“Hot Topics in Diabetes”

50th EASD, Vienna 2014

Glucose arm results

Sophia Zoungas
The George Institute
The University of Sydney
 Glucose control during ADVANCE

9.0 Standard Mean HbA1c at

8.5
Intensive the final visit

8.0
Mean HbA1c (%)

7.5
7.3%
7.0 Δ 0.67% (95% CI 0.64 - 0.70); p<0.001

6.5 6.5%

6.0

0 6 12 18 24 30 36 42 48 54 60 66

Follow-up (Months)

Patel, MacMahon, Chalmers et al. NEJM 2008;358:2560-2572

ADVANCE: Combined primary outcome
Major macrovascular or microvascular events

25 Standard
Intensive
20

15

10

5 Relative risk reduction 10%

95% CI: 2 to 18%
p=0.01
0
0 6 12 18 24 30 36 42 48 54 60 66
Follow-up (months)

NEJM 2008;358:2560-2572
 ADVANCE : primary outcomes
Major microvascular events Major macrovascular events
(kidney or eye complications) (MI, stroke or CV death)
25 25
Standard Standard
Intensive Intensive
20 20

15 15

10 10

5 5

0 0
0 6 12 18 24 30 36 42 48 54 60 66 0 6 12 18 24 30 36 42 48 54 60 66
Follow-up (months) Follow-up (months)

Relative risk reduction 14% Relative risk reduction 6%

95% CI: 3 to 23% 95% CI: -6 to 16%
p=0.01 p=0.32

NEJM 2008;358:2560-2572
 ADVANCE : Renal events

% of patients with event

Intensive Standard Favours Favours Relative risk
(n=5,571) (n=5,569) Intensive Standard reduction (95% CI)

Total renal events 26.9% 30.0% 11% (5 to 17) †

New microalbuminuria 23.7% 25.7% 9% (2 to 15)‡
New macroalbuminuria 2.9% 4.1% 30% (15 to 43) †
New or worsening nephropathy 4.1% 5.2% 21% (7 to 34) **
*
0.5 1.0 2.0
Hazard ratio
† P=<0.001
‡ P=0.02
*** P=0.006

NEJM 2008;358:2560-2572
 Key findings
ADVANCE Glucose control arm

Intensive glucose lowering (to a mean HbA1c of 6.5%) in

patients with type 2 DM resulted in:

 10% reduction in the combined primary macrovascular or

microvascular outcome (p=0.01)
 14% reduction in microvascular events (p=0.01)
 21% reduction in new or worsening nephropathy (p<0.01)
 65% reduction in end stage kidney disease (p=0.02)
 No reduction (or excess) mortality

Benefits appeared to be independent of initial HbA1c and

similar in all major subgroups
Glucose arm
 Flow-chart for glucose control arm
11,140 underwent randomisation
into the glucose control arm
ADVANCE trial

5571 assigned to intensive 5569 assigned to standard N=11,140

glucose control glucose control (100%)

411 patients died 547 patients died

N=10,082
5060 eligible for ADVANCE-ON 5022 eligible for ADVANCE-ON (91%)

883 non-participating 884 non-participating

Post-trial Follow-Up

patients and sites patients and sites

ADVANCE-ON

N=8494
4283 participated in 4211 participated in (84% of
ADVANCE-ON ADVANCE-ON patients
still alive)
631 died 584 died
1014 lost to follow-up 1134 lost to follow-up
N=5131
(70% of
2638 at final visit in 2013 2493 at final visit in 2013 patients
still alive)
 Baseline characteristics
(prior to randomisation in ADVANCE trial)
Glucose arm ADVANCE ADVANCE-ON
Standard Intensive Standard Intensive
n=5569 n=5571 n=4211 n=4283
Age (yr), mean (sd) 66 (6) 66 (6) 66 (6) 65 (6)
Age diabetes diagnosed (yr), mean (sd) 58 ± 9 58 ± 9 58 ± 9 58 ± 9
HbA1c (%), mean (sd) 7.5 (1.5) 7.5 (1.6) 7.5 (1.5) 7.5 (1.5)
FBG (mmol/L), mean (sd) 8.5 (2.8) 8.5 (2.8) 8.5 (2.7) 8.4 (2.7)
SBP (mmHg), mean (sd) 145 (21) 145 (22) 144 (21) 144 (21)
DBP (mmHg), mean (sd) 81 (11) 81 (11) 80 (11) 80 (11)
Macrovascular disease, n (%) 1796 (32) 1794 (32) 1301 (31) 1274 (30)
Microvascular disease, n (%) 584 (11) 571 (10) 415 (10) 385 (9)
Serum Cr (umol/L), mean (sd) 87 (27) 86 (24) 85 (22) 84 (22)
 HbA1c levels
Glucose arm HbA1c level (%)
Mean±SD

