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ueda2012 advance trial-d.salah
- 1. ADVANCE trial : theADVANCE trial : the present and the futurepresent and the future Salah SHELBAYA, MDSalah SHELBAYA, MD Professor of Diabetology,Professor of Diabetology, Ain Shams UniversityAin Shams University
- 2. OutlineOutline ADVANCEADVANCE in the context of megatrials.in the context of megatrials. Lessons fromLessons from ADVANCEADVANCE trial.trial. Gliclazide MR,Gliclazide MR, the best treatment strategy.the best treatment strategy. ADVANCEADVANCE what’s next?what’s next?
- 3. Global projections for Diabetes 2007-2030Global projections for Diabetes 2007-2030 A worldwide increasing epidemic over the upcoming yearsA worldwide increasing epidemic over the upcoming years +54%+54% IDF, Diabetes Atlas, 4th edition, 2009 438 million diabetics438 million diabetics
- 4. 2/3 of People With Diabetes Die of CVD2/3 of People With Diabetes Die of CVD Adapted from Alexander CM, Antonello S Pract Diabet 2002;21:21-28. Among people with diabetes, macro-vascular complications (including CHD, stroke & peripheral vascular disease) are the leading causes of morbidity and mortality. 67% CHD, stroke & peripheral vascular disease. Other. Causes of mortality in diabetics
- 5. In the context of megatrialsIn the context of megatrials
- 6. Megatrials in diabetesMegatrials in diabetes 1998 June 2008 Sept 2008 2009 UKPDSUKPDS N=3867N=3867 ACCORDACCORD N=10,251N=10,251 ADVANCEADVANCE N=11,240N=11,240 UKPDSUKPDS Long-term follow-upLong-term follow-up VADTVADT N=1791N=1791 CONTROL meta-analysis N=27,049
- 8. The UKPDSThe UKPDS The main effect in the UKPDS was the reduction ofThe main effect in the UKPDS was the reduction of microvascular complications by 25% mainly due to themicrovascular complications by 25% mainly due to the reduction in retinopathy “need for retinalreduction in retinopathy “need for retinal photocoagulation”photocoagulation” UKPDS Group. Lancet. 1998;352:837-853
- 9. The ACCORD trialThe ACCORD trial ACCORD Study Group. N Engl J Med. 2008;358:2545-2559. +35% ACCORD trial was prematurely interrupted because of excess mortality among intensively treated patients
- 10. CONTROL meta-analysisCONTROL meta-analysis Only ADVANCE decreases overall and cardiovascular mortality.Only ADVANCE decreases overall and cardiovascular mortality. Turnbull FM. Diabetologia. Epub Aug 5 2009
- 11. Evidence-based medicine shaped the new IDF algorithmEvidence-based medicine shaped the new IDF algorithm www.idf.org/treatment-algorithm-people-type-2-diabetes
- 12. ADVANCEADVANCE the largest trial in T2DMthe largest trial in T2DM
- 13. ADVANCEADVANCE the largest trial in T2DMthe largest trial in T2DM 11 140 patients, 215 centers, 20 countries11 140 patients, 215 centers, 20 countries
- 14. Study designStudy 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. HbA1c target ≤6.5% 11.140 patients Intensive glycemic controlIntensive glycemic control DIAMICRON MR Preterax Placebo Standard glycemic controlStandard glycemic control STANDARD Preterax Placebo (same BP control) 11.140 patients Intensive glycemic controlIntensive glycemic control DIAMICRON MR Preterax Placebo Standard glycemic controlStandard glycemic control STANDARD Preterax Placebo (same BP control) 11.140 patients Intensive glycemic controlIntensive glycemic control DIAMICRON MR Preterax Placebo Intensive glycemic controlIntensive glycemic control DIAMICRON MR Intensive glycemic controlIntensive glycemic control DIAMICRON MR Preterax PlaceboPreterax Placebo Standard glycemic controlStandard glycemic control STANDARD Preterax Placebo Standard glycemic controlStandard glycemic control STANDARD Standard glycemic controlStandard glycemic control STANDARD Preterax Placebo (same BP control) 11.140 patients Intensive glycemic controlIntensive