1. Practical implementation of the ADVANCE results in real life Davide Carvalho Centro Hospitalar S. João, University of Porto Medical School, Portugal 12 th Meeting of the Mediterranean Group for the Study of Diabetes (MGSD) Casablanca, April 29, 2011

2. Outline What have we learned with ADVANCE trial? Why the other Glycemic intensive control trials didn’t achieve the aims ? How to translate in clinical practice the results of ADVANCE Trial

3. Diabetic vascular complications: what is the A 1c target? Previous studies: DCCT (1993) and UKPDS (1998) showed that a tighter control of A1c helps to prevent diabetic complications But the intention of these trials was to target normal Blood Glucose and not A1c

4. What have we learned with ADVANCE trial? A 1c progressive and sustained reduction Gliclazide MR at the dose of 120 mg in 70% of patients ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72 Mean HbA 1c at final visit Mean HbA1c (%) 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 Follow-up (Months) 0612182430364248546066 7.3 % 6.5% Δ 0.67% (95% CI 0.64 – 0.70); p<0.0001 Standard Intensive (Gliclazide MR)

5. What have we learned with ADVANCE trial? Progressive and sustained blood glucose control (6.5% of A1c) Reduction of serious complications (-10% primary endpoint) Kidney protection (-21% nephropathy, regression to normoalbuminuria) Reduction of CV risk markers (-30% in albuminuria) Trend toward CV mortality reduction (-12%) Safe and weight neutral ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72

6. What have we learned with ADVANCE trial? Efficient glycemic control whatever the patient profile Gliclazide MR always provides an efficient glycemic control ADVANCE Collaborative Group. IDF Annual Meeting, 2009. Canada, Montreal. Posters

7. Zoungas Diabetes Care 2009 Cardiovascular death is reduced by 24% (p=0.04) Renal disease is reduced by 33% (p=0.005) What have we learned with ADVANCE trial? Interaction data

8. Multifactorial treatments including routine blood pressure lowering and intensive glucose control are indicated for all patients with type 2 diabetes What have we learned with ADVANCE trial? Conclusions on Joint effects The effects of the 2 treatments were independent of one another for all clinical outcomes Where both treatments had a significant effect, these effects were fully additive Where only one treatment had a significant effect, the second treatment preserved that effect

9. Outline What have we learned with ADVANCE trial? Why the other glycaemic intensive control trials didn’t achieve the aims ? How to translate in clinical pratice the results of ADVANCE Trial

10. ACCORD, ADVANCE and VADT trials Similarities and differences ACCORDADVANCEVADT No. of participants10,25111,1401,791 Age of participants (years)626660 Participants – men, (%)625897 Diabetes Duration at begining (years)10811.5 Baseline A 1C,%8.17.29.4 Participants with previous CV events (%)353240 Follow-up,(years)3.45.06 Results, intensive vs. standard A 1C, %6.4 vs. 7.56.5 vs. 7.3*6.9 vs. 8.4 Death from any cause, %5.0 vs. 4.08.9 vs. 9.6NA Death from CV events, %2.6 vs. 1.84.5 vs. 5.22.1 vs. 1.7 Non-fatal MI %3.6 vs. 4.62.7 vs. 2.86.1 vs. 6.3 Non-fatal Stroke, %1.3 vs. 1.23.8 vs. 3.82.0 vs. 3.1 New or worsening Nephropaty, %NA4.1 vs. 5.2NA Severe/Major hypoglycemias, %10.5 vs. 3.52.7 vs. 1.521.1 vs. 9.7 Weight gain, kg3.5 vs. 0.40.7 vs. - 0.0NA * Mean A1c

11. Morbidity-mortality study: ACCORD (2008) Morbidity-mortality study in type 2 diabetic patient aiming at HbA 1c  6% Increase in total mortality (HR 1.22, p=0.04) Non significant reduction in the primary end point Significant increase in cardiovascular mortality Reasons for increased mortality ? too sharp decrease in HbA 1c ? too sharp decrease in HbA 1c ? hypoglycemic events ? hypoglycemic events ? adverse events related to the choice of drugs ? adverse events related to the choice of drugs ?

12. ACCORDvs ADVANCE/ACCORD debate ADVANCE ADVANCE Collaborative Group. N Engl J Med 2008; 358:2560-72 ACCORD Study Group. N Engl J Med. 2008;358:2545-2559. ACCORD Study Group. Diabetes Care 2010; 33:983–990 Participants who were unable to reduce A1C after initiation of the intensive strategy and continued to have average A1C > 7% seemed to be at greater risk

13. ADVANCE: N Engl J Med 2008; 358, 2560-2572. ACCORD: N Engl J Med 2008; 358, 2545-2559. VADT: N Engl J Med 2009;360:129-39. StandardIntensive P<0.001P<0,01P<0.001 100 patients/year 0.3 0.6 4.0 12.0 3 6 9 12 15 VADT 3 ACCORD 2 ADVANCE 1 100 patients/year 1.0 0 100 patients/year Severe hypoglycemic events 3 6 9 12 15 0 3 6 9 12 15 0 3.2 StandardIntensiveStandardIntensive Major hypoglycaemia was uncommon in ADVANCE and only reported in 231 patients among 11,140 followed for 5 years, 150 in intensive group and 81 in standard control group ADVANCE, ACCORD and VADT trials Incidence of severe hypoglycemic events according to the type of control Severe hypoglycemic events

