endothelial NO production
[in % of buffer-treated cells] 10
-10
-20
25 mg/ml
HDL
50 mg/ml
HDL
100 mg/ml
HDL
Besler C et al. & Landmesser U. J Clin Invest (in press)

20. Dalcetrapib HDL Function Study
25 dalcetrapib treated
25 placebo-treated
PLACEBO
Baseline
12 wks
36 wks
Serum
collection
HDL isolation
density ultracentrifugation
Endothelial Nitric Oxide production
ESR spectroscopy
Endothelial anti-apoptotic capacity
Inhibition of caspase-3 expression
Endothelial anti-inflammatory capacity
Inhibition of VCAM-1 expression

21. Dalcetrapib and HDL Function
Placebo
Dalcetrapib
Effect of HDL on NO production
Anti-apoptotic capacity of HDL
Anti-inflammatory capacity of HDL

22. Late-stage Drug Development Failure
A major productivity limiting barrier
Late-stage failure
In vitro & in vivo
experiments
Hunan observational studies
Target identification
Molecule development
Phase I
Phase II
Phase III
Approval
Pre-clinical development
Clinical studies
Cost
Well-known pipeline of drug development
Preclinical target and molecule discovery/validation
Clinical phase
Huge financial and time cost
$4-11B
Time
Kola & Landis, Nat Rev Drug Disc. 2004
Arrowsmith, Nat Rev Drug Disc, 2011
Bunnage, Nature Chemical Biology, 2011
Arrowsmith, Nature Reviews Drug Disc, 2011
~12yrs

23. In Search of Fewer independent Risk Factors
Brotman Arch Intern Med. 2005; 165:

24. New approaches to refine target validation, safety and efficacy

25. RCT as an arbiter of molecule efficacy and safety, and target validity
Drug intervention
Genetics:
natural randomisation
RCT (Phase III)
Sample
Randomisation
Placebo
LDL-C unchanged
CV event
rate lower
rate higher
Protein target: HMGCR
Off target
Mendelian randomisation
Population
Random allocation of alleles
HMGCR aa
Genotype AA
LDL-C reduced
HMGCR variant (rs12916) reduce LDL-C by mmol/L, and risk of CHD (OR of 0.94; 95%CI: 0.90, 0.98).
JACC 2013
HMG-CoA red inhibitor
LDL-C reduced

26. Finding new indications for existing medications
Drug intervention
(IL6R blocker licensed for Rheumatoid arthritis)
Genetics: natural randomisation
Population
Sample
Randomisation (Tocilizumab)
Random allocation of IL6R alleles
Protein target: IL6R
Protein target: IL6R
IL6R- blocker (MAB)
Placebo
IL6R aa
IL6R AA
Reduce IL6 signalling
IL6 signalling unchanged
Reduced IL6 signalling
IL6 signalling unchanged
RA disease
Activity lower
RA disease
activity higher
CV event
rate lower
CV event
rate higher
Biomarker
Tocilizumab
IL6R SNP
IL-6
 (n=1,446)
 (n=29,838)
CRP
 (n=3,010)
 (n=76,527)
Fibrinogen
 (n=409)
 (n=52,667)
Soluble IL-6R
 (n=1,465)
 (n=1,454)
Albumin
 (n=108)
 (n=5,787)
Haemoglobin
 (n=2,072)
 (n=17,898)

27. Finding new indications for existing medications
Drug intervention
(IL6R blocker licensed for Rheumatoid arthritis)
Genetics: natural randomisation
Sample
Swerdlow, Lancet 2012
Randomisation (Tocilizumab)
Protein target: IL6R
IL6R- blocker (MAB)
Placebo
Reduce IL6 signalling
IL6 signalling unchanged
RA disease
Activity lower
RA disease
activity higher
Biomarker
Tocilizumab
IL6R SNP
IL-6
 (n=1,446)
 (n=29,838)
CRP
 (n=3,010)
 (n=76,527)
Fibrinogen
 (n=409)
 (n=52,667)
Soluble IL-6R
 (n=1,465)
 (n=1,454)
Albumin
 (n=108)
 (n=5,787)
Haemoglobin
 (n=2,072)
 (n=17,898)

28. Harmful effects of first-in-man drugs: On- vs Off-target effects
CETP genetic variant recapitulates the effects of pharmacological CETP inhibition on blood lipids, but does not share the BP raising effect of torcetrapib
TRG
HDL
No change in lipids
Sample
Torcetrapib
Control
CETP-inhibition
No-CETP inhibition
LDL
Change in lipid traits BP
(Off-target)
Drug Randomisation
CETP genotypes
Individuals
(studies)
Systolic BP
Mean Difference
(95% CI)
B1B2 v B1B1
46,412 (21)
-0.27 (-0.64, 0.10)
B2B2 v B1B1
29,050 (21)
0.16 (-0.28, 0.60) -2
mmHg 28

29. CV Risk Management: What is Needed?
Opportunities from novel therapies to reduce residual CV risk
Optimal approach will involve lifetime management of RFs
Better strategies to refine priorotization of new drug targets needed