title: Association between severe hypoglycemia, adverse macrovascular events, and inflammation in the Edinburgh Type 2 Diabetes Study.
abstract: OBJECTIVE
  To determine whether a history of severe hypoglycemia was associated with an increased risk of subsequent macrovascular events in people with type 2 diabetes and to explore possible mediation of this association by inflammation.
  
  
  METHODS
  A cohort of 1,066 adults aged 60-75 years with type 2 diabetes was evaluated prospectively. Baseline history of severe hypoglycemia and plasma levels of the inflammatory markers C-reactive protein, fibrinogen, interleukin-6, and tumor necrosis factor-α were recorded. Their association with incident macrovascular events after 4 years was explored.
  
  
  RESULTS
  At baseline, 87 participants (8.2%) reported one or more episodes of severe hypoglycemia within the preceding year, and at follow-up 99 participants (9.3%) had suffered a new macrovascular event. Hypoglycemia was associated with increased odds of macrovascular events (odds ratio [OR] 2.11 [95% CI 1.06, 4.21], P = 0.035), including coronary heart events (OR 2.44 [95% CI 1.13, 5.26], P = 0.023), largely due to increased myocardial infarction (OR 4.02 [95% CI 1.54, 10.48], P = 0.004). Hypoglycemia was also associated with increased levels of inflammatory markers, including a general inflammation factor derived using principal-components analysis (P = 0.030, after adjustment for cardiometabolic risk factors). However, the significant association between hypoglycemia and macrovascular events persisted after adjustment for inflammatory markers.
  
  
  CONCLUSIONS
  The odds of suffering a macrovascular event were higher in patients with type 2 diabetes who had a history of severe hypoglycemia. There was no evidence that a proinflammatory state had a major role in mediating this association.
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland, U.K. rbedenis@staffmail.ed.ac.uk.
authors.forename: Rachel
authors.initials: R
authors.lastname: Bedenis
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland, U.K.
authors.forename: Anna H
authors.initials: AH
authors.lastname: Price
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland, U.K.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Robertson
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland, U.K.
authors.forename: Jo R
authors.initials: JR
authors.lastname: Morling
authors.affiliation: Department of Diabetes, Royal Infirmary of Edinburgh, Edinburgh, Scotland, U.K.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Frier
authors.affiliation: Metabolic Unit, Western General Hospital, Edinburgh, Scotland, U.K.
authors.forename: Mark W J
authors.initials: MW
authors.lastname: Strachan
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland, U.K.
authors.forename: Jackie F
authors.initials: JF
authors.lastname: Price
mesh_terms: D000328:Adult; D000368:Aged; D002097:C-Reactive Protein / Q000032:analysis; D002318:Cardiovascular Diseases / Q000097:blood / Q000453:epidemiology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000453:epidemiology*; D005260:Female; D006801:Humans; D007003:Hypoglycemia / Q000097:blood / Q000453:epidemiology*; D007249:Inflammation / Q000097:blood / Q000453:epidemiology; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein