Rationale, Study Design & Study Population

1. Rationale, Study Design & Study Population

2. Rationale

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

4. Blood pressure and vascular risk in diabetes Bestevidence: 2000 UK Prospective Diabetes Study

5. UKPDS Blood pressure and vascular risk in diabetes Bestevidence: 2000 SBP UK Prospective Diabetes Study

6. Preventive therapy in type 2 diabetes: Unresolved issues in 2000 • Does standard treatment with fixed combination perindopril/indapamide on top of regular BP control: • Produce additional benefits when systolic pressure is lowered below 145 mmHg? • Produce similar benefits for hypertensive and non-hypertensive patients? • Add to the benefits produced by other cardiovascular preventive therapies including ACE inhibitors ?

7. ADVANCE: a factorial randomised trial of blood pressure lowering andintensive glucose control in11,140 patients with type 2 diabetes Effects of a fixed combination of the ACE inhibitor, perindopril, and the diuretic, indapamide, on major vascular events

8. Need for type 2 DM patients What does ADVANCE add? In ADVANCEFixed combination perindopril/indapamide • Reduction of CV events • on top of current preventive treatments • Simple, safe and well tolerated treatment • ? ? Simple, ?

9. Study design

10. Main design features • Factorial, randomised trial • double-blind, placebo-controlled comparison of blood pressure lowering with a fixed combination of perindopril and indapamide • open comparison (PROBE design) of a gliclazide MR-based regimen for intensive glucose control • 11,140 participants • Wide range of geographic regions • 4-5 years follow-up

11. ADVANCE BP hypotheses: Among individuals with type 2 diabetes, the systematic addition of a fixed combination of perindopril and indapamide will reduce the risks of: • Major macrovascular disease including coronary disease, cerebrovascular disease or death from cardiovascular disease, and • Major microvascular disease including new or worsening nephropathy or diabetic eye disease Irrespective of initial blood pressure or the background use of other preventive therapies, including ACE inhibitors

12. Study design Blood pressure lowering intervention Registration 6-week run-in phase on active perindopril and indapamide Randomisation Perindopril-indapamide combination + Intensive glucose control Perindopril-indapamide combination + Standard glucose control Placebo + Intensive glucose control Placebo + Standard glucose control End of follow-up (4-5 years)

13. Study designBlood glucose lowering intervention Registration 6-week run-in phase on active perindopril and indapamide Randomisation Perindopril-indapamide combination + Intensive glucose control Perindopril-indapamide combination + Standard glucose control Placebo + Intensive glucose control Placebo + Standard glucose control End of follow-up (4-5 years)

14. Inclusion criteria • Type 2 diabetes mellitus • Age 55 years or older • Additional risk of vascular event • Age  65 years • History of major macrovascular disease • History of major microvascular disease • First diagnosis of diabetes >10 years prior to entry • Other major risk factor • Hypertensive or normotensive

15. Randomised study treatments • Blood pressure lowering • Double-blind perindopril-indapamide versus matching placebo • 2.0 / 0.625mg or placebo for first 3 months • 4.0 / 1.25mg or placebo thereafter • Blood glucose lowering (ongoing) • Open-label gliclazide MR-based intensive therapy targeting an HbA1c of 6.5% versus usual guideline-based care

16. Randomised study treatments • Blood pressure lowering • Double-blind perindopril-indapamide versus matching placebo • 2.0 / 0.625mg or placebo for first 3 months • 4.0 / 1.25mg or placebo thereafter • Blood glucose lowering (ongoing) • Open-label gliclazide MR-based intensive therapy targeting an HbA1c of 6.5% versus usual guideline-based care

17. Why fixed combination of perindopril and indapamide ? • Fixed combination of perindopril and indapamide shown to be very effective in: • Reducing blood pressure • Reducing arterial stiffness in large arteries • Enhancing micro-circulation and tissue perfusion in the heart and the kidney • Proven CV protection in stroke/TIA patients including in diabetes subgroup (PROGRESS) • very well tolerated (PROGRESS)

