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Results

Results. 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 ?

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Results

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  1. Results

  2. 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 ?

  3. Follow-up and adherence

  4. ADVANCETrial profile 12877 with type 2 diabetes registered 1737 withdrew during run-in 11140 randomised 5569 assigned perindopril-indapamide combination 5571 assigned matching placebo 4 lost to follow-up 11 lost to follow-up Scheduled end of follow-up: 4.3 years 4908 (88%) assessed at final visit 4081 (73%) adherent to treatment Scheduled end of follow-up: 4.3 years 4863 (87%) assessed at final visit 4143 (74%) adherent to treatment

  5. Reasons for discontinuation

  6. Reasons for discontinuation

  7. Reasons for discontinuation

  8. Adherence to study treatments

  9. Mortality and morbidity

  10. Placebo Perindopril-Indapamide All-cause mortality 10 5 Cumulative incidence (%) Relative risk reduction 14%: 95% CI 2-25% p=0.025 0 0 6 12 18 24 30 36 42 48 54 60 Follow-up (months)

  11. Deaths Cardiovascular Non-cardiovascular 5% 5% Placebo Placebo Perindopril-indapamide Perindopril-indapamide Cumulative incidence (%) Relative risk reduction 18%; p=0.027 Relative risk reduction 8%; p=0.41 6 12 18 24 30 36 42 48 54 60 6 12 18 24 30 36 42 48 54 60 Follow-up (months) Follow-up (months)

  12. Combined primary outcomesMajor macro or microvascular event 20 Placebo Perindopril-Indapamide Cumulative incidence (%) 10 Relative risk reduction 9%: 95% CI: 0 to 17% p=0.041 0 0 6 12 18 24 30 36 42 48 54 60 Follow-up (months)

  13. Primary outcomesMajor macro or microvascular event Number of events Per-Ind Placebo Favours Relative risk Favours (n=5,569) (n=5,571) Per-Ind Placebo reduction (95% CI) * Combined macro+micro 861 938 9% (0 to 17) Macrovascular 480 520 8% (-4 to 19) Microvascular 439 477 9% (-4 to 20) 0.5 1.0 2.0 Hazard ratio *2P=0.04

  14. Coronary events Number of events Per-Ind Placebo Favours Favours Relative risk (n=5,569) (n=5,571) Per-Ind Placebo reduction (95% CI) * All coronary heart disease 468 535 14% (2 to 24) Major coronary heart disease† 265 294 11% (-6 to 24) Other coronary heart disease‡ 283 324 14% (-1 to 27) 0.5 1.0 2.0 Hazard ratio *2P=0.02 †Non-fatal MI or death from coronary heart disease ‡Unstable angina requiring hospitalisation, coronary revascularisation or silent MI

  15. Cerebrovascular events Number of events Per-Ind Placebo Favours Favours Relative risk (n=5,569) (n=5,571) Per-Ind Placebo reduction (95% CI) * All cerebrovascular disease 286 303 6% (-10 to 20) Major cerebrovascular disease† 215 218 2% (-18 to 19) Other cerebrovascular disease‡ 79 99 21% (-6 to 41) 2.0 0.5 1.0 Hazard ratio *2P=0.40 †Non-fatal stroke or death from cerebrovascular disease ‡Transient ischaemic attack or subarachnoid haemorrhage

  16. Renal events Number of events Per-Ind Placebo Favours Favours Relative risk (n=5,569) (n=5,571) Per-Ind Placebo reduction (95% CI) Total renal events 1243 1500 21% (15 to 27)* 18% (-1 to 32) New or worsening nephropathy 181 216 New microalbuminuria 1094 1317 21% (14 to 27) 2.0 0.5 1.0 Hazard ratio *2P=<0.01

  17. Eye events Number of events Per-Ind Placebo Favours Favours Relative risk (n=5,569) (n=5,571) Per-Ind Placebo reduction (95% CI) Total eye events 2531 2611 5% (-1 to 10)* 289 286 New or worsening eye disease -1% (-18 to 15) 2446 2514 5% (-1 to 10) Visual deterioration 2.0 0.5 1.0 Hazard ratio *2P=0.09

