CVS

Hyperlipidemia as a risk factor and its treatment

By
Dr. salim al-rubaae
Associate professor & consultant internist-endocrinologist
C.A.B.M D.M M.B.C.H.B
College of medicine-university of Baghdad
Medical department
Chief of endocrine-sector
Senior-lecturer

Lipoproteins, Lipid Metabolism and Inflammatory Markers

Structure of Lipoproteins

Free cholesterol
Phospholipid
Triglyceride
Cholesteryl ester
Apolipoprotein


Types of Lipoprotein Particles
Triglyceride-rich lipoproteins
Chylomicrons
Very low-density lipoprotein (VLDL)

Cholesterol-rich lipoproteins

Low-density lipoprotein (LDL)
High-density lipoprotein (HDL)

Chylomicrons and Very Low-density Lipoproteins

Chylomicrons are much larger than VLDL
Chlylomicrons contain more triglyceride per particle than VLDL
They contain apolipoproteins on their surface such as:
B apolipoproteins (B100 – VLDL; B48 – chylomicrons)
C apolipoproteins (CII and CIII)
A apolipoproteins (A-I and A-II)
ApoE

LDL cholesterol

Strongly associated with atherosclerosis and CVD events
10% increase results in an approximate 20% increase in CHD risk
Most of the cholesterol in plasma is found in LDL particles
Smaller denser LDL are more atherogenic than larger, less dense particles
Risk associated with LDL-C is increased by other risk factors:
low HDL-C
smoking
hypertension
diabetes and the metabolic syndrome


HDL cholesterol
HDL-C has a protective effect for risk of atherosclerosis and CHD
Epidemiological studies show the lower the HDL-C level, the higher the risk for atherosclerosis and CHD
low level (<40 mg/dL, 1 mmol/L) increases risk
HDL-C tends to be low when triglycerides are high
HDL-C is lowered by smoking, obesity and physical inactivity
ApoA-I is the major apolipoprotein in HDL and an elevated ApoA-I is linked to reduced CVD risk

Triglycerides

May be associated with increased risk of CHD events
Link with increased CHD risk is complex
may be direct effect of smaller TG-rich lipoproteins and/or
may be related to:
low HDL levels
highly atherogenic forms of LDL-C
hyperinsulinaemia/insulin resistance
procoagulation state
hypertension
abdominal obesity

Apolipoproteins

Protein content of lipoproteins
ApoB levels used to estimate LDL particle number and increased CVD risk
ApoA-I – major apolipoprotein in HDL and is linked to reduced CVD risk
Functions of apolipoproteins include:
facilitation of lipid transport
activation of three enzymes in lipid metabolism
lecithin cholesterol acyltransferase (LCAT)
lipoprotein lipase (LPL)
hepatic triglyceride lipase (HTGL)
binding to cell surface receptors


ApoB, ApoA-I and ApoB/ApoA-I as Predictors of Risk: AMORIS
Objective: to determine the relationship between levels of ApoB, ApoA-I and other lipids and death from MI
175,553 individuals screened
Follow-up approximately 65 months
Conclusions:
ApoB, ApoA-I and the ratio ApoB/ApoA-I have stronger predictive value than TG, TC and LDL-C
ApoB and ApoA-I better than LDL-C at all levels of LDL-C, but especially valuable in patients with average/low LDL-C
ApoB and ApoA-I help to identify subjects with the metabolic syndrome
Walldius G et al. Lancet 2001;358:2026-2033.

Intestine

Skeletal muscle

Adipose

tissue

Chylomicron

Chylomicron
remnant


Remnant
receptor

Liver

Dietary
triglycerides
and cholesterol

LP lipase

to atheroma

FFA
Exogenous Pathway of Lipid Metabolism

IDL

Large

VLDL
Small
VLDL
LDL
receptor
Liver
LPL Lipoprotein lipase


HL Hepatic lipase

LDL
LPL
LPL
LPL
HL
HL
HL
Endogenous Pathway of Lipid Metabolism

Reverse Cholesterol Transport

Peripheral
tissues

Cell

membrane

VLDL, IDL, LDL

LDL
receptor

LCAT

CETP

FC

CE

CE

TG

HDL

HDL3

TG


CE

Free cholesterol

Cholesteryl esters

CETP

Cholesteryl ester transfer protein

LCAT

Lecithin cholesterol acyltransferase

SRB1

FC

ABCA1

Liver
Scavenger receptor class B, member 1


Triglycerides

SRB1

ATP-binding cassette, sub-family A, member 1
ABCA1

Classification of Dyslipidaemiasand Pathogenesis of Atherosclerosis

Classification of Dyslipidaemias:Fredrickson (WHO) Classification
LDL – low-density lipoprotein; IDL – intermediate-density lipoprotein; VLDL – very low-density lipoprotein. (High-density lipoprotein (HDL) cholesterol levels are not consideredin the Fredrickson classification.)
Phenotype

I

IIa

IIb

III

IV


V
Lipoprotein
elevated

Chylomicrons

LDL

LDL and VLDL

IDL

VLDL

VLDL and
chylomicrons
Atherogenicity

None seen

+++


+++

+++

+

+
Prevalence

Rare

Common

Common

Intermediate

Common

Rare
Serum
cholesterol


mean to
mean to
mean to

Serum

TG

mean

• Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–391

Abetalipoprotinemia

AR
C&TG are extremely low
chylomicron, VLDL, LDL, APO-B are negative
Parents (heterozygote) have normal plasma lipid and APO-B
C/F : onset in early childhood
diarrhea / failure to thrive
fat mal absorption
spinocrebellar degeration ( ataxia, dismateria,
spastic-gait ( 3rd , 4th decades ), loss of
tendon-reflaxes, vibration & position senses
pigmented retinopathy- loss night & color vision
( blindness )
acanthocytosis
cardiomyophathy ( rare ) : HF & arrhythmias
DD: Friedreichs ataxia
C/F related to decrease fat soluble vit.
RX : low fat , high caloric high vit. Diet + vit. E

