1) The document summarizes the results of a large clinical trial testing the fixed-dose combination drug Preterax (perindopril and indapamide) for the treatment of type 2 diabetes patients. 2) The trial found that Preterax reduced the risk of cardiovascular mortality by 18%, total mortality by 14%, and the combined outcome of major macrovascular or microvascular events by 9% compared to placebo. 3) The beneficial effects of Preterax were consistent across patient subgroups and backgrounds in ancillary treatments.

1. The first and largest trial ever performed with a fixed antihypertensive combination in type 2 diabetic patients

2. Context

3. Global projections for diabetes (millions) 2007-2025 World 2007 = 246 million 2025 = 380 million Increase +55% Diabetes Atlas , 3rd edition, IDF 2006 28.3 40.5 +43% 16.2 32.7 +102% 10.4 18.7 +80% 53.2 64.1 +21% 24.5 44.5 +81% 67.0 99.4 +48% 46.5 80.3 +73%

4. Proportion of Treated Diabetic Patients with Controlled and Uncontrolled Blood Pressure Mancia G et al., J Hypertens 2005; 23: 1575-1581 < 130/80 3.0% n = 2491 BP is uncontrolled in most diabetics > 140/90 85.1% < 140/90 14.9%

6. “ Current guidelines recommend the lowering of blood pressure for people with type 2 diabetes to reduce the risk of cardiovascular events, though a strategy to reduce blood pressure regardless of baseline blood pressure (ie, including people with diabetes who do not have raised blood pressure) has not been proven in randomised trials to date.” Lancet Press Release Sept 2007 What is recommended by guidelines?

7. ESH-ESC Guidelines 2007 2007 Guidelines for the Management of Arterial Hypertension. ESH/ESC. Journal of hypertension 2007,25:1105-1187 “ A combination of two drugs at low dose should be preferred as first step treatment when initial BP is in the grade 2 or 3 range or total cardiovascular risk is high or very high”

9. From UKPDS to ADVANCE: 30 years of progress to improve cardiovascular-renal outcome in diabetics Glycemic control BP control Macro- and microvascular protection 1977 2007 RAAS Antiplatelet agents Statins     ACE inhibitors ARBs  Preterax ?

10.  Myocardial Infarction Stroke Microvascular complications Non-intensive group (HbA1c = 7.9 %) UKPDS 33. Lancet 1998;352:837-853 P = 0.052 P = 0.0099 Intensive glycemic control reduces risk of CV events P = 0. 52 Intensive group (HbA1c = 7%) % Events

11. Blood pressure lowering and vascular risk in diabetes. UK Prospective Diabetes Study 

12. Cardiovascular mortality Stroke Myocardial infarction Ramipril (142/80 mm Hg) placebo (142/79 mm Hg) Micro-HOPE. Lancet 2000;355:253-259 P = 0.01 P = 0.0001 P = 0.07 Major benefits with ACE inhibitors regarding coronary and renal events Nephropathy P = 0.027 % Events 

13. Antiplatelet agents reduce the risk of events In coronary diabetics: Cardiovascular mortality, MI, and stroke are reduced by 19% (p<0.01) JAMA. 2002;287:2570-2581  Statins reduce the risk of macrovascular events in diabetics  Major cardiovascular events Stroke Coronary events placebo P = 0.001 atorvastatin P = 0.001 % Events CARDS. Lancet 2004;364:685-696

14. Hypothesis and design

20. STRATHE: study design Atenolol 50 mg Valsartan 40 mg Valsartan 80 mg Losartan 50 mg Valsartan 80mg + HCTZ Amlodipine 5mg m 0 m 3 m 6 m 9 Sequential Strategy n = 176 Step-by-step Strategy n = 177 Preterax Strategy n = 180 Preterax 1 tab Preterax 1.5 tabs Preterax 2 tabs Mourad JJ. J Hypertens . 2004;22:2379-2386

21. Preterax : strong BP – lowering efficacy SBP decrease (mm Hg) -26.6 -22.6 -21.5 -27 -17 -7 Preterax Sequential Step-by-step P <0.05 P <0.01 0 61.7 48.9 46.9 0 20 40 60 Preterax Sequential Step-by-step P =0.015 P =0.005 Normalization (BP <140/90 mm Hg) Mourad JJ. J Hypertens. 2004;22:2379-2386.

22. Preterax & arterial stiffness The REASON Study: results at 1 year Asmar R, London G, O’Rourke M, et al. Hypertension 2001;38:922-927.

23. Preterax and target-organ damage The PICxEL Study: LVH regression Dahlöf B, Gosse P, et al. J Hypertens. 2005;23:2063-2070.

24. Preterax and renal disease in diabetes The PREMIER study Mogensen CE, Viberti G, Halimi S et al. Hypertension. 2003; 41:1063-1071.