Standard Intensive

Pre-randomisation 7.5±1.5 7.5±1.6

Last randomised visit 7.2±1.1 6.5±0.8

 HbA1c levels
Glucose arm HbA1c level (%)
Mean±SD

Standard Intensive

Pre-randomisation 7.5±1.5 7.5±1.6

Last randomised visit 7.2±1.1 6.5±0.8

First ADVANCE-ON visit 7.3±1.3 7.3±1.4

Final ADVANCE-ON visit 7.4±1.3 7.2±1.2

Any effect observed during ADVANCE-ON is attributable

to the glycaemic difference achieved during ADVANCE
 Medication Use
Post-trial Follow-up
 Concomitant use of medications

First visit post-trial Final visit post-trial

Standard Intensive Standard Intensive
Glucose lowering medication
Any glucose lowering drug 71.9 74.2 91.1 91.6
1 glucose lowering drug 25.1 22.2 30.7 27.4
2 glucose lowering drugs 34.9 35.7 41.7 44.4
3 or more glucose lowering drugs 12.0 16.3 18.7 19.8

Sulphonylurea or Gliclazide MR 35.2 42.0 38.5 42.8

Metformin 44.5 45.7 54.8 54.2
Other oral agents 17.5 16.4 11.0 10.5
Insulin 27.3 33.3 43.8 47.1
 Concomitant use of medications

First visit post-trial Final visit post-trial

Standard Intensive Standard Intensive
Blood pressure lowering medication
Any blood pressure lowering drug 59.8 61.5 79.1 77.8
Perindopril-Indapamide (Preterax) 7.8 9.5 9.4 10.2
Other ACE Inhibitors 24.1 23.1 29.4 27.8
Other Diuretic 16.1 15.7 20.8 20.5
Angiotensin-Receptor Blocker 14.1 14.6 20.8 21.5
Calcium-channel blocker 30.2 30.9 40.7 39.6
Beta-blocker 20.7 21.5 28.5 29.3

Other medication
Statin 32.8 34.9 49.1 49.8
Aspirin 37.2 39.5 49.4 50.0
 Key clinical characteristics

 ADVANCE-ON cohort is representative of the

original ADVANCE population
 HbA1c levels converged during the post-trial
period
 Main results: Glucose arm

Outcomes
Cumulative Incidence
Overall Follow-up
(ADVANCE and ADVANCE-ON)
median 9.9 yrs
 Mortality
(overall in-trial and post-trial follow-up)
Death from any cause Cardiovascular death
HR 1.00 (0.92, 1.08) HR 0.97 (0.86, 1.10)
Cumulative incidence (%)

Standard
Intensive

Follow-up (years)
 Major Vascular events
(overall in-trial and post-trial follow-up)
Major clinical microvascular
Major macrovascular events
events
HR 1.00 (0.92, 1.08) HR 0.92 (0.80, 1.05)
Cumulative incidence (%)

Standard
Intensive

Follow-up (years)
 Microvascular events
(overall in-trial and post-trial follow-up)
Retinal photocoagulation or End-stage kidney disease
Diabetes-related blindness
25 25
HR
HR:0.97 (0.83,
0.97 (0.83, 1.13)
1.13) HRHR:0.54
0.54 (0.34, 0.85)
(0.34, 0.85)
20 P=0.69 20
P<0.01
2
Cumulative incidence (%)

