Cognitive function and risks of cardiovascular disease and hypoglycaemia in patients with type 2 diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.
OBJECTIVE
The relationship between cognitive function, cardiovascular disease and premature death is not well established in patients with type 2 diabetes. We assessed the effects of cognitive function in 11,140 patients with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Furthermore, we tested whether level of cognitive function altered the beneficial effects of the BP-lowering and glycaemic-control regimens in the trial.


METHODS
Cognitive function was assessed using the Mini Mental State Examination at baseline, and defined by scores 28-30 ('normal', n = 8,689), 24-27 ('mild dysfunction', n = 2,231) and <24 ('severe dysfunction', n = 212). Risks of major cardiovascular events, death and hypoglycaemia and interactions with treatment were assessed using Cox proportional hazards analysis.


RESULTS
Relative to normal function, both mild and severe cognitive dysfunction significantly increased the multiple-adjusted risks of major cardiovascular events (HR 1.27, 95% CI 1.11-1.46 and 1.42, 95% CI 1.01-1.99; both p < 0.05), cardiovascular death (1.41, 95% CI 1.16-1.71 and 1.56, 95% CI 0.99-2.46; both p <or= 0.05) and all-cause death (1.33, 95% CI 1.16-1.54 and 1.50, 95% CI 1.06-2.12; both p < 0.03). Severe, but not mild, cognitive dysfunction increased the risk of severe hypoglycaemia (HR 2.10, 95% CI 1.14-3.87; p = 0.018). There was no evidence of heterogeneity of treatment effects on cardiovascular outcomes in subgroups defined by cognitive function at baseline.


CONCLUSIONS
Cognitive dysfunction is an independent predictor of clinical outcomes in patients with type 2 diabetes, but does not modify the effects of BP lowering or glucose control on the risks of major cardiovascular events.


BACKGROUND
ClinicalTrials.gov NCT00145925.
de Galan
B E
BE
The George Institute for International Health, The University of Sydney, PO Box M201, Missenden Road, Camperdown, Sydney, NSW, 2050, Australia.|Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
Zoungas
S
S
The George Institute for International Health, The University of Sydney, PO Box M201, Missenden Road, Camperdown, Sydney, NSW, 2050, Australia. szoungas@george.org.au.|Monash University, Melbourne, VIC, Australia. szoungas@george.org.au.
Chalmers
J
J
The George Institute for International Health, The University of Sydney, PO Box M201, Missenden Road, Camperdown, Sydney, NSW, 2050, Australia.
Anderson
C
C
The George Institute for International Health, The University of Sydney, PO Box M201, Missenden Road, Camperdown, Sydney, NSW, 2050, Australia.
Dufouil
C
C
INSERM U708, Paris, France.|UPMC University of Paris, Paris, France.
Pillai
A
A
The George Institute for International Health, The University of Sydney, PO Box M201, Missenden Road, Camperdown, Sydney, NSW, 2050, Australia.
Cooper
M
M
Baker IDI Heart Research Institute, Melbourne, VIC, Australia.
Grobbee
D E
DE
Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, the Netherlands.
Hackett
M
M
The George Institute for International Health, The University of Sydney, PO Box M201, Missenden Road, Camperdown, Sydney, NSW, 2050, Australia.
Hamet
P
P
Centre Hospitalier de l'Université de Montreal and Université de Montreal, Montreal, QC, Canada.
Heller
S R
SR
University of Sheffield and Sheffield Teaching Hospitals National Health Service Foundation Trust, Sheffield, UK.
Lisheng
L
L
Chinese Hypertension League Institute, Beijing, China.
MacMahon
S
S
The George Institute for International Health, The University of Sydney, PO Box M201, Missenden Road, Camperdown, Sydney, NSW, 2050, Australia.
Mancia
G
G
University of Milan-Bicocca and San Gerardo Hospital, Milan, Italy.
Neal
B
B
The George Institute for International Health, The University of Sydney, PO Box M201, Missenden Road, Camperdown, Sydney, NSW, 2050, Australia.
Pan
C Y
CY
Chinese People's Liberation Army General Hospital, Beijing, China.
Patel
A
A
The George Institute for International Health, The University of Sydney, PO Box M201, Missenden Road, Camperdown, Sydney, NSW, 2050, Australia.
Poulter
N
N
Imperial College and St Mary's Hospital, London, UK.
Travert
F
F
UPMC University of Paris, Paris, France.
Woodward
M
M
The George Institute for International Health, The University of Sydney, PO Box M201, Missenden Road, Camperdown, Sydney, NSW, 2050, Australia.|Mount Sinai School of Medicine, New York, NY, USA.
D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000401:mortality / Q000523:psychology*; D003925:Diabetic Angiopathies / Q000453:epidemiology* / Q000517:prevention & control*; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D004522:Educational Status; D005260:Female; D005907:Gliclazide / Q000627:therapeutic use*; D006801:Humans; D007003:Hypoglycemia / Q000453:epidemiology*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007190:Indapamide / Q000627:therapeutic use*; D008297:Male; D008609:Mental Status Schedule; D009203:Myocardial Infarction / Q000453:epidemiology; D020913:Perindopril / Q000627:therapeutic use*; D012307:Risk Factors; D020521:Stroke / Q000453:epidemiology
D000959:Antihypertensive Agents; D004338:Drug Combinations; D007004:Hypoglycemic Agents; C494243:indapamide, perindopril drug combination; D007190:Indapamide; D005907:Gliclazide; D020913:Perindopril
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