Atherosclerosis, Dyslipidaemia and Diabetes Slides

Atherosclerosis, Atherosclerosis, Dyslipidaemia and Dyslipidaemia and

DiabetesDiabetes

Atherosclerosis, Atherosclerosis, Dyslipidaemia and Dyslipidaemia and

DiabetesDiabetes

Section 1 - Epidemiology and Risk Factors

Section 2 - Classification of Dyslipidaemias and Pathogenesis of Atherosclerosis

Section 3 - Lipoproteins and Lipid Metabolism

Section 4 - Guidelines and Unmet Need

Section 5 - Statins and Lipid-modifying Therapies

Section 6 - Key Statin Trials

Section 7 - Diabetes: a Risk Factor for CHD?

Section 8 - The Metabolic Syndrome

Section 9 - Outcome Trials in Diabetes

Section 1 - Epidemiology and Risk Factors

Section 2 - Classification of Dyslipidaemias and Pathogenesis of Atherosclerosis

Section 3 - Lipoproteins and Lipid Metabolism

Section 4 - Guidelines and Unmet Need

Section 5 - Statins and Lipid-modifying Therapies

Section 6 - Key Statin Trials

Section 7 - Diabetes: a Risk Factor for CHD?

Section 8 - The Metabolic Syndrome

Section 9 - Outcome Trials in Diabetes

Atherosclerosis, Dyslipidaemia and Atherosclerosis, Dyslipidaemia and Diabetes Diabetes ContentsContents

Atherosclerosis, Dyslipidaemia and Atherosclerosis, Dyslipidaemia and Diabetes Diabetes ContentsContents

Section 1 Section 1 Section 1 Section 1

Epidemiology and Risk FactorsEpidemiology and Risk FactorsEpidemiology and Risk FactorsEpidemiology and Risk Factors

0

500

1000

CVD deaths

CHD deaths

Mortality from CVD and CHD in Mortality from CVD and CHD in Selected CountriesSelected Countries

Mo

rta

lity

ra

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er

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Adapted from I nternational Cardiovascular Disease S tatistics 200Adapted from I nternational Cardiovascular Disease S tatistics 200 3; American Heart Association3; American Heart Association

The Framingham Study: The Framingham Study: Relationship Between Cholesterol Relationship Between Cholesterol

and CHD Riskand CHD Risk

The Framingham Study: The Framingham Study: Relationship Between Cholesterol Relationship Between Cholesterol

and CHD Riskand CHD Risk

00

Adapted from Castelli WP. Am J Med 1984;76:4–12Adapted from Castelli WP. Am J Med 1984;76:4–12

2525

5050

7575

100100

125125

150150

<204<204 205–234205–234 235–264235–264 265–294265–294 >295>295

CH

D in

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en

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er

1000

CH

D in

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en

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er

1000

Serum cholesterol (mg/100 mL)Serum cholesterol (mg/100 mL)

35

Seven Countries Study: Seven Countries Study: Relationship of Relationship of Serum Cholesterol to MortalitySerum Cholesterol to Mortality

Seven Countries Study: Seven Countries Study: Relationship of Relationship of Serum Cholesterol to MortalitySerum Cholesterol to Mortality

Adapted from Verschuren WM et al. J Am Med Assoc 1995;274(2):131–136Adapted from Verschuren WM et al. J Am Med Assoc 1995;274(2):131–136

Serum total cholesterol (mmol/L)Serum total cholesterol (mmol/L)

3030

2525

2020

1515

1010

55

00

Death

rate

fro

m C

HD

/10

00

men

Death

rate

fro

m C

HD

/10

00

men

2.602.60 3.253.25 3.903.90 4.504.50 5.155.15 5.805.80 6.456.45 7.107.10 7.757.75 8.408.40 9.059.05

Northern EuropeNorthern Europe

United StatesUnited States

Southern Europe, InlandSouthern Europe, Inland

Southern Europe, MediterraneanSouthern Europe, Mediterranean

JapanJapan

SerbiaSerbia

Cholesterol: A Modifiable Cholesterol: A Modifiable Risk FactorRisk Factor

Cholesterol: A Modifiable Cholesterol: A Modifiable Risk FactorRisk Factor

In the USA, 37% (102 million) have elevated total cholesterol (>200 mg/dL, 5.2 mmol/L)1

In EUROASPIRE II, 58% of patients with established CHD had elevated cholesterol (5 mmol/L, 190 mg/dL)2

10% reduction in total cholesterol results in:

15% reduction in CHD mortality (p<0.001)

11% reduction in total mortality (p<0.001)3

LDL-cholesterol is the primary target to prevent CHD

In the USA, 37% (102 million) have elevated total cholesterol (>200 mg/dL, 5.2 mmol/L)1

In EUROASPIRE II, 58% of patients with established CHD had elevated cholesterol (5 mmol/L, 190 mg/dL)2

10% reduction in total cholesterol results in:

15% reduction in CHD mortality (p<0.001)

11% reduction in total mortality (p<0.001)3

LDL-cholesterol is the primary target to prevent CHD

Adapted from: 1. American Heart Association. Heart and Stroke Statistical Update; 2002; 2. EUROASPIRE II Adapted from: 1. American Heart Association. Heart and Stroke Statistical Update; 2002; 2. EUROASPIRE II Study Group. Study Group. Eur Heart JEur Heart J 2001; 2001;2222:554–572; 3. Gould AL :554–572; 3. Gould AL et al. Circulationet al. Circulation 1998; 1998;9797:946–952:946–952

Risk Factors for Cardiovascular DiseaseRisk Factors for Cardiovascular DiseaseRisk Factors for Cardiovascular DiseaseRisk Factors for Cardiovascular Disease

Modifiable Smoking Dyslipidaemia

• Raised LDL-cholesterol• Low HDL-cholesterol• Raised triglycerides

Raised blood pressure Diabetes mellitus Obesity Dietary factors Thrombogenic factors Lack of exercise Excess alcohol consumption

Modifiable Smoking Dyslipidaemia

• Raised LDL-cholesterol• Low HDL-cholesterol• Raised triglycerides

Raised blood pressure Diabetes mellitus Obesity Dietary factors Thrombogenic factors Lack of exercise Excess alcohol consumption

Non-modifiable Personal history of CHD Family history of CHD Age Gender

Non-modifiable Personal history of CHD Family history of CHD Age Gender

Adapted from: Pyörälä K Adapted from: Pyörälä K et al. Eur Heart Jet al. Eur Heart J 1994; 1994;1515:1300–1331:1300–1331

Levels of Risk Associated with Smoking, Levels of Risk Associated with Smoking, Hypertension and HypercholesterolaemiaHypertension and HypercholesterolaemiaLevels of Risk Associated with Smoking, Levels of Risk Associated with Smoking,

Hypertension and HypercholesterolaemiaHypertension and Hypercholesterolaemia

x1.6x1.6 x4x4

x3x3

x6x6

x16x16

x4.5x4.5 x9x9

HypertensionHypertension(SBP 195 mmHg)(SBP 195 mmHg)

HypertensionHypertension(SBP 195 mmHg)(SBP 195 mmHg)

Serum cholesterol levelSerum cholesterol level(8.5 mmol/L, 330 mg/dL)(8.5 mmol/L, 330 mg/dL)Serum cholesterol levelSerum cholesterol level(8.5 mmol/L, 330 mg/dL)(8.5 mmol/L, 330 mg/dL)

SmokingSmokingSmokingSmoking

Adapted from Poulter N et al., 1993Adapted from Poulter N et al., 1993

Section 2Section 2Section 2Section 2

Classification of Dyslipidaemias and Classification of Dyslipidaemias and Pathogenesis of AtherosclerosisPathogenesis of Atherosclerosis

Classification of Dyslipidaemias and Classification of Dyslipidaemias and Pathogenesis of AtherosclerosisPathogenesis of Atherosclerosis

Classification of Dyslipidaemias:Classification of Dyslipidaemias:Fredrickson (WHO) ClassificationFredrickson (WHO) ClassificationClassification of Dyslipidaemias:Classification of Dyslipidaemias:Fredrickson (WHO) ClassificationFredrickson (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.)

