title: 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.
abstract: 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.
authors.affiliation: 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.
authors.forename: B E
authors.initials: BE
authors.lastname: de Galan
authors.affiliation: 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.
authors.forename: S
authors.initials: S
authors.lastname: Zoungas
authors.affiliation: The George Institute for International Health, The University of Sydney, PO Box M201, Missenden Road, Camperdown, Sydney, NSW, 2050, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Chalmers
authors.affiliation: The George Institute for International Health, The University of Sydney, PO Box M201, Missenden Road, Camperdown, Sydney, NSW, 2050, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Anderson
authors.affiliation: INSERM U708, Paris, France.|UPMC University of Paris, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Dufouil
authors.affiliation: The George Institute for International Health, The University of Sydney, PO Box M201, Missenden Road, Camperdown, Sydney, NSW, 2050, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Pillai
authors.affiliation: Baker IDI Heart Research Institute, Melbourne, VIC, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Cooper
authors.affiliation: Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: D E
authors.initials: DE
authors.lastname: Grobbee
authors.affiliation: The George Institute for International Health, The University of Sydney, PO Box M201, Missenden Road, Camperdown, Sydney, NSW, 2050, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Hackett
authors.affiliation: Centre Hospitalier de l'Université de Montreal and Université de Montreal, Montreal, QC, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Hamet
authors.affiliation: University of Sheffield and Sheffield Teaching Hospitals National Health Service Foundation Trust, Sheffield, UK.
authors.forename: S R
authors.initials: SR
authors.lastname: Heller
authors.affiliation: Chinese Hypertension League Institute, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Lisheng
authors.affiliation: The George Institute for International Health, The University of Sydney, PO Box M201, Missenden Road, Camperdown, Sydney, NSW, 2050, Australia.
authors.forename: S
authors.initials: S
authors.lastname: MacMahon
authors.affiliation: University of Milan-Bicocca and San Gerardo Hospital, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Mancia
authors.affiliation: The George Institute for International Health, The University of Sydney, PO Box M201, Missenden Road, Camperdown, Sydney, NSW, 2050, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Neal
authors.affiliation: Chinese People's Liberation Army General Hospital, Beijing, China.
authors.forename: C Y
authors.initials: CY
authors.lastname: Pan
authors.affiliation: The George Institute for International Health, The University of Sydney, PO Box M201, Missenden Road, Camperdown, Sydney, NSW, 2050, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Patel
authors.affiliation: Imperial College and St Mary's Hospital, London, UK.
authors.forename: N
authors.initials: N
authors.lastname: Poulter
authors.affiliation: UPMC University of Paris, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Travert
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Woodward
mesh_terms: 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
chemical_list: D000959:Antihypertensive Agents; D004338:Drug Combinations; D007004:Hypoglycemic Agents; C494243:indapamide, perindopril drug combination; D007190:Indapamide; D005907:Gliclazide; D020913:Perindopril
references.citation: JAMA. 1993 May 12;269(18):2386-91
references.pmid: 8479064
references.citation: Am J Med. 1984 Dec;77(6):1043-8
references.pmid: 6334441
references.citation: J Am Geriatr Soc. 1996 Mar;44(3):237-41
references.pmid: 8600190
references.citation: Neurology. 2005 May 24;64(10):1750-5
references.pmid: 15911803
references.citation: Endocr Rev. 2008 Jun;29(4):494-511
references.pmid: 18436709
references.citation: Diabetologia. 2005 Dec;48(12):2460-9
references.pmid: 16283246
references.citation: BMC Geriatr. 2006 May 01;6:8
references.pmid: 16650284
references.citation: Diabetologia. 2004 Jul;47(7):1245-1256
references.pmid: 15241592
references.citation: Arch Intern Med. 2000 Jan 24;160(2):174-80
references.pmid: 10647755
references.citation: Am J Hypertens. 2005 Aug;18(8):1052-9
references.pmid: 16109319
references.citation: Diabetes Care. 1997 May;20(5):792-5
references.pmid: 9135944
references.citation: Am J Geriatr Psychiatry. 2003 Sep-Oct;11(5):551-60
references.pmid: 14506089
references.citation: Diabetes. 2006 Nov;55(11):2986-92
references.pmid: 17065334
references.citation: N Engl J Med. 2008 Jun 12;358(24):2560-72
references.pmid: 18539916
references.citation: Circulation. 2003 Oct 28;108(17):2154-69
references.pmid: 14581387
references.citation: Diabetes. 1996 Jan;45(1):86-90
references.pmid: 8522065
references.citation: Diabetes Care. 2004 May;27(5):1047-53
references.pmid: 15111519
references.citation: J Psychiatr Res. 1975 Nov;12(3):189-98
references.pmid: 1202204
references.citation: BMJ. 1996 Mar 9;312(7031):608-11
references.pmid: 8595334
references.citation: Diabetologia. 2009 Aug;52(8):1504-10
references.pmid: 19455303
references.citation: Diabetologia. 2001 Sep;44(9):1118-20
references.pmid: 11596665
references.citation: Circulation. 1996 May 15;93(10):1809-17
references.pmid: 8635260
references.citation: Aging Clin Exp Res. 2007 Feb;19(1):41-7
references.pmid: 17332720
references.citation: Diabetes Care. 2001 Feb;24(2):366-70
references.pmid: 11213894
references.citation: Diabetes Res Clin Pract. 2009 Mar;83(3):387-93
references.pmid: 19157618
references.citation: BMJ. 1994 Jun 18;308(6944):1604-8
references.pmid: 8025427
references.citation: J Clin Epidemiol. 1998 May;51(5):385-91
references.pmid: 9619965
references.citation: Epidemiology. 2009 Jan;20(1):100-9
references.pmid: 19234402
references.citation: Lancet. 2007 Sep 8;370(9590):829-40
references.pmid: 17765963
references.citation: Arch Neurol. 2005 Oct;62(10):1539-44
references.pmid: 16216936
references.citation: Paediatr Perinat Epidemiol. 2005 Nov;19(6):452-9
references.pmid: 16269073
references.citation: Diabetes Care. 2009 Feb;32(2):221-6
references.pmid: 19171735
references.citation: Lancet. 2005 Dec 17;366(9503):2112-7
references.pmid: 16360788