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

Context

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%

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%

Complications People with type 2 diabetes die 5-10 years earlier than those without Vascular disease causes 50-80% of deaths Type 2 diabetes doubles the risk of stroke and heart attack Diabetes Atlas , 3rd edition, IDF 2006

People with type 2 diabetes die 5-10 years earlier than those without

Vascular disease causes 50-80% of deaths

Type 2 diabetes doubles the risk of stroke and heart attack

“ 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?

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”

Goals in Diabetes and Hypertension Need for effective/simple/safe treatment to achieve: Greater blood pressure reductions Long-term blood pressure control Prevention of nonfatal/fatal complications

Greater blood pressure reductions

Long-term blood pressure control

Prevention of nonfatal/fatal complications

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 ?

 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

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

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 

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

Hypothesis and design

ADVANCE blood pressure–lowering arm hypotheses: Among individuals with type 2 diabetes, will the routine addition of Preterax: Irrespective of initial blood pressure or the background use of other preventive therapies, including ACE inhibitors Reduce macro/microvascular disease and provide additional benefits when systolic pressure is lowered below 145 mm Hg? Provide similar benefits for hypertensive and nonhypertensive patients? Provide benefits on top of other treatments, including ACE inhibitors and other antihypertensive drugs? Reduce the risk of coronary disease? Reduce the risk of renal disease?

Reduce macro/microvascular disease and provide additional benefits when systolic pressure is lowered below 145 mm Hg?

Provide similar benefits for hypertensive and nonhypertensive patients?

Provide benefits on top of other treatments, including ACE inhibitors and other antihypertensive drugs?

Reduce the risk of coronary disease?

Reduce the risk of renal disease?

Inclusion criteria Type 2 diabetes mellitus ( HbA1c = 7.5 %) Age 55 years or older Additional risk of vascular events 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 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

Type 2 diabetes mellitus ( HbA1c = 7.5 %)

Age 55 years or older

Additional risk of vascular events

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

ADVANCE Design: BP – lowering arm >5000 Diabetics BP = 145/81 mm Hg Antihypertensives (75%) CCBs ARBs ACE inhibitors (43 %) Beta-blockers Statins ( 29%) Antiplatelet agents Blood glucose – lowering drugs >5000 Diabetics BP = 145/81 mm Hg Antihypertensives (75 %) CCBs ARBs ACE inhibitors (43%) Beta-blockers Statins ( 28%) Antiplatelet agents Blood glucose–lowering drugs + Preterax + Placebo 11 140 diabetics 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

>5000 Diabetics

BP = 145/81 mm Hg

Antihypertensives (75%)

CCBs

ARBs

ACE inhibitors (43 %)

Beta-blockers

Statins ( 29%)

Antiplatelet agents

Blood glucose – lowering drugs

>5000 Diabetics

BP = 145/81 mm Hg

Antihypertensives (75 %)

CCBs

ARBs

ACE inhibitors (43%)

Beta-blockers

Statins ( 28%)

Antiplatelet agents

Blood glucose–lowering drugs

Study treatments Randomized study treatment Double-blind Preterax 2.0 / 0.625 mg or placebo for first 3 months 4.0 / 1.25 mg or placebo thereafter Ancillary treatments At discretion of treating physician Only thiazide diuretic contraindicated If an ACE inhibitor is indicated, use perindopril 2-4 mg 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 study treatment

Double-blind Preterax

2.0 / 0.625 mg or placebo for first 3 months

4.0 / 1.25 mg or placebo thereafter

Ancillary treatments

At discretion of treating physician

Only thiazide diuretic contraindicated

If an ACE inhibitor is indicated, use perindopril 2-4 mg

Why Preterax ? Preterax was shown to be very effective in: Reducing blood pressure Reducing arterial stiffness in large arteries Enhancing the microcirculation and tissue perfusion in the heart and kidney Preterax is effective in preventing vascular complications in both diabetics and hypertensives : Large artery disease Microvascular disease Preterax was shown to be very well tolerated

Preterax was shown to be very effective in:

Reducing blood pressure

Reducing arterial stiffness in large arteries

Enhancing the microcirculation and tissue perfusion in the heart and kidney

Preterax is effective in preventing vascular complications in both diabetics and hypertensives :

Large artery disease

Microvascular disease

Preterax was shown to be very well tolerated

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

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.

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

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

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

Results

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

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

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

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

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

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

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

Absolute benefits of routine treatment with Preterax *mostly new-onset microalbuminuria 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 After 5 years, Preterax would prevent: Among every One major vascular event 66 patients One death 79 patients One coronary event 75 patients One renal event* 20 patients

*mostly new-onset microalbuminuria

Potential global impact of treatment Number of diabetics 246 000 000 Number treated 123 000 000 1.55 million deaths averted 311 000 deaths/year 79 is the number needed to treat to avert 1 death every 5 years 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

Number of diabetics 246 000 000

Number treated 123 000 000

1.55 million deaths averted

311 000 deaths/year

ADVANCE BP hypotheses: Among individuals with type 2 diabetes, the routine addition of Preterax will: Irrespective of initial blood pressure or the background use of other preventive therapies, including ACE inhibitors Reduce macro/microvascular disease and provide additional benefits when systolic pressure is lowered below 145 mm Hg? YES Provide similar benefits for hypertensive and nonhypertensive patients? YES Provide benefits on top of other treatments, including ACE inhibitors and other antihypertensive drugs? YES Reduce the risk of coronary disease? YES Reduce the risk of renal disease? 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

Reduce macro/microvascular disease and provide additional benefits when systolic pressure is lowered below 145 mm Hg? YES

Provide similar benefits for hypertensive and nonhypertensive patients? YES

Provide benefits on top of other treatments, including ACE inhibitors and other antihypertensive drugs? YES

Reduce the risk of coronary disease? YES

Reduce the risk of renal disease? YES

Summary Routine treatment of type 2 diabetic patients with Preterax resulted in: 14% reduction in total mortality 18% reduction in cardiovascular death 14% reduction in total coronary events 21% reduction in total renal events 9% reduction in the composite primary end point (major macrovascular or microvascular) 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

Routine treatment of type 2 diabetic patients with Preterax resulted in:

14% reduction in total mortality

18% reduction in cardiovascular death

14% reduction in total coronary events

21% reduction in total renal events

9% reduction in the composite primary end point (major macrovascular or microvascular)

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

THANK YOU!

THANK YOU!

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

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.

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 %

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

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

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

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%

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 +++ ++ +++ +++ + +

Implications

What should the guidelines say?