The ADVANCE trial: update and The ADVANCE trial: update and new resultsnew results
Jean-François Gautier Jean-François Gautier Saint Louis Hospital, ParisSaint Louis Hospital, Paris
1212thth Meeting of the Mediterranean Group for the Study Meeting of the Mediterranean Group for the Study of Diabetes (MGSD)of Diabetes (MGSD)
Casablanca, April 29, 2011Casablanca, April 29, 2011
ADVANCE in the context ofmajor trials
1998 2003 2008 June 2008 Sept 2008 2009
UKPDSN=3867
ACCORDN=10,251
ADVANCEN=11,240
UKPDSLong-term follow-up
VADT N=1791
STENO 2N=160
CONTROLmeta-analysisN=27,049
ADVANCE-ON
ADVANCE, the largest trial in T2DM
11 140 patients, 215 centers, 20 countries
Study design
Rationale and design of the ADVANCE study. J Hypertens. 2001;19(suppl 4):S21-S28.ADVANCE-baseline characteristics. Diabet Med. 2005;22:1-7.
HbA1c target6.5%
11.140 patients
Intensive glycemic controlIntensive glycemic control
DIAMICRON MR
Preterax Placebo
Standard glycemic controlStandard glycemic control
STANDARD
Preterax Placebo
(same BP control)
11.140 patients
Intensive glycemic controlIntensive glycemic control
DIAMICRON MR
Preterax Placebo
Standard glycemic controlStandard glycemic control
STANDARD
Preterax Placebo
(same BP control)
11.140 patients
Intensive glycemic controlIntensive glycemic control
DIAMICRON MR
Preterax Placebo
Intensive glycemic controlIntensive glycemic control
DIAMICRON MRIntensive glycemic controlIntensive glycemic control
DIAMICRON MR
Preterax PlaceboPreterax Placebo
Standard glycemic controlStandard glycemic control
STANDARD
Preterax Placebo
Standard glycemic controlStandard glycemic control
STANDARDStandard glycemic controlStandard glycemic control
STANDARD
Preterax Placebo
(same BP control)
11.140 patients
Intensive glycemic controlIntensive glycemic control
DIAMICRON MR
Preterax Placebo
Standard glycemic controlStandard glycemic control
STANDARD
Preterax Placebo
(same BP control)
11.140 patients
Intensive glycemic controlIntensive glycemic control
DIAMICRON MR
Preterax Placebo
Standard glycemic controlStandard glycemic control
STANDARD
Preterax Placebo
(same BP control)
11.140 patients
Intensive glycemic controlIntensive glycemic control
DIAMICRON MR
Preterax Placebo
Intensive glycemic controlIntensive glycemic control
DIAMICRON MRIntensive glycemic controlIntensive glycemic control
DIAMICRON MR
Preterax PlaceboPreterax Placebo
Standard glycemic controlStandard glycemic control
STANDARD
Preterax Placebo
Standard glycemic controlStandard glycemic control
STANDARDStandard glycemic controlStandard glycemic control
STANDARD
Preterax Placebo
(same BP control)
Intensive
glycemic
control
Standard
glycemic
control
Local targets
Inclusion criteria
Type 2 diabetes mellitus
Age 55 years or older
Additional CV risk factor Age 65 yearsHistory of major macrovascular diseaseHistory of major microvascular diseaseFirst diagnosis of diabetes >10 years prior to entryOther major risk factor
Hypertensive or normotensiveRationale and design of the ADVANCE study. J Hypertens. 2001;19(suppl 4):S21-S28.ADVANCE-baseline characteristics. Diabet Med. 2005;22:1-7.
Efficient glycemic control
progressive and intensive glycemic controlSustained over 5 years
ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72
% of pts according to HbA1c level at the end of follow up
50.250.281.1%81.1%<< 7%7%
28.8%28.8%64.9%64.9%<< 6.5%6.5%
8.4%8.4%21.3%21.3%<< 6%6%
4372437244994499AllAllStandardStandardIntensiveIntensive
50.250.281.1%81.1%<< 7%7%
28.8%28.8%64.9%64.9%<< 6.5%6.5%
8.4%8.4%21.3%21.3%<< 6%6%
4372437244994499AllAllStandardStandardIntensiveIntensive
No. & % of patientsNo. & % of patients
50.250.281.1%81.1%<< 7%7%
28.8%28.8%64.9%64.9%<< 6.5%6.5%
8.4%8.4%21.3%21.3%<< 6%6%
4372437244994499AllAllStandardStandardIntensiveIntensive
50.250.281.1%81.1%<< 7%7%
28.8%28.8%64.9%64.9%<< 6.5%6.5%
8.4%8.4%21.3%21.3%<< 6%6%
4372437244994499AllAllStandardStandardIntensiveIntensive
No. & % of patientsNo. & % of patients
10% Significant reduction in the combined risk of
micro- and macrovascular
events
Protection from serious complications
ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72
Renal protection
Major protective effect on the kidneys21% reduction in renal events30% less albuminuriaPositive trend toward a reduction in CV death
ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72
Importance of reduction of renal events in T2DMImportance of reduction of renal events in T2DM 20% of people with diabetes die of renal disease20% of people with diabetes die of renal disease50% of patients in dialysis units have diabetes50% of patients in dialysis units have diabetesAlbuminuria is a major predictor of ESRD, CVD, and deathAlbuminuria is a major predictor of ESRD, CVD, and death
