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

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

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

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

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)

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

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

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 (0.50-0.83) p=0.0005

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 (0.56-0.96) p=0.0236

Pre-specified Subgroups: Primary End Point Area of squares is proportional to the amount of statistical information 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) 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.

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

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 (0.69-0.90) p=0.0005

ASCOT-LLA Results in Diabetes Sub-group

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

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

Plasma Concentrations by Visit and Treatment 2 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

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%

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

Atorvastatin n(%) Rate 0.67 (0.41-1.09) 0.76 (0.55-1.06) 0.73 (0.56-0.96) 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 (0.61-0.98) 0.80 (0.68-0.94) 0.79 (0.69-0.90) 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 (0.60-1.14) 0.66 (0.52-0.84) 0.71 (0.59-0.86) 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 (0.55-1.29) 0.56 (0.41-0.77) 0.64 (0.50-0.83) 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 (0.71-2.23 0.78 (0.53-1.13) 0.90 (0.66-1.23) 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

Dotted line represents the HR of Total CV events and procedures 0.67 (0.41-1.09) 0.76 (0.55-1.06) 0.73 (0.56-0.96) 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 (0.61-0.98) 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) 0.28 0.84 (0.55-1.29) 0.56 (0.41-0.77) 0.64 (0.50-0.83) 0.14 1.26 (0.71-2.23) 0.78 (0.53-1.13) 0.90 (0.66-1.23) 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

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

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