Taking the Lead

New advances in cholesterol management

Hervey Wilcox

Consultant Chemical Pathologist

Epsom and St Helier NHS Trust

Weight (kg) Waist (cm)

Triglycerides (%) HDL (%)

Rimonabant (RIO Study)

CHD RISK FACTORS: attributable risk fractions in UK

Smoking ~25%High Blood

Pressure ~15%

~10% OTHER FACTORS: Exercise, Obesity, Diabetes, Poverty, Stress, Homocysteine, etc

~50% Cholesterol / Unhealthy Diet Isles et al Lancet. 1992 Mar 21;339(8795):702-6.; Emberson et al Eur J Cardiovasc Prev Rehabil. 2004 Apr;11(2):125-34; Unal et al Circulation. 2004 Mar 9;109(9):1101-7

Poulter N, Sever P, Thom S (1993). Cardiovascular disease practical issues for prevention. St. Albans. Caroline Black.

MAJOR MODIFIABLE CHD RISK FACTORS

X16

Smoking Hypertension

Dyslipidaemia

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

Castelli WP. Am J Med. 1984;76:4-12

0

25

50

75

100

125

150

<5.3 5.3-6.1 6.1-6.8 6.8-7.6 >7.6

CH

D in

cid

en

ce p

er

1000

Serum total cholesterol, mmol/L

TNT (80 mg of atorvastatin)

TNT (10 mg of atorvastatin)

Event Rates Plotted Against LDL-C Levels (2o prevention trials)

after LaRosa et al. NEJM 2005

30

25

20

15

10

5

0

Even

t (%

)

StatinPlacebo

4S

4S

LIPID

CARE

HPS

LIPID

CARE

HPS

LDL-C (mmol/L)

0.3 0.8 1.3 1.8 2.3 2.9 3.4 3.9 4.4 4.9 5.4

Mortality rate from CVD is disproportionateMortality rate from CVD is disproportionate

3 times higher in unskilled workers than 3 times higher in unskilled workers than professionalsprofessionals– therefore more common in deprived areastherefore more common in deprived areas

this differential has doubled in the last 20 this differential has doubled in the last 20 yearsyears

40% higher for people from the Indian 40% higher for people from the Indian sub-continent than the rest of the populationsub-continent than the rest of the population

Cardiovascular diseaseCardiovascular disease

National Service Framework - CHDNational Service Framework - CHD

Case Study

Female

59 years old

TC 7.4 mmol/l

LDL 5.0 mmol/l

HDL 1.2 mmol/l

Trigs 2.5 mmol/l

BP 158/92 mm Hg

BMI 28 kg/m2

Smoker

Family History: Positive family history of ischaemic heart disease and diabetes.

Father died aged 70 after developing angina in his early 60s.

Case Study

Male

50 years old

TC 5.5 mmol/l

HDL 0.7 mmol/l

Trigs 5.7 mmol/l

BP 148/84 mm Hg

BMI 28 kg/m2

Non-Smoker

Family history of ischaemic heart disease and diabetes.

lipid core

adventitia

adventitia

lipid core

STATINS STABILIZE PLAQUES

STATIN THERAPY

BHS 2004 GuidelinesBHS 2004 Guidelines1313BHS 2004 GuidelinesBHS 2004 Guidelines1313

New guidelines published in 2004 by British Hypertension Society13

In patients with hypertension, optimal cholesterol levels:

Reduce total cholesterol by 25% or LDL-C by 30%

Total cholesterol of <4 mmol/l

LDL-C of <2 mmol/l

New guidelines published in 2004 by British Hypertension Society13

In patients with hypertension, optimal cholesterol levels:

Reduce total cholesterol by 25% or LDL-C by 30%

Total cholesterol of <4 mmol/l

LDL-C of <2 mmol/l

13. Williams B, Poulter NR, Brown MJ et al. J Human Hypertens 2004;18:139-185.

Cholesterol Targets Past, Present & Future

Guideline Year publishedLDL-C target

(mmol/l)TC target(mmol/l)

