1. CHOLESTEROL LOWERING

2. Lipids in T1D and T2D T1D T2D TC N LDL-C HDL-C N or TG
Qualitative changes ?
Small dense LDL particles

4. “ The fact that LDL-cholesterol is not raised does not exclude it as a risk factor. ”

5. CHD mortality rises in line with total cholesterol
100
Annual age-standardised CHD mortality (%) 10
The data on this slide are taken from over 356,000 men aged years screened for inclusion in the MRFIT trial2, although the majority of these patients did not go on to take part in the study itself, their baseline cholesterol was recorded and long-term outcomes monitored.
There is a clear relationship between serum total cholesterol and six-year, age-adjusted CHD mortality. The use of a logarithmic scale on the y-axis demonstrates the linearity of this relationship.
An association between treated total cholesterol and cardiovascular risk is clearly of great importance, however one cannot comment on any possible benefits of treatment from this sort of prospective cohort study. 1
3.5
4.0
4.5
5.0
5.5
6.0
6.5
7.0
7.5
8.0
Total cholesterol (mmol/l)
Stamler J, Wentworth D, Neaton JD. JAMA 1986;256(10):

6. CHD mortality rises in line with total cholesterol
100
Annual age-standardised CHD mortality (%) 10
The data on this slide are taken from over 356,000 men aged years screened for inclusion in the MRFIT trial2, although the majority of these patients did not go on to take part in the study itself, their baseline cholesterol was recorded and long-term outcomes monitored.
There is a clear relationship between serum total cholesterol and six-year, age-adjusted CHD mortality. The use of a logarithmic scale on the y-axis demonstrates the linearity of this relationship.
An association between treated total cholesterol and cardiovascular risk is clearly of great importance, however one cannot comment on any possible benefits of treatment from this sort of prospective cohort study. 1
3.5
4.0
4.5
5.0
5.5
6.0
6.5
7.0
7.5
8.0
Total cholesterol (mmol/l)
Stamler J, Wentworth D, Neaton JD. JAMA 1986;256(10):

7. Reducing cholesterol reduces CHD mortality
0.0%
0.2%
0.4%
0.6%
0.8%
1.0%
1.2%
1.4%
1.6%
1.8% 4
4.5 5
5.5 6
6.5 7
7.5
Total cholesterol (mmol/l)
Annual CHD mortality rate 4S
LIPID
HPS
High risk study groups
CARE
POSCH
Low risk study groups
The data on this slide demonstrate that in studies of lipid lowering, the reduction in CHD mortality is consistently proportional to the degree of total cholesterol reduction3-11. This effect is observed both in high-risk populations (the five studies in the upper half of the graph)3-7 and those at lower risk (the lower half of the graph)8-11. Also worthy of note is the fact that the degree of reduction in mortality is consistent across all the studies of lipid lowering shown, not simply those using statins.
WOSCOPS
LRC
Helsinki
AFCAPS/TexCAPS
Start of study
End of study

8. MRC/BHF Heart Protection Study
20,000 subjects with Increased CHD risk due to prior disease :
Myocardial infarction or other CHD ;
Occlusive disease of non-coronary arteries ; or
Diabetes mellitus or treated hypertension.
Age years
Total cholesterol >3.5 mmol/l ( >135mg/dl)
Randomised to simvastatin 40 mg or placebo

13. CARDS Collaborative Atorvastatin Diabetes Study
Helen Colhoun, John Betteridge, Paul Durrington, Graham Hitman, Andrew Neil, Shona Livingstone, Margaret Thomason, Michael Mackness, Valentine Menys, John Fuller on behalf of the CARDS Investigators

14. CARDS Design Placebo Atorvastatin 10mg 2838 Placebo patients
Primary prevention diabetes patients with one other risk factor (hypertension, smoker, micro-albuminuria, retinopathy)

15. Treatment effect on the primary endpoint
21 (1.5%)
24 (1.7%)
51 (3.6%)
83 (5.8%)
Atorva*
48% (11- 69)
39 (2.8%)
Stroke
31% (16- 59)
34 (2.4%)
Coronary revascularisation
36% (9- 55)
77 (5.5%)
Acute coronary events
37% (17- 52)
p=0.001
127 (9.0%)
Primary endpoint**
Hazard Ratio Risk Reduction (CI)
Placebo*
Event .2 .4 .6 .8 1
1.2
** Fatal MI, other acute CHD death, non fatal MI, unstable angina, CABG, fatal stroke, non fatal stroke

16. Treatment effect on the primary endpoint by lipid levels
Subgroup*
Placebo**
Atorva**
Hazard Ratio Risk Reduction (CI)
LDL-C ≥ 3.06
66 (9.5)
44 (6.1)
38% (9-58)
LDL-C < 3.06
61 (8.5)
39 (5.6)
37% (6-58)
p=0.96
HDL-C ≥ 1.35
62 (8.4)
36 (5.2)
41% (11-61)
HDL-C < 1.35
65 (9.6)
47 (6.4)
35% (5-55)
p=0.71
Trig. ≥ 1.7
67 (9.6)
40 (5.5)
44% (18-62)
Trig. < 1.7
60 (8.4)
43 (6.1)
29% (-5-52) p=0.40 .2 .4 .6 .8 1
1.2

17. JBS 2 : indications for statin therapy in type 1 or type 2 diabetes
Age > 40 years
Retinopathy of greater than background severity
Nephropathy, including microalbuminuria
Poor glycaemic control (HbA1c > 9%)
Hypertension requiring treatment
Elevated total cholesterol ( > 6.0 mmol/l)
Metabolic syndrome
Family history of premature CHD in a first degree relative

18. Total cholesterol still > 4 ?
Use a more potent statin ?
Add cholesterol absorption inhibitor : ezetimibe ?
Role of fibrate or nicotinic acid ?
There are two main sources of cholesterol: absorption from the intestine and biosynthesis in the liver20. Biliary cholesterol from the liver accounts for 50% of daily intestinal cholesterol, 30% is from dietary sources and 20% from sloughing of epithelial cells21.