glycemic control DIAMICRON MR Preterax Placebo Standard glycemic controlStandard glycemic control STANDARD Preterax Placebo (same BP control) 11.140 patients Intensive glycemic controlIntensive glycemic control DIAMICRON MR Preterax Placebo Standard glycemic controlStandard glycemic control STANDARD Preterax Placebo (same BP control) 11.140 patients Intensive glycemic controlIntensive glycemic control DIAMICRON MR Preterax Placebo Intensive glycemic controlIntensive glycemic control DIAMICRON MR Intensive glycemic controlIntensive glycemic control DIAMICRON MR Preterax PlaceboPreterax Placebo Standard glycemic controlStandard glycemic control STANDARD Preterax Placebo Standard glycemic controlStandard glycemic control STANDARD Standard glycemic controlStandard glycemic control STANDARD Preterax Placebo (same BP control) Intensive glycemic control Standard glycemic control Local targets 7% Gliclazide MRGliclazide MR
- 15. Inclusion criteriaInclusion criteria Baseline characteristics:Baseline characteristics: Age 66 yearsAge 66 years HbAHbA1c1c 7.5%7.5% BMI 28 kg/mBMI 28 kg/m22 SBP 145 mm HgSBP 145 mm Hg Duration of diabetes 8 yearsDuration of diabetes 8 years Past history of macrovascular disease 32%Past history of macrovascular disease 32% Rationale and design of the ADVANCE study. J Hypertens. 2001;19(suppl 4):S21-S28. ADVANCE-baseline characteristics. Diabet Med. 2005;22:1-7.
- 17. Progressive and tight glycemic controlProgressive and tight glycemic control Sustained over 5 years ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72 Gliclazide MR at the dose of 120 mg In 70% of patients Gliclazide MRGliclazide MR
- 18. Tight HbATight HbA1c1c controlcontrol 50.250.281.1%81.1%<< 7%7% 28.8%28.8%64.9%64.9%<< 6.5%6.5% 8.4%8.4%21.3%21.3%<< 6%6% 4372437244994499AllAll StandardStandardIntensiveIntensive 50.250.281.1%81.1%<< 7%7% 28.8%28.8%64.9%64.9%<< 6.5%6.5% 8.4%8.4%21.3%21.3%<< 6%6% 4372437244994499AllAll StandardStandardIntensiveIntensive No. & % of patientsNo. & % of patients 50.250.281.1%81.1%<< 7%7% 28.8%28.8%64.9%64.9%<< 6.5%6.5% 8.4%8.4%21.3%21.3%<< 6%6% 4372437244994499AllAll StandardStandardIntensiveIntensive 50.250.2 %%81.1%81.1%<< 7%7% 28.8%28.8%64.9%64.9%<< 6.5%6.5% 8.4%8.4%21.3%21.3%<< 6%6% 4372437244994499AllAll StandardStandardIntensiveIntensive No. & % of patientsNo. & % of patients ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72
- 19. Whatever the age at entryWhatever the age at entry Zoungas S. Diabetes Research Clinical Practice 2010; 89:126-133
- 20. Whatever the duration of the diseaseWhatever the duration of the disease Zoungas S. Diabetes Research Clinical Practice 2010; 89:126-133
- 21. Whatever the baseline of the BMIWhatever the baseline of the BMI Zoungas S. Diabetes Research Clinical Practice 2010; 89:126-133
- 22. Whatever the HbAWhatever the HbA1C1C at baselineat baseline Zoungas S. Diabetes Research Clinical Practice 2010; 89:126-133
- 23. 10%10% SignificantSignificant reduction in thereduction in the combined risk ofcombined risk of micro- andmicro- and macrovascularmacrovascular eventsevents Protection from serious complicationsProtection from serious complications ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72 Gliclazide MRGliclazide MR
- 24. Gliclazide MR : unique renal protection.Gliclazide MR : unique renal protection. ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72
- 25. Gliclazide MR :Gliclazide MR : unique renal protection.unique renal protection. NNT: we need to treat 15 diabetic patients to make 1NNT: we need to treat 15 diabetic patients to make 1 patient regain the normal range of albuminuria.patient regain the normal range of albuminuria. ADVANCE Collaborative Group. EASD Congress 2010. Stockholm,Sweden. Abstract