18. 2.0 1.0 0.5 Hazard ratio Consistent risk reduction in pre defined subgroups Favors placebo Favors active Strokes Active* Placebo Hazard ratio (95%CI) Hypertensive 163 235 Not hypertensive 144 185 Diabetes 48 65 No diabetes 259 355 Cerebral infarction 236 307 Cerebral hemorrhage 28 49 TIA/amaurosis 33 49 Total 307 420 0.67 (0.55-0.81) 0.73 (0.58-0.92) 0.67 (0.46-0.98) 0.72 (0.62-0.85) 0.76 (0.64-0.90) 0.52 (0.33-0.83) 0.66 (0.42-1.02) 0.72 (0.62-0.83) * Active treatment: perindopril 4 mg +/- indapamide 2.5 mg (or 2 mg in Japan) Reference: Lancet. 2001;358:1033-1041.

19. Ancillary drug treatment • Blood pressure lowering therapy • At discretion of treating physician • Only thiazide diuretic contraindicated • ACE inhibitor • Open-label perindopril (up to 4 mg daily), if indicated • All other treatment • At discretion of treating physician • Except glucose control for those assigned intensive therapy

20. What is a more effective preventive strategy in daily practice? What does ADVANCE add? Aim for guideline based BP goal OR • Aim for guideline based BP goal • + • standard additition of fixed per/ind combination (like statines post MI)

21. Primary study outcomes • Macrovascular • Non-fatal stroke, non-fatal myocardial infarction or death from any cardiovascular cause (including sudden death) • Microvascular • New of worsening nephropathy or diabetic eye disease • Prespecified analyses: • Macrovascular and microvascular jointly • Macrovascular and microvascular separately

22. Study population

23. 12000 10000 8000 Number of patients randomised 6000 4000 2000 0 Jul-01 Nov-02 Jan-02 Aug-01 Jul-02 Apr-03 Oct-01 Jan-03 Apr-02 Oct-02 Jun-02 Feb-03 Dec-01 Aug-02 Dec-02 Nov-01 Mar-03 Mar-02 Sep-01 May-02 Feb-02 Sep-02 ADVANCE recruitment Regional recruitment Cumulative randomisation Region Number ANZ / Asia 2,328 Canada 436 China 3,293 Continental Europe 2,879 Northern Europe 2,204 TOTAL 11,140 Registered 12,877 Randomised 11,140

24. Withdrawals during run-in

25. Blood pressure, other risk factors, ancillary treatment

26. Baseline characteristics

27. Average BP during follow-up 145 81 140.3 mmHg 137 78 134.7 mmHg 77.0 mmHg 74.8 mmHg Blood pressure reduction 165 Placebo Perindopril-Indapamide 155 Systolic 145 135 Δ5.6 mmHg (95% CI 5.2-6.0); p<0.001 125 Mean Blood Pressure (mmHg) 115 105 95 85 Diastolic 75 Δ 2.2 mmHg (95% CI 2.0-2.4); p<0.001 65 R 6 12 18 24 30 36 42 48 54 60 Follow-up (Months)

28. Conclusion • Aim for guideline based BP goal • + • standard additition of fixed per/ind combination (like statines post MI) Is a more effective BP lowering strategy than Aim for guideline based BP goal

29. UKPDS ADV ADVANCE BP reduction in context:UK Prospective Diabetes Study SBP UK Prospective Diabetes Study

30. Risk factors levelsAt end of follow-up * Measurements taken at month 48

31. Baseline characteristicsCardiovascular and diabetes drugs *By end of run-in period: 47% were receiving open label perindopril

32. Ancillary drug therapyAt end of follow-upADVANCE results will be underestimation of real effect fixed per/ind combination

33. Study population • Broad cross-section of diabetic patients: • Europe, North America, Asia-Pacific • With and without • history of vascular disease • hypertension • Other risk factors • Wide range of background treatments including ACE inhibitor/other BP lowering drugs for many • Breadth should ensure results are relevant to clinical practice worldwide