Familial chylomicronaemia

Atosomal – recessive 1/1000000
defect is either lipoprotein lipase or APO-C2
chylomicron is very high in the cir. hypertriglyceridaemia( chylomicron&VLDL)
C/F : 1. lipema- retnalis ( fundoscopy )
2. Recurrent abd. Pain (pancreatitis )
3. Eruptive-xanthomas buttouskes
4. Hepatospleeniomigaly ( reuptake of chylomicron by RE cells of live and spleen
5. no premature IHD
RX: a. in LPL def. 1. low lipid diet 15 gm /d
2. fat-soluble vit. ( A,D,K & E supply )
3. fish oil
4. plasmapharesis
b. in APO-C2 plasma infusion ( FFP)

Familial dysbetalipoprotenemia FDL ( type 3 , F.broad beta disease)

APO-E defect & deficiency ( E2/E2 genotype ) is the most one & constitute 1% of general population
mixed hyper lipoprotenemia ( IDL , C , TD )
PPT. factors ( high caloric and fat diet , DM, obesity, hypothyroidism, renal disease, alcohol , estrogen def. and presence of FHC
C/F : seldom occur before menopause in adulthood
1. zanthomas ( tuberoerubtive and palmerxanthoma )
2. premature IHD peripheral vascular disease
3. C&TG are high lipoprotein electrophoresis ( broadbeta disease )
VLDL-C /TG >= 0.3
RX should be aggressive due to IHD
1. treatment of the precipitating factor if any
2. dietary fat restriction
3. Statins, fibrates , niacin
4. Combination of drug therapy


Familial Hypercholesterolaemia (FH)
Most common genetic disorder in Europe and the
US
Higher incidence in Afrikaners , French Canadian & Christian Lebanese
Caused by a mutation of the LDL receptor
Increases risk of CVD
coroneal- arcus
eyelid xanthelasmas
Aortic-stenosis
Tendon xanthoma
Two types of FH:
Heterozygous FH
one LDL-receptor gene affected
affects about 1 in 500 people
TC 9.0-14.0 mmol/L (360-560 mg/dL) in adulthood
Homozygous FH
both LDL-receptor genes affected
rare – affects about 1 in 1,000,000 people
TC 15.0-30.0 mmol/L (600-1200 mg/dL) in adulthood

RX dietary fat restrictions

lipid lowrind drugs ( statin , resins , nicotinic acid, combination therapy , ezetimbe(inhibit intestinal cholestrol –c absorption 10mg per day , LDL- aphaeresis )


Relationship Between Cholesterol and CHD Risk: Framingham Study
Castelli WP. Am J Med. 1984;76:4-12.

0
25
50
75
100
125
150
<204
(<5.3)
205-234
(5.3-6.1)
235-264
(6.1-6.8)
265-294
(6.8-7.6)
>295
(>7.6)


CHD incidence per 1000
Serum total cholesterol, mg/dL (mmol/L)

Relationship of Serum Cholesterol to Mortality: Seven Countries Study

Verschuren WM et al. JAMA 1995;274(2):131–136
35
Serum total cholesterol, mmol/L (mg/dL)

30
25
20
15
10
5
0
Death rate from CHD/1000 men
2.60
(100)
3.25
(125)


3.90
(150)
4.50
(175)
5.15
(200)
5.80
(225)
6.45
(250)
7.10
(275)
7.75
(300)
8.40
(325)
9.05
(350)
Northern Europe
United States
Southern Europe, inland
Southern Europe, Mediterranean
Japan
Serbia


Cholesterol: A Modifiable Risk Factor
Plasma cholesterol at levels >200 mg/dL cause 4.4 million deaths a year1
Incidence of plasma cholesterol >200 mg/dL in:
51% (107 million) adults in the USA2
58% of patients with established CHD in EUROASPIRE II3
10% reduction in plasma cholesterol results in:
15% reduction in CHD mortality (p<0.001)
11% reduction in total mortality (p<0.001)4
LDL-C is a major target to prevent CHD
• 1. International CVD Statistics 2005 AHA;
• 2. Heart and Stroke Statistical Update 2004 AHA;
• 3. EUROASPIRE II Study Group. Eur Heart J 2001;22:554-572;
• 4. Gould AL et al. Circulation 1998;97:946–952.

Risk Factors for Cardiovascular Disease

Modifiable
Smoking
Dyslipidaemia
Raised LDL-C
Low HDL-C
Raised triglycerides
Raised blood pressure
Diabetes mellitus
Obesity
Dietary factors
Thrombogenic factors
Lack of exercise
Excess alcohol consumption
Non-modifiable
Personal history of CVD
Family history of CVD
Age
Gender
Pyörälä K et al. Eur Heart J 1994;15:1300–1331.


Levels of Risk Associated with Smoking, Hypertension and Hypercholesterolaemia

x1.6

x4
x3
x6
x16
x4.5
x9
Hypertension
(SBP 195 mmHg)
Serum cholesterol level
(8.5 mmol/L, 330 mg/dL)
Smoking
Poulter N et al., 1993

The Metabolic Syndrome andAssociated CVD Risk Factors

Insulin Resistance
high TGs
small dense LDL
low HDL-C
Atherosclerosis
Endothelial Dysfunction


Hypertension

Abdominal obesity

Hyperinsulinaemia

Dyslipidaemia

Diabetes
Hypercoagulability

Deedwania PC. Am J Med 1998;105(1A);1S-3S.