19. Substitute rosuvastatin
Cost Effectiveness
Intervention
Substitute rosuvastatin
Add ezetimibe
Cost
10 mg £18.03
20 mg £26.02
£ £26.31 = £27.62
Expected TC reduction
10%
25%
British National Formulary 2008

20. Patients not on target on simvastatin 40 mg
Total cholesterol
Target
< 5.0
< 4.0
Action
> 5.5
Add ezetimibe
5.5 – 5.0
Rosuvastatin
5.0 – 4.5
On target
4.5 – 4.0

21. Fibrates : FIELD Study 9795 subjects with T2D : 7664 no CVD
Fenofibrate 200 mg versus placebo
Average 5 year follow up
36% of placebo group and 19% of fenofibrate group given statins
Fenofibrate : TC  11%, LDL  12%, HDL  5% , TG  29%
Primary endpoint  11% (NS)
Reduction in laser therapy / progression of albuminuria in fenofibrate group
Myositis / rhabdomyolysis < 1%
FIELD Study Investigators, Lancet 2005; 366;

22. The Alphabet Strategy Advice Smoking , diet , exercise
Blood pressure < 140/80
Cholesterol
TC < 4.0 mmol/l , LDL ≤ 2.0 mmol/l
HDL > 1.0 mmol/l, TGs < 1.7 mmol/l
Diabetes control HbA1c ≤ 7%
Eye examination Annual examination
Feet examination Annual examination
Guardian drugs Aspirin, ACEI, ARB, statins

23. Thank you for listening !

24. Cholesterol metabolism
Two main sources of cholesterol :
Absorption of cholesterol from the intestine
Biosynthesis of cholesterol in the liver
There are two main sources of cholesterol: absorption from the intestine and biosynthesis in the liver20. Biliary cholesterol from the liver accounts for 50% of daily intestinal cholesterol, 30% is from dietary sources and 20% from sloughing of epithelial cells21.

25. Cholesterol balance: absorption and synthesis
Circulation
Dietary
intake ~
mg/day
Small bowel
absorption
~700 mg/day
Biliary
excretion
~1,000 mg/day
Faecal loss
mg/day
Liver synthesis
~800 mg/day
As we have seen, dietary cholesterol accounts for a relatively small proportion of circulating cholesterol21. From a typical dietary intake of mg/day21 about half is absorbed in the small bowel and transported to the liver. In the liver it joins the pool of cholesterol which has been synthesised de novo within the liver. Approximately one-third of this is released into the circulation as part of a lipoprotein molecule, while the remainder, approximately 1,000 mg/day is excreted back into the bowel via the bile21. Overall, 50% of cholesterol in the intestine is absorbed and metabolised, and 50% is excreted in the faeces21.
Shepherd J. Eur Heart J Supplements 2001;3:E2-E5.
Bays H. Expert Opin Invest Drugs 2002;11:

26. x x Dual inhibition Dietary intake STATINS Liver synthesis Biliary
Circulation
Dietary
intake ~
mg/day
Small bowel
absorption
~700 mg/day
Biliary
excretion
~1,000 mg/day
Faecal loss
mg/day
Liver synthesis
~800 mg/day
STATINS x x
As we have seen, dietary cholesterol accounts for a relatively small proportion of circulating cholesterol21. From a typical dietary intake of mg/day21 about half is absorbed in the small bowel and transported to the liver. In the liver it joins the pool of cholesterol which has been synthesised de novo within the liver. Approximately one-third of this is released into the circulation as part of a lipoprotein molecule, while the remainder, approximately 1,000 mg/day is excreted back into the bowel via the bile21. Overall, 50% of cholesterol in the intestine is absorbed and metabolised, and 50% is excreted in the faeces21.
EZETIMIBE
Shepherd J. Eur Heart J Supplements 2001;3:E2-E5.
Bays H. Expert Opin Invest Drugs 2002;11:

27. Co-administration therapy with ezetimibe + statin6% 6% 6%
20 mg
40 mg
80 mg
Three-step
titration
Statin 10 mg
25%
The co-administration studies demonstrate that the effect of ezetimibe when added to a 10 mg dose of statin is equivalent to the 80 mg dose of the statin alone (or a three-fold dose titration)27-29.
However, when using statins to lower cholesterol, the majority of the reduction in LDL-C is achieved at the starting dose33, and doubling the dose yields a relatively small additional reduction in LDL-C of approximately 6%. Therefore, a three-step doubling of the dose – i.e. increasing the dose from 10 mg to 80 mg, is required to produce an approximate 18% reduction in LDL-C.
One-step
co-administration
+ Ezetimibe 10 mg
Statin 10 mg
Statin 10 mg 10 20 30 40 50
% reduction in LDL-C
Stein E. Eur Heart J Supplements 2001:3(Suppl E):E11-E16.

28. Ezetimibe Consider in statin-intolerant patients Well tolerated
Rational approach to reducing TC / LDL
Consider in patients not achieving TC / LDL targets on statin alone
Consider in statin-intolerant patients
Well tolerated
Dose = 10 mg daily

29. Fibrates : VA - HIT Study
2500 patients with established CHD : 600 with diabetes
Gemfibrozil versus placebo
In diabetics HDL-C  5% , TG  20%, cardiovascular events  33%
? Mechanism :  HDL-C ? ,  TG ? , both ?
What are the targets for HDL-C and TG ?
Is this a class effect ?
Cannot extrapolate to primary prevention subjects
Rubins H et al. N Engl J Med 1999: 341: 410