new advances in cv risk reduction in high risk patients a/prof. karam kostner mater hospital and...
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New Advances in CV Risk Reduction in New Advances in CV Risk Reduction in High Risk Patients High Risk Patients
A/Prof. Karam KostnerA/Prof. Karam Kostner
Mater Hospital and University of Queensland Brisbane, Mater Hospital and University of Queensland Brisbane, AustraliaAustralia
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LL-LL-TherapyTherapy LDL-C LDL-C LoweringLowering
HDL-C HDL-C RaisingRaising
TG TG LoweringLowering
Statins Statins ++++++++ ++++ ++++
NiacinsNiacins ++++ ++++++++ ++++++
Resins Resins ++++ ++ 0/-0/-
FibratesFibrates +/-+/- ++++++ ++++++++
EzetimibeEzetimibe ++++ ++ ++
nn--33 Ethyl Esters Ethyl Esters 0/-0/- ++ ++++++++
+ = positive effect - = negative effect 0 = no effect
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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
Effect of Statins on CHD Events by Effect of Statins on CHD Events by LDL-C LDL-C achieved: ‘ the lower the better ’achieved: ‘ the lower the better ’Effect of Statins on CHD Events by Effect of Statins on CHD Events by LDL-C LDL-C achieved: ‘ the lower the better ’achieved: ‘ the lower the better ’
LDL- Cholesterol achieved, mmol/L
CH
D
Eve
nt
Rat
e (%
)
WOSCOPS – Placebo
AFCAPS - Placebo
ASCOT - Placebo
AFCAPS - Rx WOSCOPS - Rx
ASCOT - Rx
4S - Rx
HPS - Placebo
LIPID - Rx
4S - Placebo
CARE - Rx
LIPID - Placebo
CARE - Placebo
HPS - Rx
0
5
10
15
20
25
30
1.0 1.6 2.1 2.6 3.1 3.6 4.1 4.7
6
Secondary Prevention
Primary Prevention
Rx - Statin therapyPRA – pravastatinATV - atorvastatin
5.2
PROVE-IT - PRA
PROVE-IT – ATV
TNT – ATV10
TNT – ATV80
Cards - Rx
Cards - Placebo
HPS - Placebo
HPS - Rx
TNT Diab ATV 10
TNT Diab ATV 80
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Persistent Lipid Abnormalities in Patients on Statins: DYSIS
CHD or Risk
Equivalent
(n = 13,503)
(70.3%)
Two or More Risk Factors
(n = 3,522)
(18.3%)
Zero or One Risk Factor
(n = 2,171)
(11.3%)
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
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PROVE-IT:PROVE-IT: Residual CVS Events RiskResidual CVS Events Risk
Residual Risk
pravastatin 40 mgLDL-C reduction 10%
atorvastatin 80 mgLDL-C reduction 42%
16% reduction
p=0.005
Cannon CP et al. N Engl J Med 2004; 350: 1495–1504
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Approaches to Reduce Residual RiskApproaches to Reduce Residual Risk
Low Density Lipoprotein (LDL) Low Density Lipoprotein (LDL)
Triglyceride Triglyceride
High Density Lipoprotein (HDL) High Density Lipoprotein (HDL)
ApoA-1 ApoA-1
Lp(a)Lp(a)
Inflammation Inflammation
BP, Smoking, Weight, Stress, PollutionBP, Smoking, Weight, Stress, Pollution
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% C
HD
even
ts
O’Keefe, JACC 2004; 2142-6
What is the LDL-cholesterol level we What is the LDL-cholesterol level we should aim for?should aim for?
