Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes: New results from the ADVANCE trial.
OBJECTIVE
To assess the magnitude and independence of the effects of routine blood pressure lowering and intensive glucose control on clinical outcomes in patients with long-standing type 2 diabetes.


METHODS
This was a multicenter, factorial randomized trial of perindopril-indapamide versus placebo (double-blind comparison) and intensive glucose control with a gliclazide MR-based regimen (target A1C <or=6.5%) versus standard glucose control (open comparison) in 11,140 participants with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial. Annual event rates and risks of major macrovascular and microvascular events considered jointly and separately, renal events, and death during an average 4.3 years of follow-up were assessed, using Cox proportional hazards models.


RESULTS
There was no interaction between the effects of routine blood pressure lowering and intensive glucose control for any of the prespecified clinical outcomes (all P > 0.1): the separate effects of the two interventions for the renal outcomes and death appeared to be additive on the log scale. Compared with neither intervention, combination treatment reduced the risk of new or worsening nephropathy by 33% (95% CI 12-50%, P = 0.005), new onset of macroalbuminuria by 54% (35-68%, P < 0.0001), and new onset of microalbuminuria by 26% (17-34%). Combination treatment was associated with an 18% reduction in the risk of all-cause death (1-32%, P = 0.04).


CONCLUSIONS
The effects of routine blood pressure lowering and intensive glucose control were independent of one another. When combined, they produced additional reductions in clinically relevant outcomes.
Zoungas
Sophia
S
The George Institute for International Health, University of Sydney, Sydney, New South Wales, Australia. szoungas@george.org.au.
de Galan
Bastiaan E
BE
Ninomiya
Toshiharu
T
Grobbee
Diederick
D
Hamet
Pavel
P
Heller
Simon
S
MacMahon
Stephen
S
Marre
Michel
M
Neal
Bruce
B
Patel
Anushka
A
Woodward
Mark
M
Chalmers
John
J
Cass
Alan
A
Glasziou
Paul
P
Harrap
Stephen
S
Lisheng
Liu
L
Mancia
Guiseppe
G
Pillai
Avinesh
A
Poulter
Neil
N
Perkovic
Vlado
V
Travert
Florence
F
D000368:Aged; D000419:Albuminuria / Q000453:epidemiology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000517:prevention & control*; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D005907:Gliclazide / Q000627:therapeutic use; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007190:Indapamide / Q000627:therapeutic use; D008297:Male; D008833:Microcirculation / Q000502:physiology*; D008875:Middle Aged; D020913:Perindopril / Q000627:therapeutic use; D010919:Placebos
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001786:Blood Glucose; D004338:Drug Combinations; D007004:Hypoglycemic Agents; D010919:Placebos; C494243:indapamide, perindopril drug combination; D007190:Indapamide; D005907:Gliclazide; D020913:Perindopril