The ADVANCE trial: update and new results Jean-François Gautier Saint Louis Hospital, Paris

1. The ADVANCE trial: update and new resultsJean-François Gautier Saint Louis Hospital, Paris 12th Meeting of the Mediterranean Group for the Study of Diabetes (MGSD) Casablanca, April 29, 2011

2. ADVANCE-ON ADVANCE in the context ofmajor trials CONTROLmeta-analysis N=27,049 ADVANCEN=11,240 UKPDSN=3867 UKPDS Long-term follow-up STENO 2N=160 1998 2003 2008 June 2008 Sept 2008 2009 VADT N=1791 ACCORDN=10,251

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

4. Intensive glycemic control Standard glycemic control HbA1c target 6.5% Local targets 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.

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

11. Maximal dose of Diamicron MR In 70% of patients Metabolic safety • Remarkably safe at the higher doses 6 times less hypos The lowest rate of hypoglycemia ACCORD Study Group. N Engl J Med. 2008;358:2545-2559. The UKPDS Group (33). Lancet. 1998;352:837-853 ADVANCE Collaborative Group. N Engl J Med 2008; 358:2560-72

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

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

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 HbA1C 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. ZoungasFriday 24th September 2010

20. Renal events Percent 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)*** 0.4% 0.6% 36% (-8 to 62)* End stage kidney disease 0.5 1.0 2.0 Hazard ratio † P=<0.001 ‡ P=0.02 *** P=0.006 *P=0.09 ADVANCE Collaborative Group. NEJM 2008

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

22. albuminuria 20% more patients regressed to normal range vs standard treatment (P=0.0002) Majority of these patients Macroalbuminuria Microalbuminuria Normal range of albuminuria *versus standard treatment group Diamicron MR is renoprotective 20 mg/l 200 mg/l ADVANCE Collaborative Group. EASD Congress 2010. Stockholm, Sweden. Oral communication

23. J. Chalmers, Editorial in N Engl J Med2008;359:15 Proportion with event R. Holman, UKPDS 80 N Engl J Med. 2008;359:1577-1589. ADVANCE: What next ? UKPDS 10-year follow-up confirmed thepositive trend in macrovascular events observed in ADVANCE Total mortality

24. Timelines ADVANCE ON Clinical visitRegistration Informed consent 2013 2008 Clinical visit Follow-up ADVANCE ON 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

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