- 26. Gliclazide MR :Gliclazide MR : unique renal protection.unique renal protection. 20 mg/l200 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) ADVANCE Collaborative Group. EASD Congress 2010. Stockholm, Sweden. Oral communication
- 27. New results EASD 2011New results EASD 2011 The ADVANCE Collaborative Group. EASD Annual Meeting, 2011. Portugal, Lisbon. Abstract. Gliclazide MRGliclazide MR
- 28. 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 & death.Albuminuria is a major predictor of ESRD, CVD & death. Key resultsRisk of CVD predicted by albuminuriaRisk of CVD predicted by albuminuria ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72
- 29. Cardiovascular death 253 289 12% (-4 to 26) All deaths 498 533 7% (-6 to 17) Non-cardiovascular death 245 244 0% (-20 to 16) Number of patients with event Intensive Standard (n=5,571) (n=5,569) Relative risk reduction (95%CI) Favors Intensive Favors Standard Hazard ratio 0.5 1.0 2.0Cardiovascular MortalityCardiovascular Mortality -12%-12%P=0.12P=0.12 Gliclazide MR :Gliclazide MR : unique cardioprotection.unique cardioprotection.
- 30. Gliclazide MRGliclazide MR : the lowest rate of hypoglycemia: the lowest rate of hypoglycemia 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 Maximal dose of Gliclazide MR In 70% of patients Gliclazide MRGliclazide MR
- 31. Gliclazide MRGliclazide MR : the lowest rate of hypoglycemia: the lowest rate of hypoglycemia ACCORD ADVANCEADVANCE VADT Severe hypoglycemia in intensive arm [% part. with ≥ 1 episodes] 16.2% 2.7%2.7% 21.2%
- 32. Gliclazide MRGliclazide MR : strict weight neutrality: strict weight neutrality ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72 Gliclazide MRGliclazide MR
- 33. Gliclazide MRGliclazide MR : strict weight neutrality: strict weight neutrality CONTROL Group. Diabetologia. 2009, August 6. Epub ahead of print.
- 34. Gliclazide MRGliclazide MR : strict weight neutrality: strict weight neutrality There was no weight gain in the intensive group patients. On the contrary there was some weight loss in intensive group patients with BMI 25-30 & ≥ 30.
- 35. Gliclazide MRGliclazide MR : strict weight neutrality: strict weight neutrality Weight loss of 1.6 Kg in Gliclazide MR based intensive glucose control “for patients not taking Insulin or TZDs” The ADVANCE Collaborative Group. Diabetes Res Clin. Pract. Epub ahead of print.
- 36. Gliclazide MRGliclazide MR, the best, the best treatment strategy.treatment strategy.
- 37. Modified Release formulationModified Release formulation Francillard M EUGMS 2001. Reaven GM Diabetes 1988
- 38. Restores physiological insulin secretionRestores physiological insulin secretion Gregorio F et al. Diabetes Res Clin Prac. 1992;18:197-206. Gliclazide MRGliclazide MR
- 39. Satoh J, Takahashi Y, Takizawa Y et al. Diabetes Research and Clinical Practice, 2005. 0 5 10 15 TimeinYearstostartinsulinTimeinYearstostartinsulin TherapyTherapy Glibenclamide GLICLAZIDEGLICLAZIDE 8 14.5 x2 Double the time needed to start insulin therapyDouble the time needed to start insulin therapy Gliclazide MRGliclazide MR ProtectsProtects ββ-Cells-Cells
- 40. Gliclazide MRGliclazide MR reduces the risk of deathreduces the risk of death
- 42. Gliclazide MRGliclazide MR : the lowest rate of hypoglycemia: the lowest rate of hypoglycemia Al Sifri S et al. Int J Clin Pract. 2011;11,1132-1140 Gliclazide MRGliclazide MR
- 44. Megatrials in diabetesMegatrials in diabetes 1998 June 2008 Sept 2008 2009 UKPDSUKPDS N=3867N=3867 ACCORDACCORD N=10,251N=10,251 ADVANCEADVANCE N=11,240N=11,240 UKPDSUKPDS Long-term follow-upLong-term follow-up VADTVADT N=1791N=1791 CONTROL meta-analysis N=27,049 ADVANCE-ONADVANCE-ON
- 45. UKPDS 10 years follow upUKPDS 10 years follow up (Total of 25 years)(Total of 25 years) Persistence of RRR in microvascular disease. Significant RR for macrovascular related deaths.