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

Phenotype

I

IIa

IIb

III

IV

V

Lipoproteinelevated

Chylomicrons

LDL

LDL and VLDL

IDL

VLDL

VLDL and chylomicrons

Lipoproteinelevated

Chylomicrons

LDL

LDL and VLDL

IDL

VLDL

VLDL and chylomicrons

Atherogenicity

None seen

+++

+++

+++

+

+

Atherogenicity

None seen

+++

+++

+++

+

+

Prevalence

Rare

Common

Common

Intermediate

Common

Rare

Prevalence

Rare

Common

Common

Intermediate

Common

Rare

Serumcholesterol

Serumcholesterol

Normal toNormal to

Normal toNormal to

Normal toNormal to

Serumtriglyceride

Serumtriglyceride

NormalNormal

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

Normal Arterial WallNormal Arterial WallNormal Arterial WallNormal Arterial Wall

Tunica adventitiaTunica adventitia

Tunica mediaTunica media

Tunica intimaTunica intima

EndotheliumEndothelium

Subendothelial connective tissueSubendothelial connective tissue

Smooth muscle cellSmooth muscle cell

Internal elastic membraneInternal elastic membrane

Elastic/collagen fibresElastic/collagen fibres

External elastic membraneExternal elastic membrane

Adapted from Weissberg PL. Eur Heart J Supplements 1999:1:T13–18Adapted from Weissberg PL. Eur Heart J Supplements 1999:1:T13–18

Pathogenesis of Atherosclerotic Pathogenesis of Atherosclerotic PlaquesPlaques

Pathogenesis of Atherosclerotic Pathogenesis of Atherosclerotic PlaquesPlaques

Protective response results in production of cellular adhesion molecules

Protective response results in production of cellular adhesion molecules

Monocytes and T lymphocytes attach to ‘sticky’ surface of endothelial cells

Monocytes and T lymphocytes attach to ‘sticky’ surface of endothelial cells

Migrate through arterial wall to subendothelial spaceMigrate through arterial wall to subendothelial space

Lipid-rich foam cellsLipid-rich foam cells

Endothelial damageEndothelial damage

Macrophages take up oxidised LDL-cholesterolMacrophages take up oxidised LDL-cholesterol

Fatty streak and plaqueFatty streak and plaque

CELLULAR ADHESION MOLECULES

CELLULAR ADHESION MOLECULES

induces cell proliferation and a prothrombic state

induces cell proliferation and a prothrombic state

activated activated endotheliumendotheliumactivated activated endotheliumendothelium

attracts monocytes and T lymphocytes

which adhere to endothelial cells

attracts monocytes and T lymphocytes

which adhere to endothelial cells

cytokines (e.g. IL-1, TNF-)cytokines (e.g. IL-1, TNF-)

chemokines (e.g.MCP-1, IL-8)chemokines (e.g.MCP-1, IL-8)

growth factors (e.g. PDGF, FGF)growth factors (e.g. PDGF, FGF)

Adapted from Koenig W. Eur Heart J 1999;1(Suppl T);T19–26Adapted from Koenig W. Eur Heart J 1999;1(Suppl T);T19–26

The ‘Activated’ EndotheliumThe ‘Activated’ EndotheliumThe ‘Activated’ EndotheliumThe ‘Activated’ Endothelium

Adapted from Adapted from Ross RRoss R. N Engl J Med. N Engl J Med 1999; 1999;362362:115–126:115–126Adapted from Adapted from Ross RRoss R. N Engl J Med. N Engl J Med 1999; 1999;362362:115–126:115–126

Endothelial Dysfunction in Endothelial Dysfunction in AtherosclerosisAtherosclerosis

Endothelial Dysfunction in Endothelial Dysfunction in AtherosclerosisAtherosclerosis

Upregulation of endothelial

adhesion molecules

Upregulation of endothelial

adhesion molecules

Increased endothelial

permeability

Increased endothelial

permeability

Migration of leukocytesinto the

artery wall

Migration of leukocytesinto the

artery wall

Leukocyteadhesion

Leukocyteadhesion

Adapted from Ross R. N Engl J Med 1999;362:115–126Adapted from Ross R. N Engl J Med 1999;362:115–126

Fatty Streak Formation in Fatty Streak Formation in AtherosclerosisAtherosclerosis

Fatty Streak Formation in Fatty Streak Formation in AtherosclerosisAtherosclerosis

Formationof foam cellsFormation

of foam cells

Activation of T cellsActivation of T cells

Adherence and aggregation ofplatelets

Adherence and aggregation ofplatelets

Adherence andentry of

leukocytes

Adherence andentry of

leukocytes

Migration ofsmooth

muscle cells

Migration ofsmooth

muscle cells


Formation of the Complicated Formation of the Complicated Atherosclerotic PlaqueAtherosclerotic Plaque

Formation of the Complicated Formation of the Complicated Atherosclerotic PlaqueAtherosclerotic Plaque

Formation of the fibrous capFormation of

the fibrous cap

Accumulation ofmacrophages

Accumulation ofmacrophages

Formation ofnecrotic coreFormation ofnecrotic core


The Unstable Atherosclerotic PlaqueThe Unstable Atherosclerotic PlaqueThe Unstable Atherosclerotic PlaqueThe Unstable Atherosclerotic Plaque

Rupture of the

fibrous cap

Rupture of the

fibrous cap

Thinning of thefibrous cap

Thinning of thefibrous cap Haemorrhage from

plaquemicrovessels

Haemorrhage from plaque

microvessels

Adapted from Weissberg PL. Eur Heart J Supplements 1999:1:T13–18Adapted from Weissberg PL. Eur Heart J Supplements 1999:1:T13–18

Atherosclerotic Plaque Rupture and Atherosclerotic Plaque Rupture and Thrombus FormationThrombus Formation

Atherosclerotic Plaque Rupture and Atherosclerotic Plaque Rupture and Thrombus FormationThrombus Formation

Intraluminal thrombusIntraluminal thrombusGrowth of thrombusGrowth of thrombus

Intraplaque thrombusIntraplaque thrombus Lipid poolLipid pool

Blood FlowBlood Flow

Adapted from Libby P. Circulation 1995;91:2844–2850Adapted from Libby P. Circulation 1995;91:2844–2850

The Synthesis and Breakdown ofThe Synthesis and Breakdown of Atheromatous Plaques

The Synthesis and Breakdown ofThe Synthesis and Breakdown of Atheromatous Plaques

Adapted from Libby P. Circulation 1995;91:2844–2850Adapted from Libby P. Circulation 1995;91:2844–2850

The Vulnerable Atherosclerotic PlaqueThe Vulnerable Atherosclerotic PlaqueThe Vulnerable Atherosclerotic PlaqueThe Vulnerable Atherosclerotic Plaque

Clinical Manifestations of Clinical Manifestations of AtherosclerosisAtherosclerosis

Clinical Manifestations of Clinical Manifestations of AtherosclerosisAtherosclerosis

Coronary heart disease

Angina pectoris, myocardial infarction, sudden cardiac death

Cerebrovascular disease

Transient ischaemic attacks, stroke

Peripheral vascular disease

Intermittent claudication, gangrene

Coronary heart disease

Angina pectoris, myocardial infarction, sudden cardiac death

Cerebrovascular disease

Transient ischaemic attacks, stroke

Peripheral vascular disease

Intermittent claudication, gangrene


Lipoproteins and Lipid MetabolismLipoproteins and Lipid MetabolismLipoproteins and Lipid MetabolismLipoproteins and Lipid Metabolism

Structure of LipoproteinsStructure of LipoproteinsStructure of LipoproteinsStructure of Lipoproteins

Free cholesterolFree cholesterol

PhospholipidPhospholipid TriglycerideTriglyceride

Cholesteryl esterCholesteryl esterApolipoproteinApolipoprotein

Classification of LipoproteinsClassification of LipoproteinsClassification of LipoproteinsClassification of Lipoproteins

Based on density:

Chylomicrons

Very low-density lipoprotein (VLDL)

Intermediate-density lipoprotein (IDL)

Low-density lipoprotein (LDL)

High-density lipoprotein (HDL)

Based on density:

Chylomicrons

Very low-density lipoprotein (VLDL)

Intermediate-density lipoprotein (IDL)

Low-density lipoprotein (LDL)

High-density lipoprotein (HDL)

LDL-CholesterolLDL-CholesterolLDL-CholesterolLDL-Cholesterol

Strongly associated with atherosclerosisand CHD events

10% increase results in a 20% increasein CHD risk

Risk associated with LDL-C is increased by other risk factors:

low HDL-cholesterol

smoking

hypertension

diabetes

Strongly associated with atherosclerosisand CHD events

10% increase results in a 20% increasein CHD risk

Risk associated with LDL-C is increased by other risk factors:

low HDL-cholesterol

smoking

hypertension

diabetes

TriglyceridesTriglyceridesTriglyceridesTriglycerides

Associated with increased risk of CHD events

Link with increased CHD risk is complex may be related to:

