The ADVANCE trial: update and new results Jean-François Gautier Saint Louis Hospital, Paris 12 th Meeting of the Mediterranean Group for the Study of Diabetes

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


DIAMICRON MR

Preterax Placebo


STANDARD

Preterax Placebo

(same BP control)

11.140 patients


DIAMICRON MR

Preterax Placebo


DIAMICRON MRIntensive glycemic controlIntensive glycemic control

DIAMICRON MR

Preterax PlaceboPreterax Placebo


STANDARD

Preterax Placebo


STANDARDStandard glycemic controlStandard glycemic control

STANDARD

Preterax Placebo

(same BP control)

11.140 patients


DIAMICRON MR

Preterax Placebo


STANDARD

Preterax Placebo

(same BP control)

11.140 patients


DIAMICRON MR

Preterax Placebo


STANDARD

Preterax Placebo

(same BP control)

11.140 patients


DIAMICRON MR

Preterax Placebo


DIAMICRON MRIntensive glycemic controlIntensive glycemic control

DIAMICRON MR

Preterax PlaceboPreterax Placebo


STANDARD

Preterax Placebo


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%


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%


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%


No. & % of patientsNo. & % of patients

10% Significant reduction in the combined risk of

micro- and macrovascular

events

Protection from serious complications


Renal protection

Major protective effect on the kidneys21% reduction in renal events30% less albuminuriaPositive trend toward a reduction in CV death


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


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


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


Efficient glycemic control whatever baseline BMI


Efficient glycemic control whatever the HbA1C at baseline


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

Documents

The ADVANCE trial: update and new results Jean-François Gautier Saint Louis Hospital, Paris 12 th Meeting of the Mediterranean Group for the Study of Diabetes