Overweight and Obesity as a Risk Factor
• Associated with significant mortality and morbidity
• Now reached epidemic proportions in Western society and causes:
• 220,000 deaths per year in US and Canada
• 320,000 deaths per year in Western Europe
• An independent risk factor for CVD
• Abdominal obesity associated with the metabolic syndrome which also includes:
• dyslipidaemia, hypertension and insulin resistance
The World Health Report 2002 and International Cardiovascular Disease Statistics 2003; AHA.


The Progression from CV Risk Factors to Endothelial Injury and Clinical Events

Risk factors

Oxidative stress
Endothelial dysfunction

NO

Local mediators

Tissue ACE-Ang II
PAI-1
VCAM
ICAM cytokines
Endothelium
Growth factors matrix
Proteolysis
LDL-C
BP
Heart failure
Smoking
Diabetes


Vasoconstriction

Vascular lesion and remodelling

Plaque rupture

Inflammation

Thrombosis

Clinical endpoints

NO Nitric oxide
Gibbons GH, Dzau VJ. N Engl J Med 1994;330;1431-1438.

Normal Arterial Wall

Lumen
Media:
Smooth muscle cell
Matrix proteins
Internal elastic membrane
Endothelium
Intima:
External elastic membrane


Historical Model of Atherogenesis

healthy

subclinical
symptomatic

Threshold

Decades
Years-Months
Months-Days
Plaque

Intima

Media

Lumen

Stable angina
Stable plaques with narrowing
Simple diagnostic (ECG, angiography)
Rare MI
Easy to treat


Antischkow N. Beitr Path Anat Allg Path 1913;56:379-404.

Pathogenesis of Atherosclerotic Plaques

Protective response results in production of
cellular adhesion molecules
Monocytes and T lymphocytes attach to
‘sticky’ surface of endothelial cells
Migrate through arterial wall to subendothelial space
Lipid-rich foam cells
Endothelial damage
Macrophages take up oxidised LDL-C
Fatty streak and plaque

‘activated’ endothelium

CELLULAR ADHESION MOLECULES
induces cell proliferation and a prothrombic state
attracts monocytes and T lymphocytes
which adhere to endothelial cells

cytokines (eg. IL-1, TNF-)

chemokines (eg.MCP-1, IL-8)
growth factors (eg. PDGF, FGF)


Koenig W. Eur Heart J Suppl 1999;1(Suppl T);T19-26.
The ‘Activated’ Endothelium

Upregulation of endothelial

adhesion molecules
Increased endothelial permeability
Migration of leucocytes into the artery wall
Leucocyte adhesion
Lipoprotein infiltration

Endothelial Dysfunction in Atherosclerosis

Formation of foam cells
Adherence and entry of leucocytes
Activation of T cells
Migration of smooth muscle cells
Adherence and aggregation of platelets

Fatty Streak Formation in Atherosclerosis

Formation of
the fibrous cap
Accumulation of
macrophages
Formation of
necrotic core


Formation of the Complicated Atherosclerotic Plaque

Imaging Techniques Used to Assess Atherosclerosis

• Invasive techniques
• Intravascular ultrasound (IVUS)
• Coronary angiography
• Non-invasive techniques
• Magnetic resonance imaging (MRI)
• Computed tomography (CT)
• Ultrasound (B-mode)

Intravascular Ultrasound (IVUS) Showing Atheromatous Plaque

Reproduced from Circulation 2001;103:604–616, with permission from Lippincott Williams & Wilkins.

Angiogram

IVUS

atheroma

normal vessel


Coronary Angiographyof Stenotic Coronary Artery
6
Arrow indicates atherosclerosis (stenosis) of the coronary artery

Magnetic Resonance Image (MRI) of a Stenotic Carotid Artery Bifurcation

left carotid artery bifurcation with an atherosclerotic plaque with a necrotic core
relatively normal artery
Chu B et al. Stroke 2004;8:2444–2448.

Computed Tomography (CT)Showing Atherosclerotic Artery

B-mode Ultrasound

Reproduced with permission from Kastelein, JJP et al. Am Heart J 2005;149:234–239.

Clinical Manifestations of Atherosclerosis
Coronary heart disease
Angina pectoris, myocardial infarction, sudden cardiac death, congestive heart failure (CHF), and arrhythmias


Cerebrovascular disease
Transient ischaemic attack, stroke

Peripheral vascular disease

Intermittent claudication, gangrene, cold feet, painful feet, impotence

Unmet Need and Guidelines

Benefits of Cholesterol Lowering

Meta-analysis of 38 primary and secondary intervention trials

% in cholesterol reduction
Total mortality (p=0.004)
CHD mortality (p=0.012)
Mortality log odds ratio

0

4


8

12

16

20

24

28

32

36

-1.0

-0.8

-0.6

-0.4

-0.2

-0.0

40

Gould AL et al. Circulation. 1998;97:946-952.

Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk
Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm

1% decreasein LDL-C reduces CHD risk by1%

1% increasein HDL-C reduces CHD risk by3%

Many patients fail to achieve NCEP ATP II LDL-C Goal on Lipid-modifying Therapy: L-TAP

0
20
40
60
80
100
Percentage of patients
85%
of patientsreceived lipid-modifying therapy
39%
of patients receiving lipid-modifying therapy reached their NCEP ATP II LDL-C goal
(n=4888)
(n=4137)
<20%
of CHD patients who receiving lipid-modifying therapy reached NCEP ATP II LDL-C goal (100 mg/dL; 2.6 mmol/L)


(n=1352)
Pearson TA et al. Arch Intern Med 2000;160:459-467.

