Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy...

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Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of Medicine Division of Cardiology Hotel Dieu de France Saint Joseph University

Transcript of Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy...

Page 1: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Beyond LDL Cholesterol: Reduction of Small Dense LDL and of

Oxidized LDL With Combined Lipid Therapy

Rabih R. Azar, MD, MSc, FACCAssociate Professor of Medicine

Division of CardiologyHotel Dieu de France

Saint Joseph University

Page 2: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Risk of CAD according to LDL and HDL

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Relationship between LDL-C and CV Event Rate

Adapted from Ballantyne CM et al. Am J Cardiol 1998;82:3Q– 12Q.

LDL-C achieved mg/ dL (mmol/ L)

WOSCOPS - Pl

AFCAPS/ TexCAPS - Pl

ASCOT - PlAFCAPS/ TexCAPS- Rx

WOSCOPS - Rx

ASCOT - Rx

ALLHAT - RxALLHAT - Pl

4S - Rx

HPS - Pl

LIPID - Rx

4S - Pl

CARE - Rx

LIPID - Pl

PROSPER - PlCARE - Pl

HPS - Rx

PROSPER - Rx

0

5

10

15

20

25

30

70 (1.8) 90 (2.3) 110 (2.8) 130 (3.4) 150 (3.9) 170 (4.4) 190 (5.0) 210 (5.4)

Even

t ra

te (

%)

- Secondary prevention

- Primary prevention

Rx - Statin therapy

Pl - Placebo

I s Very Low LDL the Answer to Better Prevention?

Page 4: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

NCEP ATP I I I : LDL-C Goals(2004 proposed modifications)

NCEP ATP I I I : LDLNCEP ATP I I I : LDL--C GoalsC Goals(2004 proposed modifications)(2004 proposed modifications)

* Therapeutic option

70 mg/ dL =1.8 mmol/ L; 100 mg/ dL = 2.6 mmol/ L; 130 mg/ dL = 3.4 mmol/ L; 160 mg/ dL = 4.1 mmol/ L

High Risk

CHD or CHD risk equivalents

(10-yr risk >20% )

LD

L-C

level

100 -

160 -

130 -

190 -

Lower Risk

< 2 risk factors

Moderately High Risk

≥ 2 risk factors

(10-yr risk 10-20% )

goal

160mg/ dL

goal

130mg/ dL

70 -

goal

100 mg/ dL

or optional

70 mg/ dL*

Moderate Risk

≥ 2 risk factors

(10-yr risk <10% )

goal

130 mg/ dL

or optional

100 mg/ dL*

Grundy SM et al. Circulation 2004;110:227-239.

Existing LDL-C goals

Proposed LDL-C goals

Page 5: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

IS LDL CHOLESTEROL THE “ONLY” PLAYER IN

ATHEROSCLEROSIS?

Page 6: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

LUMEN

MEDIA

INTIMA

Stages of Atherosclerosis

LDL

Page 7: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

LUMEN

MEDIA

INTIMA

Oxidized LDL

Adhesion molecules

Lyso-PCOxFA

Lp-PLA2

Stages of Atherosclerosis

Page 8: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

CytokinesPlaque formation

Foam cell

Monocytes

Macrophage

Stages of AtherosclerosisLUMEN

MEDIA

INTIMA

Oxidized LDL

Adhesion molecules

Lyso-PCOxFA

Lp-PLA2

Page 9: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

CytokinesPlaque formation

Foam cell

Monocytes

Macrophage

Stages of AtherosclerosisLUMEN

MEDIA

INTIMA

Oxidized LDL

Adhesion molecules

Lyso-PCOxFA

Lp-PLA2

LDL

Page 10: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Cholesterol distribution in CHD and non-CHD populations

In spite of major advances made in the screening, detection, and management of heart disease, a major need exists for more accurate ways to predict CV risk

– Approximately 50% of individuals diagnosed with coronary artery disease do not have high blood cholesterol levels

– Therefore, other factors must be involved

35% of CHD occurs in people with TC considered optimal (<200mg/dL)

Adapted from Castelli W. Atherosclerosis 1996

Framingham Heart Study — 26-year follow-up

150 200

No CHD

Total cholesterol (mg/dL)250 300

CHD

Page 11: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.
Page 12: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

20+ years of studies:Patients with smaller LDL size have greater

CHD risk at any given level of LDL-C.