Key resultsRisk of CVD predicted by
albuminuria
ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72
The lowest rate of hypoglycemia
Metabolic safety
Remarkably safe at the higher doses
ADVANCE Collaborative Group. N Engl J Med 2008; 358:2560-72 ACCORD Study Group. N Engl J Med. 2008;358:2545-2559. The UKPDS Group (33). Lancet. 1998;352:837-853
6 times less hypos
Maximal dose of Diamicron MR
In 70% of patients
Weight neutrality
Weight Change
Remarkably safe at the higher doses
ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72
ADVANCEADVANCE UKPDSUKPDS(glibenclamide arm)(glibenclamide arm)
ACCORDACCORD
Median HbAMedian HbA1c1c 6.4 %6.4 % 7 %7 % 6.4%6.4%
Weight Weight changechange +0.0 kg+0.0 kg +1.7 kg+1.7 kg
+3.5 kg+3.5 kg(>10 kg in 1/3 of (>10 kg in 1/3 of
patients)patients)
Key results
Only in ADVANCE patients do not gain weight
ADVANCE Collaborative Group. N Engl J Med 2008; 358:2560-72 ACCORD Study Group. N Engl J Med. 2008;358:2545-2559. The UKPDS Group (33). Lancet. 1998;352:837-853
Recent results
Efficient glycemic control whatever the age at entry
Zoungas S. Diabetes Research Clinical Practice 2010; 89:126-133
Efficient glycemic control whatever the duration of the disease
Zoungas S. Diabetes Research Clinical Practice 2010; 89:126-133
Efficient glycemic control whatever baseline BMI
Zoungas S. Diabetes Research Clinical Practice 2010; 89:126-133
Efficient glycemic control whatever the HbA1C at baseline
Zoungas S. Diabetes Research Clinical Practice 2010; 89:126-133
New results EASD 2010
Intensive glucose control is Intensive glucose control is renoprotective in type 2 diabetes: renoprotective in type 2 diabetes: new analyses from ADVANCEnew analyses from ADVANCE
Oral communication S. ZoungasFriday 24th September 2010
0.5 1.0 2.0
End stage kidney disease
Percent of patients with eventIntensive Standard(n=5,571) (n=5,569)
Relative riskreduction (95% CI)
FavoursIntensive
FavoursStandard
New microalbuminuria 23.7% 25.7%
Total renal events 26.9% 30.0%
9% (2 to 15)‡
11% (5 to 17)†
New macroalbuminuria 2.9% 4.1% 30% (15 to 43)†
New or worsening nephropathy 4.1% 5.2% 21% (7 to 34)***
Hazard ratio† P=<0.001
‡ P=0.02
*** P=0.006
*P=0.09
36% (-8 to 62)*0.4% 0.6%
Renal events
ADVANCE Collaborative Group. NEJM 2008
OutcomeOutcome IntensiveIntensiven (%)n (%)
StandardStandardn (%)n (%)
HR (95%CI)HR (95%CI) P valueP value NNTNNT
Regression to normoalbuminuria
All at riskAll at risk 922/1623 922/1623 (56.8)(56.8)
814/1638 814/1638 (49.7)(49.7)
1.20 (1.09-1.31)1.20 (1.09-1.31) 0.00020.0002 1515
Microalbuminuric Microalbuminuric patientspatients
869/1434 869/1434 (60.6)(60.6)
755/1423 755/1423 (53.1)(53.1)
1.19 (1.08-1.31)1.19 (1.08-1.31) 0.00040.0004 1313
Macroalbuminuric Macroalbuminuric patientspatients
53/89 (28)53/89 (28) 59/215 (27.4)59/215 (27.4) 1.06 (0.73-1.54)1.06 (0.73-1.54) 0.7620.762 NANA
New renal results EASD 2010
ADVANCE Collaborative Group. EASD Congress 2010. Stockholm, Sweden. Oral communication
Diamicron MR is renoprotective
ADVANCE Collaborative Group. EASD Congress 2010. Stockholm, Sweden. Oral communication
20 mg/l200 mg/lalbuminuria
Macroalbuminuria
Normal range of albuminuria
Majority of these patients
*versus standard treatment group
Microalbuminuria
20% more patients regressed to normal range vs standard treatment
(P=0.0002)
J. Chalmers, Editorial in N Engl J Med 2008;359:15
UKPDS 10-year follow-up confirmed thepositive trend in macrovascular events
observed in ADVANCE
Total mortality
Pro
port
ion
wit
h e
ven
t
UKPDS 10 years follow-up
Total mortality
-13%
HR 0.94p=0.44
HR 0.87p=0.007
Prop
ortio
n w
ith e
vent
ConventionalIntensive (SUs, insulin)
Holman et al. N Engl J Med 2008;359
1977 1997 2007 Follow-up
R. Holman, UKPDS 80 N Engl J Med. 2008;359:1577-1589.
ADVANCE: What next ?
Timelines ADVANCE ON
2008
Follow-up ADVANCE ON
Clinical visitRegistration
Informed consentClinical visit
2013
Continued observational follow up from last visit up to 5 yearsPatients returning to their usual clinical care community
All ADVANCE survival participants in 213 clinical centres in Australasia, Europe, North America, Asia
Conclusion
Long-term evidence-based clinical results with Diamicron MR in ADVANCE study- effective and sustained glucose lowering control- excellent safety and weight neutrality- protection against vascular complications, mainly microvascular
New results reinforcing the benefits in different clinical settings with unique data on the regression of nephropathy
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