joint effects of routine blood pressure lowering and intensive glucose control advance adapted from...
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Joint Effects of Routine Blood Pressure Lowering
and Intensive Glucose Control
ADVANCE
Adapted from EASD 2008.
Timeline
June 2001
January 2002
January 2003
January 2004
January 2005
January 2006
January 2007
January 2008
Blood glucose lowering comparison
Decision to extend study follow-up
Nov. 2005
Blood pressure lowering comparison
May 2007
Recruitment period
March 2003
Joint effectsJoint effects
Adapted from EASD 2008.
Joint Effects of Routine Blood Pressure Lowering and Intensive Glucose Control
Statistical tests (Cox models) confirm that the effects of the 2 treatments were independent of one another for all clinical outcomes (P>0.1 for all)
Adapted from EASD 2008.
Joint Effects: Independence of BP Lowering and Glucose Control (Lack of Interaction)
Outcome P for interaction
Combined primary outcome P=0.13
Major macrovascular events P=0.44
Major microvascular events P=0.32
All cause mortality P=0.90
Cardiovascular mortality P=0.62
Total coronary events P=0.62
Total renal events P=0.35
New or worsening nephropathy P=0.92
Adapted from EASD 2008.
Joint Effects of Routine Blood Pressure Lowering and Intensive Glucose Control
Statistical tests (Cox models) confirm that the effects of the 2 treatments were independent of one another for all clinical outcomes (P>0.1 for all)
Where both treatments have a significant effect, these effects are fully additive (eg New or worsening nephropathy).
Adapted from EASD 2008.
New or Worsening Nephropathy
Standard
Intensive
Placebo
Per-Ind
1.02
0.820.84
0.680.6
0.8
1.0
1.2
Annual event rate % Hazard ratios
P for interaction=0.93
All participants 19% (2 to 34)
Placebo 20% (-4 to 39)
Per-Ind 18% (-9 to 39)
Relative riskreduction (95% CI)
FavoursIntensive
FavoursStandard
Hazard ratio
0.5 1.0 2.0
BP arm
Glucose arm
All participants 18% (-1 to 32)
Standard 18% (-7 to 37)
Intensive 17% (-12 to 38)
Hazard ratio
0.5 1.0 2.0
Relative riskreduction (95% CI)
FavoursPer-Ind
FavoursPlacebo
0.820.84
RRR 33%, P=0.005
BPGlucose
Adapted from EASD 2008.
Joint Effects of Routine Blood Pressure Lowering and Intensive Glucose Control
Statistical tests (Cox models) confirm that the effects of the 2 treatments were independent of one another for all clinical outcomes (P>0.1 for all)
Where both treatments have a significant effect, these effects are fully additive (eg New or worsening nephropathy).
Where only one treatment had a significant effect, the second treatment did not undo that effect & in some cases augmented it (eg All-cause mortality)
Adapted from EASD 2008.
All-cause Mortality
Annual event rate % Hazard ratios
All participants 4% (-9 to 16)
Placebo 4% (-15 to 20)
Per-Ind 5% (-15 to 22)
Relative riskreduction (95% CI)
FavoursIntensive
FavoursStandard
Hazard ratio
0.5 1.0 2.0
BP arm
Glucose arm
All participants 14% (2 to 25)
Standard 13% (-4 to 28)
Intensive 15% (-3 to 29)
Hazard ratio
0.5 1.0 2.0
Relative riskreduction (95% CI)
FavoursPer-Ind
FavoursPlacebo
Standard
Intensive
Placebo
Per-Ind
2.01
1.94
1.75
1.651.5
1.7
1.9
2.1
2.3
P for interaction=0.90
2.01
1.94
1.75
1.65
RRR 18%, P=0.04
BPGlucose
Adapted from EASD 2008.