LDLCholesterol

Balance

130 mg/dL 130 mg/dL

Large LDL(Pattern A)

Small LDL(Pattern B)

Higher riskLower risk

But they also have more particles!

Page 13: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Similar LDL Levels Do NOT Mean Similar Risk

LDL = 66

Phenotype B

LDL = 81

Phenotype A

Page 14: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Small Dense LDLSmall Dense LDL

• LDL particles are heterogeneous in size, density and composition. Individual can be classified according to their predominant LDL size into:

– Phenotype A: large particle size > 26.3 nm in diameter– Phenotype B: Small particle size < 25.8 nm– Phenotype I: Intermediate particle size, 25.8-26.3 nm

• LDL phenotype B is in part genetically determined

• LDL phenotype B is also influenced by acquired conditions such as:– Obesity– Type 2 DM– Metabolic syndrome

Page 15: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.
Page 16: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Role of Small Dense LDL in Predicting Ischemic Heart Disease: The Quebec Cardiovascular Study

• 2034 men; all initially free of IHD

• Followed for 5 years

• 108 first IHD recorded

• Polyacrylamide gradient gel electrophoresis was used to measure small dense LDL

Circulation 2001, 104:2295-9

Page 17: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Variable IHD free IHD Cases p

Age 56.3 + 6.9 59.3 + 7.7 <0.001

BMI 26.1 + 3.7 26.8 + 4.1 0.07

Systolic BP 130 + 17 137 + 18 < 0.001

Type 2 DM 4.4% 14.8% 0.003

Cholesterol, mmol/L

5.7 + 1.0 6.1 + 1.1 <0.001

HDL, mmol/L 1.04 + 0.2 0.96 + 0.24 0.002

Cholesterol/HDL ratio

5.8 + 1.7 6.7 + 1.9 < 0.001

TG, mmol/L 1.7 + 0.7 2.0 + 0.7 < 0.001

Apo B, mg/L 116 + 30 130 + 32 < 0.001

Lp(a), mg/dL 328 + 347 419 + 471 0.01

The Quebec Cardiovascular Study: Risk Factors for IHD

Page 18: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Small Dense LDL (<255Å) is the Best Predictor of Small Dense LDL (<255Å) is the Best Predictor of Ishemic Heart Disease (IHD) in a Multivariate Ishemic Heart Disease (IHD) in a Multivariate

ModelModel

RRs of IHD according to baseline LDL, apoB, and TG and small dense LDL (proportion of small dense LDL above or below median of 39.6%). RR were

adjusted for age, BMI, BP, DM, medication use at baseline and family history.

Circulation 2001, 104:2295-9

Page 19: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

The Quebec Cardiovascular StudyRESULTS:

Among all lipid parameters, small dense LDL (< 255 Å) showed the

strongest association with the risk of IHD (RR in men = 4.6; p < 0.001)

This was independent of all nonlipid risk factors and of LDL cholesterol,

HDL, TG and Lp(a)

Page 20: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

LDL particle number and risk of future cardiovascular disease in the Framingham Offspring Study (J Clin Lipidol 2007;1:583-92)

Page 21: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

CytokinesPlaque formation

Foam cell

Monocytes

Macrophage

Stages of AtherosclerosisLUMEN

MEDIA

INTIMAOxidized LDL

Adhesion molecules

Lyso-PCOxFA

Lp-PLA2

Page 22: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.
Page 23: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Pro-atherogenic effects of oxidized LDLPro-atherogenic effects of oxidized LDL

•Oxidized LDL is degraded at a faster rate than native LDL by macrophages leading to lipid accumulation.

