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Rationale, Study Design Study Population
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Rationale
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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
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Blood pressure and vascular risk in diabetes Best
evidence 2000
UK Prospective Diabetes Study
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Blood pressure and vascular risk in diabetes Best
evidence 2000
SBP
UK Prospective Diabetes Study
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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 ?

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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
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Need for type 2 DM patients
What does ADVANCE add?
In ADVANCEFixed combination perindopril/indapamid
e

• Reduction of CV events
• on top of current preventive treatments
• Simple, safe and well tolerated treatment

• ?
• ?
• Simple, ?

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Study design
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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

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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
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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)
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Study design Blood 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 gluc
ose control
Placebo Intensive glucose control
Placebo Standard glucose control
End of follow-up (4-5 years)
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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 gt10 years prior to
  entry
• Other major risk factor
• Hypertensive or normotensive

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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

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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

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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)

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Consistent risk reduction in pre defined subgroups
Favors placebo
Strokes Active Placebo
Favors active
Hazard ratio (95CI)
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. 20013581033-1041.
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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

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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)
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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

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Study population
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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
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Withdrawals during run-in
Reason for withdrawal N of registered patients (N12877)
Patient ineligible 394 3.1
Patient wishes 391 3.0
Poor compliance with study drug 269 2.1
Cough 238 1.8
Hypotension 99 0.8
Other suspected intolerance to study drug 133 1.0
Other reasons 213 1.7
TOTAL 1737 13.5
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Blood pressure, other risk factors, ancillary
treatment
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Baseline characteristics
Randomised treatment Randomised treatment
Active (n5569) Placebo (n5571)
Age (years) 66 66
Systolic blood pressure (mmHg) 145 145
Diastolic blood pressure (mmHg) 81 81
Haemoglobin A1c () 7.5 7.5
History of macrovascular disease 32 32
History of microvascular disease 10 10
Microalbuminuria 26 26
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Blood pressure reduction
165
Placebo
Perindopril-Indapamide
155
Systolic
145
135
? 5.6 mmHg (95 CI 5.2-6.0) plt0.001
125
Mean Blood Pressure (mmHg)
115
105
95
85
Diastolic
75
? 2.2 mmHg (95 CI 2.0-2.4) plt0.001
65
R
6
12
18
24
30
36
42
48
54
60
Follow-up (Months)
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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
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ADVANCE BP reduction in contextUK Prospective
Diabetes Study
SBP
UK Prospective Diabetes Study
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Risk factors levelsAt end of follow-up
Parameter Randomised treatment Randomised treatment
Active (n5569) Placebo (n5571)
Systolic BP (mmHg) 135.6 139.9
Diastolic BP (mmHg) 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
Measurements taken at month 48
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Baseline characteristicsCardiovascular and
diabetes drugs
Randomised treatment Randomised treatment
Active (n5569) Placebo (n5571)
Any blood pressure lowering drug 75 75
ACE inhibitor ARB 43 5 43 6
Oral hypoglycaemic drugs 91 91
Statin 28 29
Other lipid modifying drug 9 8
Aspirin 44 44
Other antiplatelet drugs 4 5
By end of run-in period 47 were receiving open
label perindopril
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Ancillary drug therapy At end of follow-up
ADVANCE results will be underestimation of real
effect fixed per/ind combination
Randomised treatment Randomised treatment
Active (n5569) Placebo (n5571)
Any BP lowering drug 74 83
ACE inhibitor ARB 50 10 60 13
Oral hypoglycaemic drugs 90 91
Insulin 33 30
Statin 44 45
Other lipid modifying drug 8 7
Aspirin 56 55
Other antiplatelet drugs 6 6
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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

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ADVANCE substudies

• ADVANCE echocardiography substudy
• ADVANCE retinopathy measurements substudy (AdRem)
• ADVANCE cost effective and quality of life
  substudy (CEQol)
• ADVANCE genetics substudy (Prognomix)