- 46. ““Intensive glucose control mayIntensive glucose control may have a legacy effect...have a legacy effect... This may explain why theThis may explain why the macrovascular and mortalitymacrovascular and mortality benefits of intensive glucosebenefits of intensive glucose lowering may take severallowering may take several years to become apparent.”years to become apparent.” ““Intensive glucose control mayIntensive glucose control may have a legacy effect...have a legacy effect... This may explain why theThis may explain why the macrovascular and mortalitymacrovascular and mortality benefits of intensive glucosebenefits of intensive glucose lowering may take severallowering may take several years to become apparent.”years to become apparent.” Professor J. Chalmers,Professor J. Chalmers, Chairman of the ADVANCE Study ManagementChairman of the ADVANCE Study Management GroupGroup
- 48. RecruitmentRecruitment Primary end points:Primary end points: 1.1. Death from any cause.Death from any cause. 2.2. Major macrovascular events:Major macrovascular events: nonfatal myocardial infarction.nonfatal myocardial infarction. nonfatal stroke.nonfatal stroke. Cardiovascular death.Cardiovascular death. ADVANCE ON recruitment progress; August 2011
- 50. Tight glycemic control using Gliclazide MR,Tight glycemic control using Gliclazide MR, based treatment strategybased treatment strategy Superior glycemic control.Superior glycemic control. Preservation of thePreservation of the ββ- cell of the pancreas.- cell of the pancreas. Unique Cardioprotection.Unique Cardioprotection. Unique neproprotection.Unique neproprotection. Excellent safety.Excellent safety.
Editor's Notes
- This slide illustrates the global projections of Diabetes world wide & how it is growing to become a pandemic.
- CVDs are the leading cause of death among individuals with diabetes.6 Approximately two-thirds of individuals with diabetes die of CVD, including CHD, stroke, and peripheral vascular disease.10 But main question asked being if an intensive glycemic target as compared to the conventional one would result in favourable cardiovascular outcomes In the past, answers to this question were equivocal
- The first study is the UKPDS. It was published in the lancet 1998. It startwd in 1977. It was done on 4209 patients.
- The results of the UKPDS showed that intensive treatment, as opposed to the conventional approach, was associated with a significant reduction in microvascular-related events. However , in spite of a 16% reduction in the risk of myocardial infarction, borderline statistical significance was achieved (p=0.052).
- Population representative of a daily practice
- 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.
- % of pts according to HbA1c level at the end of follow up
- Major protective effect on the kidneys 21% reduction in renal events 30% less albuminuria Positive trend toward a reduction in CV death
- 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 dying from kidney disease That goes without saying Even confirmed with the nice correlation demonstrated in ADVANCE between degree of albuminuria and CV events - mortality
- CV mortality was reduced by 12% in only 5 years, however the curves started to separate after 4 years.
- Results show that contrary to glibenclamide, Diamicron MR was able to protect β-cells from cell death induced by H2O2 to 55.9%. This study provides the first evidence for a protective effect of Diamicron MR on pancreatic β-cells damaged by oxidative stress, most likely due to Diamicron MR’s capacity to reduce this oxidative stress. Therefore the authors state that “Diamicron MR may be effective in preventing β-cells from the toxic action of reactive oxygen species in diabetes.”
- Novel data from the UKPDS come from post-trial monitoring for a further 10 years . Notably, between-group differences in HbA1c levels were lost within one year of stopping the randomly assigned therapies. But relative reductions in risk persisted at 10 years for microvascular disease outcomes and significant risk reductions emerged for macrovascular related deaths
- 7550 forms entered by 31st of August 2011 Target of 8500 to be achieved by the end of the year
- What makes the use of Diamicron MR extremely rational in ADVANCE?