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

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

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

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

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

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

% 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)

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

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

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

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

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

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

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 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

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

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

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

-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%

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

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

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

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.

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

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

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..For any given RF, LP(a) augments risk..

ATHEROGENICITY of Lp(a): MECHANISMS

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

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

-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%

Inverse Relationship between Bile Acids and Plasma Lp(a)

20 patients with obstructive cholestasis before and after surgery

Bile acids are ligands for FXR

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

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

0

5

10

15

20

**

ap

o(a

) le

vels

in

pla

sm

a m

g/d

L

q-PCR

0.0

0.5

1.0

1.5

***

ap

o(a

) m

RN

A levels

/ c

yclo

ph

ilin

I. Chennamsetty, T. Claudel, K.Kostner et al. J Clin Invest.doi:10.1172/JCI45277;2011

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.

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 ’

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%)

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%)

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

Cholesterol Ester Transfer Protein (CETP)Cholesterol Ester Transfer Protein (CETP)

Lipoprotein Binding Surface

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

Results: HDL-cholesterol Results: HDL-cholesterol

Bloomfield D et al. Am Heart J 2009;157:352-60.e2

Results: LDL-cholesterol Results: LDL-cholesterol

Bloomfield D et al Am Heart J 2009;157:352-60.e2

Results: Lp(a) 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