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12 th Meeting of the Mediterranean Group for the Study of Diabetes (MGSD)

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. Outline.

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12 th Meeting of the Mediterranean Group for the Study of Diabetes (MGSD)

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  1. Practicalimplementation of the ADVANCE results in real lifeDavide CarvalhoCentro Hospitalar S. João, University of Porto MedicalSchool , Portugal 12th 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 A1ctarget? Previousstudies:DCCT (1993) and UKPDS (1998) showedthat a tighter control of A1c helps to preventdiabetic complications But the intention of these trials was to targetnormal Blood Glucose and not A1c

  4. What have we learned with ADVANCE trial?A1cprogressive and sustained reduction 10.0 Standard Intensive (Gliclazide MR) 9.5 9.0 8.5 Δ 0.67% (95% CI 0.64 – 0.70); p<0.0001 Mean HbA1cat final visit 8.0 Mean HbA1c (%) 7.5 7.3 % 7.0 6.5% 6.5 6.0 5.5 5.0 0 6 12 18 24 30 36 42 48 54 60 66 Follow-up (Months) Gliclazide MR at the dose of 120 mg in 70% of patients ADVANCE collaborative group.N Engl J Med 2008; 358:2560-72

  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 alwaysprovides an efficient glycemic control ADVANCE Collaborative Group.IDF Annual Meeting, 2009. Canada, Montreal. Posters

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

  8. 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 Multifactorial treatments including routineblood pressure lowering and intensive glucose controlare indicated for all patients with type 2 diabetes

  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 * Mean A1c

  11. Morbidity-mortality study:ACCORD (2008) Morbidity-mortalitystudy in type 2 diabetic patient aimingat HbA1c6% Increase in total mortality (HR 1.22, p=0.04) Non significantreduction in the primary end point Significantincrease in cardiovascularmortality Reasons for increasedmortality ? toosharpdecrease in HbA1c ? hypoglycemicevents ? adverse eventsrelated to the choice of drugs ?

  12. ADVANCE ACCORD vs ADVANCE/ACCORD debate 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 ACCORD Study Group.Diabetes Care 2010; 33:983–990 ACCORD Study Group. N Engl J Med. 2008;358:2545-2559. ADVANCE Collaborative Group. N Engl J Med 2008; 358:2560-72

  13. ADVANCE, ACCORD and VADT trialsIncidence of severe hypoglycemic events according to the type of control ADVANCE1 ACCORD2 VADT3 100 patients/year 100 patients/year 100 patients/year 15 15 15 12.0 12 12 12 9 9 9 Severe hypoglycemic events Severe hypoglycemic events Severe hypoglycemic events 6 6 6 4.0 3.2 3 3 3 1.0 0.6 0.3 0 0 0 Standard Intensive Standard Intensive Standard Intensive P<0.001 P<0.001 P<0,01 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: 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.

  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. ACCORDHypoglycaemia and A1c Standard therapy Intensive therapy 6 5 4 Incidence per 100 person years 3 2 1 0 6.0 7.0 8.0 9.0 Updated average HbA1C Adapted from Bonds D., data presented at ADA 2009

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

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

  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 TrialPopulation representative of a daily practice Baseline characteristics: Age 66 years HbA1c 7.5% BMI 28 kg/m2 SBP 145 mm Hg Duration of diabetes 8 years Pasthistory of macrovasculardisease 32%microvasculardisease 10%

  20. How to translate in clinical practice the results of ADVANCE TrialIntensive glucose control (at start of the study) Gliclazide MR—based therapy with a target HbA1C of 6.5% or less • HbA1c 6.5% (target level): • Maintain current therapy • HbA1c 6.5%-7.5% • Maintain or titrate up existing therapy • HbA1c 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 TrialMethods for achieving intensive glucose control target • Additional drug treatments • Increase dose of gliclazide MR • Add/increase dose of other oral agents (metformin, thiazolidinedione, -glucosidase inhibitor) • Low-dose insulin (bedtime or mealtime) • Full-dose insulin • Additional non-drug interventions • Home glucose monitoring, regular dietician review, more frequent follow-up, etc

  22. 30 mg 60 mg 90 mg 70% of the patients 120 mg ADVANCE intensive glucose control strategy Other SUs Metformin No drug Initiation Add-on Switch Gliclazide MR Drug titration at physician’s discretion based on HbA1c and FBG levels Progressively maximize the dose HbA1c target6.5% Add other OADs Add insulin

  23. Innovative formulation for an effective 24-hour coveragein 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 1. Guillausseau PJ and Greb W. Diabetes Metab. 2001;27:133-137 - 2. Schernthaner G, et al. Eur J Clin Invest. 2004;34:535-5423. 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

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

  25. How to translate in clinical practice the results of ADVANCE Trial The less the number of intake, the better the compliance GuillausseauPJ, 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 Reduced serious complications, primarily renal disease With low rates of hypoglycemia and no weight gain Thanks to the full range of doses up to 120 mg daily Place of Gliclazide MR in practice An intensive regimen based on Gliclazide MR is a suitabletreatment for routine implementation in daily clinical practice

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