New Advances in CV Risk Reduction in
High Risk Patients
A/Prof. Karam Kostner
Mater Hospital and University of Queensland Brisbane,
Australia
LDL-C
Lowering
HDL-C
Raising
TG
Lowering
Statins
++++
++
++
Niacins
++
++++
+++
Resins
++
+
0/-
Fibrates
+/-
+++
++++
Ezetimibe
++
+
+
0/-
+
++++
LL-Therapy
n-3 Ethyl Esters
+ = positive effect
- = negative effect 0 = no effect
Effect of Statins on CHD Events by
LDL-C achieved: ‘ the lower the better ’
30
4S - Placebo
CHD Event Rate (%)
25
Rx - Statin therapy
PRA – pravastatin
ATV - atorvastatin
Secondary Prevention
4S - Rx
20
TNT Diab ATV 10
15
10
LIPID - Placebo
HPS - Placebo
TNT Diab ATV 80
CARE - Placebo
LIPID - Rx
CARE - Rx
Primary Prevention
HPS - Placebo
HPS - Rx
TNT – ATV10
PROVE-IT - PRA Cards - Placebo
WOSCOPS – Placebo
TNT – ATV80
HPS - Rx
PROVE-IT – ATV
AFCAPS - Placebo
6
5
Cards - Rx
AFCAPS - Rx
WOSCOPS - Rx
ASCOT - Placebo
ASCOT - Rx
0
1.0
1.6
2.1
2.6
3.1
3.6
4.1
4.7
LDL- Cholesterol achieved, mmol/L
Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279
LaRosa JC et al. N Engl J Med 2005;352:1425-1435
5.2
Persistent Lipid Abnormalities in Patients on Statins:
DYSIS
CHD or
Risk
Equivalent
Two or
More Risk
Factors
Zero or One
Risk Factor
(n =
13,503)
(n = 3,522)
(11.3%)
(n = 2,171)
(18.3%)
(70.3%)
LDL-C not at goal
(%)
43.4
35.7
16.7
Non–HDL-C not at
goal (%)*
71.1
56.8
35.8
Low HDL-C (%)
35.9
33.6
1.4
Elevated triglycerides
(%)
40.9
41.5
20.7
High triglycerides
(%)**
67.4
70.2
69.5
Alexander W. American college of cardiology, 58th annual scientific session. P
T. 2009;34(5):258-260
PROVE-IT:
Residual CVS Events Risk
pravastatin 40 mg
LDL-C reduction 10%
Residual Risk
atorvastatin 80 mg
LDL-C reduction 42%
Cannon CP et al. N Engl J Med 2004; 350: 1495–1504
16%
reduction
p=0.005
Approaches to Reduce Residual Risk
 Low Density Lipoprotein (LDL) 
 Triglyceride 
 High Density Lipoprotein (HDL) 
 ApoA-1 
 Lp(a) 
 Inflammation 
 BP, Smoking, Weight, Stress,
Pollution
What is the LDL-cholesterol level we
should aim for?