14. All cause mortality according to A1c in the ACCORD Trial RIDDLE MC, et al.Epidemiologic Relationships Between A1C and All-Cause Mortality During a Median 3.4-Year Follow-up of Glycemic Treatment in the ACCORD Trial. Diabetes Care 33:983–990, 2010

15. ACCORD Hypoglycaemia and A 1c 6 5 4 3 2 1 0 6.07.08.09.0 Updated average HbA 1C Incidence per 100 person years Standard therapy Intensive therapy Adapted from Bonds D., data presented at ADA 2009

16. Kovatchev et al, J Clin Endocrinol Metab 2000;85:4287-92 Glycemic instability precedes severe hypoglycemia 48 h before Severe Hypoglycemia, glycemic instability increases

17. Different issues between ACCORD and ADVANCE 87 % 95 % 92 % 77% 92 % 74 % 17 % 40% % of drugs prescribed secretagogues metformin glitazones insulin 16.2 %2.5 % Severe hypoglycemias 6.4 % Median HbA1c ACCORDADVANCE Results at the end of follow up in the intensive glucose lowering arms of ADVANCE and ACCORD studies Gliclazide MR Glibenclamide Glimepiride

18. Outline What have we learned with ADVANCE trial? Why the other Glycemic intensive control trials didn’t achieve the aims ? How to translate in clinical practice the results of ADVANCE Trial

19. How to translate in clinical practice the results of ADVANCE Trial Population representative of a daily practice Baseline characteristics: Age 66 years Age 66 years HbA 1c 7.5% HbA 1c 7.5% BMI 28 kg/m 2 BMI 28 kg/m 2 SBP 145 mm Hg SBP 145 mm Hg Duration of diabetes 8 years Duration of diabetes 8 years Past history of macrovascular disease 32% microvascular disease 10% Past history of macrovascular disease 32% microvascular disease 10%

20. How to translate in clinical practice the results of ADVANCE Trial Intensive glucose control (at start of the study) Gliclazide MR—based therapy with a target Hb A1C of 6.5% or less Hb A1c  6.5% (target level): Maintain current therapy Hb A1c 6.5%-7.5% Maintain or titrate up existing therapy Hb A1c  7.5% (Threshold level) Titrate up existing therapy and/or introduce additional therapy Unrestricted use of other glucose-lowering agents (except sulfonylureas)

21. How to translate in clinical practice the results of ADVANCE Trial Methods for achieving intensive glucose control target Additional drug treatments Increase dose of gliclazide MR Increase dose of gliclazide MR Add/increase dose of other oral agents (metformin, thiazolidinedione,  -glucosidase inhibitor) Add/increase dose of other oral agents (metformin, thiazolidinedione,  -glucosidase inhibitor) Low-dose insulin (bedtime or mealtime) Low-dose insulin (bedtime or mealtime) Full-dose insulin Full-dose insulin Additional non-drug interventions Home glucose monitoring, regular dietician review, more frequent follow-up, etc Home glucose monitoring, regular dietician review, more frequent follow-up, etc

22. Gliclazide MR Drug titration at physician’s discretion based on HbA 1c and FBG levels No drug Other SUs Metformin Initiation Add-on Switch Add other OADs Add insulin Progressively maximize the dose 70% of the patients 60 mg 90 mg 120 mg 30 mg HbA 1c target 6.5% ADVANCE intensive glucose control strategy

23. 1. Guillausseau PJ and Greb W. Diabetes Metab. 2001;27:133-137 - 2. Schernthaner G, et al. Eur J Clin Invest. 2004;34:535-542 3. data on file - 4. Satoh J, et al. Diabetes Res Clin Pract. 2005;70:291-297 - 5. O’Brien RC, et al. J Diabetes Complications. 2000;14:201-206 - 6. Katakami N, et al. Diabetologia. 2004;47:1906-1913 - 7. Johnsen SP, et al. Am J Ther. 2006;13:134-140 Innovative formulation for an effective 24-hour coverage in a single intake at breakfast 1 Effective and long-lasting glycemic control 2,3,4 Well tolerated even at higher doses 2,3 Antioxidant properties and direct vascular protection 5,6,7 How to translate in clinical practice the results of ADVANCE Trial Rationale for the choice of Gliclazide MR

24. How to translate in clinical practice the results of ADVANCE Trial - Compliance "Keep a watch also on the faults of the patients, which often make them lie about the taking of things prescribed.“ Hippocrate A major issue in type 2 diabetes

25. How to translate in clinical practice the results of ADVANCE Trial The less the number of intake, the better the compliance Guillausseau PJ, Diabetes Metab 2003

26. Practical implementation of the ADVANCE results in real life Conclusions A pragmatic approach to glucose control Intensified Glucose Control maintained in the long term Intensified Glucose Control maintained in the long term Reduced serious complications, primarily renal disease Reduced serious complications, primarily renal disease With low rates of hypoglycemia and no weight gain With low rates of hypoglycemia and no weight gain Thanks to the full range of doses up to 120 mg daily Thanks to the full range of doses up to 120 mg daily An intensive regimen based on Gliclazide MR is a suitable treatment for routine implementation in daily clinical practice Place of Gliclazide MR in practice