Joint British Societies 1998 <3.0 <5.0

NSF for CHD 2000 <3.0 & >30% ↓ <5.0 & >25% ↓

EAS 2003<2.5

in high risk<4.5

in high risk

BHS IV 2004<2.0

in high risk <4.0

in high risk

Joint British Societies December 2005

<2.0 >30% ↓

In high risk

<4.0 >25% ↓

In high risk

JBS 2: Targets in High Risk JBS 2: Targets in High Risk IndividualsIndividuals

JBS 2: Targets in High Risk JBS 2: Targets in High Risk IndividualsIndividuals

BP < 140 mm Hg systolic and < 85 mm Hg diastolic

Total Cholesterol < 4.0 mmol/l (LDL Cholesterol < 2.0 mmol/l) Or a 25% reduction in TC and 30% reduction

in LDL-C, whichever is greater

Diabetes mellitus optimally controlled HbAIC < 6.5 % BP <130 mm/Hg systolic and < 80 mm Hg

diastolic

BP < 140 mm Hg systolic and < 85 mm Hg diastolic

Total Cholesterol < 4.0 mmol/l (LDL Cholesterol < 2.0 mmol/l) Or a 25% reduction in TC and 30% reduction

in LDL-C, whichever is greater

Diabetes mellitus optimally controlled HbAIC < 6.5 % BP <130 mm/Hg systolic and < 80 mm Hg

diastolic

NON-DIABETIC WOMANNON-DIABETIC MAN

JBS 2 CVD Risk Prediction Charts

Figure 1: Joint British Societies’ cardiovascular disease (CVD) risk prediction chart: non-diabetic men

Figure 2: Joint British Societies’ cardiovascular disease (CVD) risk prediction chart: non-diabetic women

Heart: December 2005 Vol 91 Supplement V (Inside Covers) Reproduced with permission from the BMJ Publishing Group

How cholesterol links to CHD risk

Third Report of the NCEP Expert Panel (2002). NIH Publication No. 02-5213 http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf

1% decrease in LDL-C reduces

CHD risk by 1%

1% increase% increasein HDL-C reduces in HDL-C reduces CHD risk by 2-3% CHD risk by 2-3%

LDL-C: % Change from Baseline

0

–60

–50

–40

–30

–20

–10

10 20 40 80

Statin dose (mg)

LD

L m

ean

% c

han

ge f

rom

baselin

e

rosuvastatin

atorvastatin

simvastatin

pravastatin

Adapted from Jones et al. Am J Cardiol 2003

Statin efficacy across the dose range: change in HDL-C

*p<0.002 vs pravastatin 10 mg†p<0.002 vs atorvastatin 20, 40, 80 mg; simvastatin 40 mg; pravastatin 20, 40 mg‡p<0.002 vs atorvastatin 40, 80 mg; simvastatin 40 mg; pravastatin 40 mgObserved data in ITT population

Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160

10 20 40

3.2

4.4

5.6

10 20 40 80 10 20 40 0

2

4

6

8

10

12

5.74.8

4.4

2.1

*7.7

†9.5

‡9.6

10 20 40 80

5.3

6.0

5.2

6.8

Dose (mg)

Rosuvastatin

Atorvastatin PravastatinSimvastatin

Ch

an

ge in

HD

L-C

fro

m

baselin

e (

%)

Statin efficacy across the dose range: change in Triglycerides

*p<0.002 vs pravastatin 10, 20 mg†p<0.002 vs simvastatin 40 mg; pravastatin 20, 40 mg‡p<0.002 vs simvastatin 40 mg; pravastatin 40 mg

Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160

Dose (mg)

–20.0

–22.6

–26.8–28.2

–11.9

–17.6

–14.8

–18.2

10 20 40 80

–23.7

† –26.1

‡

–19.8

*

10 20 40 10 20 40 80

–8.2 –7.7

–13.2

10 20 40

–30

–25

–20

–15

–10

0

–5

Rosuvastatin Atorvastatin PravastatinSimvastatin

Ch

an

ge in

TG

fro

m

baselin

e (

%)

Using statins safely

Get the right dose for the right patient

In certain circumstances, prescribe statins with caution* e.g.– Elderly patients (Age >70 years)– Patients with history of muscle disorders,

renal or hepatic impairment and hypothyroidism and patients of Asian orgin

– Combination with other drugs/ foods;• Cyclosporin, erythromycin, amiodarone,

fibrates, warfarin, grapefruit juice

*See individual SmPCs for details*See individual SmPCs for details

Statin Benefit : RiskCK >10 X ULN: Frequency by % LDL-C Reduction

0.0

0.5

1.0

1.5

2.0

2.5

3.0

20 30 40 50 60 70

% LDL-C reduction

% C

K >

10

× U

LN

Rosuvastatin (5- 40 mg)

Pravastatin (40 - 80 mg)

Atorvastatin (10 - 80 mg)

Simvastatin (40 - 80 mg)

Adapted from Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K 34

Cholesterol metabolismCholesterol metabolism1616Cholesterol metabolismCholesterol metabolism1616

Two main sources of plasma cholesterol

Absorption of cholesterol from the intestine

Production of cholesterol in the liver

Two main sources of plasma cholesterol

Absorption of cholesterol from the intestine

Production of cholesterol in the liver

Shepherd J. Eur Heart J Supplements 2001;3:E2-E5.

