1. The overwhelming case for LDL-C lowering
Prof Kausik Ray,
BSc (hons), MBChB, FRCP, MD, MPhil (Cantab), FACC, FESC
Professor of Cardiovascular Disease Prevention
St Georges University of London
Honorary Consultant Cardiologist St Georges Hospital

2. Years Since Randomization
4S Primary Endpoint: Total Mortality
1.00
Simvastatin
0.95
30% Risk
Reduction
(P=0.0003)
0.90
Placebo
Proportion
Alive
0.85
0.80
0.00 1 2 3 4 5 6
Years Since Randomization
Scandinavian Simvastatin Survival Study Group. Lancet ;344:

3. Heart Protection Study Collaborative Group. Lancet 2002; 360:7-22.
HPS: Effects of Simvastatin on First Major Vascular Event According to Baseline LDL-C
Risk ratio and 95% CI
STATIN
PLACEBO
(n=10269)
(n=10267)
LDL-C (mg/dL)
< 116
598/3389
756/3404
484/2549
646/2514
139
951/4331
1183/4349
24% reduction
p<0.0001
ALL PATIENTS
2033
2585
(19.8%)
(25.2%)
0.4
0.6
0.8
1.0
1.2
1.4
STATIN better
STATIN worse
Heart Protection Study Collaborative Group. Lancet 2002; 360:7-22.

4. ASCOT-LLA: Primary Prevention in HTN Nonfatal MI and Fatal CHD
Atorvastatin 10 mg Number of events 100
Placebo Number of events 154 4
Baseline LDL 132 mg/dl
3.0%
36% reduction 3
Cumulative Incidence (%) 2
1.9%
LLA: Primary Endpoint: Nonfatal MI and Fatal CHD
The primary endpoint of non-fatal myocardial infarction, including silent myocardial infarction, and fatal CHD was significantly lower by 36% (hazard ratio 0·64 [95% CI 0·50–0·83], p=0·0005) in the atorvastatin group than in the placebo group 1
HR = 0.64 ( )
p=0.0005
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Years
Sever PS et al, for the ASCOT Investigators. Lancet. 2003;361:

5. CARDS-Cumulative Hazard for Primary Endpoint
Relative Risk -37% (95% CI: -52, -17) 15
P=0.001
Placebo
127 events 10
Cumulative Hazard (%)
Atorvastatin
10mg
83 events 5 1 2 3 4
4.75
Years
Placebo
1410
1351
1306
1022
651
305
Atorva
1428
1392
1361
1074
694
328

6. CTT Collaboration Effects on Major Coronary Events per mmol/L LDL Cholesterol Reduction Subdivided by Baseline Lipid Values
Groups (mmol/L)
Events (%)
RR & CI
Heterogeneity/trend
p-value
Treatment
Control
(Treatment :
Control)
Total cholesterol:
≤5.2
748 (6·9)
940 (8·6)
1678 (7·0)
2246 (9·4)
p = 0·7
>6.5
896 (8·8)
1220 (12·1)
LDL cholesterol:
≤3.5
1130 (6·8)
1443 (8·7)
1374 (7·3)
1814 (9·6)
p = 0·5
>4.5
801 (9·3)
1120 (12·9)
HDL cholesterol:
≤0.9
1167 (9·3)
1538 (12·1)
939 (7·4)
1270 (10·2)
p = 0·8
>1.1
1207 (6·2)
1595 (8·1)
Triglycerides:
≤1.4
1162 (7·3)
1521 (9·6)
937 (7·1)
1304 (9·8)
p = 0·6
>2.0
1217 (7·9)
1564 (10·2)
0·77 (0·74 – 0·80)
Overall
3337 (7·4)
4420 (9·8)
p < 0·00001
0·5
1·0
1·5
Treatment
Control
better
better
CTT Collaborators. Lancet. 2005; 366:

7. Cholesterol Trialist Collaboration Meta-Analysis of Dyslipidemia Trials
50%
40%
30%
20%
10% 0%
-10%
Major Vascular Events
Proportional Reduction in Event Rate (SE)
Relation between proportional reduction in incidence of major coronary events and major vascular events and mean absolute LDL cholesterol reduction at 1 year
Square represents a single trial plotted against mean absolute LDL cholesterol reduction at 1 year, with vertical lines above and below corresponding to one SE of unweighted event rate reduction. Trials are plotted in order of magnitude of difference in LDL cholesterol difference at 1 year (webtable 1). For each outcome, regression line (which is forced to pass through the origin) represents weighted event rate reduction per mmol/L LDL cholesterol reduction.
Reduction in LDL Cholesterol (mmol/L)
Adapted from CTT Collaborators. Lancet. 2005; 366:

8. Only high dose statins have been tested immediately after ACS16
ACS 4S
CARE
LIPID/ HPS/IDEAL 12
Death/ Nonfatal MI (%) 8
PROVE IT-TIMI 22/ A to Z/ IDEAL 4
Stable CAD 2 4 6 4 5 6
Months Of Follow-Up
Years

9. All-Cause Death or Major CV Events in All Randomized Subjects30
Pravastatin 40mg
(26.3%) 25 20
% with Event
Atorvastatin 80mg
(22.4%) 15 10
16% RR
(P = 0.005) 5 3 18 21 24 27 30 6 9 12 15
Months of Follow-up
Cannon CP, et al. NEJM 2004;350:

10. Is there benefit from an LDL of 2 mmol/L vs 2.6mmol/L in stable CAD?
IDEAL
TNT
-13% RRR 15 16
Atorvastatin 10 mg
Simvastatin 20/40
Atorvastatin 80 mg
Atorvastatin 80
-22% RRR 12 10
Major CV Event* (%)
MCVE Cumulative Hazard (%) 8 5 4
HR = 0.78, P<.001
HR = 0.87, P=.02
Time (years) 1 2 3 4 5
Years Since Randomization
*CHD death, nonfatal non-procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke.
LaRosa JC, et al. NEJM. 2005; 352:
Pedersen TR, et al. JAMA. 2005; 294:

11. Cholesterol Trialist Collaboration Meta-Analysis of Dyslipidemia Trials
50%
40%
30%
20%
10% 0%
-10%
Major Vascular Events
TNT
Proportional Reduction in Event Rate (SE)
IDEAL
Relation between proportional reduction in incidence of major coronary events and major vascular events and mean absolute LDL cholesterol reduction at 1 year
Square represents a single trial plotted against mean absolute LDL cholesterol reduction at 1 year, with vertical lines above and below corresponding to one SE of unweighted event rate reduction. Trials are plotted in order of magnitude of difference in LDL cholesterol difference at 1 year (webtable 1). For each outcome, regression line (which is forced to pass through the origin) represents weighted event rate reduction per mmol/L LDL cholesterol reduction.
Reduction in LDL Cholesterol (mmol/L)
Adapted from CTT Collaborators. Lancet. 2005; 366:

12. Meta-Analysis of Intensive Statin Therapy LDL Cholesterol by Trial
Patients n
Prior Statin Use
ACS
Stable CAD
Pooled
4162
4497
10001
8888
27548
25.2% 0%
75.5%
28.2%
160
140
120 
Baseline  
LDL-C (mg/dL)  .  
100
Standard  
Intensive   80   60 40
LDL-C
PROVE IT-
A-to-Z
TNT
IDEAL
Pooled
TIMI 22
Baseline*
108.4
112.9
152
121.5
(3.32)
Standard*
97.1
101
104
101.4 (2.6)
Intensive*
65.5
69.1 77 81
75.4 (1.93)
Cannon CP, et al. JACC 2006; 48:

13. Meta-Analysis of Intensive Statin Therapy - All Endpoints
Odds Reduction
Event Rates
No./Total (%)
High Dose
Std Dose
-16%
3972/13798 (28.8)
4445/13750 (32.3)
1097/13798 (8.0)
1288/13750 (9.4)
-12%
462/13798 (3.3)
520/13750 (3.8)
+3%
340/13798 (2.5)
331/13750 (2.4)
-6%
808/13798 (5.9)
857/13750 (6.2)
-18%
316/13798 (2.3)
381/13750 (2.8)
Odds Ratio (95% CI)
Coronary Death or Any Cardiovascular Event
Coronary Death or MI
Cardiovascular Death
Non-Cardiovascular Death
Total Mortality
Stroke
OR, 0.84
95% CI, P=
OR, 0.84
95% CI, p=
OR, 0.88
95% CI,
p=.054
OR, 1.03
95% CI,
p=0.73
OR, 0.94
95% CI,
P=0.20
OR 0.82
95% CI,
p=0.012
0.5 1
2.5
High-dose statin better
High-dose statin worse
Cannon CP, et al. JACC 2006; 48:

14. PROVE IT-TIMI 22: Relationship Between Month 4 LDL and Long-Term Risk of Death or Major CV Event
Hazard Ratio
Referent
>2.05 – 2.56
0.80 (0.59, 1.07)
>1.54 – 2.05
>
0.67 (0.50, 0.92)
<1.03
0.61 (0.40, 0.91) 1 2
Lower Better
Higher Better
*Adjusted for age, gender, DM, prior MI, baseline LDL
Wiviott SD, Cannon, Ray et al. JACC. 2005