•Oxidized LDL is chemotactic to monocytes, smooth muscle cells, and T lymphocytes, and induces T-cell activation and monocyte differentiation.

•Oxidized LDL inhibits macrophage motility, potentially trapping macrophages in the artery.

•Components of oxidized LDL are cytotoxic to cells.

•Oxidized LDL inhibits endothelium-dependent relaxation factor.

•Oxidized LDL enhances monocyte adhesion to endothelium.

•Oxidized LDL induces the expression of monocyte chemotactic protein-1 and granulocyte-macrophage colony stimulating factors.

•Oxidized LDL inhibits the migration of endothelial cells.

•Oxidized LDL induces the expression of adhesion molecules on the endothelium.Components of oxidized LDL induces interleukin-1 synthesis and secretion by macrophages

Page 24: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

OxLDLOxLDL, a strong predictor for acute coronary heart , a strong predictor for acute coronary heart disease events in apparently healthy middledisease events in apparently healthy middle--aged men aged men

from the general populationfrom the general population

•• Prospective, nested, caseProspective, nested, case--control study control study (MONICA/KORA population)(MONICA/KORA population)

•• Men without coronary heart disease (CHD) or Men without coronary heart disease (CHD) or diabetes mellitus at baselinediabetes mellitus at baseline

•• Mean followMean follow--up time 5.6 up time 5.6 ++ 2.6 years2.6 years

•• OxLDLOxLDL was measured in 88 men who developed CHD was measured in 88 men who developed CHD and in 258 ageand in 258 age--and surveyand survey--matched controlsmatched controls

•• Hazard ratios (HR) were estimated from conditional Hazard ratios (HR) were estimated from conditional logisticlogistic--regression models with matching for age regression models with matching for age and surveyand survey

Circulation 2005; 112: 651-657

Page 25: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Demographic and clinical characteristics of Demographic and clinical characteristics of CHD patients and controlsCHD patients and controls

CHDCHD ControlsControls ppAgeAge 61 61 ++ 99 61 61 ++ 88 NSNSBMI (kg/mBMI (kg/m22)) 29 29 ++ 44 28 28 ++ 44 0.0490.049HTNHTN 76%76% 56%56% 0.0010.001Current smokerCurrent smoker 37%37% 22%22% 0.0180.018Total cholesterolTotal cholesterol 257257++4242 243243++4242 0.0120.012HDLHDL 5050++1515 5252++1515 NSNSTC/HDL ratioTC/HDL ratio 5.55.5++1.61.6 55++1.81.8 0.020.02LDLLDL 171171++3939 157157++4040 0.0050.005oxLDLoxLDL (U/L)(U/L) 110110++3232 9393++2828 <0.001<0.001

Circulation 2005; 112: 651-657

Page 26: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

oxLDLoxLDL is better than all other lipid parameters in is better than all other lipid parameters in prediction of acute CHD after adjustment for various prediction of acute CHD after adjustment for various

cardiovascular risk factorscardiovascular risk factors

HR for upper vs. lower thirdHR for upper vs. lower third p valuep value

OxLDLOxLDL 4.25 (2.094.25 (2.09--8.63)8.63) 0.0120.012

HDL HDL 0.69 (0.370.69 (0.37--1.29)1.29) 0.0740.074

TC/HDLTC/HDL 2.32 (1.232.32 (1.23--4.37)4.37) 0.0090.009

LDLLDL 2.38 (1.252.38 (1.25--4.52)4.52) 0.0650.065

Circulation 2005; 112: 651-657

Page 27: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Improved Improved indentificationindentification of patient with CAD by of patient with CAD by oxLDLoxLDL

•• 431 healthy men and women vs. 490 patients with 431 healthy men and women vs. 490 patients with established CADestablished CAD