• low HDL levels

• highly atherogenic forms of LDL-cholesterol

• hyperinsulinaemia/insulin resistance

• procoagulation state

• hypertension

• abdominal obesity

May have accompanying dyslipidaemias

Normal triglyceride levels <150 mg/dL

Very high triglycerides (>1000 mg/dL, 11.3 mmol/L) increase pancreatitis risk

Associated with increased risk of CHD events

Link with increased CHD risk is complex may be related to:

• low HDL levels

• highly atherogenic forms of LDL-cholesterol

• hyperinsulinaemia/insulin resistance

• procoagulation state

• hypertension

• abdominal obesity

May have accompanying dyslipidaemias

Normal triglyceride levels <150 mg/dL

Very high triglycerides (>1000 mg/dL, 11.3 mmol/L) increase pancreatitis risk

HDL-CholesterolHDL-CholesterolHDL-CholesterolHDL-Cholesterol

HDL-cholesterol has a protective effect for risk of atherosclerosis and CHD

The lower the HDL-cholesterol level, the higher the risk for atherosclerosis and CHD

low level (<40 mg/dL) increases risk

HDL-cholesterol tends to be low when triglycerides are high

HDL-cholesterol is lowered by smoking, obesity and physical inactivity

HDL-cholesterol has a protective effect for risk of atherosclerosis and CHD

The lower the HDL-cholesterol level, the higher the risk for atherosclerosis and CHD

low level (<40 mg/dL) increases risk

HDL-cholesterol tends to be low when triglycerides are high

HDL-cholesterol is lowered by smoking, obesity and physical inactivity

ApolipoproteinsApolipoproteinsApolipoproteinsApolipoproteins

Main protein content of lipoproteins

Functions 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

Main protein content of lipoproteins

Functions 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

IntestineIntestine

Skeletal muscleSkeletal muscle

Adipose tissue

Adipose tissue

ChylomicronChylomicron

Chylomicron remnant

Chylomicron remnant

Remnant receptorRemnant receptor

LiverLiver

Dietary triglycerides and cholesterol

Dietary triglycerides and cholesterol

LP lipaseLP lipase

Exogenous Pathway of Lipid Metabolism

Exogenous Pathway of Lipid Exogenous Pathway of Lipid MetabolismMetabolism

to atheromato atheroma

FFAFFA

Endogenous Pathway of Lipid Metabolism

Endogenous Pathway of Lipid Endogenous Pathway of Lipid MetabolismMetabolism

IDLIDLIDL

Large VLDL

Large VLDL

SmallVLDLSmallVLDL

LDLreceptorLDLreceptor

LiverLiver

LPL Lipoprotein lipaseLPL Lipoprotein lipase

HL Hepatic lipaseHL Hepatic lipase

LDLLDL

LPLLPL

LPLLPL

LPLLPL

HLHL

HLHL

HLHL

Reverse cholesterol transportReverse Cholesterol Transport

Peripheraltissuestissues

CellCell

membranemembrane

VLDL, IDL, LDLVLDL, IDL, LDL

LDLLDL receptorreceptor

LCATLCAT CETPCETPFCFC

CECECECE

TGTGHDLHDL HDL3HDL3

TGTGCECE

Free cholesterolFree cholesterolTriglyceridesTriglyceridesCholesterol estersCholesterol esters

CETPCETP Cholesteryl ester transfer proteinCholesteryl ester transfer proteinLCATLCAT Lecithin cholesterol acyl transferaseLecithin cholesterol acyl transferase

SRB1SRB1

FCFC

ABCA1ABCA1

LiverLiver


Guidelines and Unmet NeedGuidelines and Unmet NeedGuidelines and Unmet NeedGuidelines and Unmet Need

Joint European Guidelines: ESC, Joint European Guidelines: ESC, EAS, ESH, ISBM, ESGP/FM, EHN EAS, ESH, ISBM, ESGP/FM, EHN Joint European Guidelines: ESC, Joint European Guidelines: ESC, EAS, ESH, ISBM, ESGP/FM, EHN EAS, ESH, ISBM, ESGP/FM, EHN

Estimate absolute CV risk using chart and initial TC value

Estimate absolute CV risk using chart and initial TC value

Absolute CHD risk <20% over 10 years, TC 5 mmol/L

Absolute CHD risk <20% over 10 years, TC 5 mmol/L

Absolute CHD risk 20% over 10 years

Absolute CHD risk 20% over 10 years

Measure fasting lipids, give lifestyle advice, with repeat lipids after

3 months

Measure fasting lipids, give lifestyle advice, with repeat lipids after

3 months

Lifestyle adviceAim: TC<5 mmol/L and

LDL-C <3.0 mmol/L Follow-up at 5-year intervals

Lifestyle adviceAim: TC<5 mmol/L and

LDL-C <3.0 mmol/L Follow-up at 5-year intervals

TC <5 mmol/L and LDL-C <3.0 mmol/LMaintain lifestyle advice with annual

follow-up

TC <5 mmol/L and LDL-C <3.0 mmol/LMaintain lifestyle advice with annual

follow-up

TC 5 mmol/L and/or LDL-C 3 mmol/LMaintain lifestyle advice with drug

therapy

TC 5 mmol/L and/or LDL-C 3 mmol/LMaintain lifestyle advice with drug

therapy

Adapted from Wood D et al. Atherosclerosis 1998;140:199–270Adapted from Wood D et al. Atherosclerosis 1998;140:199–270

NCEP ATP III: Focus on NCEP ATP III: Focus on Multiple Risk factorsMultiple Risk factors

NCEP ATP III: Focus on NCEP ATP III: Focus on Multiple Risk factorsMultiple Risk factors

Uses Framingham projections of 10-year absolute CHD risk to identify certain patients with 2 risk factors for more intensive treatment

Raises persons with diabetes without CHD to the level of CHD risk equivalent

Identifies persons with multiple metabolic risk factors (metabolic syndrome) as candidates for intensified TLC*

Uses Framingham projections of 10-year absolute CHD risk to identify certain patients with 2 risk factors for more intensive treatment

Raises persons with diabetes without CHD to the level of CHD risk equivalent

Identifies persons with multiple metabolic risk factors (metabolic syndrome) as candidates for intensified TLC*

National Cholesterol Education Program, Adult Treatment Panel III, 2001. JAMA 2001:285;2486–2497National Cholesterol Education Program, Adult Treatment Panel III, 2001. JAMA 2001:285;2486–2497

*TLC: therapeutic lifestyle changes*TLC: therapeutic lifestyle changes

NCEP ATP III: Modifications of NCEP ATP III: Modifications of Lipid ClassificationLipid Classification

NCEP ATP III: Modifications of NCEP ATP III: Modifications of Lipid ClassificationLipid Classification

Identifies LDL-cholesterol <100 mg/dL (2.6 mmol/L) as optimal

Raises categorical low HDL-cholesterol from <35 to <40 mg/dL (<0.9 to <1 mmol/L)

Lowers TG cutpoints to:

normal: <150 mg/dL (<1.7 mmol/L)

borderline high: 150–199 mg/dL (1.7–2.2 mmol/L)

high: 200–499 mg/dL (2.2–5.6 mmol/L)

very high: 500 mg/dL (5.6 mmol/L)

Identifies LDL-cholesterol <100 mg/dL (2.6 mmol/L) as optimal

Raises categorical low HDL-cholesterol from <35 to <40 mg/dL (<0.9 to <1 mmol/L)

Lowers TG cutpoints to:

normal: <150 mg/dL (<1.7 mmol/L)

borderline high: 150–199 mg/dL (1.7–2.2 mmol/L)

high: 200–499 mg/dL (2.2–5.6 mmol/L)

very high: 500 mg/dL (5.6 mmol/L)


NCEP ATP III GuidelinesNCEP ATP III Guidelines

Patients withPatients withDrug therapy Drug therapy

considered if LDLconsidered if LDL-C

* TLC: therapeutic lifestyle changes* TLC: therapeutic lifestyle changes

National Cholesterol Education Program, Adult Treatment Panel III. National Cholesterol Education Program, Adult Treatment Panel III. JAMA JAMA 2001;2001;285285:2486–2497:2486–2497

Initiate TLC* Initiate TLC* if LDLif LDL-CC

LDLLDL-C C treatment treatment

goalgoal

00-1 risk factors1 risk factors 160 mg/dL160 mg/dL†† 190 mg/dL 190 mg/dL (160(160 – 189 mg/dL:189 mg/dL:

drug optional)drug optional)

