Hot Topics in Diabetes 50 th EASD, Vienna 2014 ADVANCE post trial ObservatioNal Study Sophia Zoungas The George Institute The University of Sydney
Rationale and Study Design Sophia Zoungas The George Institute The University of Sydney
A factorial randomised trial of blood pressure lowering and intensive glucose control in 11,140 patients with type 2 diabetes
Inclusion criteria Type 2 diabetes mellitus Age 55 years or older Additional risk of vascular event 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 Any level of blood pressure Any level of glucose control but no definite indication for long-term insulin
Randomised BP treatment Blood pressure lowering Double-blind perindopril-indapamide versus matching placebo 2.0 / 0.625mg or placebo for first 3 months 4.0 / 1.25mg or placebo thereafter Median follow up 4.4 years Mean reduction in blood pressure achieved during trial with active treatment was Systolic BP 5.6 mmhg Diastolic BP 2.2 mmhg
Effects on Total Mortality Death from any cause Cardiovascular death 10 Placebo Perindopril-indapamide 10 Placebo Perindopril-indapamide 0 Relative risk reduction 14%; p=0.025 0 6 12 18 24 30 36 42 48 54 60 Follow-up (months) 0 0 6 12 18 24 30 36 42 48 54 60 Follow-up (months) Relative risk reduction 18%; p=0.027 Patel, MacMahon, Chalmers et al. Lancet 2007;370: 829-840
Separate primary outcomes Major macro or microvascular events Number of patients with events Per-Ind Placebo (n=5,569) (n=5,571) Favors Per-Ind Favors Placebo Relative risk reduction (95% CI) Combined macro + micro 861 938 9% (0 to 17) Macrovascular 480 520 8% (-4 to 19) * Microvascular 439 477 9% (-4 to 20) 0.5 1.0 2.0 Hazard ratio *P=0.04 Patel, MacMahon, Chalmers et al. Lancet 2007;370: 829-840
Key results -ADVANCE Blood pressure lowering arm Routine treatment of patients with type 2 DM with perindopril-indapamide resulted in: 14% reduction in total mortality 18% reduction in cardiovascular death 9% reduction in major vascular events 14% reduction in total coronary events 21% reduction in total renal events Benefits appeared to be independent of initial blood pressure, similar in all major subgroups and additional to other protective therapies, including ACE inhibition
Randomised glucose control strategy Open label glucose control (Intensive vs standard) Intensive control Gliclazide MR in all participants Unrestricted additional therapy to achieve target HbA1c 6.5% Standard control Therapy and targets according to standard local guidelines Sulfonylurea other than Gliclazide MR Median follow up 5 years Mean difference in HbA1c achieved during trial was 0.67%
ADVANCE: Combined primary outcome Major macro or microvascular events 25 20 Standard Intensive 15 10 5 0 0 6 12 18 24 30 36 42 48 54 60 66 Follow-up (months) Relative risk reduction 10%: 95% CI: 2 to 18% p=0.013 NEJM 2008;358:2560-2572
ADVANCE : primary outcomes Major microvascular events (kidney and eye complications) Major macrovascular events (MI, stroke or CV death) 25 20 Standard Intensive 25 20 Standard Intensive 15 15 10 10 5 5 0 0 0 6 12 18 24 30 36 42 48 54 60 66 Follow-up (months) 0 6 12 18 24 30 36 42 48 54 60 66 Follow-up (months) Relative risk reduction14% 95% CI: 3 to 23% p=0.014 Relative risk reduction 6% 95% CI: -6 to 16% p=0.32 NEJM 2008;358:2560-2572
ADVANCE : Renal events % of patients with event Intensive Standard (n=5,571) (n=5,569) Favours Intensive Favours Standard Relative risk reduction (95% CI) Total renal events 26.9% 30.0% New microalbuminuria 23.7% 25.7% 0.5 1.0 2.0 Hazard ratio 11% (5 to 17) 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) ** * P=<0.001 P=0.02 *** P=0.006 NEJM 2008;358:2560-2572
End-stage kidney disease (dialysis or renal transplantation) Relative risk reduction 65% 95% CI: 15 to 83% p=0.02 Standard Intensive Kidney Int 2013;83:517-523
ADVANCE : Effects on Mortality All cause mortality Cardiovascular death 25 20 Standard Intensive 25 20 Standard Intensive 15 15 10 10 5 5 0 0 6 12 18 24 30 36 42 48 54 60 66 Follow-up (months) 0 0 6 12 18 24 30 36 42 48 54 60 66 Follow-up (months) Relative risk reduction 7% p=0.28 Relative risk reduction 12% p=0.12 NEJM 2008;358:2560-2572
Key results-advance Glucose control arm Intensive glucose control in patients with type 2 DM resulted in: 10% reduction in combined macro and microvascular events 14% reduction in microvascular events 21% reduction in new or worsening nephropathy 65% reduction in end-stage kidney disease No reduction in total mortality Benefits appeared to be independent of initial HbA1c, and similar in all major subgroups
New evidence UKPDS 10 year post trial monitoring Prior intensive glucose control Maintained benefits for microvascular complications Emerging benefits for MI and mortality Prior tight blood pressuring control In trial benefits for mortality and vascular complications were not maintained NEJM 2008;359:1565-1589
Hypotheses During post-trial follow-up and following completion of randomised intervention, there will be persistent and/or emerging health benefits in the ADVANCE participants that were initially assigned to the intervention groups (perindopril-indapamide and intensive glucose control) as compared to those assigned to the control groups (placebo and standard glucose control).
Study design Post-trial observational study All ADVANCE local clinical sites All surviving ADVANCE participants at completion of randomised intervention BP arm (T1- median 4.4 years) Glucose arm (T2- median 5.0 years) Up to 5 years further follow-up
Primary outcomes Death from any cause Major macrovascular events: a composite of non-fatal myocardial infarction, nonfatal stroke and death from any cardiovascular cause Based on investigator diagnosis
Secondary outcomes Major clinical microvascular events: a composite of end-stage kidney disease, death from renal disease and severe diabetes-related eye disease End-stage kidney disease (dialysis or renal transplantation) Death from renal disease Severe diabetes-related eye disease (requirement for retinal photocoagulation therapy or diabetes-related blindness occurring in either eye)
Secondary outcomes Death from any cardiovascular cause Myocardial infarction (non-fatal and fatal) Stroke (non-fatal and fatal) Major hypoglycaemia
Visit 1 - subset In approximately 2000 randomly selected participants: Blood Pressure SBP and DBP Haemoglobin A1c, fasting blood glucose
Final visit in 2013 In participants attending clinic: Blood Pressure SBP and DBP Haemoglobin A1c, fasting blood glucose
Participant care during follow-up After the last randomised visit participants returned to the care of their usual medical practitioners.
Study timeline June 2001 January 2003 January 2005 January 2007 January 2009 January 2011 January 2013 Recruitment period Decision to extend study follow-up Blood pressure lowering comparison Blood glucose control comparison Post-trial visits start 2010 End of follow up Blood pressure lowering observational follow up Blood glucose control observational follow up Median 9.9 yrs
Hot Topics in Diabetes 50 th EASD, Vienna 2014 ADVANCE post trial ObservatioNal Study Sophia Zoungas The George Institute The University of Sydney