1. Lipid-Lowering Arm (ASCOT-LLA): Results in the Subgroup of Patients with Diabetes
Peter S. Sever, Bjorn Dahlöf, Neil Poulter, Hans Wedel, for the ASCOT Steering Committee and ASCOT Investigators

2. Presenter Disclosure Information
Lipid-Lowering Arm (ASCOT-LLA):
Results in the Subgroup of Patients with Diabetes
Disclosure Information
The authors have all served as consultants to and received travel expenses, payment for speaking at meetings, or funding for research from pharmaceutical companies marketing lipid-lowering drugs including Merck Sharp and Dohme, Bristol-Myers Squibb, Astra-Zeneca, Sanofi, Schering, Servier, Pharmacia, Bayer, Novartis, Aventis, Pfizer
The authors have all received financial support from Pfizer to cover administrative and staffing costs of ASCOT, and travel, accommodation expenses or both incurred by attending relevant meetings

3. The Anglo-Scandinavian Cardiac Outcomes Trial
Randomised controlled trial of prevention of CHD and other vascular events by blood pressure lowering and by cholesterol lowering (factorial design) 1

4. ASCOT Study Design 19342 hypertensive patients
Atenolol ± bendrofluazide
Amlodipine ± perindopril
10305 patients
TC ≤ 6.5 mmol/L
(250 mg/dL)
Atorvastatin 10mg
Placebo

5. Lipid-Lowering Arm (LLA) Primary Objective
To compare the primary preventive effects on the combined outcome of nonfatal MI (including silent MI) and fatal CHD of atorvastatin 10 mg with those of placebo in well controlled hypertensive patients with TC levels of 6.5 mmol/L (250 mg/dL)

6. Secondary and Tertiary End Points
Primary outcome without silent MI
All-cause mortality
CV mortality
Fatal + nonfatal stroke
Fatal + nonfatal heart failure
Total coronary end points
All CV events and procedures
Tertiary
Silent MI
Unstable angina
Chronic stable angina
Peripheral vascular disease
Development of diabetes
Development of renal impairment
Major study end points in specific subpopulations

7. Patient Population Eligibility criteria
Hypertension: SBP ≥160 mm Hg and/or DBP ≥100 mm Hg (untreated) or SBP ≥140 mm Hg and/or DBP ≥90 mm Hg (treated).
No prior myocardial infarction
40-79 years of age
3+ CVD risk factors, including
Smoking
LVH
Specific ECG abnormalities
Type 2 diabetes
Peripheral vascular disease
History of cerebrovascular event
Male
Age (≥55 years)
Microalbuminuria/proteinuria
TC:HDL-C ratio of ≥6
History of early CHD in first-degree relative

8. Primary End Point: Nonfatal MI and Fatal CHD
Atorvastatin 10 mg Number of events 100
Placebo Number of events 154
36% reduction
The primary end point of nonfatal MI (including silent MI) and fatal CHD was significantly lower by 36% (hazard ratio 0.64, CI 0.5 – 0.83, p=0.005) in the atorvastatin group compared with the placebo group.
HR = 0.64 ( )
p=0.0005

9. Secondary End Point: Fatal and Nonfatal Stroke
Atorvastatin 10 mg Number of events 89
Placebo Number of events 121
27% reduction
The secondary end point of fatal and nonfatal stroke was significantly lowered by 27% (hazard ratio 0.73, CI 0.56 – 0.96, p=0.0236) in the atorvastatin group compared with the placebo group.
HR = 0.73 ( )
p=0.0236

