The ADVANCE trial: update and new results

Jean-Franois Gautier Saint Louis Hospital, Paris12th Meeting of the Mediterranean Group for the Study of Diabetes (MGSD)Casablanca, April 29, 2011

ADVANCE in the context ofmajor trials 19982003 2008 June 2008 Sept 2008 2009UKPDS N=3867ACCORD N=10,251ADVANCE N=11,240UKPDSLong-term follow-upVADT N=1791STENO 2 N=160CONTROL meta-analysisN=27,049

ADVANCE, the largest trial in T2DM

Study designRationale and design of the ADVANCE study. J Hypertens. 2001;19(suppl 4):S21-S28.ADVANCE-baseline characteristics. Diabet Med. 2005;22:1-7.

Inclusion criteriaType 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 controlprogressive and intensive glycemic controlSustained over 5 yearsADVANCE collaborative group. N Engl J Med 2008; 358:2560-72

% of pts according to HbA1c level at the end of follow up

Protection from serious complicationsADVANCE collaborative group. N Engl J Med 2008; 358:2560-72

Renal protectionMajor protective effect on the kidneys21% reduction in renal events30% less albuminuriaPositive trend toward a reduction in CV deathADVANCE collaborative group. N Engl J Med 2008; 358:2560-72

Importance of reduction of renal events in T2DM 20% of people with diabetes die of renal disease50% of patients in dialysis units have diabetesAlbuminuria is a major predictor of ESRD, CVD, and death

Key resultsRisk of CVD predicted by albuminuriaADVANCE collaborative group. N Engl J Med 2008; 358:2560-72

The lowest rate of hypoglycemiaMetabolic safetyRemarkably safe at the higher dosesADVANCE Collaborative Group. N Engl J Med 2008; 358:2560-72ACCORD Study Group. N Engl J Med. 2008;358:2545-2559.The UKPDS Group (33). Lancet. 1998;352:837-8536 times less hypos

Weight neutralityWeight ChangeRemarkably safe at the higher doses

ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72

Key resultsOnly in ADVANCE patients do not gain weightADVANCE Collaborative Group. N Engl J Med 2008; 358:2560-72ACCORD Study Group. N Engl J Med. 2008;358:2545-2559.The UKPDS Group (33). Lancet. 1998;352:837-853

ADVANCEUKPDS(glibenclamide arm)ACCORDMedian HbA1c6.4 %7 %6.4%Weight change+0.0 kg+1.7 kg+3.5 kg(>10 kg in 1/3 of patients)

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 diseaseZoungas 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 baselineZoungas S. Diabetes Research Clinical Practice 2010; 89:126-133

New results EASD 2010Intensive glucose control is renoprotective in type 2 diabetes: new analyses from ADVANCE Oral communication S. Zoungas Friday 24th September 2010

0.51.02.0 End stage kidney diseasePercent of patients with eventIntensiveStandard(n=5,571)(n=5,569)Relative riskreduction (95% CI)FavoursIntensiveFavoursStandard New microalbuminuria23.7%25.7%Total renal events26.9%30.0% 9% (2 to 15) 11% (5 to 17) New macroalbuminuria2.9%4.1%30% (15 to 43) New or worsening nephropathy4.1%5.2% 21% (7 to 34)***Hazard ratio P=

New renal results EASD 2010ADVANCE Collaborative Group. EASD Congress 2010. Stockholm, Sweden. Oral communication

OutcomeIntensive n (%)Standard n (%)HR (95%CI)P valueNNTRegression to normoalbuminuriaAll at risk922/1623 (56.8)814/1638 (49.7)1.20 (1.09-1.31)0.000215Microalbuminuric patients869/1434 (60.6)755/1423 (53.1)1.19 (1.08-1.31)0.000413Macroalbuminuric patients53/89 (28)59/215 (27.4)1.06 (0.73-1.54)0.762NA

Diamicron MR is renoprotectiveADVANCE Collaborative Group. EASD Congress 2010. Stockholm, Sweden. Oral communication20 mg/l200 mg/l

UKPDS 10-year follow-up confirmed the positive trend in macrovascular events observed in ADVANCE

Total mortality

ADVANCE: What next ?

Timelines ADVANCE ON2008Follow-up ADVANCE ONClinical visit Registration Informed consentClinical visit2013Continued observational follow up from last visit up to 5 years Patients returning to their usual clinical care communityAll ADVANCE survival participants in 213 clinical centres in Australasia, Europe, North America, Asia

ConclusionLong-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

*UGDP tolbutamidelaunched in 1960placebo-controlled, multi-center clinical trial devised to determine which, if any, of the treatments for type 2 diabetes was efficacious. the differences seen in the cumulative total mortality were not statistically significant, but a sub-group analysis suggested that cardiac deaths occurred more frequently in the tolbutamide group

1978 Design UKPDS

2001 Design ADVANCE

PROActive : will not be mentionned thereafterAs 1- more marketing study2- DNS on primary end point and lot of debate to be convinced on the results

**ADVANCE, with more than 11 000 patients, is the largest ever prospective study carried out in type 2 diabetes for the prevention of vascular disease.

***What makes the use of Diamicron MR extremely rational in ADVANCE?Four main reasons:

Knowing the high %of db patients suffering from ESRD, or even dyingfrom kidney disease

That goes without saying

Even confirmed with the nice correlation demonstrated in ADVANCE between degree of albuminuria and CV events - mortality

*What makes the use of Diamicron MR extremely rational in ADVANCE?Four main reasons:

*What makes the use of Diamicron MR extremely rational in ADVANCE?Four main reasons:

*What makes the use of Diamicron MR extremely rational in ADVANCE?Four main reasons:

*ADVANCE ONEmbargo till IDF Abstract submitted

A lot of communication around this event is planned, including Press Release