Standard
Intensive
Placebo
Per-Ind
1.14
1.02
0.89
0.870.7
0.9
1.1
1.3
Cardiovascular Death
Annual event rate % Hazard ratios
P for interaction=0.62
BP arm
All participants 18% (2 to 32)
Standard 22% (0 to 40)
Intensive 14% (-11 to 34)
Hazard ratio
0.5 1.0 2.0
Relative riskreduction (95% CI)
FavoursPer-Ind
FavoursPlacebo
1.14
1.02
0.89
0.87
RRR 24%, P=0.04
BPGlucose
Adapted from EASD 2008.
Joint Effects of Routine Blood Pressure Lowering and Intensive Glucose Control
Statistical tests (Cox models) confirm that the effects of the 2 treatments were independent of one another for all clinical outcomes (P>0.1 for all)
Where both treatments had a significant effect, these effects were fully additive (eg New or worsening nephropathy).
Where only one treatment had a significant effect, the second treatment did not undo that effect & in some cases augmented it (eg All-cause mortality)
The effects of the 2 interventions were independent and fully additive
Adapted from EASD 2008.
Importance of Reduction of Renal Events in T2D
• 20% of people with diabetes die of renal disease
• 50% of patients with ESRD in dialysis units have diabetes
• Proteinuria is major predictor of ESRD, CVD and death
Adapted from EASD 2008.
*Adjusted for age, sex, HbA1c, serum lipids, BMI, smoking, alcohol use, and study drug
Risks of ESRD or Creatinine Doubling >200 μmol/L by Baseline Albuminuria in ADVANCE
3 30 300
0.25
0.5
1.0
2.0
4.0
8.012.016.020.0
Baseline UACR (μg/mg)
Normoalbuminuria Microalbuminuria Macroalbuminuria
P for trend <0.0001*Haz
ard
ratio
(95
% C
I)
Adapted from EASD 2008.
Haz
ard
rat
io (
95%
CI)
3 30 300
0.7
1.0
2.0
3.0
4.0
5.0
P for trend <0.0001*
Baseline UACR (μg/mg)
Normo Micro Macro
*Adjusted for age, sex, HbA1c, serum lipids, BMI, smoking, alcohol use, and study drug
Risk of CV Death by Albuminuria at Baseline and Achieved During Follow-up in ADVANCE
Achieved UACR (μg/mg)
3 30 300
P for trend <0.0001*
Normo Micro Macro
At baseline During follow-up
Adapted from EASD 2008.
Conclusions I (BP Lowering)
Routine blood pressure lowering with the fixed combination of perindopril and indapamide:
Reduces all-cause and CV death
Prevents macro & microvascular events
Especially coronary events
Especially renal events
ImplicationsThese results provide the evidence
To support the recommendations of current guidelines for lower BP targets in T2D (<130/80 mmHg)
To confirm that BP should be lowered routinely in all patients with T2D regardless of initial BP
Adapted from EASD 2008.
Conclusions II (Glucose Control)
Intensive glucose control with a gliclazide-MR based regimen achieved an HbA1c of 6.5% and:
Prevented combined macro or microvascular events Prevented new or worsening nephropathy With acceptable rate of side effects
Implications These results provide the evidence
To support the current guideline recommendations to lower HbA1c to ≤ 6.5% or ≤7%
That a pragmatic and progressive glucose control regimen as used in ADVANCE can achieve an HbA1c of ≤ 6.5%, & reduce serious complications, primarily renal, with safety
That this regimen will provide these benefits with acceptable rates of hypoglycaemia and no weight gain
Adapted from EASD 2008.
Conclusions III (Joint Effects)
The separate effects of BP lowering (perindopril-indapamide) and glucose control (gliclazide MR-based) are independent for all outcomes, (no interaction)
The joint effects of these two treatments provide very substantial benefits Around one third reduction in nephropathy and renal
events One quarter reduction in cardiovascular death Close to one fifth reduction in all-cause mortality
Multifactorial treatments including routine blood pressure lowering and intensive glucose control are indicated for all patients with type 2 diabetes
Adapted from EASD 2008.