Heart of the Matter

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Taking the Lead New advances in cholesterol
management Hervey Wilcox Consultant Chemical
Pathologist Epsom and St Helier NHS Trust
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Weight (kg)
Waist (cm)


Triglycerides ()
HDL ()


Rimonabant (RIO Study)
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CHD RISK FACTORS attributable risk fractions in
UK
10 OTHER FACTORS Exercise, Obesity,
Diabetes, Poverty, Stress, Homocysteine, etc
50 Cholesterol / Unhealthy Diet
Isles et al Lancet. 1992 Mar 21339(8795)702-6.
Emberson et al Eur J Cardiovasc Prev Rehabil.
2004 Apr11(2)125-34 Unal et al Circulation.
2004 Mar 9109(9)1101-7
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MAJOR MODIFIABLE CHD RISK FACTORS
Smoking
Hypertension
X16
Dyslipidaemia
Poulter N, Sever P, Thom S (1993). Cardiovascular
disease practical issues for prevention. St.
Albans. Caroline Black.
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The Framingham Study Relationship Between
Cholesterol and CHD Risk
150
125
100
75
CHD incidence per 1000
50
25
0
lt5.3
5.3-6.1
6.1-6.8
6.8-7.6
gt7.6
Serum total cholesterol, mmol/L
Castelli WP. Am J Med. 1984764-12
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Event Rates Plotted Against LDL-C Levels (2o
prevention trials)
4S
Statin Placebo
30 25 20 15 10 5 0
4S
LIPID
Event ()
LIPID
CARE
CARE
HPS
HPS
0.3
0.8
1.3
1.8
2.3
2.9
3.4
3.9
4.4
4.9
5.4
LDL-C (mmol/L)
after LaRosa et al. NEJM 2005
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Cardiovascular disease

• Mortality rate from CVD is disproportionate
• 3 times higher in unskilled workers than
  professionals
• therefore more common in deprived areas
• this differential has doubled in the last 20
  years
• 40 higher for people from the Indian
  sub-continent than the rest of the population

National Service Framework - CHD
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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.
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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.
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STATINS STABILIZE PLAQUES
lipid core
adventitia
STATIN THERAPY
lipid core
adventitia
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BHS 2004 Guidelines13

• 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 lt4 mmol/l
• LDL-C of lt2 mmol/l

13. Williams B, Poulter NR, Brown MJ et al. J
Human Hypertens 200418139-185.
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Cholesterol Targets Past, Present Future
Guideline Year published LDL-C target (mmol/l) TC target(mmol/l)
Joint British Societies 1998 lt3.0 lt5.0
NSF for CHD 2000 lt3.0 gt30 ? lt5.0 gt25 ?
EAS 2003 lt2.5 in high risk lt4.5in high risk
BHS IV 2004 lt2.0in high risk lt4.0in high risk
Joint British Societies December 2005 lt2.0 gt30 ? In high risk lt4.0 gt25 ? In high risk
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JBS 2 Targets in High Risk Individuals

• BP lt 140 mm Hg systolic and lt 85 mm Hg diastolic
• Total Cholesterol lt 4.0 mmol/l (LDL Cholesterol lt
  2.0 mmol/l)
• Or a 25 reduction in TC and 30 reduction in
  LDL-C, whichever is greater
• Diabetes mellitus optimally controlled
• HbAIC lt 6.5
• BP lt130 mm/Hg systolic and lt 80 mm Hg diastolic

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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
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How cholesterol links to CHD risk
1 increasein HDL-C reduces CHD risk by 2-3
1 decrease in LDL-C reduces CHD risk by 1
Third Report of the NCEP Expert Panel (2002). NIH
Publication No. 02-5213 http//www.nhlbi.nih.gov/g
uidelines/cholesterol/atp3full.pdf
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LDL-C Change from Baseline
Statin dose (mg)
10
20
40
80
0
10
20
LDL mean change from baseline
30
40
50
60
Adapted from Jones et al. Am J Cardiol 2003
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Statin efficacy across the dose range change in
HDL-C
Change in HDL-C from baseline ()
Rosuvastatin
9.5
9.6
7.7
Pravastatin
Simvastatin
Atorvastatin
10
20
40
10
20
40
80
10
20
40
10
20
40
80
Dose (mg)
plt0.002 vs pravastatin 10 mg plt0.002 vs
atorvastatin 20, 40, 80 mg simvastatin 40 mg
pravastatin 20, 40 mg plt0.002 vs atorvastatin
40, 80 mg simvastatin 40 mg pravastatin 40
mg Observed data in ITT population Adapted from
Jones PH et al. Am J Cardiol 200392152160
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Statin efficacy across the dose range change in
Triglycerides
Rosuvastatin
Atorvastatin
Pravastatin
Simvastatin
Dose (mg)
0
Change in TG from baseline ()
5
7.7
8.2
10
11.9
13.2
15
14.8
17.6
18.2
20
19.8
20.0
22.6
23.7
25
26.1
26.8
28.2
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plt0.002 vs pravastatin 10, 20 mg plt0.002 vs
simvastatin 40 mg pravastatin 20, 40 mg plt0.002
vs simvastatin 40 mg pravastatin 40 mg Adapted
from Jones PH et al. Am J Cardiol 200392152160
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Using statins safely