Many patients fail to reach European TC goal: EUROASPIRE II

0
20
40
60
80
100
Percentage of patients
61%
of high-risk patients* received lipid-modifying therapy
51%
of patients reached Joint European TC goal**
*CABG, PTCA, MI or ischaemia, ** TC<5 mmol/L (190 mg/dL)
EUROASPIRE II. Euro Heart J 2001;22:554-572.

Many patients who are treated are still not getting to goal

LDL-C=low-density lipoprotein cholesterol; CHD=coronary heart disease; HDL-C=high-density lipoprotein cholesterol


†Patients with LDL-C >100 mg/dL, HDL-C <45 mg/dL, CHD and/or diabetes mellitus
*LDL-C goal of <100 mg/dL

Foley KA et al. Am J Cardiol 2003; 92: 79–81
2829 patients†
1464
not at goal on
initial dose
1365
at goal on initial dose

813 not titrated

651
titrated

448 not at goal

203at goal
52%
48%
55%
45%
31%
69%
Overall:
1568 (55.4%) patients achieve goal
1261 (44.6%) patients do not achieve goal


Even With Dose Titration, Many Patients Fail to Achieve LDL-C Goals: ACCESS
Ballantyne CM et al. Am J Cardiol 2001;88:265–269.

At week 54, n=2543 CHD patients

Patients at LDL-C goal (%)

0
20
40
60
80

atorvastatin 10–80 mg

simvastatin 10–40 mg

lovastatin 20–80 mg

fluvastatin 20–80 mg
pravastatin 10–40 mg


72%
52%
44%
30%
25%
n=1286
n322
n=303
n=332
n=300

Estimate total CVD risk of fatal

CVD event in 10 years using SCORE chart

Total CVD risk <5%

TC 5 mmol/L (190 mg/dL)
Total CVD risk 5%
TC 5 mmol/L (190 mg/dL)
Measure fasting lipids, give lifestyle
advice, with repeat lipids after
3 months
Lifestyle advice
Aim: TC<5 mmol/L (190 mg/dL)
LDL-C <3.0 mmol/L (115 mg/dL)
Follow-up at 5-year intervals


TC <5 mmol/L (190 mg/dL)
and LDL-C <3.0 mmol/L (115 mg/dL)
Maintain lifestyle advice with annual
follow-up. If total risk remains 5%,
consider drugs to lower TC to <4.5 mmol/L
(175 mg/dL) and LDL-C to
<2.5 mmol/L (100 mg/dL)

TC 5 mmol/L (190 mg/dL) or

LDL-C 3 mmol/L (115 mg/dL)
Maintain lifestyle
advice and start drug
therapy

De Backer G et al. Eur Heart J 2003;24:1601–1610.

2003 European Guidelines:Guide to lipid management in asymptomatic subjects

NCEP ATP III Guidelines

* TLC: therapeutic lifestyle changes
Adapted from NCEP, Adult Treatment Panel III. JAMA 2001;285:2486-2497.
Patients with


Drug therapy
considered if LDL
-
C
Initiate TLC*
if LDL
-
C
LDL
-
C
treatment
goal

0
-
1 risk factors
³
160 mg/dL†
³
190 mg/dL
(160
-
189
mg/dL: drug
optional)
<160 mg/dL†
³
2 risk factors
(10
-
year risk
£
20%)
³
130 mg/dL†
10-yr risk 10-20%:

³
130 mg/dL
10-yr risk <10%:
³
160 mg/dL
<130 mg/dL†
CHD and CHD risk
equivalents
(10
-
year risk >20%)
³
100 mg/dL†
³
130 mg/dL
(100
-
129
mg/dL: drug
optional)
<100 mg/dL†


† 100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L; 190 mg/dL = 5 mmol/L

NCEP ATP III: LDL-C Goals

Adapted from NCEP, Adult Treatment Panel III, 2001. JAMA 2001:285;2486-2497.

CHD or CHD risk equivalents

< 2 risk factors
≥ 2 risk factors

LDL-C level

100 -
160 -
130 -
190 -

goal

100
mg/dL
goal
130
mg/dL


goal
160
mg/dL

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

NCEP ATP III: LDL-C Goals (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%)

LDL-C level

100 -
160 -
130 -
190 -
Lower Risk
< 2 risk factors


Moderately High Risk
≥ 2 risk factors
(10-yr risk 10-20%)

goal

160
mg/dL

goal

130
mg/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

Primary target

LDL-C <100 mg/dL (2.6 mmol/L)
<70 mg/dL (1.8 mmol/L)#

…and if TG 200 mg/dL (2.2 mmol/L), a secondary target is:

Non-HDL-C <130 mg/dL (3.4 mmol/L)
#An optional goal for high-risk patients with diabetes and overt CVD
NCEP ATP III Recommendations for Lipid Goals in Patients With Diabetes
NCEP ATP III. JAMA 2001;285:2486–2497.


LDL-C <100 mg/dL (2.6 mmol/L) or a reduction of 30-40%
<70 mg/dL (1.8 mmol/L)#
HDL-C* >40 mg/dL (1.15 mmol/L)
TG <150 mg/dL (1.7 mmol/L)

*For women, HDL value should be increased by 10 mg/dL

#An optional goal for high-risk patients with diabetes and overt CVD

ADA. Diabetes Care 2005;28(suppl 1):S4–S36.
ADA Recommendations for Lipid Goals in Patients With Diabetes

Lipid-modifying Therapies and Statins

Effect of Lipid-modifying Therapies on Lipids
Therapy

Bile acid

sequestrants

Nicotinic acid

Fibrates

Probucol

Statins*

Ezetimibe

TC–total cholesterol, LDL–low density lipoprotein, HDL–high density lipoprotein, TG–triglyceride. *Daily dose of 40 mg of atorvastatin, simvastatin, pravastatin and fluvastatin.
TC

Down

20%

Down

25%

Down

15%

Down

25%


Down
19–37%

-

LDL

Down

15–30%

Down

25%

Down

5–15%

Down

10–15%

Down

25–50%


Down
18%
HDL

Up
3–5%

Up
15–30%

Up
20%

Down

20–30%

Up
4–12%

Up
1%
TG


Neutral or up

Down

20–50%

Down

20–50%

Neutral

Down
14-29%

Down

8%
Patient
tolerability

Poor

Poor to
reasonable


Good

Reasonable

Good

Good

Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–391. Knopp RH. N Engl J Med 1999;341:498–511. Product Prescribing Information. Gupta EK, Ito MK. Heart Dis 2002;4:399-409.