<160 mg/dL<160 mg/dL††

2 risk factors2 risk factors(10(10-year risk year risk 20%)20%)

130 mg/dL130 mg/dL†† -1010 year risk 10year risk 10–

20%: 20%: 130 mg/dL 130 mg/dL

10-year risk <10%:10-year risk <10%: 160 mg/dL160 mg/dL

<130 mg/dL<130 mg/dL††

CHD and CHD risk CHD and CHD risk equivalentsequivalents(10(10- year risk >20%)year risk >20%)

100 mg/dL100 mg/dL†† <100 mg/dL<100 mg/dL††

†† 100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L

130 mg/dL 130 mg/dL

drug optional)drug optional)(100–129 mg/dL:(100–129 mg/dL:

NCEP ATP III: LDL-Cholesterol Goals NCEP ATP III: LDL-Cholesterol Goals NCEP ATP III: LDL-Cholesterol Goals NCEP ATP III: LDL-Cholesterol Goals


CHD or CHD risk

equivalents

CHD or CHD risk

equivalents

<2 risk factors<2 risk factors

≥2 risk factors≥2 risk factors

LD

L-c

hole

ste

rol le

vel

LD

L-c

hole

ste

rol le

vel

100 -100 -

160 -160 -

130 -130 -

190 -190 -

Target

100mg/dL

Target

130mg/dL

Target

160mg/dL

100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L

NCEP ATP III Guidelines Increase the NCEP ATP III Guidelines Increase the Number of Patients Eligible for TreatmentNumber of Patients Eligible for Treatment

NCEP ATP III Guidelines Increase the NCEP ATP III Guidelines Increase the Number of Patients Eligible for TreatmentNumber of Patients Eligible for Treatment

RiskRisk NCEP NCEP

ATP IIATP II

NCEP NCEP

ATP IIIATP III

% increase in % increase in drug-eligible drug-eligible

patientspatients

HighHigh

Moderate Moderate

LowLow

TotalTotal

8,6128,612

19,55519,555

1,2641,264

29,43129,431

14,71314,713

23,66323,663

1,2641,264

39,64039,640

7171

2121

00

3535

Adapted from Davidson MH. Am J Cardiol 2002;89(Suppl 5A):1C–2C Adapted from Davidson MH. Am J Cardiol 2002;89(Suppl 5A):1C–2C

L-TAP: Achieving NCEP ATP II Goal L-TAP: Achieving NCEP ATP II Goal on Lipid-modifying Therapyon Lipid-modifying Therapy

L-TAP: Achieving NCEP ATP II Goal L-TAP: Achieving NCEP ATP II Goal on Lipid-modifying Therapyon Lipid-modifying Therapy

00

2020

4040

6060

8080

100100

Perc

en

tag

e o

f p

ati

en

tsP

erc

en

tag

e o

f p

ati

en

ts85%

of patientsreceived lipid-

modifying therapy

85%

of patientsreceived lipid-

modifying therapy

39%

of patients receiving lipid-modifying

therapy reached NCEP ATP II LDL-C goal

39%

of patients receiving lipid-modifying

therapy reached NCEP ATP II LDL-C goal

* LDL-C 100 mg/dL * LDL-C 100 mg/dL

(n=4888)(n=4888) (n=4137)(n=4137)

<20%

of CHD patients who receiving lipid-modifying

therapy reached NCEP ATP II LDL-C goal*

<20%

of CHD patients who receiving lipid-modifying

therapy reached NCEP ATP II LDL-C goal*

(n=1352)(n=1352)

Adapted from Pearson TA et al. Arch Intern Med 2000;160:459–467Adapted from Pearson TA et al. Arch Intern Med 2000;160:459–467

EUROASPIRE II: Achieving Joint EUROASPIRE II: Achieving Joint European TC GoalEuropean TC Goal

EUROASPIRE II: Achieving Joint EUROASPIRE II: Achieving Joint European TC GoalEuropean TC Goal

00

2020

4040

6060

8080

100100

Perc

en

tag

e o

f p

ati

en

tsP

erc

en

tag

e o

f p

ati

en

ts

61%

of high-risk patients* received

lipid-modifying therapy

61%

of high-risk patients* received

lipid-modifying therapy

51%

of patients reached Joint European TC

goal**

51%

of patients reached Joint European TC

goal**

*CABG, PTCA, MI or ischaemia, ** TC <5 mmol/L *CABG, PTCA, MI or ischaemia, ** TC <5 mmol/L

Adapted from EUROASPIRE II. Euro Heart J 2001;22:554–772 Adapted from EUROASPIRE II. Euro Heart J 2001;22:554–772


Statins and Lipid-modifying Statins and Lipid-modifying TherapiesTherapies

Statins and Lipid-modifying Statins and Lipid-modifying TherapiesTherapies

Effect of lipid-modifying therapies Effect of lipid-modifying therapies on lipids on lipids

Therapy

Bile acidsequestrants

Nicotinic acid

Fibrates(gemfibrozil)

Probucol

Statins*

Ezetimibe

TC–total cholesterol, LDL–low density lipoprotein, HDL–high density lipoprotein, TG–triglyceride. * Daily dose of 40mg of each drug, excluding rosuvastatin.

TC

Down 20%

Down 25%

Down 15%

Down 25%

Down 15–30%

LDL

Down 15–30%

Down 25%

Down 5–15%

Down 10–15%

Down 24–50%

Down15–20%

HDL

Up 3–5%

Up 15–30%

Up 20%

Down20–30%

Up 6–12%

Up4–9%

TG

Neutral or up

Down 20–50%

Down 20–50%

Neutral

Down 10–29%

Patienttolerability

Poor

Poor toreasonable

Good

Reasonable

Good

Good

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

Mechanism of Action of Statins: Mechanism of Action of Statins: Cholesterol Synthesis PathwayCholesterol Synthesis Pathway

Mechanism of Action of Statins: Mechanism of Action of Statins: Cholesterol Synthesis PathwayCholesterol Synthesis Pathway

acetyl CoAacetyl CoA

HMG-CoAHMG-CoA

mevalonic acidmevalonic acid

mevalonate pyrophosphatemevalonate pyrophosphate

isopentenyl pyrophosphateisopentenyl pyrophosphate

geranyl pyrophosphategeranyl pyrophosphate

farnesyl pyrophosphatefarnesyl pyrophosphate

squalenesqualene

cholesterolcholesterol

dolicholsdolicholsubiquinonesubiquinones

HMG-CoA synthaseHMG-CoA synthase

HMG-CoA reductaseHMG-CoA reductase

Squalene synthaseSqualene synthase

XX StatinsStatins

StatinStatin Protein binding

(%)

Protein binding

(%)

Metabolisedby CYP450

Metabolisedby CYP450

LipophilicLipophilic Half-life (h)Half-

life (h)

rosuvastatin

atorvastatin

simvastatin

pravastatin

fluvastatin

rosuvastatin

atorvastatin

simvastatin

pravastatin

fluvastatin

~90%

>98%

95–8%

~50%

>98%

~90%

>98%

95–8%

~50%

>98%

No

Yes

Yes

No

Yes

No

Yes

Yes

No

Yes

No

Yes

Yes

No

No

No

Yes

Yes

No

No

~19

~15

~3

~2

~3

~19

~15

~3

~2

~3

Pharmacokinetics of StatinsPharmacokinetics of StatinsPharmacokinetics of StatinsPharmacokinetics of Statins

Adapted from 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

Adapted from 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

Effects of Statins on LipidsEffects of Statins on LipidsEffects of Statins on LipidsEffects of Statins on Lipids

rosuvastatin (10 mg)

atorvastatin (10 mg)

simvastatin (20 mg)

pravastatin (20 mg)

fluvastatin (20 mg)

rosuvastatin (10 mg)

atorvastatin (10 mg)

simvastatin (20 mg)

pravastatin (20 mg)

fluvastatin (20 mg)

LDL-C% change

LDL-C% change

-52

-39

-38

-32

-22

-52

-39

-38

-32

-22

HDL-C% change

HDL-C% change

+14

+6

+8

+2

+3

+14

+6

+8

+2

+3

TG% change

TG% change

-10

-19

-19

-11

-12

-10

-19

-19

-11

-12

Adapted from Product Data Sheets.Adapted from Product Data Sheets.