10. Pre-specified Subgroups: Primary End Point
Area of squares is proportional to the amount of statistical information
0.84 ( )
0.56 ( )
0.56 ( )
0.70 ( )
0.59 ( )
0.67 ( )
0.67 ( )
0.64 ( )
0.64 ( )
0.66 ( )
1.10 ( )
0.59 ( )
0.80 ( )
0.61 ( )
0.61 ( )
0.70 ( )
0.77 ( )
0.56 ( )
0.64 ( )
Hazard Ratio
Diabetes
Nondiabetes
Current smoker
Noncurrent smoker
Obese
Nonobese
LVH
No LVH
Older (>60 years)
Younger (≤60 years)
Female
Male
Previous vascular disease
No previous vascular disease
Renal dysfunction
No renal dysfunction
With metabolic syndrome
Without metabolic syndrome
All patients
0.5
1.0
1.5
Atorvastatin better
Placebo better
Risk Ratio
The proportionate effect of atorvastatin on the primary end point was not significantly different in any prespecified subgroup from that noted overall, although the benefit was not significant in five subgroups, including patients with diabetes, and among women. However, no significant interaction was noted between sex and the impact of statin on the primary end point, and total cardiovascular and total coronary evens were reduced by 20% (p=0.17) and 14% (p=0.56), respectively among women.

11. Hazard ratio of allocation to Atorvastatin in relation to subgroups
Total CV Events and Procedures by Subgroups
Subgroups
Diabetes
Non diabetes
Current smoker
Non current smoker
Obese
Non obese
LVH
No LVH
Older (>60)
Younger (<=60)
Female
Male
Previous Vascular Disease
No previous Vascular Disease
Renal dysfunction
No renal dysfunction
With Metabolic syndrome
Without Metabolic syndrome
All patients
0.5
1.0
1.5
Atorvastatin better
Placebo better
Hazard ratio of allocation to Atorvastatin in relation to subgroups
Red squares area are proportional to the amount of statistical information

12. Secondary End Point: All CV Events and Procedures
Atorvastatin 10 mg Number of events 389
Placebo Number of events 486
21% reduction
The secondary end point of all CV events and procedures was significantly lowered by 21% (hazard ratio 0.79, CI 0.69 – 0.90, p=0.0005) in the atorvastatin group compared with the placebo group.
HR= 0.79 ( )
p=0.0005

13. ASCOT-LLA Results in Diabetes Sub-group

14. Baseline Characteristics
Atorvastatin (n=1258)
Placebo (n=1274)
Age* (years)
Male (%)
Caucasian (%)
SBP* (mm Hg)
DBP* (mm Hg)
TC* (mmol/L)
LDL-C* (mmol/L)
TG* (mmol/L)
HDL-C* (mmol/L)
Number of risk factors*
63.6 ± 8.5 77
89.9
165.1 ± 17.6
92.9 ± 10.3
5.3 ± 0.8
3.3 ± 0.7
1.9 ± 1.0
1.2 ± 0.3
4.1 ± 1.0
64.0 ± 8.2 76
91.3
164.8 ± 17.1
92.4 ± 10.3
5.3 ± 0.8
3.3 ± 0.8
1.9 ± 1.0
1.2 ± 0.3
4.0 ± 1.0
*Mean ± SD

15. Mean BP by visit – all patients
Blood Pressure (mm Hg)
Patients with Diabetes
Patients without Diabetes
Randomisation
165/93
164/96
1 year
146/82
145/85
3.3 years
139/77
138/81
130/80 mm Hg in Patients with Diabetes
Blood pressure goals
140/90 mm Hg in Patients without Diabetes

16. Plasma Concentrations by Visit and Treatment2 4 6 1 3
Atorvastatin 10 mg
Placebo
Total cholesterol (mmol/L)
1.3 mmol/L
0.9 mmol/L
200
150
100
(mg/dL)
LDL cholesterol (mmol/L) 1 2 3 4
Years
Close-out
1.2 mmol/L
0.9 mmol/L
150 75
125
100
(mg/dL)
There were no differences in HDL-C between treatment groups

17. Percent of Patients on Lipid-Lowering Treatment by Treatment Group
Atorvastatin 10 mg
Placebo
87%
The primary end point of nonfatal MI (including silent MI) and fatal CHD was significantly lower by 36% (hazard ratio 0.64, CI 0.5 – 0.83, p=0.005) in the atorvastatin group compared with the placebo group.
14%

18. Diabetes Total CV events and procedures
Atorvastatin Number of events = 116
Placebo Number of events = 151
HR=0.77 ( ) p=0.036