• Get the right dose for the right patient
• In certain circumstances, prescribe statins with
  caution e.g.
• Elderly patients (Age gt70 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
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Statin Benefit RiskCK gt10 X ULN Frequency by
LDL-C Reduction
Rosuvastatin (5- 40 mg)
Atorvastatin (10 - 80 mg)
3.0
Simvastatin (40 - 80 mg)
2.5
Pravastatin (40 - 80 mg)
2.0
1.5
CK gt 10 ULN
1.0
0.5
0.0
20
30
40
50
60
70
LDL-C reduction
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Adapted from Brewer HB. Am J Cardiol
200392(Suppl)23K29K
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Cholesterol metabolism16

• Two main sources of plasma cholesterol
• Absorption of cholesterol from the intestine
• Production of cholesterol in the liver

Shepherd J. Eur Heart J Supplements 20013E2-E5.
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Cholesterol production
Liver
Production 900 mg/day
Cholesterol in the circulation
Remnants (blood)
Biliary cholesterol 1,000 mg/day
Chylomicrons (lymph) 750 mg/day
Faecal loss 750 mg/day
Absorption
Dietary cholesterol 300-700 mg/day
Intestine
Shepherd J. Eur Heart J Supplements
20013E2-E5. Bays H. Expert Opin Invest Drugs
2002111587-1604.
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Dual Inhibition
Inhibit cholesterol production using statins
x
Liver
Production 900 mg/day
Reduced cholesterol in the circulation
Remnants (blood)
Biliary cholesterol 1,000 mg/day
Chylomicrons (lymph)
Inhibit cholesterol absorption using ezetimibe
x
Increased faecal loss
Absorption
Dietary cholesterol 300-700 mg/day
Intestine
Shepherd J. Eur Heart J Supplements
20013E2-E5. Bays H. Expert Opin Invest Drugs
2002111587-1604.
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Cholesterol absorption site within small bowel
brush border
Uptake of a fluorescent cholesterol analogue in
hamster small intestine
Sparrow CP, Patel S, Baffic J et al. J Lipid Res
1999 101747-1757.
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Reductions of CRP with Ezetimibe/Simvastatin vs
Simvastatin Alone
EZES10
EZES20
EZES40
EZES80

S10
S20
S40
S80
Median Change in CRP ()

• Simvastatin (pooled n443)
• Ezetimibe/simvastatin (pooled n443)

Sager PT et al. Am J Cardiol 2003921414-1418.
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Rationale for therapy with combination ezetimibe
statin39
Three-step titration
Statin 10 mg
One-step co-administration
Statin 10 mg
10
20
30
40
50
60
0
reduction in LDL-C
Stein E. Eur Heart J Supplements 20013(Suppl
E)E11-E16.
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The Fenofibrate Intervention and Event Lowering
in Diabetes
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FIELD

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

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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.
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Adjustment for Statin Use
Primary End Point CHD Events
Secondary End Point Total CVD Risk
P.16
P.01
P.035
P.004
Abbreviations Adj, adjusted for statin use
Nonadj, nonadjusted risk
The FIELD Study Investigators. Lancet Early
Online Publication. November 14, 2005.
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Primary Prevention
P.014
P.004
(n 7664)
(n 7664)
The FIELD Study Investigators. Lancet Early
Online Publication. November 14, 2005.
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Improved Quality of Life Reductions in Macro and
Microvascular Disease Tertiary End Point Data -
presented at AHA - 2005
These effects cannot be explained by changes in
HbA1C or concomitant medications, or by the
minor reduction in blood pressure in the Supralip
group
FIELD Study Investigators. Lancet 2005,
e-publication November 14
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