ADVANCE: a factorial randomised trial of blood pressure lowering and intensive glucose control in 11,140 patients with type

2 diabetes
Effects of a fixed combination of the ACE inhibitor, perindopril, and the diuretic, indapamide on major vascular events

Blood pressure and vascular risk in diabetes Best evidence: 2000

UK Prospective Diabetes Study

Blood pressure and vascular risk in diabetes Best evidence: 2000

UKPDS

SBP

UK Prospective Diabetes Study

Blood pressure lowering in diabetes: Unresolved issues 2000

Among patients with diabetes, does blood pressure lowering therapy:
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?

ADVANCE study hypotheses

Perindopril-indapamide arm
Among patients with diabetes, does blood pressure lowering therapy:
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?

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

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

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

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

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

ADVANCE
Trial profile
12877 with type 2 diabetes registered 1737 withdrew during run-in 11140 randomised

5569 assigned perindoprilindapamide combination

4 lost to follow-up

5571 assigned matching placebo

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

Baseline characteristics
Randomised treatment Active (n=5569) Age (years) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Haemoglobin A1c (%) History of macrovascular disease History of microvascular disease Microalbuminuria 66 145 81 7.5 32% 10% 26% Placebo (n=5571) 66 145 81 7.5 32% 10% 26%

Baseline characteristics
Cardiovascular and diabetes drugs
Randomised treatment Active (n=5569) Any blood pressure lowering drug ACE inhibitor* Oral hypoglycaemic drugs Statin Other lipid modifying drug Aspirin Other antiplatelet drugs 75% 43% 91% 28% 9% 44% 4% Placebo (n=5571) 75% 43% 91% 29% 8% 44% 5%

*By end of run-in period: 47% were receiving open label perindopril

Main results
Blood pressure

Blood pressure reduction

165 155 Mean Blood Pressure (mmHg) 145 135 125 115 105 95 85 75 65 R Placebo Perindopril-Indapamide

Average BP during follow-up

Systolic

140.3 mmHg 134.7 mmHg

5.6 mmHg (95% CI 5.2-6.0); p<0.001

Diastolic 2.2 mmHg (95% CI 2.0-2.4); p<0.001

6 12 18 24 30 36 42 48 54 60 Follow-up (Months)

77.0 mmHg 74.8 mmHg

ADVANCE BP reduction in context:

UK Prospective Diabetes Study

ADV

UKPDS

SBP

UK Prospective Diabetes Study

Main results
Mortality and morbidity

All-cause mortality
10

Placebo Perindopril-Indapamide

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)

Deaths
Cardiovascular
5%

Non-cardiovascular
5%

Cumulative incidence (%)

Placebo Perindopril-indapamide

Placebo Perindopril-indapamide

Relative risk reduction 18%; p=0.027

6 12 18 24 30 36 42 48 54 60 Follow-up (months) 6

Relative risk reduction 8%; p=0.41

12 18 24 30 36 42 48 54 60 Follow-up (months)

Combined primary outcomes

Major 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)

Primary outcomes
Major macro or microvascular event
Number of events Per-Ind Placebo (n=5,569) (n=5,571) Favours Favours Per-Ind Placebo Relative risk reduction (95% CI)

Combined macro+micro 861

Macrovascular Microvascular 480 439

938
520 477 0.5 1.0 Hazard ratio

9% (0 to 17)*
8% (-4 to 19) 9% (-4 to 20) 2.0

*2P=0.04

Effects by age, sex, BP and HbA1c

Combined primary endpoint
Number of events Per-Ind Placebo (n=5,569) (n=5,571) Favours Per-Ind Favours Placebo Relative risk reduction (95% CI)

Age (years)
< 65 >= 65 325 536 546 315 309 552 121 740 406 451 861 346 592 594 344 341 597 136 802 456 481 938 0.5 1.0 Hazard ratio 2.0 6% (-10 to 19) 11% (0 to 21) 10% (-1 to 20) 8% (-7 to 21) 10% (-5 to 23) 9% (-2 to 19) 9% (-17 to 29) 9% (0 to 18) 9% (-4 to 20) 11% (-1 to 22) 9% (0 to 17)

Sex
Male Female

SBP (mmHg)
< 140 140

History of hypertension
No Yes

HbA1c (%)
7.5 > 7.5

All participants

Phomogeneity all >0.1

Effects by ancillary treatment

Combined primary endpoint
Number of events Per-Ind Placebo (n=5,569) (n=5,571) Favours Favours Per-Ind Placebo Relative risk reduction (95% CI)