•• Lipid parameters, Lipid parameters, oxLDLoxLDL, Lp, Lp--PLA2 were compared in PLA2 were compared in the 2 groupsthe 2 groups

•• Diagnostic accuracy for CAD was determined by Diagnostic accuracy for CAD was determined by receiverreceiver--operating characteristic curve analysis by operating characteristic curve analysis by measuring the area under the curvemeasuring the area under the curve

Johnston et al. Am J Cardiol 2006;97:640-645

Page 28: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

oxLDLoxLDL and and oxLDLoxLDL/HDL ratio are the best /HDL ratio are the best predictors of CADpredictors of CAD

Johnston et al. Am J Cardiol 2006;97:640-645

Page 29: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Effect of Ezetimibe/Atorvastatin Combination on Oxidized LDL-Cholesterol in Patients With CAD or CAD Equivallent

Rabih Azar, Georges Badaoui, Antoine Sarkis, Mireille Azar, Hermine Aydanian, Serge Harb,

Guy Achkouty and Roland Kassab

• Will be presented on March 14 at the Meeting of the American College of Cardiology in Atlanta, USA

• In press: J Am Coll Cardiol March 2010 (abstract)

• In press: Am J Cardiol July 2010 (manuscript)

• Sponsored by Pharmaline

Page 30: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

RATIONAL

• Ox-LDL and small dense LDL are more potent predictors of cardiovascular risk than standard lipid parameters

• The majority of clinical trials have tested the efficacy of lipid lowering therapy against standard lipid parameters

• Few studies have shown that statins decrease ox-LDL. The effect of ezetimibe on ox-LDL is however, unknown

• This effect is important to investigate given the controversy surrounding ezetimibe’s use

Page 31: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

OBJECTIVE

TO EVALUATE THE EFFECT OF ATORVASTATIN 40 mg and of

ATORVASTATIN 40 mg + EZETIMIBE ON OX-LDL CHOLESTEROL

Page 32: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Effect of Ezetimibe/Atorvastatin Combination on Oxidized LDL-Cholesterol in Patients With CAD or

CAD Equivallent

- Prospective, randomized, double-blind, placebo-controlled trial

- Inclusion criteria:- Patients with CAD

- > 50% stenosis on angiography- MI- PCI or CABG

- Patients with CAD equivalent- Diabetes requiring medications- Peripheral vascular disease- Stroke

- Lipid levels were not entry criteria

Page 33: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Exclusion Criteria• Therapy with a statin more potent than atorvastatin 20

mg/day (atorvastatin 40 or above, rosuvastatin any dose)

• Therapy with ezetimibe, any other cholesterol absorption inhibitor, niacine, fibrate within the last 3 months

• MI, CABG, PCI within the last 3 months

• Age > 80 years

• EF < 35% or CHF with NYHA class > 2

• Creatinin clearance < 30 mL/min

• CPK or SGPT > 2 times upper normal

Page 34: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Study Protocol

• The statin taken by the patient was stopped and replaced by atorvastatin 40 mg/day

• Patients were then randomized to ezetimibe 10 mg/day vs. placebo

• Duration of treatment 8 weeks

Page 35: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

MEASURMENTS

• Standard lipid profile (Total cholesterol, VLDL, LDL, HDL)

• LDL subfractions: small dense LDL and large buoyant LDL

• Mean LDL particle size

• Oxidized LDL

• CPK, SGPT

Page 36: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

End-Points

• Primary end-point• Change in ox-LDL

• Secondary end-points• Change in small dense LDL• Change in LDL particle size

• Safety end-points• Elevation of CPK or SGPT more than twice

upper normal

Page 37: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Inclusion Criteria

Ezetimibe Placebon = 50 n = 50

Stenosis > 50% 19 (38%) 23 (46%)Prior MI 18 (36%) 12 (24%)PCI 23 (46%) 15 (30%)CABG 26 (52%) 21 (42%)Diabetes 18 (36%) 21 (42%)Stroke 1 (2%) 1 (2%)PVD 6 (12%) 5 (10%)