Pleiotropic Effects of StatinsPleiotropic Effects of StatinsPleiotropic Effects of StatinsPleiotropic Effects of Statins

Improving or restoring endothelial function

Enhancing the stability of atherosclerotic plaques

Decreasing oxidative stress

Decreasing vascular inflammation

Anti-thrombotic effects

Improving or restoring endothelial function

Enhancing the stability of atherosclerotic plaques

Decreasing oxidative stress

Decreasing vascular inflammation

Anti-thrombotic effects

Adapted from Takemoto M, Liao JK. Arterioscler Thromb Vasc Biol 2001;21:1712–1719 Adapted from Takemoto M, Liao JK. Arterioscler Thromb Vasc Biol 2001;21:1712–1719


Key Statin TrialsKey Statin TrialsKey Statin TrialsKey Statin Trials

Design of Key Statin TrialsDesign of Key Statin TrialsDesign of Key Statin TrialsDesign of Key Statin Trials

4S1

WOSCOPS2

CARE3

LIPID4

AFCAPS/TexCAPS5

HPS6

ASCOT-LLA7

4S1

WOSCOPS2

CARE3

LIPID4

AFCAPS/TexCAPS5

HPS6

ASCOT-LLA7

StatinStatin

Existing CHD

Existing CHD

PatientsPatients CholesterolCholesterol

Follow-up (years)

Follow-up (years)

simvastatin20 mg od

pravastatin 40 mg od



lovastatin 40 mg od

simvastatin20 mg od




lovastatin 40 mg od

Yes

No MI,angina(5%)

Yes

Yes

No

Yes

No MI,angina(5%)

Yes

Yes

No

Raised Mean LDL-C 4.87 mmol/L,

188 mg/dL


192 mg/dL

Average Mean LDL-C 3.59 mmol/L,

139 mg/dL


147 mg/dL


150 mg/dL


188 mg/dL


192 mg/dL


139 mg/dL


147 mg/dL


150 mg/dL

5.4

4.9

5.0

6.1

5.2

5.4

4.9

5.0

6.1

5.2

4444 male and female, aged 35–70

6595 male, aged 45–64





6595 male, aged 45–64




StudyStudy

YesYes

In some In some patientspatients

simvastatinsimvastatin

40 mg od40 mg od

20536 male 20536 male and female, and female, aged 40–80aged 40–80

Low/average Low/average Mean LDL-C 3.4 mmol/L, Mean LDL-C 3.4 mmol/L,

130 mg/dL130 mg/dL

5.05.0

3.33.3atorvastatinatorvastatin

10 mg od10 mg od

Low/averageLow/averageMean LDL-C 3.4 mmol/L, Mean LDL-C 3.4 mmol/L,

130 mg/dL130 mg/dL

10305 male 10305 male and female, and female, aged 40–79aged 40–79

Key Statin Trials and Key Statin Trials and Spectrum of Risk Spectrum of Risk

Key Statin Trials and Key Statin Trials and Spectrum of Risk Spectrum of Risk

4S4S114S4S11

LIPIDLIPID22LIPIDLIPID22

CARECARE44CARECARE44

WOSCOPSWOSCOPS66WOSCOPSWOSCOPS66

AFCAPS/TexCAPSAFCAPS/TexCAPS77AFCAPS/TexCAPSAFCAPS/TexCAPS77

CHD/high cholesterolCHD/high cholesterol

CHD/average to high cholesterolCHD/average to high cholesterol

CHD/average cholesterolCHD/average cholesterol

No MI/high cholesterolNo MI/high cholesterol

No CHD/average cholesterolNo CHD/average cholesterol

HPSHPS33HPSHPS33 CHD*/average to high cholesterolCHD*/average to high cholesterol

*CHD or CHD risk equivalent, e.g. diabetes*CHD or CHD risk equivalent, e.g. diabetes

Increasing absolute CHD risk

Increasing absolute CHD risk

ASCOT-LLAASCOT-LLA55ASCOT-LLAASCOT-LLA55 Some patients with CHD/average cholesterol

Some patients with CHD/average cholesterol

simvastatin(n=2221)

simvastatin(n=2221)

4S Cardiovascular Endpoints4S Cardiovascular EndpointsPost-MI or Angina Patients with Raised CholesterolPost-MI or Angina Patients with Raised Cholesterol

4S Cardiovascular Endpoints4S Cardiovascular EndpointsPost-MI or Angina Patients with Raised CholesterolPost-MI or Angina Patients with Raised Cholesterol

Number of eventsNumber of events

OutcomesOutcomes placebo

(n=2223)placebo

(n=2223)

Risk reduction (%)

Risk reduction (%)

p-valuep-value

Total mortality*

Coronary death

Major coronary events

PCTA/CABG

Total mortality*

Coronary death

Major coronary events

PCTA/CABG

256

189

622

383

256

189

622

383

182

111

431

252

182

111

431

252

30

42

34

37

30

42

34

37

<0.001

<0.001

<0.001

<0.001

<0.001

<0.001

<0.001

<0.001

* primary endpoint* primary endpoint

The Scandinavian Simvastatin Survival Study Group. Lancet 1994;344:1383–1389The Scandinavian Simvastatin Survival Study Group. Lancet 1994;344:1383–1389

4S: Total Mortality4S: Total Mortality4S: Total Mortality4S: Total Mortality

0.850.85

0.800.80

0.000.00

0.00.0

1.001.00

0.950.95

0.900.90

Pro

port

ion a

live

Pro

port

ion a

live

Years since randomisationYears since randomisation

placeboplaceboplaceboplacebosimvastatinsimvastatinsimvastatinsimvastatin

6644332211 55

Log rank p=0.0003Log rank p=0.0003

This improvement in survival is accounted for by the 42% reduction in coronary death.

This improvement in survival is accounted for by the 42% reduction in coronary death.

The Scandinavian Simvastatin Survival Study Group. Lancet 1994;344:1383–1389The Scandinavian Simvastatin Survival Study Group. Lancet 1994;344:1383–1389

placebo(n=3293)placebo

(n=3293)

pravastatin(n=3302)

pravastatin(n=3302)

Risk reduction (%)

Risk reduction (%)

p-valuep-value

Non-fatal MI/CHD death*CHD deathNon-fatal MIPCTA/CABGStrokeAll cardiovascular deathsTotal mortality#

Non-fatal MI/CHD death*CHD deathNon-fatal MIPCTA/CABGStrokeAll cardiovascular deathsTotal mortality#

248

52204805173

135

248

52204805173

135

174

38143514650

106

174

38143514650

106

31

283137032

22

31

2831370

32

22

<0.001

ns<0.0010.009

ns0.033

0.051

<0.001

ns<0.0010.009

ns0.033

0.051

* primary endpoint# study not powered to detect differences in this endpoint* primary endpoint# study not powered to detect differences in this endpoint

WOSCOPS: Cardiovascular EndpointsWOSCOPS: Cardiovascular EndpointsSubjects with No Previous MI but Raised CholesterolSubjects with No Previous MI but Raised CholesterolWOSCOPS: Cardiovascular EndpointsWOSCOPS: Cardiovascular EndpointsSubjects with No Previous MI but Raised CholesterolSubjects with No Previous MI but Raised Cholesterol

OutcomesOutcomes


Shepherd J et al. N Engl J Med 1995;333:1301–1307 Shepherd J et al. N Engl J Med 1995;333:1301–1307

WOSCOPS: Non-fatal MI and CHD WOSCOPS: Non-fatal MI and CHD DeathDeath

WOSCOPS: Non-fatal MI and CHD WOSCOPS: Non-fatal MI and CHD DeathDeath

YearsYearsYearsYears

0000

1111

2222

4444

6666

Perc

ent

wit

h e

vent

Perc

ent

wit

h e

vent

Perc

ent

wit

h e

vent

Perc

ent

wit

h e

vent

8888

10101010

12121212

2222 3 3 3 3 4444 5555 6666

pravastatin (n=3302)pravastatin (n=3302)pravastatin (n=3302)pravastatin (n=3302)placebo (n=3293)placebo (n=3293)placebo (n=3293)placebo (n=3293)

31% 31% relativerelativerisk risk reductionreductionpp<0.001<0.001

31% 31% relativerelativerisk risk reductionreductionpp<0.001<0.001

Shepherd J et al. N Engl J Med 1995;333:1301–1307 Shepherd J et al. N Engl J Med 1995;333:1301–1307

placebo(n=2078)placebo

(n=2078)

pravastatin(n=2081)

pravastatin(n=2081)

Risk reduction (%)