““in secondary prevention the in secondary prevention the event rate is predicted to event rate is predicted to approach zero at LDL of 30 approach zero at LDL of 30 mg/dl = 0.8 mmol/L”mg/dl = 0.8 mmol/L”
““in primary prevention the in primary prevention the event rate is predicted to event rate is predicted to
approach zero at LDL of 57 approach zero at LDL of 57 mg/dl = 1.5 mmol/L”mg/dl = 1.5 mmol/L”
CARDS-S
CARDS-P
% C
HD
even
ts
IMPROVE-IT (Ezetimibe +Sim 40)
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THREE-STEP
TITRATION
10 20 30 40 50 60
% Reduction in LDL Cholesterol
0
-6% -6%
Statin 10 mg 20 mg
40 mg
80 mg
-6%
Effect of Statin Therapy on LDL-C Levels: “The Rule of 6”
““The Rule of 6” for StatinsThe Rule of 6” for Statins
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Ezetimibe: Efficacy
-0.4 -1.3-0.2
-18.5
-4.9
3.5
-20
-15
-10
-5
0
5
Me
an
% C
ha
ng
e f
rom
Ba
se
line
Placebo Ezetimibe 10 mg (n=123)
LDL-C Triglyceride HDL-C
* P < 0.05 vs placebo*
*
J Am Coll Cardiol 2000; 35(supp A):257A
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Effect of ezetimibe coadministered with Effect of ezetimibe coadministered with statins in heterozygous FH patientsstatins in heterozygous FH patients
Piciotta L et al. Atherosclerosis 2006Piciotta L et al. Atherosclerosis 2006
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Risk ratio & 95% CIEvent PlaceboEze/simv(n=4620)(n=4650)
Major coronary event 213 (4.6%) 230 (5.0%) Non-haemorrhagic stroke 131 (2.8%) 174 (3.8%) Any revascularization 284 (6.1%) 352 (7.6%)
Major atherosclerotic event 526 (11.3%) 619 (13.4%) 16.5% SE 5.4 reduction (p=0.0022)
Other cardiac death 162 (3.5%) 182 (3.9%) Haemorrhaghic stroke 45 (1.0%) 37 (0.8%)
Other major vascular events 207 (4.5%) 218 (4.7%) 5.4% SE 9.4 reduction (p=0.57)
Major vascular event 701 (15.1%) 814 (17.6%) 15.3% SE 4.7 reduction (p=0.0012)
0.6 0.8 1.0 1.2 1.4
SHARP: Major Atherosclerotic Events
Eze/simv better
Placebo better
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Risk Factor Components of the Atherogenic Lipid Profile
Lp(a)
HDL-C
LDL-C
Remnant Lipoproteins
Chylomicrons VLDL
AcceleratedAtherosclerosis
+Cardiovascular
Disease
TriglyceridesTG-rich
Lipoproteins Fasting
Nonfasting
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Treatment of elevated triglyceridesTreatment of elevated triglycerides
1) achieve LDL goal2) low fat diets,weight red. and physical activity3) fibrates, nicotinic acid4) high dose fish oil5) improve diabetic control
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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)
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Common CombinationCommon CombinationTherapies in Lipid LoweringTherapies 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
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Ezetimibe/Simvastatin (VYTORIN) Significantly Reduces LDL-C Across the Dose Range Compared with ROSUVASTATIN
0
–50
–55
–45
–65
–60
aP<0.001; bP=0.001 vs rosuvastatin
Adapted from Catapano AL et al Curr Med Res Opin. 2006;22:2041–2053.
–54.8%b
–52.3%
10/40 mg(n=477)
20 mg(n=478)
–51.5%a
–45.8%
10/20 mg(n=476)
10 mg(n=475)
–61%a
–56.7%
10/80 mg(n=474)
40 mg(n=475)
Mea
n %
ch
ang
e fr
om
b
asel
ine
to w
eek
6
Ezetimibe/simvastatinRosuvastatin
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SAFARI Trial: Combination Therapy with SAFARI Trial: Combination Therapy with Simvastatin and Fenofibrate in Patients With Simvastatin and Fenofibrate in Patients With
Combined HyperlipidemiaCombined Hyperlipidemia
Grundy SM et al Am J Cardiol 2005;95:462-468.*P<.001 versus simvastatin
**
*
*
N=618
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Efficacy of Fixed-Dose Niacin ER/Simvastatin Efficacy of Fixed-Dose Niacin ER/Simvastatin Combination TherapyCombination Therapy
SEACOAST ISEACOAST I
-7.4 -7.1
6.7
-15.3
-7.6
-13.9 -13.1
18.3
-26.5
-16.7
-22.5
-14.2
24.9
-38.0
-25.0
-40
-30
-20
-10
0
10
20
30
Simvastatin 20 mg (n = 90)
Niacin ER/Simvastatin 1000/20 mg (n = 78)
Niacin ER/Simvastatin 2000/20 mg (n = 40)
Med
ian
% C
han
ge
Fro
m B
asel
inea
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
Non–HDL-C HDL-C TGLDL-C Lp(a)
163.5Median Baseline, mg/dL
156.3155.0 119.0 112.8115.0 42.5 42.843.0 194.5 212.3196.5 12.0 10.017.0
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-50
-40
-30
-20
-10
0
10
20
30
Efficacy of Extended-Release NiacinEfficacy of Extended-Release NiacinC
han
ge f
rom
Base
line
2500 mg
3000 mg
Goldberg A et al Am J Cardiol 2000;85:1100-1105.