15. TNT: Incidence of First Major Cardiovascular Events Across Quintiles
P < *
P < *
% patients
P < 0.05*
P < 0.01*
*P-value for trend across LDL-C
LaRosa JC. AJC. 2007, 100,

19. Event rates by achieved LDL-C in trials
Optimal
standard
Minimum audit
standard
ATP III
JBS2
ESC
GMS
2° Prevention
Stable CHD 30 25 20
% with
CHD event 15
1° Prevention 10 5
1.8
2.3
2.8
3.3
3.8
4.4
Mean LDL-C level at follow-up (mmol/L)
Ray IJCP 2007, 61,

20. PROVE IT Safety Results: Side Effects
Atorvastatin 80 mg
LDL (mmmol/L)
p value
Event*
<1.04
Myositis or Myalgia (AE)
1.6
3.1
3.2
2.8 NS
CK > 3x ULN
2.3
0.7
1.9
1.0
CK > 10x ULN
0.3
Rhabdomyolysis
ALT > 3X ULN
3.0
3.6
Wiviott, et al. JACC. 2005

21. Adverse Event Profiles Across Quintiles- TNT
Number (%) of patients
Quintile 1
<64 mg/dL
(114/1722)*
Quintile 2
64-<77 mg/dL
(529/1403)*
Quintile 3
77-<90 mg/dL
(1019/968)*
Quintile 4
90-<106 mg/dL
(1515/515)*
Quintile 5
≥106 mg/dL
(1718/266)*
Withdrawals due to treatment-associated AEs
122 (6.6)
107 (5.5)
100 (5.0)
106 (5.2)
143 (7.2)
Treatment-associated myalgia
84 (4.6)
85 (4.4)
93 (4.7)
96 (4.7)
104 (5.2)
Persistent† CPK >10  ULN
Persistent† ALT and/or AST >3  ULN
20 (1.1)
15 (0.8)
18 (0.9)
8 (0.4)
10 (0.5)
Patients in both treatment groups were well matched for age, gender, race, cardiovascular risk factors and cardiovascular history.
A little over half of the patients had a history of hypertension, and 15% were diabetic in each group.
All had histories of coronary heart disease.
*Number of patients: Atorvastatin 10 mg/atorvastatin 80 mg
†Occurring twice within 4-10 days

22. CTT Lancet 2012

23. Statins increase risk of Dysglycaemia
Sattar N, ……Ray. Lancet 2010; 375:

24. Statins and DYSGLYCAEMIA vs CVD Risk
Preiss .... Ray. JAMA 2011;305:

25. Prognosis of Patients with New-Onset T2DM
TNT, IDEAL and SPARCL
TNT, IDEAL and SPARCL Atorvastatin 80 mg groups
With new-onset T2DM
Without new- onset T2DM
Diabetes at baseline*
Incidence of MCVE n / N (%)
157 / 1,387 (11.3%)
1,884/ 17,472 (10.8%)
832 / 4,761 (17.5%)
76 / (10.1%)
867 / 8,684 (10.0%)
358 / 2,359 (15.2%)
Univariate analysis**
(HR=1.03, 95% CI , p=0.83) –
(HR=0.90, 95% CI , p=0.59)
Multivariate analysis**
(HR=1.02, 95% CI , p=0.69)
(HR=0.87, 95% CI , p=0.49)
*Patients were excluded from the new-onset T2DM study **MCVEs in patients with and without new-onset T2DM were assessed with an extensive time-dependent Cox proportional hazard analysis
Waters DD et al. JACC. 2011;

26. The Evidence for Clinical Benefit of Statin Therapy for the prevention of CAD
ACS
Pravastatin
L-CAD
PACT
Simvastatin
A to Z
Atorvastatin
MIRACL
PROVE IT-TIMI 22
Primary Prev
Pravastatin
WOSCOPS
PROSPER
Simvastatin
HPS
Atorvastatin
ASCOT
CARDS
Rosuvastatin
JUPITER
Lovastatin
TEXCAPS/AFCAPS
Secondary Prev
Pravastatin
CARE
LIPID
PROSPER
Simvastatin 4S
HPS
SEARCH
Atorvastatin
AVERT
TNT
IDEAL

27. Summary
LDL-C lowering offers similar proportional reductions among those with and without vascular disease
The magnitude of benefit is related to the degree of LDL-C reduction
LDL-C lowering is safe in general
The greatest benefit are in those with the greatest absolute risk