19. Atorvastatin n(%) Rate
0.67 ( )
0.76 ( )
0.73 ( )
p<0.024
Fatal and Non-Fatal Stroke
Diabetes
No Diabetes
Subtotal: Fatal and Non-Fatal Stroke
0.66
27 (2.1%) 6.8
62 (1.6%) 4.9
89 (1.7%) 5.4
41 (3.2%) 10.2
80 (2.1%) 6.4
121 (2.4%) 7.4
Hazard Ratio (95% CI)
0.5
1.0
1.5
Atorvastatin better
Placebo better
p-value for hetero- geneity
Atorvastatin n(%) Rate
Placebo n(%) Rate
0.77 ( )
0.80 ( )
0.79 ( )
p<0.001
Total CV events and procedures
Subtotal: Total CV events and procedures
0.82
116 (9.2%) 30.2
273 (7.0%) 22.2
389 (7.5%) 24.1
151 (11.9%) 39.1
335 (8.7%) 27.8
486 (9.5%) 30.6
0.83 ( )
0.66 ( )
0.71 ( )
Total Coronary Endpoint
Subtotal: Total Coronary Endpoint
0.28
66 (5.2%) 16.9
112 (2.9%) 8.9
178 (3.4%) 10.8
81 (6.4%) 20.4
166 (4.3%) 13.5
247 (4.8%) 15.2
0.84 ( )
0.56 ( )
0.64 ( )
Non-fatal MI (incl silent) + fatal CHD
Subtotal: Non-fatal MI (incl silent) + fatal CHD
0.14
38 (3.0%) 9.6
100 (1.9%) 6.0
46 (3.6%) 11.4
108 (2.8%) 8.7
154 (3.0%) 9.4
1.26 (
0.78 ( )
0.90 ( )
p<0.507
Cardiovascular mortality
Subtotal: Cardiovascular mortality
0.17
26 (2.1%) 6.5
48 (1.2%) 3.8
74 (1.4%) 4.4
21 (1.6%) 5.1
61 (1.6%) 4.9
82 (1.6%) 4.9
Area of squares is proportional to the amount of statistical information
Dotted line represents the HR of Total CV events and procedures

20. Dotted line represents the HR of Total CV events and procedures
0.67 ( )
0.76 ( )
0.73 ( )
p<0.024
0.66
Hazard Ratio (95% CI)
0.5
1.0
1.5
Atorvastatin better
Placebo better
p-value for hetero- geneity
0.77 ( )
0.80 ( )
0.79 ( )
p<0.001
0.82
0.83 ( )
0.66 ( )
0.71 ( )
0.28
0.84 ( )
0.56 ( )
0.64 ( )
0.14
1.26 ( )
0.78 ( )
0.90 ( )
p<0.507
0.17
Total CV events and procedures
Diabetes
No Diabetes
Subtotal: Total CV events and procedures
Total Coronary Endpoint
Diabetes
No Diabetes
Subtotal: Total Coronary Endpoint
Non-fatal MI (incl silent) + fatal CHD
Diabetes
No Diabetes
Subtotal: Non-fatal MI (incl silent) + fatal CHD
Fatal and Non-Fatal Stroke
Diabetes
No Diabetes
Subtotal: Fatal and Non-Fatal Stroke
Cardiovascular mortality
Diabetes
No Diabetes
Subtotal: Cardiovascular mortality
Area of squares is proportional to the amount of statistical information
Dotted line represents the HR of Total CV events and procedures

21. Summary
In hypertensive patients with Type 2 diabetes, but no prior history of CHD, relative risk reductions in all cardiovascular events and procedures with atorvastatin (10mg) were similar to those in the non- diabetic subgroup, and occurred early in the trial
Small numbers of events in the individual components of the composite end-point, resulting (in part) from early stopping of the trial reduced the power to test significant reductions in CHD and stroke
There was no significant heterogeneity amongst subgroups

22. Conclusion
Present results indicate that treating 26 diabetic patients for 5 years would prevent one major cardiovascular event
ASCOT together with HPS confirms the benefits of lipid lowering with statins in patients with Type 2 diabetes