2000 mg
1500 mg
1000 mg
500mg
HDL-C
LDL-CLp(a)
TG
–9%–14%
–22% –21%–17%
29.5%30%26%
22%15%
10%
–28%
–35% –44%–39%
–11%
–5%
–26%
–3%
–12%
–30%
–24%–17%
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Slide SourceLipids Online Slide Librarywww.lipidsonline.org
Use of NiacinUse 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
Kostner, 2011
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Most Patients on ER Niacin Therapy Do Not Reach Therapeutic 2g Dose
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.
N=14,386 N=6,349 N=5,277 N=5,402 N=2,104
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0
20
40
60
80
100Extreme (GFSS 10)Severe (GFSS 7-9)Moderate (GFSS 4-6)None/Mild (GFSS 0-3)
PBO (n=66) ERN/LRPT(n=130)
N-ER (n=134)
88%
12%
76%
14%
8.5%1.5%
50%
26%
18%
6%
Per
cent
of P
atie
nts
Maximum GFSS, Presented as Percent of Patients
• 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)
Asia Flushing Study (PN 056): Asia Flushing Study (PN 056): ResultsResults
Debra Kush et al. Cardiology 2009;114:192–198
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Summary of Adverse Experiences (AEs)
Study ParameterERN/LRPTN=2,548
ERN or NSPN=1,268
Simvastatin orPlaceboN=931
n % n % n %
Treatment-related clinical AE 901 35.4c,d 501 39.5 156 16.8
Treatment-related serious clinical AE 8 0.3e,f 1 0.1 1 0.1
Discontinued due to treatment-related clinical AEb
328 12.9 204 16.1 28 3.0
Incidence of treatment-relateda AEs was similar between ERN/LRPT and ERN or NSP
aDetermined by the investigator to be possibly, probably, or definitely treatment-related.bSome 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.
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%
Paolini et al. Cardiol Clin. 2008;26:547–560.
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Dose Range of Omega-3 Required To Reduce Triglycerides
TG 1.8-5.0 mmol/L at baseline (after 8-week run-in)
4 capsules of Omacor® to reduce triglycerides
27
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Combination Omega-3 and Simvastatin Combination Omega-3 and Simvastatin (COMBOS) in Patients with HyperTG(COMBOS) in Patients with HyperTG
TG LDL-C HDL-CVLDL-C
Omaacor 4 g/d + simvastatin 40 mg/d
Placebo + simvastatin 40 mg/d
Davidson MH et al. Clin Ther. 2007;29(7):1354-1367.
*P <0.0001 between groups†P = 0.0232 between groups‡P = 0.0522 between groups
Me
dia
n C
han
ge
Fro
m B
ase
line
(%) 5
–5
–10
–15
–20
–25
–30
3.4*
–6.3 –7.2
–1.2–2.8
–29.5*
0.7‡0
–27.5*
–4.2†–1.9
Apo BNon-HDL-C
–9.0*
–2.2
Additional changes to baseline simvastatin
therapy
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Lp(a): Epidemiology, Pathophysiology and Therapeutic Considerations
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Risk of Myocardial Infarction by Extreme Levels of Lipoprotein(a) in the General
Population
Kamstrup, P. R. et al. JAMA 2009;301:2331-2339
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For any given RF, LP(a) augments risk..For any given RF, LP(a) augments risk..
