ADVANCE: a factorial randomised trial of blood pressure lowering and intensive glucose control in 11,140 patients with type 2 diabetes

(1)

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

(2)

Blood pressure and vascular risk in diabetes Best evidence: 2000

UK Prospective Diabetes Study

(3)

SBP

UKPDS

Blood pressure and vascular risk in diabetes

Best evidence: 2000

(4)

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?

Blood pressure lowering in diabetes:

Unresolved issues 2000

(5)

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

(6)

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

(7)

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

(8)

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

(9)

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

(10)

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

(11)

ADVANCE

Trial profile

12877 with type 2 diabetes registered

11140 randomised

5569 assigned perindopril- indapamide combination

1737 withdrew during run-in

Scheduled end of follow-up: 4.3 years 4908 (88%) assessed at final visit 4081 (73%) adherent to treatment

4 lost to follow-up

11 lost to follow-up

Scheduled end of follow-up: 4.3 years 4863 (87%) assessed at final visit 4143 (74%) adherent to treatment

5571 assigned matching placebo

(12)

10%

History of microvascular disease

7.5 7.5

Haemoglobin A1c (%)

32%

History of macrovascular disease

26%

Microalbuminuria

Placebo (n=5571) Active

(n=5569)

145 145

Systolic blood pressure (mmHg)

81 81

Diastolic blood pressure (mmHg)

66 66

Age (years)

Randomised treatment

Baseline characteristics

(13)

Baseline characteristics

Cardiovascular and diabetes drugs

75%

Any blood pressure lowering drug

43%

ACE inhibitor*

91%

Oral hypoglycaemic drugs

5%

4%

Other antiplatelet drugs

(n=5569)

29%

28%

Statin

44%

Aspirin

8%

9%

Other lipid modifying drug

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

(14)

Blood pressure

Main results

(15)

Blood pressure reduction

Δ 2.2 mmHg (95% CI 2.0-2.4); p<0.001 Δ 5.6 mmHg (95% CI 5.2-6.0); p<0.001

Diastolic Systolic Placebo

Perindopril-Indapamide

Mean Blood Pressure (mmHg)

65 75 85 95 105 115 125 135 145 155 165

Follow-up (Months)

R 6 12 18 24 30 36 42 48 54 60

140.3 mmHg 134.7 mmHg Average BP during follow-up

77.0 mmHg 74.8 mmHg

(16)

SBP

ADVANCE BP reduction in context:

UK Prospective Diabetes Study

UKPDS ADV

(17)

Mortality and morbidity

Main results

(18)

All-cause mortality

Follow-up (months) 0

10

0 6 12 18 24 30 36 42 48 54 60

Placebo

Cumulative incidence (%)

Relative risk reduction 14%: 95% CI 2-25%

p=0.025

5

(19)

Deaths

Cardiovascular

Follow-up (months)

6 12 18 24 30 36 42 48 54 60 Placebo

Perindopril-indapamide

Non-cardiovascular

6 12 18 24 30 36 42 48 54 60

Placebo

Perindopril-indapamide

Relative risk reduction 18%; p=0.027

Relative risk reduction 8%; p=0.41

5% 5%

(20)

Combined primary outcomes

Major macro or microvascular event

0 10 20

0 6 12 18 24 30 36 42 48 54 60

Placebo

Relative risk reduction 9%: 95% CI: 0 to 17%

p=0.041

(21)

Macrovascular 480 520 8% (-4 to 19)

Microvascular 439 477 9% (-4 to 20)

Combined macro+micro 861 938 9% (0 to 17)

Number of events Per-Ind Placebo (n=5,569) (n=5,571)

Relative risk reduction (95% CI) Favours

Per-Ind

Favours Placebo

Hazard ratio

0.5 1.0 2.0

*

*2P=0.04

Primary outcomes

Major macro or microvascular event

(22)

Effects by age, sex, BP and HbA1c

Combined primary endpoint

Phomogeneity all >0.1

2.0 Number of events

Per-Ind Placebo (n=5,569) (n=5,571)

Relative risk reduction (95% CI) Favours

Per-Ind

Favours 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 (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 861 938 9% (0 to 17)

(23)