  18. Absolute benefits of routine treatment with perindopril and indapamide • *mostly new onset microalbuminuria

  19. Subgroups Combined primary outcome

  20. Effects by age, sex, BP and HbA1cCombined primary endpoint Number of events Per-Ind Placebo Favours Favours Relative risk (n=5,569) (n=5,571) Per-Ind Placebo reduction (95% CI) 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 (mmHg) < 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 9% (0 to 17) 861 938 2.0 0.5 1.0 Phomogeneity all >0.1 Hazard ratio

  21. Effects by ancillary treatmentCombined primary endpoint Number of events Per-Ind Placebo Favours Favours Relative risk (n=5,569) (n=5,571) Per-Ind Placebo reduction (95% CI) Treatment with any BP lowering drug 177 183 6% (-15 to 24) No 684 755 10% (0 to 19) Yes Treatment with ACE inhibitor No 417 455 10% (-3 to 21) 444 483 8% (-4 to 20) Yes Treatment with statins No 638 687 10% (0 to 19) 223 251 8% (-10 to 23) Yes Treatment with anti-platelet drug No 408 454 11% (-2 to 22) Yes 453 484 7% (-5 to 18) All participants 9% (0 to 17) 861 938 Phomogeneity all >0.1 2.0 0.5 1.0 Hazard ratio

  22. Subgroups New onset microalbuminuria

  23. Effects by age, sex, BP and HbA1cMicroalbuminuria Number of events Per-Ind Placebo Favours Favours Relative risk (n=5,569) (n=5,571) Per-Ind Placebo reduction (95% CI) Age (years) < 65 448 522 16% (5 to 26) ≥ 65 646 795 24% (15 to 31) Sex Male 601 724 21% (12 to 29) Female 493 593 20% (9 to 29) SBP (mmHg) < 140 465 535 16% (4 to 25) ≥ 140 629 782 24% (16 to 32) History of hypertension No 178 218 19% (1 to 34) Yes 916 1099 21% (14 to 28) HbA1c (%) ≤ 7.5 640 795 20% (11 to 28) > 7.5 444 517 22% (11 to 31) All participants 1094 1317 21% (14 to 27) Phomogeneity all >0.1 2.0 0.5 1.0 Hazard ratio

  24. Effects by ancillary treatmentMicroalbuminuria Number of events Per-Ind Placebo Favours Favours Relative risk (n=5,569) (n=5,571) Per-Ind Placebo reduction (95% CI) Treatment with any BP lowering drug No 264 312 21% (7 to 33) 830 1005 20% (13 to 27) Yes Treatment with open-label perindopril No 588 671 16% (6 to 25) 506 646 25% (16 to 33) Yes Treatment with statins No 816 987 23% (15 to 30) Yes 278 330 15% (1 to 28) Treatment with anti-platelet drug 568 697 22% (13 to 30) No Yes 526 620 19% (9 to 28) All participants 1094 1317 21% (14 to 27) 2.0 0.5 1.0 Phomogeneity all >0.1 Hazard ratio

  25. Summary • Routine treatment of type 2 diabetic patients with perindopril-indapamide resulted in: • 14% reduction in total mortality • 18% reduction in cardiovascular death • 9% reduction in major vascular events • 14% reduction in total coronary events • 21% reduction in total renal events Similar benefits in all major subgroups. Benefits additional to those produced by other treatments, including ACE inhibitor. Treatment very well tolerated.

  26. 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? YES • Produce similar benefits for hypertensive and non-hypertensive patients? YES • Add to the benefits produced by other cardiovascular preventive therapies including ACE inhibitors ? YES

  27. Need for type 2 DM patients Summary In ADVANCEFixed combination perindopril/indapamide • Reduction of CV events • on top of current preventive treatments • Simple, safe and well tolerated treatment • Reduces • Mortality • CV events • renal failure • on top of current preventive treatments • irrespective of usage of • BP lowering agents including ACEi • statines Simple, safe and well tolerated treatment

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

  29. Discussie Wat betekent ADVANCE voor de dagelijkse diabeteszorg?

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