CARDS-P
CARDS-S
“in primary prevention the event
rate is predicted to approach zero
at LDL of 57 mg/dl = 1.5 mmol/L”
IMPROVE-IT (Ezetimibe +Sim 40)
“in secondary prevention the
event rate is predicted to approach
zero at LDL of 30 mg/dl = 0.8
mmol/L”
O’Keefe, JACC 2004; 2142-6
“The Rule of 6” for Statins
Effect of Statin Therapy on LDL-C Levels: “The Rule of 6”
-6%
Statin 10 mg
0
10
20
30
-6%
20
mg
40
mg
40
% Reduction in LDL Cholesterol
-6%
80
mg
50
THREE-STEP
TITRATION
60
Ezetimibe: Efficacy
Mean % Change from Baseline
LDL-C
Triglyceride
HDL-C
5
3.5
*
0
-0.4
-0.2
-1.3
-5
-4.9
-10
-15
* P < 0.05 vs placebo
-20
-18.5
*
Placebo
Ezetimibe 10 mg (n=123)
J Am Coll Cardiol 2000; 35(supp A):257A
Effect of ezetimibe coadministered with
statins in heterozygous FH patients
Piciotta L et al. Atherosclerosis 2006
SHARP: Major Atherosclerotic Events
Event
Eze/simv
(n=4650)
Placebo
(n=4620)
Major coronary event
Non-haemorrhagic stroke
Any revascularization
213 (4.6%) 230
131 (2.8%) 174
284 (6.1%) 352
Major atherosclerotic event
526 (11.3%) 619 (13.4%)
Other cardiac death
Haemorrhaghic stroke
162 (3.5%) 182
45 (1.0%) 37
Risk ratio & 95% CI
(5.0%)
(3.8%)
(7.6%)
16.5% SE 5.4
reduction
(p=0.0022)
(3.9%)
(0.8%)
Other major vascular events 207 (4.5%) 218 (4.7%)
5.4% SE 9.4
reduction
(p=0.57)
Major vascular event
15.3% SE 4.7
reduction
(p=0.0012)
701 (15.1%) 814 (17.6%)
0.6
0.8
Eze/simv
better
1.0
1.2
1.4
Placebo
better
Risk Factor Components
of the Atherogenic Lipid Profile
LDL-C
Lp(a)
HDL-C
Accelerated
Atherosclerosis
+
Cardiovascular
Disease
Triglycerides
TG-rich
Lipoproteins
 Fasting
 Nonfasting
Remnant
Lipoproteins
 Chylomicrons
 VLDL
Treatment of elevated triglycerides
1)
2)
3)
4)
5)
achieve LDL goal
low fat diets,weight red. and physical activity
fibrates, nicotinic acid
high dose fish oil
improve diabetic control
Reasons for Combination Therapy
 To achieve LDL-C goal when monotherapy
inadequate (elevated LDL-C)
 To achieve Non- HDL-C or apoB, Lp(a) goal
after LDL-C goal achieved (mixed HL)
 To reduce Triglycerides in severe
hypertriglyceridaemia (TG > 5 mmol/L)
Common Combination
Therapies in Lipid Lowering
“Safer” combinations
• Statins + BABRs for LDL-C lowering
• Statins + ezetemibe for LDL-C lowering
• Statins + niacin for LDL-C and TG lowering
• Statins + omega-3 ethyl esters for TG lowering
Combinations that may require additional monitoring
• Statin + fibric acid for combined dyslipidemias
• Statin + fibric acid + niacin + for combined dyslipidemias
Ezetimibe/Simvastatin (VYTORIN)
Significantly Reduces LDL-C Across the Dose
Range Compared with ROSUVASTATIN
Ezetimibe/simvastatin
Rosuvastatin
10/20 mg
(n=476)
10 mg
(n=475)
10/40 mg 20 mg
(n=477) (n=478)
10/80 mg
(n=474)
40 mg
(n=475)
Mean % change from
baseline to week 6
0
–45
–45.8%
–50
–51.5%a
–52.3%
–55
–54.8%b
–56.7%
–60
–61%a
–65
aP<0.001; bP=0.001
vs rosuvastatin
Adapted from Catapano AL et al Curr Med Res Opin. 2006;22:2041–2053.
SAFARI Trial: Combination Therapy with
Simvastatin and Fenofibrate in Patients With
Combined Hyperlipidemia
*
*
*
*
N=618
*P<.001 versus simvastatin
Grundy SM et al Am J Cardiol 2005;95:462-468.
