CHOLESTEROL
LOWERING
Lipids in T1D and T2D
T1D
T2D
TC
N
N
LDL-C
N
N
HDL-C
N or
TG
N or
Qualitative
changes
?
Small dense
LDL particles
Annual age-standardised CHD mortality (%)
CHD mortality rises in line with
total cholesterol
100
10
1
3.5
4.0
4.5
5.0
5.5
6.0
6.5
Total cholesterol (mmol/l)
7.0
7.5
8.0
Stamler J, Wentworth D, Neaton JD. JAMA 1986;256(10):2823-2828.
Annual age-standardised CHD mortality (%)
CHD mortality rises in line with
total cholesterol
100
10
1
3.5
4.0
4.5
5.0
5.5
6.0
6.5
Total cholesterol (mmol/l)
7.0
7.5
8.0
Stamler J, Wentworth D, Neaton JD. JAMA 1986;256(10):2823-2828.
Reducing cholesterol reduces
CHD mortality
1.8%
Annual CHD mortality rate
1.6%
4S
LIPID
1.4%
HPS
High risk study
groups
CARE
1.2%
POSCH
1.0%
Low risk
study groups
0.8%
0.6%
WOSCOPS
0.4%
LRC
0.2%
AFCAPS/TexCAPS
Helsinki
0.0%
4
Start of study
4.5
End of study
5
5.5
6
Total cholesterol (mmol/l)
6.5
7
7.5
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 40-80 years
Total cholesterol >3.5 mmol/l ( >135mg/dl)
• Randomised to simvastatin 40 mg or placebo
STATINworse
SIMVASTATIN: VASCULAR EVENT by PRIOR DISEASE
Baseline
feature
STATIN
(10269)
PLACEBO
(10267)
1007
1255
452
597
CVD
182
215
PVD
332
427
Diabetes
279
369
Previous MI
Other CHD (not MI)
Risk ratio and 95% CI
STATIN better STATIN worse
No prior CHD
ALL PATIENTS
2042
(19.9%)
2606
(25.4%)
24%SE 2.6
reduction
(2P<0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
SIMVASTATIN: VASCULAR EVENT by PRIOR LIPID LEVELS
Baseline
feature
STATIN
(10269)
PLACEBO
(10267)
Risk ratio and 95% CI
STATIN better STATIN worse
LDL (mmol/l)
< 3.0 (116 mg/dl)
³ 3.0 < 3.5
602
761
483
655
³ 3.5 (135 mg/dl)
957
1190
<5.0 (193 mg/dl)
361
476
³ 5.0 < 6.0
³ 6.0 (232 mg/dl)
746
965
935
1165
Het c2 = 3.0
2
Total cholesterol (mmol/l)
ALL PATIENTS
2042
(19.9%)
Het c2 = 0.5
2
2606
(25.4%)
24%SE 2.6
reduction
(2P<0.00001)
0.4 0.6 0.8
1.0 1.2 1.4
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
CARDS Design
Placebo
Placebo
2838
patients
Atorvastatin
10mg
Primary prevention diabetes patients with one
other risk factor (hypertension, smoker, microalbuminuria, retinopathy)
Treatment effect on the primary
endpoint
Event
Placebo*
Atorva*
Hazard Ratio
Risk Reduction
(CI)
Primary endpoint** 127 (9.0%) 83 (5.8%)
37% (17- 52)
p=0.001
Acute coronary
events
77 (5.5%) 51 (3.6%)
36% (9- 55)
Coronary
revascularisation
34 (2.4%) 24 (1.7%)
31% (16- 59)
Stroke
39 (2.8%) 21 (1.5%)
48% (11- 69)
** Fatal MI, other acute CHD death, non fatal MI,
unstable angina, CABG, fatal stroke, non fatal stroke
.2 .4 .6 .8 1 1.2
Treatment effect on the primary
endpoint by lipid levels
Subgroup*
Hazard Ratio Risk Reduction
(CI)
Placebo**
Atorva**
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
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
Total cholesterol still > 4 ?
•
•
•
Use a more potent statin ?
Add cholesterol absorption
inhibitor : ezetimibe ?
Role of fibrate or nicotinic acid ?
Cost Effectiveness
Intervention
Cost
Expected TC
reduction
Substitute
rosuvastatin
Add ezetimibe
10 mg £18.03
20 mg £26.02
£1.31 + £26.31
= £27.62
10%
25%
British National Formulary 2008
Patients not on target on simvastatin 40
mg
Target
Total
cholesterol
< 5.0
> 5.5
Add ezetimibe
5.5 – 5.0
Rosuvastatin
Add ezetimibe
On target
Rosuvastatin
< 4.0
Action
5.0 – 4.5
4.5 – 4.0
< 4.0
On target
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; 1849-1861
The Alphabet Strategy
• Advice
• Blood pressure
• Cholesterol
Smoking , diet , exercise
< 140/80
TC < 4.0 mmol/l , LDL ≤ 2.0 mmol/l
HDL > 1.0 mmol/l, TGs < 1.7 mmol/l
• Diabetes control
• Eye examination
• Feet examination
• Guardian drugs
HbA1c ≤ 7%
Annual examination
Annual examination
Aspirin, ACEI, ARB, statins