,

Main Effects of Statins

Effects on lipids:
Reduce LDL-C, TC and TG
Increase HDL-C
Pleiotropic effects:
Improve or restore endothelial function
Enhance the stability of atherosclerotic plaques
Decrease oxidative stress
Decrease vascular inflammation
Anti-thrombotic effects
Takemoto M, Liao JK. Arterioscler Thromb Vasc Biol 2001;21:1712-1719.


Mechanism of Action of Statins: Cholesterol Synthesis Pathway

acetyl CoA

HMG-CoA
mevalonic acid
mevalonate pyrophosphate
isopentenyl pyrophosphate
geranyl pyrophosphate
farnesyl pyrophosphate
squalene
cholesterol
dolichols
ubiquinones

HMG-CoA synthase

HMG-CoA reductase
Squalene synthase
X
Statins

Pharmacokinetics of Statins

Horsmans Y. Eur Heart J Supplements 1999;1(Suppl T):T7–12, Vaughan CJ et al. J Am Coll Cardiol 2000;35:1–10. Rosuvastatin data from Core Data Sheet.
Statin
Protein
binding (%)
Metabolised
by CYP450
Lipophilic
Half-
life (h)
rosuvastatin
atorvastatin
simvastatin
pravastatin
fluvastatin
~90%
>98%
95–8%
~50%
>98%
Yes
Yes
No
Yes


No
Yes
Yes
No
~19
~15
~3
~2
~3

* intermediate between hydrophilic and lipophilic

intermediate*
minimal

Key Statin Trials

Making an impact in abroad range of patiantsAtorvastatin LDL-c reduction & clinical results in landmark trials

Summary

• Atherosclerosis is associated with CVD, which is a major cause of death in developed countries
• Dyslipidaemia, in particular elevated LDL-C and low HDL-C, is associated with increased risk for CVD
• Large statin trials have shown that the lower the level of LDL-C achieved the greater the reduction in CV events
• Diabetes is a risk factor for CVD, which is the leading cause of death amongst people with diabetes
• Dyslipidaemia is associated with diabetes and the metabolic syndrome
• Guidelines recommend lipid levels to reduce the morbidity and mortality caused by dyslipidaemia, and proposed recommendations suggest even more stringent levels for the future

63
ASCOT STUDY(Anglo-Scandinavian Cardiac Outcomes Trial)
Aim:
Investigating effects of atorvastatin on nonfatal MI and fatal CHD in patients with total cholesterol ≤ 250 mg/dl.
Comprehensively investigating effects of atorvastatin in primary prophylaxis of coronary heart disease
Patient Profile:
Disease: Having at least 3 of below written risk factors in addition to hypertension
Left ventricular hypertrophy
ECG abnormalities
Diabetes
Previous stroke or transient ischemic attack
Peripheral vascular disease
Age above 55 years
Male
Proteinuria or microalbuminuria
Smoking


64
ASCOT STUDY(Anglo-Scandinavian Cardiac Outcomes Trial)
Number of patients:
10.305 patients
Duration:
3.3 years
Groups:
Patients received atorvastatin 10 mg/day or placebo (in addition, all groups received anti-hypertensive treatment).

65
Conclusions:
Study is prematurely ended in September of 2002 by ethics committee due to positive results about atorvastatin.
No serious side effect is observed.
Decrease observed in cardiovascular events occurred earlier in comparison with many other studies.
ASCOT STUDY (Anglo-Scandinavian Cardiac Outcomes Trial)

CV Event Reduction with Statin Therapy: ASCOT-LLA

Sever PS et al. Lancet 2003;361:1149-1158.
RRR relative risk reduction

0
1
2
3
4
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Years
Cumulative incidence of nonfatal
MI plus fatal CHD)(%)
36%
RRR


p=0.0005

atorvastatin

placebo

67
Comments:
In hypertensive patients with risk to develop moderate cardiovascular event, a serious reduction in risk is obtained with Atorvastatin 10 mg.
Although baseline dose of atorvastatin (10mg) was not titrated, said results could be obtained; if dose was increased, benefit would be much higher.
If the study could be sustained for 5 years, the resultant risk reduction would reach to 50 percent.
Lack of adequate efficiency in diabetes sub-group can be explained regarding low event number in this group.
ASCOT STUDY (Anglo-Scandinavian Cardiac Outcomes Trial)

Lancet. 2003;361:1149-1158.

68
GREACE Study (GREek Atorvastatin and Coronary Heart disease Evaluation study)

1600 patients with coronary heart disease are randomized to receive atorvastatin (10-80 mg/day) or general care.
Duration of study:3 years


69
% 
TC
LDL-C
HDL-C
CM
Mortality
MI
UA
Subjects: 1600
78% male, 58 years old
22% female, 59 years old

Treatment: atorvastatin 10-80 mg/day

Duration: 3 years
CM=coronary mortality
MI=nonfatal myocardial infarction;
UA=unstable angina;
Stroke
GREACE Study (GREek Atorvastatin and Coronary Heart disease Evaluation study)


70
AVERT Study (Atorvastatin versus revascularization treatment)

It has significant position in improving percutaneous coronary revascularization symptoms and exercise performance in patients with ischemic heart disease and angina pectoris.