Efficacy of Fixed-Dose Niacin ER/Simvastatin
Combination Therapy
SEACOAST I
Median % Change From Baselinea
30
**
24.9
Simvastatin 20 mg (n = 90)
**
20
Niacin ER/Simvastatin 1000/20 mg (n = 78)
Niacin ER/Simvastatin 2000/20 mg (n = 40)
10
6.7
18.3
0
-10
-7.1
-7.4
-7.6
-13.1-14.2
-13.9
-15.3
-20
*
-30
-40
-22.5
*
-26.5
**
163.5
156.3
-25.0
*
Non–HDL-C
Median Baseline, 155.0
mg/dL
-16.7
HDL-C
LDL-C
115.0
119.0
112.8
43.0
42.5
42.8
Lp(a)
TG
**
-38.0
196.5
194.5
**
212.3
17.0
12.0
10.0
aSimvastatin
20 mg baseline
*P<.01 versus simvastatin 20 mg; **P<.001 versus simvastatin 20 mg
Ballantyne C et al Am J Cardiol 2008;101:1428
Efficacy of Extended-Release Niacin
HDL-C
Change from Baseline
30
20
10
10%
0
–3%
-10
-20
–5%
-30
22%
–9%
–14% –17%
–12%
–22%
–17%
–11%
–24%
–28%
-40
-50
15%
500
mg
26%
30% 29.5%
–21%
LDL-C
Lp(a)
–30%
–26%
–35%
–44%
TG
–39%
1000 1500 2000 2500 3000
mg
mg
mg
mg
mg
Goldberg A et al Am J Cardiol 2000;85:1100-1105.
Use of Niacin
 1) High risk (post MI, ACS, DM)
Addition to statin in patients with low
HDL
 2) Combined Hyperlipidemia (elevated
TG and LDL)
 3) Elevated Lp(a)
 Other Uses: Statin intolerant patients
and FH
Slide Source
Lipids Online Slide Library
www.lipidsonline.org
Kostner, 2011
Most Patients on ER Niacin Therapy Do
Not Reach Therapeutic 2g Dose
100%
Percent Users
80%
>1500 mg
1001-1500 mg
751-1000 mg
501-750 mg
<=500 mg
60%
40%
20%
0%
4 wk
8 wk
N=14,386 N=6,349
12 wk
24 wk
1y
N=5,277
N=5,402
N=2,104
Retrospective cohort study using administrative claims data from 2000 to 2003 Ingenix Lab/Rx Database™.
Kamal-Bahl et al. Dosage and Titration Patterns of Extended Release Niacin in Clinical Practice. Abstract presented at AHA 7th Scientific Forum on
Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke, Washington, D.C., May, 2006.
Asia Flushing Study (PN 056): Results
Percent of Patients
100
80
60
40
Maximum GFSS, Presented as Percent of
Patients
1.5%
6%
8.5%
12%
Extreme (GFSS 10)
18%
14%
Severe (GFSS 7-9)
Moderate (GFSS 4-6)
26%
None/Mild (GFSS 0-3)
88%
76%
50%
20
0
PBO (n=66)
ERN/LRPT
(n=130)
N-ER (n=134)
• ERN/LRPT patients had significantly (p<0.001) less flushing vs. N-ER patients, as
measured by maximum GFSS categorized as none/mild, moderate, severe, or extreme.
• Significantly fewer ERN/LRPT vs. N-ER patients had:
– Moderate or greater flushing: 24% vs. 50% (p<0.001)
– Severe or greater flushing: 10% vs. 24% (p=0.003)
– Discontinuation due to flushing: 0.8% vs. 3.7% (p<0.001)
Debra Kush et al. Cardiology 2009;114:192–198
Summary of Adverse Experiences (AEs)
Incidence of treatment-relateda AEs was similar between ERN/LRPT
and ERN or NSP
Study Parameter
Treatment-related clinical AE
Treatment-related serious clinical AE
Discontinued due to treatment-related
clinical AEb
ERN/LRPT
N=2,548
ERN or NSP
N=1,268
Simvastatin or
Placebo
N=931
n
%
n
%
n
%
901
35.4c,d
501
39.5
156
16.8
8
0.3e,f
1
0.1
1
0.1
328
12.9
204
16.1
28
3.0
 The 2 primary reasons for discontinuation:
 Flushing symptoms: ERN/LRPT 7.2%; ERN or NSP 16.6%
 Clinical AEs: ERN/LRPT 9.7%; ERN or NSP 7.0%
aDetermined
by the investigator to be possibly, probably, or definitely treatment-related.
patients discontinued due to flushing without an associated AE report.
c95% CI for difference with ERN or NSP does not include 0.
d95% CI for difference with simvastatin or placebo does not include 0.
e95% CI for difference with ERN or NSP includes 0.
f95% CI for difference with simvastatin or placebo includes 0.
bSome
Paolini et al. Cardiol Clin.