The number of inclusion criteria is superior to 100% because each patient may have more than 1 criterion that defines CAD

Page 38: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Baseline Characteristics

Ezetimibe Placebon = 50 n = 50

Age (year) 64 + 8 65 + 11Male 44 (88%) 41 (82%)Smoking 14 (28%) 12 (24%)Hyperlipidemia 47 (94%) 43 (86%)Hypertension 35 (70%) 38 (76%)Fam. Hist. CAD21 (42%) 14 (28%)BMI (kg/m2) 27 + 3 28 + 4

Page 39: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Concomitant Medications

Ezetemibe Placebon = 50 n = 50

Aspirin 45 (90%) 43 (86%)Clopidogrel 11 (22%) 11 (22%)ACE inhb. or ARB 41 (82%) 34 (68%)Beta-blockers 37 (74%) 35 (70%)CCB 8 (16%) 18 (36%)*Nitrates 10 (20%) 11 (22%)Diuretics 6 (12%) 6 (12%)OAD 15 (30%) 17 (34%)Insulin 6 (12%) 6 (12%)

* P = 0.02

Page 40: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Statin Use at Baseline

• 90% of patients were using a statin prior to randomization

• Simvastatin 53%

• Atorvastatin 30%

• Fluva or pravastatin 7%

• None 10%

Page 41: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Change in LDL

P < 0.001 P < 0.001

Final LDL levels were lower in ezetimibe vs. placebo; p < 0.001

10% additional reduction

20% additional reduction

Page 42: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Change in Large, Buoyant LDL

P < 0.001 P < 0.001

Final levels ezetimibe vs. placebo: p = 0.007

10% additional reduction

24% additional reduction

Page 43: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Change in Small Dense LDL

P < 0.001 P < 0.001

No difference between ezetimibe and placebo in lowering small dense LDL

36% additional reduction

32% additional reduction

Page 44: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Qualitative Lipid Analysis: Change in Particle Size

Particle Size in AngstromParticle Size in AngstromPlacebo/atorva: 268 270 p = 0.002

Ezetimibe/atorva 268 270 p = 0.006

Prevalence of type A phenotype increased from 62% to 70% in the placebo group and from 58% to 74% in the ezetimibe group

Page 45: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Change in VLDL

P = 0.07 P < 0.001

Page 46: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

P = ns P = ns

Page 47: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.
Page 48: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Correlation Between the Changes in ox-LDL and Total LDL

Page 49: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Safety End-Point

There was no elevation of CPK or SGPT in any patient of the 2

groups

Page 50: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Summary of Results: Effects of Atorvastatin and Ezetimibe on Various

Lipid Parameters

LDL Large LDL

Small dense LDL

Particle size

HDL VLDL Ox-LDL

More potent statin

Ezetimbe

The changes induced by statin are quantitative and The changes induced by statin are quantitative and qualitativequalitativeThe Changes induced by ezetimibe are only quantitativeThe Changes induced by ezetimibe are only quantitative

Page 51: Beyond LDL Cholesterol: Reduction of Small Dense LDL and of Oxidized LDL With Combined Lipid Therapy Rabih R. Azar, MD, MSc, FACC Associate Professor of.

Conclusions • Aggressive reduction of LDL is currently recommended for high risk

patients

• Potent statins should be used as first line therapy

• In our study, increasing the potency of statin therapy by switching to atorvastatin 40mg:• Did not affect ox-LDL• Resulted in quantitative and qualitative improvement in lipid

profile• Was extremely safe and well tolerated

• Ezetimibe in combination with atorvastatin:• Significantly decreased ox-LDL• Resulted in quantitative improvement in lipid profile• Was extremely safe and well tolerated