In this study, it is compared with lipid lowering treatment in reducing ischemic event incidence of percutaneous coronary revascularization.

71
N Engl J Med. 1999;341:70-76.

0
5
10
15
20
25
Atorvastatin
Angioplasty/GB
Patients
Experiencing ischemic event (%)
13%
21%
-36% difference*
(P=0.048)
n=22 (164)
n=37 ( 177)


AVERT Study (Atorvastatin versus revascularization treatment)

72
Aggressive lipid lowering therapy with atorvastatin in patients with stable CAD:
Reduces ischemic events at rate of 36 %
Delays time to occurrence of first event
It is safe
It delays or prevents need to percutaneous revascularization.
N Engl J Med. 1999;341:70-76
Comments
AVERT Study (Atorvastatin versus revascularization treatment)

73

Aim of the study is to determine whether atorvastatin 80 mg/day administered within 24-96 hours following acute coronary syndrome would reduce fatal and non-fatal ischemic events.

Study enrolled 3086 patients with unstable angina or with acute myocardial infarction not associated with Q wave.
MIRACL Study (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering)

74
0
5
10
15
0
4
8
12
16
week
Cummulative
incidence(%)


RR = 0.84P = 0.048
Atorvastatin
Placebo
17.4
14.8

• JAMA. 2001;285:1711-1718.

Time to First Ischemic Event
MIRACL Study (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering)

75
Comments
Aggressive lipid lowering treatment and atorvastatin, started at acute phase of unstable angina and non-Q MI, reduces early recurrent ischemic events.
It is observed that benefit is gained in patients with low – normal baseline LDL-C levels.
Conclusions provides support to the idea that treatment should be considered at hospital irrespective of baseline LDL-C levels.
Treatment is safe and well tolerated.
JAMA. 2001;285:1711-1718.
MIRACL Study (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering)

76
ASAP Study


325 patients with familial hypercholesterolemia were monitored for 2 years under treatment with atorvastatin or simvastatin.
Baseline values:
TC: 386 mg/dL (atorvastatin), 397 mg/dL (simvastatin)
LDL-C: 309 mg/dL (atorvastatin), 322 mg/dL (simvastatin)
Patients received atorvastatin at dose of 40 mg/day or simvastatin at dose of 20 mg/day; doses were doubled 4 weeks later.
Parimary evaluation criterion was change in carotid and femoral intimal media thickness.

77
REVERSAL (Reversing Atherosclerosis with Aggressive Lipid Lowering)
Aim:
It examined influence of aggressive treatment on progression or regression of coronary atherosclerosis.
The main aim was to measure, using intravascular ultrasonography (IVUS), the effect of treatment with Atorvastatin 80 mg/day (aggressive treatment) or pravastatin 40 mg/day (moderate treatment) on coronary atherosclerotic lesions in coronary arteries of patients CHD.
Effects of LDL and CRP levels on progression or regression of atherosclerosis were also evaluated.

78
REVERSAL (Reversing Atherosclerosis with Aggressive Lipid Lowering)
Patient Profile:
654 patients with history of CHD and diagnosed using coronary angiography or percutaneous coronary intervention
Duration:
18 months
Groups:
Atorvastatin 80mg vs Pravastatin 40mg (Highest doses at market when the study was started)


79
LDL-C Baseline
150.2 mg/dL
AHA 2003, Orlando, FL
REVERSAL (Reversing Atherosclerosis with Aggressive Lipid Lowering)

LDL-C Completion

79 mg/dL
LDL-C Completion
110 mg/dL
Atorvastatin
Pravastatin
46.3%
25.2%

80
REVERSAL (Reversing Atherosclerosis with Aggressive Lipid Lowering)
Conclusions:
LDL-C reduced at rate of 25 % in Pravastatin group, while corresponding figure was 46 % in the group receiving atorvastatin.
The volume of atheroma, the primary evaluation criterion determined with IVUS, had 0.4 % regression with atorvastatin, while 2.7 % increase was observed in pravastatin group; the difference between two groups was significant (p=0.02)
CRP level reduced at rate of 5.2 % in pravastatin group, while it regressed at rate of 36.4 % in atorvastatin group (p<0.0001).


81
REVERSAL (Reversing Atherosclerosis with Aggressive Lipid Lowering)
Comments:
This is the first study comparing highest doses of two popular statins in market.
Progression of coronary heart disease stopped in atorvastatin group, while it persisted in pravastatin group.
Mean LDL level reached in pravastatin group was 110, higher than the guideline target which was 100.
CRP level, important indicator of arterial inflammation, might have contributed to this result.
Selection of statin is important. Highest dose of an efficient statin should be used.

82
PROVE IT Study (PRavastatin Or atorVastatin Evaluation and Infection Therapy)
Reducing lipid levels using statins decreases cardiovascular events, but the target reduction level in CRP is not clear.

Aim of this study is to examine whether there is any difference between pravastatin at standard dose and atorvastatin at high dose in terms of following incidences considered as primary evaluation criteria: all-cause death, myocardial infarction, hospitalization due to unstable angina, revascularization and stroke.

83

Atorvastatin 62 mg /dL

Pravastatin 95 mg/dL


Mean LDL-C levels following the study
PROVE IT Study (PRavastatin Or atorVastatin Evaluation and Infection Therapy)

84

PROVE IT Study (PRavastatin Or atorVastatin Evaluation and Infection Therapy)

Recurrent event rates were found at lowest level (1.9 %) in patients with CRP level below 1 mg/dl and LDL cholesterol level below 70 mg/dl following treatment with statin.

