Joint Effects of Routine Blood Pressure Lowering and Intensive Glucose Control ADVANCE Adapted from EASD 2008

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


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)


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




Where both treatments have a significant effect, these effects are fully additive (eg New or worsening nephropathy).


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


FavoursPer-Ind

FavoursPlacebo

0.820.84

RRR 33%, P=0.005

BPGlucose




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)


All-cause Mortality


All participants 4% (-9 to 16)

Placebo 4% (-15 to 20)

Per-Ind 5% (-15 to 22)


FavoursIntensive

FavoursStandard

Hazard ratio

0.5 1.0 2.0

BP arm

Glucose arm


Standard 13% (-4 to 28)


Hazard ratio

0.5 1.0 2.0


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


2.01

1.94

1.75

1.65

RRR 18%, P=0.04

BPGlucose


Standard

Intensive

Placebo

Per-Ind

1.14

1.02

0.89

0.870.7

0.9

1.1

1.3

Cardiovascular Death



BP arm


Standard 22% (0 to 40)


Hazard ratio

0.5 1.0 2.0


FavoursPer-Ind

FavoursPlacebo

1.14

1.02

0.89

0.87

RRR 24%, P=0.04

BPGlucose




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


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


*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)


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


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


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


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


Documents

Joint Effects of Routine Blood Pressure Lowering and Intensive Glucose Control ADVANCE Adapted from EASD 2008