Treatment with any BP lowering drug

No Yes 177 684 417 444 638 223 408 453 861 183 755 455 483 687 251 454 484 938 0.5 1.0 Hazard ratio 2.0 6% (-15 to 24) 10% (0 to 19) 10% (-3 to 21) 8% (-4 to 20) 10% (0 to 19) 8% (-10 to 23) 11% (-2 to 22) 7% (-5 to 18) 9% (0 to 17)

Treatment with ACE inhibitor

No Yes

Treatment with statins

No Yes

Treatment with anti-platelet drug

No Yes

All participants

Phomogeneity all >0.1

Coronary events
Number of events Per-Ind Placebo (n=5,569) (n=5,571) Favours Favours Per-Ind Placebo Relative risk reduction (95% CI)

All coronary heart disease 468

Major coronary heart disease Other coronary heart disease 265 283

535
294 324 0.5 1.0 Hazard ratio

14% (2 to 24)*
11% (-6 to 24) 14% (-1 to 27) 2.0

Non-fatal Unstable

MI or death from coronary heart disease angina requiring hospitalisation, coronary revascularisation or silent MI

*2P=0.02

Cerebrovascular events
Number of events Per-Ind Placebo (n=5,569) (n=5,571) Favours Favours Per-Ind Placebo Relative risk reduction (95% CI)

All cerebrovascular disease 286

Major cerebrovascular disease Other cerebrovascular disease 215 79

303
218 99 0.5 1.0 Hazard ratio

6% (-10 to 20)*
2% (-18 to 19) 21% (-6 to 41) 2.0

Non-fatal Transient

stroke or death from cerebrovascular disease ischaemic attack or subarachnoid haemorrhage

*2P=0.40

Renal events
Number of events Per-Ind Placebo (n=5,569)(n=5,571) Favours Favours Per-Ind Placebo Relative risk reduction (95% CI)

Total renal events

1243

1500
216 1317 0.5 1.0 Hazard ratio

21% (15 to 27)*

18% (-1 to 32) 21% (14 to 27) 2.0

New or worsening nephropathy 181 New microalbuminuria 1094

*2P=<0.01

Eye events
Number of events Per-Ind Placebo (n=5,569) (n=5,571) Favours Favours Per-Ind Placebo Relative risk reduction (95% CI)

Total eye events

New or worsening eye disease Visual deterioration

2531
289 2446

2611
286 2514 0.5 1.0 Hazard ratio

5% (-1 to 10)*
-1% (-18 to 15) 5% (-1 to 10) 2.0

*2P=0.09

Absolute benefits of routine treatment with perindopril and indapamide

After 5 years, treatment would prevent: One major vascular event One death One coronary event One renal event*

Among every 66 patients 79 patients 75 patients 20 patients

*mostly new onset microalbuminuria

Risk factors levels

At end of follow-up
Parameter Randomised treatment Active (n=5569) Systolic BP (mmHg) Diastolic BP (mmHg) Haemoglobin A1c (%) Total cholesterol (mmol/L) * HDL cholesterol (mmol/L) * LDL cholesterol (mmol/L) * Triglycerides (mmol/L) * 135.6 73.6 6.9 4.7 1.3 2.7 1.8 Placebo (n=5571) 139.9 75.1 6.9 4.6 1.3 2.6 1.7

* Measurements taken at month 48

Ancillary drug therapy

At end of follow-up
Randomised treatment Active (n=5569) Any BP lowering drug ACE inhibitor Oral hypoglycaemic drugs Insulin Statin Other lipid modifying drug Aspirin Other antiplatelet drugs 74% 50% 90% 33% 44% 8% 56% 6% Placebo (n=5571) 83% 60% 91% 30% 45% 7% 55% 6%

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 Benefits appeared to be similar in all major subgroups. Treatment was very well tolerated, with few side effects and adherence similar to that with placebo.

Blood pressure lowering in diabetes: Unresolved issues 2000

Among patients with diabetes, does blood pressure lowering therapy:
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

Global projections for diabetes (millions)

2007-2025
28.3 40.5 +43% 53.2 64.1 +21% 24.5 44.5 +81% 16.2 32.7 +102% 10.4 18.7 +80%

46.5 80.3 +73%

67.0 99.4 +48%

World 2007 = 246 million 2025 = 380 million Increase +55%

Diabetes Atlas, 3rd edition, IDF 2006

Potential global benefits of treatment

2010-2015 If the benefits observed in ADVANCE were applied to just half the worlds diabetic population Approximately 1.5 million deaths could be avoided over this period

Diabetes Atlas, 3rd edition, IDF 2006