85
In Atorvastatin Group;

16%  : Death, MI, Stroke, hospitalization

due to UE or revascularization
14%  : CHD-related death, MI or revascularization
25%  : Death, myocardial infarction or emergency revascularization

PROVE IT Study (PRavastatin Or atorVastatin Evaluation and Infection Therapy)

86
ALLIANCE (Aggressive Lipid Lowering Initiation Abates New Cardiac Events)
Aim:
It is to compare patients receiving aggressive treatment with atorvastatin at dose of 10-80 mg/day with patients receiving conventional care in reducing cardiovascular complications.


Patient Profile:
2242 CHD patients with at least one of following conditions were enrolled:
Acute myocardial infarction
Percutaneous transluminal coronary angioplasty
Coronary artery bypass graft
Unstable angina

J Am Coll Cardiol. 2004;44:1772-1779

87
ALLIANCE (Aggressive Lipid Lowering Initiation Abates New Cardiac Events)
Duration:
52 months
Groups:
Atorvastatin 10-80mg (Atorvastatin dose was titrated to 80 mg/day or to ensure LDL-K <80 mg/dL) vs standard treatment (Initially, 2/3 of patients were receiving lipid lowering therapy)
Conclusions:
Mean atorvastatin dose was 40.5 mg in the study.
In the atorvastatin group, 45 % of patients received dose of 80 mg.

J Am Coll Cardiol. 2004;44:1772-1779

88
LDL-C Baseline
147 mg/dL

LDL-C Completion

95 mg/dL
LDL-C Completion
111 mg/dL
Atorvastatin
Standard Treatment
34.3 %
23.3 %
ALLIANCE (Aggressive Lipid Lowering Initiation Abates New Cardiac Events)
LDL-C Baseline
146 mg/dL
J Am Coll Cardiol. 2004;44:1772-1779.

89
Patients reaching the target of 100mg/dL

Atorvastatin

Standard Treatment
72 %
40 %
ALLIANCE (Aggressive Lipid Lowering Initiation Abates New Cardiac Events)
J Am Coll Cardiol. 2004;44:1772-1779


90
Atorvastatin 80 mg
n=4,995
Primary evaluation criteria: Major cardiovascular event defined as CHD, nonfatal MI, resuscitated cardiac arrest and fatal and nonfatal stroke.
TNT Study
Presented at ACC 2005
Atorvastatin 10 mg
n=5,006
10.003 patient with stable coronary heart disease
35-75 years old, LDL : 130 -250 mg/dL, triglyceride ≤ 600 mg/dL
In the 8-week open period at the beginning of the study, patients received atorvastatin 10 mg.

6 yıl

91
TNT Study
LDL-C values
Presented at ACC 2005

92
TNT Study
Major cardiovascular events
Hazard Ratio [HR]=0.78
p<0.001
Presented at ACC 2005


93
TNT Study - Summary
It is demonstrated that in patients with stable coronary heart disease, reducing LDL-C values below 100 mg/dL with high dose atorvastatin further reduces major cardiovascular events at the Year 6 in comparison with keeping LDL-C levels around 100 mg/dL with atorvastatin 10 mg.
Presented at ACC 2005

94
High dose atorvastatin
80 mg/day
If LDL-C<40 mg/dL at Week 24, dose is reduced to 40 mg/day.(13%)
n=4,439
Primary Eva. Criteria: Major coronary event defined as coronary death, hospitalization due to non-fatal acute MI or resuscitated cardiac arrest.

IDEAL Study (Incremental Decrease in Clinical Endpoints Through Aggressive Lipid Lowering Trial)
Presented at AHA 2005
Standard-dose simvastatin
20 mg/day
If cholesterol>190 mg/dL at Week 24, dose is increased to 40 mg/day (23%)
n=4,449
8.888 patients aged at or below 80 years; patients with previous myocardial infarction
Patients receiving statin treatment at baseline: baseline LDL 121.5 mg/dL; total cholesterol 196 mg/dL; mean follow-up period 4,8 years


95
IDEAL Study
Major coronary events

p = 0.07

Presented at AHA 2005
%
* Major coronary event; defined as coronary death, hospitalization due to non-fatal acute MI or resuscitated cardiac arrest.

%11

96
IDEAL Study
In patients with previous myocardial infarction, a significant, although not significant, reduction is ensured in cardiovascular events with high dose atorvastatin for 5 years in comparison with standard dose simvastatin treatment.
With high dose atorvastatin treatment, significant reduction in recurrent MI, one of secondary evaluation criteria, is observed.
Hepatic enzyme elevation was higher in high dose atorvastatin group.
Presented at AHA 2005

97
ARMYDA-3 Study (Atorvastatin for Reduction of Myocardial Dysrhythmia After Cardiac Surgery)
Aim:


Investigating influences of statin treatment on atrial fibrillation occurring after cardiac operations.
It is considered that inflammatory mechanisms may play a role in post-operative atrial fibrillation.
In addition to reducing LDL-C, statins also have other pleitropic effects and modulation of inflammatory response may be one of those effects. Thus, they may possibly reduce incidence of atrial fibrillation.

98
Study Design:

200 patients naive to statins were treated with atorvastatin 40 mg or placebo.

All patients were scheduled for elective CABP operation or heart valve replacement / correction.
Patients with history of atrial fibrillation were excluded.
Patients included in the study were preoperatively treated with atorvastatin or placebo for 1 week.