2008;26:547–560.
Dose Range of Omega-3 Required To
Reduce Triglycerides
4 capsules of Omacor® to reduce triglycerides
TG 1.8-5.0 mmol/L at baseline (after 8-week run-in)
27
Median Change From Baseline (%)
Combination Omega-3 and Simvastatin
(COMBOS) in Patients with HyperTG
5
Non-HDL-C
TG
VLDL-C
0
–5
–10
0.7‡
–2.2
–9.0*
HDL-C
3.4*
–2.8
–6.3
Apo B
–1.2
–1.9
–4.2†
–7.2
Additional changes to
baseline simvastatin
therapy
–15
–20
–25
–30
LDL-C
Omaacor 4 g/d + simvastatin 40 mg/d
–29.5*
–27.5*
Placebo + simvastatin 40 mg/d
*P <0.0001 between groups
†P = 0.0232 between groups
‡P = 0.0522 between groups
Davidson MH et al. Clin Ther. 2007;29(7):1354-1367.
Lp(a): Epidemiology, Pathophysiology
and Therapeutic Considerations
Risk of Myocardial Infarction by Extreme
Levels of Lipoprotein(a) in the General
Population
Kamstrup, P. R. et al. JAMA 2009;301:2331-2339
For any given RF, LP(a) augments
risk..
ATHEROGENICITY of Lp(a): MECHANISMS
Treatment of elevated Lp(a)
1)
2)
3)
4)
5)
achieve LDL goal
ACE in proteinuric patients
Nicotinic acid
LDL-apheresis
Anti Lp(a) antisense and other novel therapies
Aggressive LDL und Lp(a) Reduction in FH
Patients
Hoffmann U, Kostner K et al. Am J Cardiol. 2003 Feb 15;91(4):461-4
3000
2500
Calcified Plaque Volume in mm3
80
60
change (%)
40
20
0
-20
-40
2000
1500
1000
-60
-80
TC
TG
LDL
Lp (a)
HDL
500
-100
0
Baseline
1
Follow-up
2
Efficacy of Extended-Release Niacin
HDL-C
Change from Baseline
30
20
10
10%
0
–3%
-10
-20
–5%
15%
22%
–9%
–14% –17%
–12%
–22%
–17%
–11%
–24%
-30
–28%
-40
-50
500
mg
26%
30% 29.5%
1000
mg
1500
mg
Goldberg A et al. Am J Cardiol 2000;85:1100-1105.
–21%
LDL-C
Lp(a)
–30%
–26%
–35%
–44%
–39%
TG
2000
mg
2500
mg
3000
mg
Inverse Relationship between Bile
Acids and Plasma Lp(a)
20 patients with obstructive cholestasis before and after surgery
200
70
60
150
100
Lp(a) in mg/dl
Total bile acids µmol/L
50
Mean ± SEM
98.9 ± 9.2
40
Mean ± SEM
20.3 ± 4.4
30
20
50
10
Mean ± SEM
2.7 ± 1.1
Mean ± SEM
7.1 ± 0.6
0
Before therapy
After therapy
0
Before therapy
After therapy
Bile acids are ligands for FXR
0.2% cholic acid treatment reduces plasma
apo(a)
concentration in wt – mice but not in FXR-/- mice
100
50
0
ko
-C
A
A
-C
wt
-C
on
tro
l
0
ns
l
*
50
150
ko
-c
on
tro
100
Double tg apo(a)-YAC X FXR-/apo(a) levels in plasma (% )
150
wt
apo(a) levels in plasma (%)
Single tg apo(a)-YAC
Plasma apo(a) levels were measured using DELFIA
I. Chennamsetty, T. Claudel, K.Kostner et al. J Clin
Invest.doi:10.1172/JCI45277;2011
The selective FXR ligand GW4064 decreases apo(a) gene
expression in YAC- apo(a) Tg mice (n=3)
i.p. injection of the FXR ligand GW4064
20
15
10
**
5
0
G
1.5
1.0
***
0.5
0.0
g/
kg
30
m
40
6
W
G
I. Chennamsetty, T. Claudel, K.Kostner et al. J Clin
Invest.doi:10.1172/JCI45277;2011
4
V
Quantifying
hepatic apo(a)
gene and protein
expression
q-PCR
eh
ic
le
16hr-harvesting
the tissues
apo(a) mRNA levels / cyclophilin
V
W
40
6
4
eh
ic
le
(30mg/kg body wt) (n=3)
apo(a) levels in plasma mg/dL
ELISA
Selected Pipeline Therapies
 Therapies to decrease LDL
particle production
 Therapies to increase LDL
particle clearance
 Microsomal triglyceride transfer
protein (MTP) inhibitors
 Apolippoprotein B antisense
 Therapies to increase HDL
 CETP Inhibitors
Stein EA. Endocrinol Metab Clin North Am 2009;38:99-119.