Standard
15 Intensive 15
1

10 10

0
5 5 5 10

0 0
0 2 4 6 8 10 0 2 4 6 8 10
ll ( ) F ll ( )
Follow-up (years)
 End-stage kidney disease
(overall in-trial and post-trial follow-up)

In-trial Post-trial Overall

Cumulative incidence (%)

Standard (5.0 yrs) (5.4 yrs) (9.9 years)

Intensive
Standard
Intensive End-stage kidney disease

HR (95%CI) 0.35 (0.15- 0.65 (0.38- 0.54 (0.34-

0.83) 1.11) 0.85)
Event no.
(intensive vs (7 vs 20) (22 vs 33) (29 vs 53)
standard) -13 -11 -24
Follow-up (years)

Relative risk reduction 46%

95% CI: 15 to 66%
p<0.01
Main results: Glucose arm

Outcomes
By Calendar Year
 Effects on Mortality by calendar year

Death from any cause Cardiovascular death

2.0 2.0

1.5 T2 1.5
T2
Hazard ratio

P=0.28 P=0.91 P=0.12 P=0.63

1.0 1.0

0.5 0.5

T2 = last visit ADVANCE glucose arm

0.0 0.0
2008 2009 2010 2011 2012 2013 2008 2009 2010 2011 2012 2013

Time (years)
 Effects on Vascular Events by calendar year

Major macrovascular events Major clinical microvascular

events
2.0 2.0

1.5 T2 1.5
T2
Hazard ratio

P=0.32 P=0.93 P=0.11 P=0.23

1.0 1.0

0.5 0.5

T2 = last visit ADVANCE glucose arm

0.0 0.0
2008 2009 2010 2011 2012 2013 2008 2009 2010 2011 2012 2013

Time (years)
 Effects on Microvascular events
by calendar year
Retinal photocoagulation or
End-stage kidney disease
Diabetes-related blindness
2.0 2.0

1.5 T2 1.5 T2
Hazard ratio

P=0.29 P=0.69 P=0.02 P<0.01

1.0 1.0

0.5 0.5

T2 = last visit ADVANCE glucose arm

0.0 0.0
2008 2009 2010 2011 2012 2013 2008 2009 2010 2011 2012 2013

Time (years)
Main results: Glucose arm

Outcomes
Subgroup analyses
All cause death
 Effects by Subgroups
(all cause death overall in-trial and post-trial follow-up)

P for heterogeneity >0.1

 Summary

 ADVANCE-ON cohort was representative of the original trial

population with type 2 diabetes:
 presenting on average 8 years after diagnosis and
 at high risk of vascular events
 The difference in HbA1c achieved during the trial (intensive vs
standard -0.7%) was lost by the first post-trial visit and
remained similar at the conclusion of post-trial follow-up
 Other cardiovascular risk factors and preventive therapies
were similar between the glucose control groups during post
trial follow-up
 Summary

 There was no evidence that the in-trial differences in glucose

control produced any benefit or harm in the long term for
 mortality,
 major macrovascular events or
 major clinical microvascular events
However,
 There was evidence of a sustained and significant reduction in
end-stage kidney disease in the long term due to the benefits
arising from the original trial period of intensive glucose
control persisting into the post-trial period.
 Interpretation

• Why do the ADVANCE-ON post-trial follow up

results differ from the previous post-trial
studies?
– Differences in the response to glucose lowering in
an older population with long diabetes duration
– Insufficient difference in glucose control or
insufficient period of intensive treatment to
produce changes to the vasculature that would
translate into long term benefits…
 Take home message - Glucose arm

 Intensive glucose did not confer not any benefit or harm in

the long term for all cause mortality and major macrovascular
events

 Intensive glucose control did confer legacy benefits in the

long term for end-stage kidney disease

 Intensive glucose control is important for preventing serious

renal complications and does not cause harm (does not
increase risk of mortality or cardiovascular events) in people
with established type 2 diabetes
 “Hot Topics in Diabetes”
50th EASD, Vienna 2014

BP and Glucose arm results

available online at
www.nejm.org/