ARMYDA-3 Study (Atorvastatin for Reduction of Myocardial Dysrhythmia After Cardiac Surgery)

99
Primary endpoint:
Post-operative atrial fibrillation lasting more than 5 minutes.

Secondary endpoints:

Incidence of major adverse cardiovascular and cerebral event occurring within 30 days
Correlation between CRP levels and occurrence of atrial fibrillation.
ARMYDA-3 Study (Atorvastatin for Reduction of Myocardial Dysrhythmia After Cardiac Surgery)


100

Atrial tachy-arrhythmia (Atrial fibrillation or atrial flutter):
It is a frequent complication observed following cardiac operations.
It is closely related with hemodynamic disorder, stroke, other thromboembolic events , prolonged hospitalization period and increased treatment costs.
Post-operative atrial fibrillation occurs in 40 % of patients undergoing to CABG.
This incidence is more frequent than valve operations and combined CABG + valve surgery.
ARMYDA-3 Study (Atorvastatin for Reduction of Myocardial Dysrhythmia After Cardiac Surgery)

101
Results:

In comparison with placebo, atorvastatin treatment significantly reduced incidence of postoperative atrial fibrillation and shortened hospitalization period.
It is found that group treated with atorvastatin showed reduction in atrial fibrillation risk at rate of 601 % in comparison with placebo.
ARMYDA-3 Study is the first randomized study indicating that a specific statin treatment may have positive effects on incidence of atrial fibrillation occurring after cardiac operations.
Moreover, it is also reported that shortened hospitalization period is an important contribution.

ARMYDA-3 Study (Atorvastatin for Reduction of Myocardial Dysrhythmia After Cardiac Surgery)

102
CURVES Study
Aim:
Comparing efficiency and safety of atorvastatin, simvastatin, pravastatin, lovastatin and fluvastatin on lipids in patients with baseline LDL-C 160 mg/dL and TG 400 mg/dL.
Patient Profile:
534 patients with baseline LDL-C 160 mg/dL and TG 400 mg/dL
Duration:
8 weeks
Groups:
Atorvastatin 10,20,40,80mg, simvastatin 10,20,40mg, pravastatin 10,20,40mg, lovastatin 20,40,80mg and fluvastatin 20,40mg


103

10 mg

20 mg
40 mg
10 mg
20 mg
40 mg
80 mg

10 mg

20 mg
40 mg
20 mg
40 mg
20 mg
40 mg
80 mg

6-weeks

diet
8-weeksactive treatment


Fluvastatin (24 patients)
Pravastatin (82 patients)
Atorvastatin (198 patients)

Simvastatin (187 patients)

Randomization
Lovastatin (43 patients)

Am J Cardiol 1998; 81:582-587

CURVES Study

104
Comparison of LDL-C Reductions
Am J Cardiol 1998; 81:582-587

Mean change in LDL-C

-50

-40


-30

-20
-10
Dose range (mg)
-60

20
40
80

10

Fluvastatin

Pravastatin
Simvastatin
*
*
†
†
†
*
*
*
*
*


‡
‡
‡
Lovastatin

(40 mg bid)

Atorvastatin

(80 mg qd)

CURVES Study
*atorvastatin less than 10 mg (P<0.02)
†.atorvastatin less than 20 mg (P<0.01)
‡ higher than mg equivalent doses of comparison agents (P0.01)

105

Am J Cardiol 1998; 81:582-587

Results: Comment
At general baseline and general initial titration doses, atorvastatin produced higher reduction in LDL-C levels in comparison with other statins.
All statins are well tolerated and serious side effect is observed with none of study drugs.
CURVES Study


106
TARGET/TANGIBLE Study
Aim:

Aim of this study is to determine efficiency and safety level of atorvastatin treatment conducted in comparison with simvastatin in terms of reducing LDL cholesterol levels to < 100 mg/dl in a large patient group with coronary heart disease.
Totally, 2586 patients were enrolled

107

Sixty seven (67) percent of patients in atorvastatin group and 53% of patients in simvastatin group could achieve to reach LDL cholesterol levels at or below 100 mg/dl and there was significant difference between groups.
In patients under secondary prevention due to coronary heart disease, both atorvastatin and simvastatin are safe drugs and adverse event rates are similar with both drugs.
TARGET/TANGIBLE Study

108

It is the largest safety study conducted, to date, in order to compare atorvastatin treatment with another statin in a CHD patient population.
In comparison with simvastatin, atorvastatin ensured ability to reach LDL cholesterol targets under secondary prevention in a larger population and in addition, it offered equivalent safety profile.
TARGET/TANGIBLE Study

109
WATCH Study (Women’s Atorvastatin Trial on Cholesterol)
In previous studies, it was demonstrated that female with high risk of cardiovascular disease gained similar benefits, in comparison with that of male, from cholesterol lowering therapy. In women with defined risk factor, ability to reach LDL-C target was not examined in details.
Aim of the study is to examine ability to reach treatment targets for LDL-C with lipid lowering therapy in 318 women with CHD or CHD risk factor.
Patients received atorvastatin at dose of 10-80 mg in order to reach LDL-C targets.


110
Sixty three (63) % of patients receiving 10 mg atorvastatin and 79 % of patients receiving 20 mg atorvastatin reached the target LDL cholesterol levels.
Of female patients with CHD, 34 % reached target LDL cholesterol levels (<100 mg/dL) with 10 mg atorvastatin, while 60 % of patients reached the target with 20 mg atorvastatin.
Eighty seven (87) of patients without CHD and 80 % of patients with cardiovascular disease reached target LDL value with maximum dose of atorvastatin (80 mg).
WATCH Study (Women’s Atorvastatin Trial on Cholesterol)

111
Comments:
Atorvastatin offers efficient treatment in reaching target LDL-C levels in women with CHD or CHD risk factor.

WATCH Study (Women’s Atorvastatin Trial on Cholesterol)