1. Rationale, Study Design & Study Population

2. Rationale

3. Global projections for diabetes (millions)
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%
16.2
32.7
+102%
10.4
18.7
+80%
World
2007 = 246 million
2025 = 380 million
Increase +55%
Diabetes Atlas, 3rd edition, IDF 2006

4. Blood pressure and vascular risk in diabetes Best evidence: 2000
UK Prospective Diabetes Study

5. Blood pressure and vascular risk in diabetes Best evidence: 2000
UKPDS
SBP
UK Prospective Diabetes Study

6. 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 ?

7. 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

8. Need for type 2 DM patients
What does ADVANCE add?
Need for type 2 DM patients
In ADVANCE Fixed combination perindopril/indapamide
Reduction of CV events
on top of current preventive treatments
Simple, safe and well tolerated treatment ?
Simple, ?

9. Study design

10. Main design features Factorial, randomised trial 11,140 participants
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
Both arms of the trial are fully randomised through a computerised assignment to active treatment or control. Whereas the blood pressure lowering arm is double blind and placebo controlled, the glucose control arm utilises the PROBE design (Prospective, Randomised, Open with Blinded End-points).
An independent End-Point Advisory Committee, blinded to all treatment assignments, adjudicates all primary end points and all deaths.

11. 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

12. 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)
Our original power calculations were based on a total of 10,000 participants with type 2 diabetes, with an annual event rate of 3%, requiring an average follow up of 4.5 years.
All participants entered a preliminary 6 week open run-in phase, during which they received one tablet daily of perindopril 2mg – indapamide mg (“Preterax”).

13. 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
glucose control
Placebo +
Intensive glucose control
Placebo +
Standard glucose control
End of follow-up (4-5 years)
Our original power calculations were based on a total of 10,000 participants with type 2 diabetes, with an annual event rate of 3%, requiring an average follow up of 4.5 years.
All participants entered a preliminary 6 week open run-in phase, during which they received one tablet daily of perindopril 2mg – indapamide mg (“Preterax”).

14. 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

15. 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

16. 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

17. 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)
This measure was considered necessary due to the large number of people with diabetes who would be receiving ACE Inhibitors and whose medical practitioners would be reluctant to allow to enter a clinical trial in which they might be randomized to a placebo arm.
In the event 47% of all participants received open-label perindopril at the time of randomization and this proportion has remained remarkably constant throughout follow-up.

18. Consistent risk reduction in pre defined subgroups
Strokes
Active* Placebo
Favors
active
Favors
placebo
Hazard ratio
(95%CI)
Hypertensive
Not hypertensive
Diabetes
No diabetes
Cerebral infarction
Cerebral hemorrhage
TIA/amaurosis
Total
0.67 ( )
0.73 ( )
0.67 ( )
0.72 ( )
0.76 ( )
0.52 ( )
0.66 ( )
0.72 ( )
This slide shows the breakdown of reduction in stroke in hypertensives and normotensives, diabetics, and nondiabetics or per subtype of stroke at the entry.
As can be clearly seen that in the PROGRESS study, benefit was seen regardless of the patient’s type.
All patients, whatever their blood pressure at entry, benefit from perindopril-based therapy treatment. This suggests the idea that when one is considering the target blood pressure in stroke patients, whatever the level, its too high! (since even normotensive patients who had their BP reduced with perindopril-based therapy were shown to experience clear benefits).
* Active treatment: perindopril 4 mg +/- indapamide 2.5 mg (or 2 mg in Japan)
0.5
2.0
Hazard ratio
1.0
Reference: Lancet. 2001;358:

19. 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
Except glucose control for those assigned intensive therapy

20. What is a more effective preventive strategy in daily practice?
What does ADVANCE add?
What is a more effective preventive strategy in daily practice?
Aim for guideline based BP goal OR
Aim for guideline based BP goal +
standard additition of fixed per/ind combination (like statines post MI)

21. 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

22. Study population

23. Cumulative randomisation
ADVANCE recruitment
Cumulative randomisation
Regional recruitment
2000
4000
6000
8000
10000
12000
Jul-01
Aug-01
Sep-01
Oct-01
Nov-01
Dec-01
Jan-02
Feb-02
Mar-02
Apr-02
May-02
Jun-02
Jul-02
Aug-02
Sep-02
Oct-02
Nov-02
Dec-02
Jan-03
Feb-03
Mar-03
Apr-03
Number of patients randomised
Region Number
ANZ / Asia 2,328
Canada
China 3,293
Continental Europe 2,879
Northern Europe 2,204
TOTAL ,140
Registered 12,877
Randomised 11,140
The first study participant was randomised in July 2001 and recruitment of 11,140 randomised participants was completed in March At the outset 4 regions of approximately 2500 participants were planned, but subsequently Canada joined the study as a smaller region that was managed separately though a Regional Coordinating Centre in Montreal.

24. Withdrawals during run-in
Reason for withdrawal N
% of registered patients (N=12877)
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%

25. Blood pressure,
other risk factors,
ancillary treatment

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

27. Blood pressure reduction
165
Placebo
140.3 mmHg
134.7 mmHg
Average BP during follow-up
77.0 mmHg
74.8 mmHg
Perindopril-Indapamide
155
145
137 81 78
145
Systolic
135
Δ 5.6 mmHg (95% CI ); p<0.001
125
Mean Blood Pressure (mmHg)
115
105 95 85
Diastolic 75
Δ 2.2 mmHg (95% CI ); p<0.001 65 R 6 12 18 24 30 36 42 48 54 60
Follow-up (Months)

28. 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

29. ADVANCE BP reduction in context: UK Prospective Diabetes Study
UKPDS
SBP
UK Prospective Diabetes Study

30. Risk factors levels At end of follow-up
Parameter
Randomised treatment
Active (n=5569)
Placebo (n=5571)
Systolic BP (mmHg)
135.6
139.9
Diastolic BP (mmHg)
73.6
75.1
Haemoglobin A1c (%)
6.9
Total cholesterol (mmol/L) *
4.7
4.6
HDL cholesterol (mmol/L) *
1.3
LDL cholesterol (mmol/L) *
2.7
2.6
Triglycerides (mmol/L) *
1.8
1.7
* Measurements taken at month 48

31. Baseline characteristics Cardiovascular and diabetes drugs
Randomised treatment
Active (n=5569)
Placebo (n=5571)
Any blood pressure lowering drug
75%
ACE inhibitor*
ARB
43% 5% 6%
Oral hypoglycaemic drugs
91%
Statin
28%
29%
Other lipid modifying drug 9% 8%
Aspirin
44%
Other antiplatelet drugs 4%
*By end of run-in period: 47% were receiving open label perindopril

32. Ancillary drug therapy
Ancillary drug therapy At end of follow-up ADVANCE results will be underestimation of real effect fixed per/ind combination
Randomised treatment
Active (n=5569)
Placebo (n=5571)
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%

33. 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

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