Effects by ancillary treatment

Combined primary endpoint

2.0 Number of events

Per-Ind Placebo (n=5,569) (n=5,571)

Relative risk reduction (95% CI) Favours

Per-Ind

Favours 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 anti-platelet drug

408 454 11% (-2 to 22)

453 484 7% (-5 to 18)

All participants ₈₆₁ ₉₃₈ 9% (0 to 17)

No Yes

Phomogeneity all >0.1

(24)

Coronary events

*2P=0.02

†Non-fatal MI or death from coronary heart disease

‡Unstable angina requiring hospitalisation, coronary revascularisation or silent MI

Major coronary heart disease^† 265 294 11% (-6 to 24)

All coronary heart disease 468 535 14% (2 to 24)

Other coronary heart disease^‡ 283 324 14% (-1 to 27)

* Number of events

Per-Ind Placebo

(n=5,569) (n=5,571) Relative risk

reduction (95% CI) Favours

Per-Ind

Favours Placebo

Hazard ratio

0.5 1.0 2.0

(25)

Cerebrovascular events

Major cerebrovascular disease^† 215 218 2% (-18 to 19)

All cerebrovascular disease 286 303 6% (-10 to 20)

Other cerebrovascular disease^‡ 79 99 21% (-6 to 41)

2.0

*

*2P=0.40

†Non-fatal stroke or death from cerebrovascular disease

‡Transient ischaemic attack or subarachnoid haemorrhage Number of events

Per-Ind Placebo

(n=5,569) (n=5,571) Relative risk

reduction (95% CI) Favours

Per-Ind

Favours Placebo

Hazard ratio

0.5 1.0

(26)

Renal events

2.0 Hazard ratio

0.5 1.0

New or worsening nephropathy 181 216 18% (-1 to 32)

New microalbuminuria 1094 1317 21% (14 to 27)

Total renal events 1243 1500 21% (15 to 27)*

*2P=<0.01

Number of events Per-Ind Placebo (n=5,569)(n=5,571)

Per-Ind

Favours Placebo

(27)

Eye events

2.0 Hazard ratio

0.5 1.0

*2P=0.09

New or worsening eye disease 289 286 -1% (-18 to 15)

Visual deterioration 2446 2514 5% (-1 to 10)

Total eye events 2531 2611 5% (-1 to 10)*

Number of events Per-Ind Placebo (n=5,569) (n=5,571)

Per-Ind

Favours Placebo

(28)

66 patients One major vascular event

79 patients One death

75 patients One coronary event

20 patients One renal event*

Among every After 5 years, treatment

would prevent:

*mostly new onset microalbuminuria

Absolute benefits of routine treatment

with perindopril and indapamide

(29)

Risk factors levels

At end of follow-up

139.9 135.6

Systolic BP (mmHg)

75.1 73.6

Diastolic BP (mmHg)

2.6 2.7

LDL cholesterol (mmol/L) *

1.3 1.3

HDL cholesterol (mmol/L) *

4.6 4.7

Total cholesterol (mmol/L) *

(n=5569)

1.7 1.8

Triglycerides (mmol/L) *

6.9 6.9

Haemoglobin A1c (%)

Randomised treatment Parameter

* Measurements taken at month 48

(30)

83%

74%

Any BP lowering drug

60%

50%

ACE inhibitor

91%

90%

Oral hypoglycaemic drugs

30%

33%

Insulin

6%

Other antiplatelet drugs

(n=5569)

45%

44%

Statin

55%

56%

Aspirin

7%

8%

Other lipid modifying drug

Ancillary drug therapy

At end of follow-up

(31)

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.

(32)

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?

Blood pressure lowering in diabetes:

Unresolved issues 2000

YES YES

YES

(33)

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 46.5 +48%

80.3 +73%

(34)

Diabetes Atlas, 3rd edition, IDF 2006

If the benefits observed in

ADVANCE were applied to just half the world’s diabetic population

Approximately 1.5 million deaths could be avoided over this period

Potential global benefits of treatment

2010-2015

(35)

ADVANCE: a factorial randomised trial of blood pressure lowering and intensive glucose control in 11,140 patients with type 2 diabetes