1. 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 (MGSD) Casablanca, April 29, 2011

2. ADVANCE in the context of major trials 19982003 2008 June 2008 Sept 2008 2009 UKPDS N=3867 ACCORD N=10,251 ADVANCE N=11,240 UKPDS Long-term follow-up VADT N=1791 STENO 2 N=160 CONTROL meta-analysis N=27,049 ADVANCE-ON

3. ADVANCE, the largest trial in T2DM 11 140 patients, 215 centers, 20 countries

4. 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. HbA 1c target  6.5% Intensive glycemic control Standard glycemic control Local targets

5. Inclusion criteria Type 2 diabetes mellitus Age 55 years or older Additional CV risk factor 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 Rationale and design of the ADVANCE study. J Hypertens. 2001;19(suppl 4):S21-S28. ADVANCE-baseline characteristics. Diabet Med. 2005;22:1-7.

6. Efficient glycemic control progressive and intensive glycemic control Sustained over 5 years ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72

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

8. 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

9. Renal protection Major protective effect on the kidneys 21% reduction in renal events 30% less albuminuria Positive trend toward a reduction in CV death ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72

10. Importance of reduction of renal events in T2DM 20% of people with diabetes die of renal disease 20% of people with diabetes die of renal disease 50% of patients in dialysis units have diabetes 50% of patients in dialysis units have diabetes Albuminuria is a major predictor of ESRD, CVD, and death Albuminuria is a major predictor of ESRD, CVD, and death Key results Risk of CVD predicted by albuminuria ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72

11.  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

12.  Weight neutrality Weight Change Remarkably safe at the higher doses ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72

13. ADVANCEUKPDS (glibenclamide arm) ACCORD Median HbA 1c 6.4 % 7 % 6.4% Weight change +0.0 kg +1.7 kg +3.5 kg (>10 kg in 1/3 of 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

14. Recent results

15. Efficient glycemic control whatever the age at entry Zoungas S. Diabetes Research Clinical Practice 2010; 89:126-133

16. Efficient glycemic control whatever the duration of the disease Zoungas S. Diabetes Research Clinical Practice 2010; 89:126-133

17. Efficient glycemic control whatever baseline BMI Zoungas S. Diabetes Research Clinical Practice 2010; 89:126-133

18. Efficient glycemic control whatever the HbA 1C at baseline Zoungas S. Diabetes Research Clinical Practice 2010; 89:126-133

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

20. 0.51.02.0 End stage kidney disease Percent of patients with event IntensiveStandard (n=5,571)(n=5,569) Relative risk reduction (95% CI) Favours Intensive Favours Standard 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=<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

21. Outcome Intensive n (%) Standard n (%) HR (95%CI) P value NNT Regression to normoalbuminuria All at risk 922/1623 (56.8) 814/1638 (49.7) 1.20 (1.09-1.31) 0.000215 Microalbuminuric patients 869/1434 (60.6) 755/1423 (53.1) 1.19 (1.08-1.31) 0.000413 Macroalbuminuric patients 53/89 (28) 59/215 (27.4) 1.06 (0.73-1.54) 0.762NA New renal results EASD 2010 ADVANCE Collaborative Group. EASD Congress 2010. Stockholm, Sweden. Oral communication

22. Diamicron MR is renoprotective ADVANCE Collaborative Group. EASD Congress 2010. Stockholm, Sweden. Oral communication 20 mg/l 200 mg/l albuminuria 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)

23. J. Chalmers, Editorial in N Engl J Med 2008;359:15 UKPDS 10-year follow-up confirmed the positive trend in macrovascular events observed in ADVANCE Total mortality Proportion with event R. Holman, UKPDS 80 N Engl J Med. 2008;359:1577-1589. ADVANCE: What next ?

24. Timelines ADVANCE ON 2008 Follow-up ADVANCE ON Clinical visit Registration Informed consent Clinical visit 2013 Continued observational follow up from last visit up to 5 years Patients returning to their usual clinical care community All ADVANCE survival participants in 213 clinical centres in Australasia, Europe, North America, Asia

25. 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