Faecal loss750 mg/day

Dietary cholesterol300-700 mg/day

Intestine

Liver

Biliary cholesterol1,000 mg/day

Chylomicrons(lymph)

750 mg/day

Cholesterol in the circulation

Absorption

Remnants(blood)

Production900 mg/day

Cholesterol production

Shepherd J. Eur Heart J Supplements 2001;3:E2-E5.Bays H. Expert Opin Invest Drugs 2002;11:1587-1604.

Increased faecal loss

Dietary cholesterol300-700 mg/day

Intestine

Liver

Biliary cholesterol1,000 mg/day Chylomicrons

(lymph)

Reducedcholesterol in the circulation

Absorption

Remnants(blood)

Production900 mg/day

Dual Inhibition

Shepherd J. Eur Heart J Supplements 2001;3:E2-E5.Bays H. Expert Opin Invest Drugs 2002;11:1587-1604.

x

x

Inhibit cholesterol production using statins

Inhibit cholesterol absorption using ezetimibe

Uptake of a fluorescent cholesterol analogue in hamster small intestine

Cholesterol absorption site within

small bowel brush border

Sparrow CP, Patel S, Baffic J et al. J Lipid Res 1999; 10:1747-1757.

Slide SourceLipidsOnline

www.lipidsonline.org

-50

-40

-30

-20

-10

0

10

Reductions of CRP with Ezetimibe/Simvastatin vs Reductions of CRP with Ezetimibe/Simvastatin vs Simvastatin AloneSimvastatin Alone

Media

n C

hange in C

RP (

%)

Sager PT et al. Am J Cardiol 2003;92:1414-1418.

Simvastatin (pooled n=443) Ezetimibe/simvastatin (pooled n=443)

S10

EZE+

S10 S20

EZE+

S20 S40

EZE+

S40 S80

EZE+

S80

One-step

co-administration

Three-step

titration

10 20 30 40 50 60

% reduction in LDL-C

0

Statin 10 mg

Statin 10 mg

Rationale for therapy with combination ezetimibe + statin39

20 mg

6%

40 mg

6%

80 mg

6%

+ Ezetimibe10 mg

18%

Stein E. Eur Heart J Supplements 2001:3(Suppl E):E11-E16.

The Fenofibrate Intervention and Event Lowering in Diabetes

FIELD

To assess whether early intervention with fenofibrate could prevent cardiovascular events in type 2 diabetics who had relatively normal lipid levels.

Study Design

• Randomised, double blind, placebo controlled, parallel group trial

• 63 centres: Australia, New Zealand, Finland

• 9795 middle-aged to elderly people with type 2 diabetes, considered to be at increased risk of CHD

The FIELD Study Investigators. Lancet [Early Online Publication]. November 14, 2005.

Adjustment for Statin Use

-11%

-19%-20

-18

-16-14

-12

-10

-8

-6-4

-2

0

Nonadj Adj

Re

lati

ve

Ris

k,

%

P=.16 P=.01

Primary End Point:CHD Events

Abbreviations: Adj, adjusted for statin use; Nonadj, nonadjusted risk

-11%

-15%-16

-14

-12

-10

-8

-6

-4

-2

0

Nonadj Adj

Re

lati

ve

Ris

k,

%

P=.035 P=.004

Secondary End Point:Total CVD Risk

The FIELD Study Investigators. Lancet [Early Online Publication]. November 14, 2005.

-25%

-19%

-30

-25

-20

-15

-10

-5

0

CHD Events Total CVD

Ris

k R

ed

uc

tio

n,

%

Primary Prevention

(n = 7664) (n = 7664)

P=.014 P=.004

The FIELD Study Investigators. Lancet [Early Online Publication]. November 14, 2005.

* FIELD Study Investigators. Lancet 2005, e-publication November 14

Improved Quality of Life:Reductions in Macro and Microvascular Disease

Tertiary End Point Data - presented at AHA - 2005

Improved Quality of Life:Reductions in Macro and Microvascular Disease

Tertiary End Point Data - presented at AHA - 2005

-16%-18%

-30% -31%-35

-30

-25

-20

-15

-10

-5

0

p=0.002 p=0.04 p=0.0003 p=0.04

Re

lati

ve

Ris

k,

%

Laser Treatmentfor Retinopathy*

Hospitalisation for Angina Pectoris

Progression ofAlbuminuria* Amputation

These effects cannot be explained by changes in HbA1C or concomitant medications, or by the minor reduction in blood pressure in the Supralip group