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

2. 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 effects Adapted from EASD 2008.

3. 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.

4. Joint Effects: Independence of BP Lowering and Glucose Control (Lack of Interaction) OutcomeP for interaction Combined primary outcomeP=0.13 Major macrovascular eventsP=0.44 Major microvascular eventsP=0.32 All cause mortalityP=0.90 Cardiovascular mortalityP=0.62 Total coronary eventsP=0.62 Total renal eventsP=0.35 New or worsening nephropathyP=0.92 Adapted from EASD 2008.

5. 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.

6. New or Worsening Nephropathy Standard Intensive Placebo Per-Ind 1.02 0.82 0.84 0.68 0.6 0.8 1.0 1.2 Annual event rate % Hazard ratios P for interaction=0.93 BP arm Glucose arm All participants 18% (-1 to 32) Standard 18% (-7 to 37) Intensive 17% (-12 to 38) Hazard ratio 0.51.02.0 Relative risk reduction (95% CI) Favours Per-Ind Favours Placebo 0.82 0.84 RRR 33%, P=0.005 BP Glucose Adapted from EASD 2008.

7. 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.

8. 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 risk reduction (95% CI) Favours Intensive Favours Standard Hazard ratio 0.51.02.0 BP arm Glucose arm All participants 14% (2 to 25) Standard 13% (-4 to 28) Intensive 15% (-3 to 29) Hazard ratio 0.51.02.0 Relative risk reduction (95% CI) Favours Per-Ind Favours Placebo Standard Intensive Placebo Per-Ind 2.01 1.94 1.75 1.65 1.5 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 BP Glucose Adapted from EASD 2008.

9. Standard Intensive Placebo Per-Ind 1.14 1.02 0.89 0.87 0.7 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 0.51.02.0 Relative risk reduction (95% CI) Favours Per-Ind Favours Placebo All participants 7% (-11 to 23) Placebo 11% (-14 to 30) Per-Ind 2% (-28 to 25) Relative risk reduction (95% CI) Favours Intensive Favours Standard Hazard ratio 0.51.02.0 Glucose arm 1.14 1.02 0.89 0.87 RRR 24%, P=0.04 BP Glucose Adapted from EASD 2008.

10. 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.

11. 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.

12. *Adjusted for age, sex, HbA 1c, serum lipids, BMI, smoking, alcohol use, and study drug Risks of ESRD or Creatinine Doubling >200 μmol/L by Baseline Albuminuria in ADVANCE 330300 0.25 0.5 1.0 2.0 4.0 8.0 12.0 16.0 20.0 Baseline UACR (μg/mg) NormoalbuminuriaMicroalbuminuria Macroalbuminuria P for trend <0.0001* Hazard ratio (95% CI) Adapted from EASD 2008.

13. Hazard ratio (95% CI) 330300 0.7 1.0 2.0 3.0 4.0 5.0 P for trend <0.0001* Baseline UACR (μg/mg) NormoMicro Macro *Adjusted for age, sex, HbA 1c, 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) 330300 P for trend <0.0001* NormoMicro Macro At baselineDuring follow-up Adapted from EASD 2008.

14. 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 Implications These 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.

15. 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.

16. 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.