25. Results

26. Preterax reduces CV mortality by 18% - 18% P = 0.027 ADVANCE Collaborative group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007. 2007;370:829-840

27. Preterax reduces total mortality by 14% - 14% P = 0.025 ADVANCE Collaborative group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007. 2007;370:829-840

28. Preterax reduces coronary and renal events ADVANCE Collaborative group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007. 2007;370:829-840

29. Major macro or microvascular event Preterax reduces combined primary outcomes by 9%- - 9 % P = 0.041 ADVANCE Collaborative group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007. 2007;370:829-840

30. Effects are consistent by age, sex, BP, and HbA1c Combined primary end point 2.0 Number of events Preterax Placebo (n=5569) (n=5571) Relative risk reduction (95% CI) Favors Preterax Favors Placebo Hazard ratio 0.5 1.0 Age (years) < 65 325 346 6% (-10 to 19) >= 65 536 592 11% (0 to 21) Sex Male 546 594 10% (-1 to 20) Female 315 344 8% (-7 to 21) SBP (mm Hg) < 140 309 341 10% (-5 to 23) ≥ 140 552 597 9% (-2 to 19) History of hypertension No 121 136 9% (-17 to 29) Yes 740 802 9% (0 to 18) HbA1c (%) ≤ 7.5 406 456 9% (-4 to 20) > 7.5 451 481 11% (-1 to 22) All participants 861 938 9% (0 to 17) ADVANCE Collaborative group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007. 2007;370:829-840

31. Effects are consistent whatever the ancillary treatment Combined primary end point 2.0 Number of events Preterax Placebo (n=5569) (n=5571) Relative risk reduction (95% CI) Favors Preterax Favors Placebo Hazard ratio 0.5 1.0 Treatment with any BP–lowering drug 177 183 6% (-15 to 24) 684 755 10% (0 to 19) Treatment with ACE inhibitor 417 455 10% (-3 to 21) 444 483 8% (-4 to 20) Treatment with statins 638 687 10% (0 to 19) 223 251 8% (-10 to 23) Treatment with antiplatelet drug 408 454 11% (-2 to 22) 453 484 7% (-5 to 18) All participants 861 938 9% (0 to 17) No Yes No Yes No Yes No Yes ADVANCE Collaborative group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007. 2007;370:829-840

32. Blood pressure reduction ADVANCE Collaborative group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007. 2007;370:829-840 140.3 mmHg 134.7 mmHg Average BP during follow-up 77.0 mmHg 74.8 mmHg

37. From UKPDS to ADVANCE: 30 years of progress in improving cardiovascular-renal outcome in diabetics Glycemic control BP control Macro- and microvascular protection 1977 2007 RAAS Antiplatelet agents Statins     ACE inhibitors ARBs  Preterax: YES 6

39. If the benefits observed in ADVANCE were applied to just half the world’s diabetic population, approximately 1.5 million deaths would be avoided Potential global benefits of treatment in diabetic hypertensives. “ There is now a case for considering such treatment routinely for patients with type 2 diabetes” ADVANCE Collaborative group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007. 2007;370:829-840 EASD-ESC Guidelines 2007

40. ESH-ESC Guidelines 2007 2007 Guidelines for the Management of Arterial Hypertension. ESH/ESC. Journal of hypertension 2007,25:1105-1187 benefits of treatment in diabetic hypertensives.

41. Only ACE inhibitors have been proven to reduce mortality in diabetics Events ACE inhibitors vs placebo 36 trials n = 4008 ARBs vs placebo 4 trials n = 3331 Creatinemia - 40 % - 21 % Strippoli GF et al. BMJ. 2004;329:828-838 P = 0.04 Renal impairment - 36 % - 22 % Microalbuminuria - 51 % - 55 % Mortality - 1 % - 21 %

42. Preterax improves myocardial perfusion Mourad JJ. JRAAS 2003;4:94-95.

43. Preterax: an additional efficacy on BP reduction UK Prospective Diabetes Study UKPDS ADV

44. Risk factor levels at the end of follow-up * Measurements taken at month 48 ADVANCE Collaborative group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007. 2007;370:829-840 Randomized treatment Preterax (n=5569) Control (n=5571) Systolic BP (mm Hg) 135.6 139.9 Diastolic BP (mm Hg) 73.6 75.1 Haemoglobin A1c (%) 6.9 6.9 Total cholesterol (mmol/L) * 4.7 4.6 HDL cholesterol (mmol/L) * 1.3 1.3 LDL cholesterol (mmol/L) * 2.7 2.6 Triglycerides (mmol/L) * 1.8 1.7

45. Ancillary drug therapy At the end of follow-up ADVANCE Collaborative group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007. 2007;370:829-840 Randomized treatment Preterax (n=5569) Control (n=5571) Any BP–lowering drug 74% 83% ACE inhibitor 50% 60% Oral hypoglycemic drugs 90% 91% Insulin 33% 30% Statin 44% 45% Other lipid-modifying drug 8% 7% Aspirin 56% 55% Other antiplatelet drugs 6% 6%

46. ADVANCE started where UKPDS and Micro-HOPE left off Comparative patient profiles UKPDS Micro-HOPE ADVANCE BP (mm Hg) Active treatment at end follow-up 145/82 139/77 136/73 Use background ACE inhibitors No No Yes Use statins No + ++ HbA1c end follow-up 8. 3% 9.5% 6.9% Event rate, Total and CV mortality Stroke +++ ++ +++ +++ + +

47. Implications

48. What should the guidelines say?