Risk reduction (%)

p-valuep-value

Non-fatal MI/CHD death*CHD deathNon-fatal MIPCTA/CABGUnstable anginaStroke

Non-fatal MI/CHD death*CHD deathNon-fatal MIPCTA/CABGUnstable anginaStroke

274

11917339135978

274

11917339135978

212

9613529431754

212

9613529431754

24

2023271331

24

2023271331

0.003

ns0.020.0090.070.03

0.003

ns0.020.0090.070.03

CARE: Cardiovascular EndpointsCARE: Cardiovascular EndpointsPost-MI Patients with Average CholesterolPost-MI Patients with Average Cholesterol

CARE: Cardiovascular EndpointsCARE: Cardiovascular EndpointsPost-MI Patients with Average CholesterolPost-MI Patients with Average Cholesterol


OutcomesOutcomes


Sacks FM et al. N Engl J Med 1996;335:1001–1009Sacks FM et al. N Engl J Med 1996;335:1001–1009

CARE: Non-fatal MI or CHD DeathCARE: Non-fatal MI or CHD DeathCARE: Non-fatal MI or CHD DeathCARE: Non-fatal MI or CHD Death

00

55

1010

Inci

dence

%In

cid

ence

%

YearsYears

0.00.0

1515

5544332211

Change in risk,Change in risk,24% reduction24% reductionpp=0.003=0.003

Change in risk,Change in risk,24% reduction24% reductionpp=0.003=0.003

pravastatinpravastatinpravastatinpravastatinplaceboplaceboplaceboplacebo

Sacks FM et al. N Engl J Med 1996;335:1001–1009Sacks FM et al. N Engl J Med 1996;335:1001–1009

placebo(n=4502)placebo(n=4502)

pravastatin(n=4512)

pravastatin(n=4512)

Riskreduction (%)

Riskreduction (%)

p-valuep-value

CHD death*CVD deathAll-cause mortalityCHD death or non-fatal MIAny MIPCTA or CABGHosp. for unstable anginaStroke

CHD death*CVD deathAll-cause mortalityCHD death or non-fatal MIAny MIPCTA or CABGHosp. for unstable anginaStroke

373433633715

463708

1106

204

373433633715

463708

1106

204

287331498557

336585

1005

169

287331498557

336585

1005

169

24252224

292012

19

24252224

292012

19

<0.001<0.001<0.001<0.001

<0.001<0.0010.005

0.048

<0.001<0.001<0.001<0.001

<0.001<0.0010.005

0.048


OutcomesOutcomes

LIPID: Cardiovascular EndpointsLIPID: Cardiovascular EndpointsPost-MI or Unstable Angina Patients with Average/raised Post-MI or Unstable Angina Patients with Average/raised

CholesterolCholesterol

LIPID: Cardiovascular EndpointsLIPID: Cardiovascular EndpointsPost-MI or Unstable Angina Patients with Average/raised Post-MI or Unstable Angina Patients with Average/raised

CholesterolCholesterol


LIPID. N Engl J Med 1998;339:1349–1357LIPID. N Engl J Med 1998;339:1349–1357

LIPID: Cumulative Risk of Death LIPID: Cumulative Risk of Death from CHDfrom CHD

LIPID: Cumulative Risk of Death LIPID: Cumulative Risk of Death from CHDfrom CHD

Years after Years after randomisationrandomisationYears after Years after randomisationrandomisation

0000

1111

5555

Cum

ula

tive r

isk

(%)

Cum

ula

tive r

isk

(%)

Cum

ula

tive r

isk

(%)

Cum

ula

tive r

isk

(%)

10101010

2222 3 3 3 3 4444 5555 7777

pravastatinpravastatinpravastatinpravastatinplaceboplaceboplaceboplacebo

24% risk 24% risk reductionreductionpp<0.001<0.001

24% risk 24% risk reductionreductionpp<0.001<0.001

66660000

LIPID. N Engl J Med 1998;339:1349–1357LIPID. N Engl J Med 1998;339:1349–1357

AFCAPS/TexCAPS: Cardiovascular EndpointsAFCAPS/TexCAPS: Cardiovascular EndpointsSubjects with No History of CHD and Average CholesterolSubjects with No History of CHD and Average Cholesterol

AFCAPS/TexCAPS: Cardiovascular EndpointsAFCAPS/TexCAPS: Cardiovascular EndpointsSubjects with No History of CHD and Average CholesterolSubjects with No History of CHD and Average Cholesterol

placeboplacebo((n=3301n=3301))placeboplacebo

((n=3301n=3301))

lovastatinlovastatin((n=3304n=3304))lovastatinlovastatin((n=3304n=3304))

RiskRiskreduction (%)reduction (%)

RiskRiskreduction (%)reduction (%)

pp-value-valuepp-value-value

Fatal or non-fatal MI + unstable angina + sudden cardiac death*

Revascularisations

Fatal and non-fatal MI

Unstable angina

Fatal or non-fatal MI + unstable angina + sudden cardiac death*

Revascularisations

Fatal and non-fatal MI

Unstable angina

183

157

95

87

183

157

95

87

116

10657

60

116

10657

60

37

3340

32

37

3340

32

<0.001

<0.0010.002

0.02

<0.001

<0.0010.002

0.02


OutcomesOutcomesOutcomesOutcomes

Number of eventsNumber of eventsNumber of eventsNumber of events

Downs JR et al. J Am Med Assoc 1998;279:1615–1622Downs JR et al. J Am Med Assoc 1998;279:1615–1622

AFCAPS/TexCAPS: Fatal/Non-fatal MI, AFCAPS/TexCAPS: Fatal/Non-fatal MI, Sudden Cardiac Death, Unstable AnginaSudden Cardiac Death, Unstable Angina

AFCAPS/TexCAPS: Fatal/Non-fatal MI, AFCAPS/TexCAPS: Fatal/Non-fatal MI, Sudden Cardiac Death, Unstable AnginaSudden Cardiac Death, Unstable Angina

0.030.03

0.060.06

0.040.04

0.010.01

0.000.00

Cum

ula

tive inci

dence

Cum

ula

tive inci

dence

Years of follow-upYears of follow-upYears of follow-upYears of follow-up

0.00.0 >5>5

0.070.07

5544332211

0.050.05

0.020.02

37% riskreductionp<0.001

37% riskreductionp<0.001

lovastatinlovastatinlovastatinlovastatinplaceboplaceboplaceboplacebo

Downs JR et al. J Am Med Assoc 1998;279:1615–1622Downs JR et al. J Am Med Assoc 1998;279:1615–1622

Meta-analysis of 38 primary and secondary intervention trials Meta-analysis of 38 primary and secondary intervention trials Meta-analysis of 38 primary and secondary intervention trials Meta-analysis of 38 primary and secondary intervention trials

Benefits of Cholesterol LoweringBenefits of Cholesterol LoweringBenefits of Cholesterol LoweringBenefits of Cholesterol Lowering

Total mortality (Total mortality (pp=0.004)=0.004)Total mortality (Total mortality (pp=0.004)=0.004)

CHD mortality (CHD mortality (pp=0.012)=0.012)CHD mortality (CHD mortality (pp=0.012)=0.012)

% in cholesterol reduction% in cholesterol reduction% in cholesterol reduction% in cholesterol reduction

Mort

alit

y log o

dds

rati

oM

ort

alit

y log o

dds

rati

oM

ort

alit

y log o

dds

rati

oM

ort

alit

y log o

dds

rati

o

0000 4444 8888 12121212 16161616 20202020 24242424 28282828 32323232 36363636-1.0-1.0-1.0-1.0

-0.8-0.8-0.8-0.8

-0.6-0.6-0.6-0.6

-0.4-0.4-0.4-0.4

-0.2-0.2-0.2-0.2

-0.0-0.0-0.0-0.0

40404040 44444444 48484848 52525252

Adapted from Gould AL et al. Circulation. 1998;97:946–952Adapted from Gould AL et al. Circulation. 1998;97:946–952

HPS: Statin Benefits Patients with HPS: Statin Benefits Patients with Low Baseline Cholesterol LevelsLow Baseline Cholesterol Levels

HPS: Statin Benefits Patients with HPS: Statin Benefits Patients with Low Baseline Cholesterol LevelsLow Baseline Cholesterol Levels

RR - relative reduction vs. placeboRR - relative reduction vs. placebo

0

10

20

30

40

All-causemortality

Major vascularevents

All stroke

Inci

den

ce %

placebo (n=10,267)

simvastatin(n=10,269)

0

10

20

30

40

All-causemortality

Major vascularevents

All stroke

Inci

den

ce %

placebo (n=10,267)

simvastatin(n=10,269)-13% RR

P=0.0003

-13% RRP=0.0003

-24% RRp<0.0001

-24% RRp<0.0001

-25% RRp<0.0001

-25% RRp<0.0001

Adapted from HPS Collaborative Group, Lancet 2002;360:7–22Adapted from HPS Collaborative Group, Lancet 2002;360:7–22