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ATHEROGENICITY of Lp(a): MECHANISMS
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Treatment of elevated Lp(a)Treatment of elevated Lp(a)
1) achieve LDL goal2) ACE in proteinuric patients3) Nicotinic acid4) LDL-apheresis5) Anti Lp(a) antisense and other novel therapies
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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
-100
-80
-60
-40
-20
0
20
40
60
80
chan
ge
(%)
TC TG HDLLp (a)LDL
0
500
1000
1500
2000
2500
3000
1 2C
alci
fied
Pla
que
Vol
ume
in m
m3
Baseline Follow-up
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-50
-40
-30
-20
-10
0
10
20
30
Efficacy of Extended-Release NiacinC
han
ge f
rom
Base
line
2500 mg
3000 mg
Goldberg A et al. Am J Cardiol 2000;85:1100-1105.
2000 mg
1500 mg
1000 mg
500mg
HDL-C
LDL-CLp(a)
TG
–9%–14%
–22% –21%–17%
29.5%30%26%
22%15%
10%
–28%
–35% –44%–39%
–11%
–5%
–26%
–3%
–12%
–30%
–24%–17%
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Inverse Relationship between Bile Acids and Plasma Lp(a)
20 patients with obstructive cholestasis before and after surgery
Bile acids are ligands for FXR
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0.2% cholic acid treatment reduces plasma apo(a)
concentration in wt – mice but not in FXR-/- mice
Plasma apo(a) levels were measured using DELFIA
0
50
100
150
ns
apo(
a) le
vels
in p
lasm
a (%
)
0
50
100
150
*
apo(
a) le
vels
in p
lasm
a (%
)Single tg apo(a)-YAC Double tg apo(a)-YAC X FXR-/-
I. Chennamsetty, T. Claudel, K.Kostner et al. J Clin Invest.doi:10.1172/JCI45277;2011
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i.p. injection of the FXR ligand GW4064 (30mg/kg body wt) (n=3)
Quantifying hepatic apo(a)
gene and protein expression
16hr-harvesting the tissues
The selective FXR ligand GW4064 decreases apo(a) gene expression in YAC- apo(a) Tg mice (n=3)
ELISA
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I. Chennamsetty, T. Claudel, K.Kostner et al. J Clin Invest.doi:10.1172/JCI45277;2011
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Selected Pipeline TherapiesSelected Pipeline Therapies
Therapies to increase LDL Therapies to increase LDL particle clearanceparticle clearance
Thyroid hormone analogue
Proprotein convertase subtilisin/kexin type 9 inhibitor
Squalene synthase inhibitors
Therapies to decrease LDL Therapies to decrease LDL particle productionparticle production
Microsomal triglyceride transfer protein (MTP) inhibitors
Apolippoprotein B antisense
Therapies to increase HDLTherapies 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.
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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 lipid-lowering agents showed mipomersen dose-dependently reduced: 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.
‘ ‘ Shooting the Messenger ’Shooting the Messenger ’
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Results – LDL Cholesterol
Raal FJ et al Lancet 2010;375:998-1006.
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%)
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Results – Lipoprotein (a)
Raal FJ et al. Lancet 2010;375:998-1006.
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%)
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Proprotein Convertase Subtilisin/Kexin Type 9Proprotein 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
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Cholesterol Ester Transfer Protein (CETP)Cholesterol Ester Transfer Protein (CETP)
Lipoprotein Binding Surface
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Effects and Safety of AnacetrapibEffects and Safety of Anacetrapib
Bloomfield D et al Am Heart J 2009;157:352-60.e2Cannon CP et al N Eng J Med 2010, November 17 on-line
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Results: HDL-cholesterol Results: HDL-cholesterol
Bloomfield D et al. Am Heart J 2009;157:352-60.e2
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Results: LDL-cholesterol Results: LDL-cholesterol
Bloomfield D et al Am Heart J 2009;157:352-60.e2
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Results: Lp(a) Results: Lp(a)
Bloomfield D et al. Am Heart J 2009;157:352-60.e2
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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
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