Davidson MH. Curr Atheroscler Rep 2008;11:67-70.
 Thyroid hormone analogue
 Proprotein convertase
subtilisin/kexin type 9
inhibitor
 Squalene synthase inhibitors
Apolipoprotein B-100 Antisense
Oligonucleotide (ASO) Therapy: Mipomersen
 Mipomersen: second
generation ASO that inhibits
apolipoprotein B-100 protein
synthesis1
 Phase 2 studies2,3 in patients
on statins and other lipidlowering agents showed
mipomersen dose-dependently
reduced:




‘ Shooting the Messenger ’
Apo B
LDL-C
Non-HDL-C
Triglycerides (TGs)
1. Crooke R, et al. In: Crooke ST, ed. Antisense drug technology: principles, strategies and applications. 2nd ed. Boca Raton,
Florida: CRC Press, 2007:601-639.
2. Kastelein JJ, et al. Circulation. 2006;114(16):1729-1735.
3. Stein EA. Endocrin Metab Clin N Am. 2009; 38:99-119.
Results – LDL Cholesterol
 Mean LDL-C change from baseline to PET
 Mipomersen: 11.4 mmol/L to 8.4 mmol/L (mean reduction 24.7%)
 Placebo: 10.4 mmol/L to 10.1 mmol/L (mean reduction 3.3%)
Raal FJ et al Lancet 2010;375:998-1006.
Results – Lipoprotein (a)
 Mean LDL-C change from baseline to PET
 Mipomersen: 0.6 g/L to 0.4 g/L (mean reduction 31.1%)
 Placebo: 0.7 mmol/L to 0.6 mmol/L (mean reduction 7.9%)
Raal FJ et al. Lancet 2010;375:998-1006.
Proprotein Convertase Subtilisin/Kexin Type 9
 Member of family of proteases that degrade LDL-Receptor
 Mutations leading to loss of function are associated with lifelong
low LDL-C levels and decreased risk of cardiovascular disease
 Inhibitors of PCSK9 are in development
Stein EA Endocrinol Metab Clin North Am 2009;38:99-119.
Horton JD, Cohen JC, Hobbs HH J Lipid Res 2009; 50: S172-177
Cholesterol Ester Transfer Protein (CETP)
Lipoprotein Binding Surface
Effects and Safety of Anacetrapib
Bloomfield D et al Am Heart J 2009;157:352-60.e2
Cannon CP et al N Eng J Med 2010, November 17 on-line
Results: HDL-cholesterol
Bloomfield D et al. Am Heart J 2009;157:352-60.e2
Results: LDL-cholesterol
Bloomfield D et al Am Heart J 2009;157:352-60.e2
Results: Lp(a)
Bloomfield D et al. Am Heart J 2009;157:352-60.e2
Conclusions
Extensive evidence suggests statins as initial therapy for
dyslipidemia ( FH, DM, CHD), except in severe hyperTG
Consider adding second or third agent when LDL-C
(ezetimibe) or non-HDL-C goal (niacin, fenofibrate) not
achieved
For high risk patients with elevated TG and/or low HDL-C,
consider adding a fibrate, niacin or n-3 acid ethyl esters to
LDL-C lowering therapy
Combination therapy holds great promise for reducing
residual CVD risk, especially with new agents in pipeline