ASCOT-LLA: Statin Benefits ASCOT-LLA: Statin Benefits Hypertensive Patients with Average Hypertensive Patients with Average or Low Baseline Cholesterol Levelsor Low Baseline Cholesterol Levels

ASCOT-LLA: Statin Benefits ASCOT-LLA: Statin Benefits Hypertensive Patients with Average Hypertensive Patients with Average or Low Baseline Cholesterol Levelsor Low Baseline Cholesterol Levels

Adapted from Sever PS et al. Lancet 2003;361:1149–1158Adapted from Sever PS et al. Lancet 2003;361:1149–1158

placeboplacebo((n=5137n=5137))placeboplacebo

((n=5137n=5137))

atorvastatinatorvastatin((n=5168n=5168))

atorvastatinatorvastatin((n=5168n=5168))

Hazard Hazard ratioratio

Hazard Hazard ratioratio

pp-value-valuepp-value-value

154

486

247

137

121

154

486

247

137

121

* primary endpoint, # includes silent MI, excludes silent MI * primary endpoint, # includes silent MI, excludes silent MI

OutcomesOutcomesOutcomesOutcomesNumber of eventsNumber of eventsNumber of eventsNumber of events

Non-fatal MI# plus fatal CHD*

Total CV events and procedures

Total coronary events

Non-fatal MI plus fatal CHD

Fatal and non-fatal stroke

Non-fatal MI# plus fatal CHD*

Total CV events and procedures

Total coronary events

Non-fatal MI plus fatal CHD

Fatal and non-fatal stroke

100

389

178

86

89

100

389

178

86

89

0.64

0.79

0.71

0.62

0.73

0.64

0.79

0.71

0.62

0.73

0.0005

0.0005

0.0005

0.0005

0.0236

0.0005

0.0005

0.0005

0.0005

0.0236


Diabetes: a Risk Factor for CHD?Diabetes: a Risk Factor for CHD?Diabetes: a Risk Factor for CHD?Diabetes: a Risk Factor for CHD?

Diabetes MellitusDiabetes MellitusDiabetes MellitusDiabetes Mellitus

One of the most common non-communicable diseases

Fourth or fifth leading cause of death in most developed countries

More than 177 million people with diabetes worldwide

Incidence of diabetes is increasing – estimated to rise to 300 million by 2025 expected to triple in Africa, the Eastern Mediterranean and

Middle East, and South-East Asia

to double in the Americas

to almost double in Europe

One of the most common non-communicable diseases

Fourth or fifth leading cause of death in most developed countries

More than 177 million people with diabetes worldwide

Incidence of diabetes is increasing – estimated to rise to 300 million by 2025 expected to triple in Africa, the Eastern Mediterranean and

Middle East, and South-East Asia

to double in the Americas

to almost double in Europe

Adapted from: International Diabetes Federation websiteAdapted from: International Diabetes Federation website

The Chronic Complications of The Chronic Complications of Diabetes MellitusDiabetes Mellitus

The Chronic Complications of The Chronic Complications of Diabetes MellitusDiabetes Mellitus

Macrovascular complications: Heart disease

Leading cause of diabetes related deaths (increases mortality and stroke by 2 to 4 times)

Microvascular complications: Retinopathy

Leading cause of adult blindness

Nephropathy Accounts for 43% of new cases of ESRD

Neuropathy 60–70% of patients with diabetes have nervous

system damage

Macrovascular complications: Heart disease

Leading cause of diabetes related deaths (increases mortality and stroke by 2 to 4 times)

Microvascular complications: Retinopathy

Leading cause of adult blindness

Nephropathy Accounts for 43% of new cases of ESRD

Neuropathy 60–70% of patients with diabetes have nervous

system damage

Adapted from National Diabetes Statistics US 2000Adapted from National Diabetes Statistics US 2000

UKPDS: Typical Lipid Profile in Patients with UKPDS: Typical Lipid Profile in Patients with Diabetes Compared with No DiabetesDiabetes Compared with No Diabetes

Adapted from UKPDS. Adapted from UKPDS. Diabetes CareDiabetes Care 1997; 1997;20:20:1683–16871683–1687

p<0.001 p<0.001

MenMen WomenWomen

no DMDM DMno DM

1

1.2

1.4

1.6

1.8

2

Triglycerides (mmol/ L)

5

5.2

5.4

5.6

5.8

6

Total cholesterol (mmol/ L)

MenMen

WomenWomen

DMno DM

no DM DM

1

1.2

1.4

1.6

HDL-cholesterol (mmol/ L)

DM DMno DM

no DM

p<0.001

p<0.001

MenMen

WomenWomen

3

3.2

3.4

3.6

3.8

4

LDL-cholesterol (mmol/ L)

p<0.001

MenMen

DMno DM

no DM DM

WomenWomen

PROCAM: Combination of Risk PROCAM: Combination of Risk Factors Increases Risk of MIFactors Increases Risk of MI

PROCAM: Combination of Risk PROCAM: Combination of Risk Factors Increases Risk of MIFactors Increases Risk of MI

0

20

40

60

80

100

120

Incid

ence o

f M

I/1000 p

ts

0

20

40

60

80

100

120

Incid

ence o

f M

I/1000 p

ts

None

None

Hyper

tens

ion

only

Hyper

tens

ion

only

Diabe

tes on

ly

Diabe

tes on

ly

Hyper

tens

+

diabet

es

Hyper

tens

+

diabet

es

Dyslip

idae

mia

Dyslip

idae

mia

Dyslip

idae

mia

+

hype

rten

s +/-

diab

etes

Dyslip

idae

mia

+

hype

rten

s +/-

diab

etes

Prevalence (%): 54.9 22.9 2.6 2.3 9.4 8.0Prevalence (%): 54.9 22.9 2.6 2.3 9.4 8.0

Adapted from Assman G, Schulte H. Am Heart J 1988;116:1713–1724Adapted from Assman G, Schulte H. Am Heart J 1988;116:1713–1724

Adapted from Malmberg K et al. Circulation 2000;102:1014–1019Adapted from Malmberg K et al. Circulation 2000;102:1014–1019

OASIS:OASIS: Patients with Diabetes at Similar Patients with Diabetes at Similar Risk to No Diabetes with CVDRisk to No Diabetes with CVD

OASIS:OASIS: Patients with Diabetes at Similar Patients with Diabetes at Similar Risk to No Diabetes with CVDRisk to No Diabetes with CVD

BARI: Diabetes Results in Less Favourable BARI: Diabetes Results in Less Favourable Outcome After Angioplasty Than No Outcome After Angioplasty Than No

DiabetesDiabetes

BARI: Diabetes Results in Less Favourable BARI: Diabetes Results in Less Favourable Outcome After Angioplasty Than No Outcome After Angioplasty Than No

DiabetesDiabetes

00

55

1010

1515

2020

2525

3030

3535

No diabetesNo diabetesNo diabetesNo diabetes DiabetesDiabetesDiabetesDiabetes

5-y

ear

mort

ality

(%

)5

-year

mort

ality

(%

)

CABGCABG PTCAPTCA

Adapted from BARI Investigators. N Engl J Med 1996:335:217–225Adapted from BARI Investigators. N Engl J Med 1996:335:217–225

NHANES: Smaller Changes in CAD Mortality NHANES: Smaller Changes in CAD Mortality Rates in Patients with Diabetes than No Rates in Patients with Diabetes than No

Diabetes Over TimeDiabetes Over Time

NHANES: Smaller Changes in CAD Mortality NHANES: Smaller Changes in CAD Mortality Rates in Patients with Diabetes than No Rates in Patients with Diabetes than No

Diabetes Over TimeDiabetes Over Time

-50

-40

-30

-20

-10

0

10

20

% c

han

ge in

mort

ality

Men

Women

-50

-40

-30

-20

-10

0

10

20

% c

han

ge in

mort

ality

Men

Women

*p<0.001 vs. baseline

*

DiabetesDiabetes No diabetesNo diabetes

Adapted from Gu K et al. JAMA;281:1291–1297Adapted from Gu K et al. JAMA;281:1291–1297


The Metabolic SyndromeThe Metabolic SyndromeThe Metabolic SyndromeThe Metabolic Syndrome

The Metabolic Syndrome andThe Metabolic Syndrome andAssociated CVD Risk FactorsAssociated CVD Risk FactorsThe Metabolic Syndrome andThe Metabolic Syndrome andAssociated CVD Risk FactorsAssociated CVD Risk Factors

