Lipid-Lowering Arm (ASCOT-LLA): Results in the Subgroup of Patients with Diabetes

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

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 CardiacOutcomes Trial Randomised controlled trial of prevention of CHD and other vascular events by blood pressure lowering and by cholesterol lowering (factorial design)

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 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 Secondary and Tertiary End Points

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 • Male • Age (≥55 years) • Microalbuminuria/proteinuria • TC:HDL-C ratio of ≥6 • History of early CHD in first-degree relative • Smoking • LVH • Specific ECG abnormalities • Type 2 diabetes • Peripheral vascular disease • History of cerebrovascular event

8. Primary End Point: Nonfatal MI and Fatal CHD Atorvastatin 10 mg Number of events 100 Placebo Number of events 154 36% reduction HR = 0.64 (0.50-0.83) 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 HR = 0.73 (0.56-0.96) p=0.0236

10. Risk Ratio 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 0.84 (0.55-1.29) 0.56 (0.41-0.77) 0.56 (0.37-0.85) 0.70 (0.51-0.96) 0.59 (0.39-0.90) 0.67 (0.49-0.92) 0.67 (0.35-1.29) 0.64 (0.49-0.84) 0.64 (0.47-0.86) 0.66 (0.41-1.06) 1.10 (0.57-2.12) 0.59 (0.44-0.77) 0.80 (0.45-1.42) 0.61 (0.46-0.81) 0.61 (0.44-0.84) 0.70 (0.47-1.04) 0.77 (0.52-1.12) 0.56 (0.40-0.79) 0.64 (0.50-0.83) Atorvastatin better Placebo better 0.5 1.0 1.5 Area of squares is proportional to the amount of statistical information Pre-specified Subgroups: Primary End Point

11. 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 Atorvastatin better Placebo better 0.5 1.0 1.5 Total CV Events and Procedures by Subgroups 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 HR= 0.79 (0.69-0.90) p=0.0005

13. ASCOT-LLA Results in Diabetes Sub-group

14. Baseline Characteristics Characteristic 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 130/80 mm Hg in Patients with Diabetes Blood pressure goals 140/90 mm Hg in Patients without Diabetes

16. Atorvastatin 10 mg Placebo 6 200 1.3 mmol/L 0.9 mmol/L Total cholesterol (mmol/L) (mg/dL) 150 4 100 2 0 1 2 3 150 4 125 3 (mg/dL) LDL cholesterol (mmol/L) 1.2 mmol/L 100 0.9 mmol/L 2 75 1 0 1 2 3 Close-out Years Plasma Concentrations by Visit and Treatment 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% 14%

18. DiabetesTotal CV events and procedures Atorvastatin Number of events = 116 Placebo Number of events = 151 HR=0.77 (0.61-0.98) p=0.036

19. Total CV events and procedures Diabetes No Diabetes Subtotal: Total CV events and procedures 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 Total Coronary Endpoint Diabetes No Diabetes Subtotal: Total Coronary Endpoint Cardiovascular mortality Diabetes No Diabetes Subtotal:Cardiovascular mortality 0.67 (0.41-1.09) 0.76 (0.55-1.06) 0.73 (0.56-0.96) p<0.024 0.83 (0.60-1.14) 0.66 (0.52-0.84) 0.71 (0.59-0.86) p<0.001 0.84 (0.55-1.29) 0.56 (0.41-0.77) 0.64 (0.50-0.83) p<0.001 0.77 (0.61-0.98) 0.80 (0.68-0.94) 0.79 (0.69-0.90) p<0.001 1.26 (0.71-2.23 0.78 (0.53-1.13) 0.90 (0.66-1.23) p<0.507 38 (3.0%) 9.6 62 (1.6%) 4.9 100 (1.9%) 6.0 66 (5.2%) 16.9 112 (2.9%) 8.9 178 (3.4%) 10.8 116 (9.2%) 30.2 273 (7.0%) 22.2 389 (7.5%) 24.1 26 (2.1%) 6.5 48 (1.2%) 3.8 74 (1.4%) 4.4 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 46 (3.6%) 11.4 108 (2.8%) 8.7 154 (3.0%) 9.4 81 (6.4%) 20.4 166 (4.3%) 13.5 247 (4.8%) 15.2 21 (1.6%) 5.1 61 (1.6%) 4.9 82 (1.6%) 4.9 151 (11.9%) 39.1 335 (8.7%) 27.8 486 (9.5%) 30.6 p-valuefor hetero-geneity Atorvastatinn(%) Rate Placebon(%) Rate 0.28 0.82 0.66 0.14 0.17 Hazard Ratio (95% CI) Atorvastatin better Placebo better 0.5 1.0 1.5 Area of squares is proportional to the amount of statistical information Dotted line represents the HR of Total CV events and procedures

20. p-valuefor hetero-geneity Hazard Ratio (95% CI) 0.77 (0.61-0.98) 0.80 (0.68-0.94) 0.79 (0.69-0.90) p<0.001 0.82 0.83 (0.60-1.14) 0.66 (0.52-0.84) 0.71 (0.59-0.86) p<0.001 0.28 0.84 (0.55-1.29) 0.56 (0.41-0.77) 0.64 (0.50-0.83) p<0.001 0.14 0.67 (0.41-1.09) 0.76 (0.55-1.06) 0.73 (0.56-0.96) p<0.024 0.66 1.26 (0.71-2.23) 0.78 (0.53-1.13) 0.90 (0.66-1.23) p<0.507 0.17 Atorvastatin better Placebo better 0.5 1.0 1.5 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