AtherosclerosisAtherosclerosisAtherosclerosisAtherosclerosis

Endothelial DysfunctionEndothelial Dysfunction

HypertensionHypertension

Abdominal obesityAbdominal obesity

HyperinsulinaemiaHyperinsulinaemia

DyslipidaemiaDyslipidaemia• high TGs• high TGs

• small dense LDL• small dense LDL• low HDL-C• low HDL-C

DiabetesDiabetes

HypercoagulabilityHypercoagulability

Insulin Resistance

Insulin Resistance

NCEP ATP III: The Metabolic SyndromeNCEP ATP III: The Metabolic SyndromeNCEP ATP III: The Metabolic SyndromeNCEP ATP III: The Metabolic Syndrome

<40 mg/dL (1.0 mmol/L)<50 mg/dL (1.3 mmol/L)

MenWomen

>102 cm (>40 in)>88 cm (>35 in)

MenWomen

110 mg/dL (6.0 mmol/L)Fasting glucose

130/85 mm HgBlood pressure

HDL-C

150 mg/dL (1.7 mmol/L)TG

Abdominal obesity (Waist circumference)

Defining LevelRisk Factor

Diagnosis is established when 3 of these risk factors are present

National Cholesterol Education Program, Adult Treatment Panel III, 2001. JAMA 2001:285;2486–2497

WHO: The Metabolic SyndromeWHO: The Metabolic SyndromeWHO: The Metabolic SyndromeWHO: The Metabolic Syndrome

A working definition is glucose intolerance, IGT or diabetes mellitus and/or insulin resistance together with two or more of the following:

• Impaired glucose regulation or diabetes

• Insulin resistance

• Raised arterial pressure 160/90 mmHg

• Raised plasma triglycerides (1.7 mmol/L, 150 mg/dL) and/or low HDL-C (men <0.9 mmol/L, 35 mg/dl; women <1.0 mmol/L, 39 mg/dL)

• Central obesity

• Microalbuminuria (UAER 20 g/min or albumin: creatinine ratio 20 mg/g)

Alberti KGMM, Zimmet PZ for the WHO. Diabet Med 1998:15;539–553

AIR: LDL Particle Size is Related to AIR: LDL Particle Size is Related to the Metabolic Syndromethe Metabolic Syndrome

AIR: LDL Particle Size is Related to AIR: LDL Particle Size is Related to the Metabolic Syndromethe Metabolic Syndrome

25

25.5

26

26.5

27LD

L p

ea

k p

art

icle

siz

e (

nm

)

Metabolic Syndrome (n=62)No Metabolic syndrome but 1 or more risk factors (n=252)No risk factors (n=77)

25

25.5

26

26.5

27LD

L p

ea

k p

art

icle

siz

e (

nm

)

Metabolic Syndrome (n=62)No Metabolic syndrome but 1 or more risk factors (n=252)No risk factors (n=77)

p<0.001p<0.001

Adapted from Hulthe J et al. Arterioscler Thromb Vasc Biol 2000;20:2140–2147Adapted from Hulthe J et al. Arterioscler Thromb Vasc Biol 2000;20:2140–2147

PARIS: CHD Mortality Increases with PARIS: CHD Mortality Increases with Increased Impaired Glucose ToleranceIncreased Impaired Glucose TolerancePARIS: CHD Mortality Increases with PARIS: CHD Mortality Increases with

Increased Impaired Glucose ToleranceIncreased Impaired Glucose Tolerance

0

1

2

3

4

5

CH

D m

orta

lity

ra

te/

10

00

0

1

2

3

4

5

CH

D m

orta

lity

ra

te/

10

00

G <140 mg/dL

G <140 mg/dL

IGTIGT G 200 mg/dL

Newly diagnosed diabetes

G 200 mg/dL

Newly diagnosed diabetes

Known diabetesKnown

diabetes

p<0.001p<0.001

n=6055n=6055 n=690n=690 n=158n=158 n=135n=135

Adapted from Eschwege E et al. Horm Metab Res 1995;17(Suppl):41–46Adapted from Eschwege E et al. Horm Metab Res 1995;17(Suppl):41–46

G - glucoseG - glucose


Outcome Trials in DiabetesOutcome Trials in DiabetesOutcome Trials in DiabetesOutcome Trials in Diabetes

Trials with Fibrates in Patients with Trials with Fibrates in Patients with DiabetesDiabetes

Trials with Fibrates in Patients with Trials with Fibrates in Patients with DiabetesDiabetes

Frick MH et al. N Engl J Med 1987;317:1237–1245, Koskinen P et al. Diabetes Care 1992;15:820–825, Elkeles RS, Diamond JR, Poulter C et al. Diabetes Care 1998;21(4):641–648, Rubins HB et al. N Engl J

Med 1999;341:410–418, DAIS Investigators. Lancet 2001;357:905–910

Study Effect p-value Comment

Helsinki Helsinki Heart StudyHeart Study

(gemfibrozil)(gemfibrozil)

75% 75%

eventsevents

nsns Primary prevention; Primary prevention; post-hoc subgroup analysispost-hoc subgroup analysis

SENDCAPSENDCAP

(bezafibrate)(bezafibrate)

65% 65%

eventsevents

0.010.01 Specifically conducted in Specifically conducted in Type 2 diabetes; post-hoc Type 2 diabetes; post-hoc analysis for IHDanalysis for IHD

VA-HITVA-HIT

(gemfibrozil)(gemfibrozil)

24%24%

eventsevents

0.050.05 Secondary intervention; Secondary intervention; pre-planned subgroup pre-planned subgroup analysisanalysis

DAISDAIS

(fenofibrate)(fenofibrate)

40-42%40-42%

focal angio focal angio changeschanges

0.020.02 Specifically conducted in Specifically conducted in Type 2 diabetes; mixed Type 2 diabetes; mixed primary and secondary primary and secondary intervention; angio studyintervention; angio study

Statins Reduce CHD Risk in Patients Statins Reduce CHD Risk in Patients with Diabeteswith Diabetes

Statins Reduce CHD Risk in Patients Statins Reduce CHD Risk in Patients with Diabeteswith Diabetes

StudyStudy % LDL-C % LDL-C loweringlowering

% CHD risk % CHD risk reduction reduction (overall)(overall)

% CHD risk % CHD risk reduction reduction (diabetes)(diabetes)

Primary preventionPrimary prevention

AFCAPS/TexCAPSAFCAPS/TexCAPS11 (lovastatin; n=239) (lovastatin; n=239) 2525 37 (37 (pp<0.001)<0.001) 4343

Secondary preventionSecondary prevention

CARECARE2 2 (pravastatin; n=586) (pravastatin; n=586)

4S4S33 (simvastatin; n=202) (simvastatin; n=202)

LIPIDLIPID44 (pravastatin; n=782) (pravastatin; n=782)

2828

3636

25*25*

23 (23 (pp<0.001)<0.001)

32 (32 (pp<0.001)<0.001)

2525

25 (25 (pp=0.05)=0.05)

55 (55 (pp=0.002)=0.002)

1919

* value for overall group* value for overall group

Adapted from Kreisberg RA. Am J Cardiol 1998;82:67U–73UAdapted from Kreisberg RA. Am J Cardiol 1998;82:67U–73U

4S/CARE: LDL Lowering in Patients 4S/CARE: LDL Lowering in Patients with Diabeteswith Diabetes

4S/CARE: LDL Lowering in Patients 4S/CARE: LDL Lowering in Patients with Diabeteswith Diabetes

Adapted from Pyörälä K et al. Diabetes Care 1997;20:614–620Adapted from Pyörälä K et al. Diabetes Care 1997;20:614–620

4S: CHD Event Reduction in Patients 4S: CHD Event Reduction in Patients with Diabeteswith Diabetes

4S: CHD Event Reduction in Patients 4S: CHD Event Reduction in Patients with Diabeteswith Diabetes

WOSCOPS: Statin Treatment WOSCOPS: Statin Treatment Protects Against Development of Protects Against Development of

DiabetesDiabetes

WOSCOPS: Statin Treatment WOSCOPS: Statin Treatment Protects Against Development of Protects Against Development of

DiabetesDiabetes

Total Total number of number of patientspatients

Patients Patients developing developing diabetesdiabetes

% risk % risk reductionreduction

pp-value-value

59745974 139139 3030 0.0420.042

Adapted from Freeman DJ et al. Circulation 2001;103:357–362Adapted from Freeman DJ et al. Circulation 2001;103:357–362

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