title: Biomarkers related to severe hypoglycaemia and lack of good glycaemic control in ACCORD.
abstract: OBJECTIVE
  In patients with diabetes, intensive glycaemic control reduces microvascular complications. However, severe hypoglycaemia frequently complicates intensive glycaemic control. Blood biomarkers that predict successful intensification of glycaemic control in patients with type 2 diabetes without the development of severe hypoglycaemia would advance patient care. In patients who received intensive treatment for type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, we hypothesised that insulin deficiency and islet autoantibodies would be associated with severe hypoglycaemia and failure to achieve near-normal glycaemia (HbA1c <6.0% [42 mmol/mol]).
  
  
  METHODS
  A nested case-control design was used. Cases (n = 326) were defined as participants having severe hypoglycaemia and failure to achieve an HbA1c level of <6.0% (42 mmol/mol) prior to the ACCORD transition or death. Controls (n = 1,075) were those who achieved an HbA1c level of <6.0% (42 mmol/mol) prior to the ACCORD transition or death without severe hypoglycaemia. Each case was matched (for race, age and BMI) by up to four controls. Baseline insulin deficiency (fasting C-peptide ≤0.15 nmol/l) and islet autoantibodies (glutamic acid decarboxylase [GAD], tyrosine phosphatase-related islet antigen 2 [IA2], insulin [IAA] and zinc transporter 8 [ZnT8]) were measured. Conditional logistic regression with and without adjustment for age, BMI and diabetes duration was used on the full cohort and after removal of patients who died and their respective controls.
  
  
  RESULTS
  Severe hypoglycaemia accompanied by an inability to achieve an HbA1c level of <6.0% (42 mmol/mol) was associated with insulin deficiency (adjusted OR 23.2 [95% CI 9.0, 59.5], p < 0.0001), the presence of IAA autoantibodies or baseline insulin use (adjusted OR 3.8 [95% CI 2.7, 5.3], p < 0.0001), GAD autoantibodies (OR 3.9 [95% CI 2.5, 6.0], p < 0.0001), IA2 autoantibodies (OR 16.7 [95% CI 3.9, 71.6], p = 0.0001) and ZnT8 autoantibodies (adjusted OR 3.9 [95% CI 1.2, 12.4], p = 0.02).
  
  
  CONCLUSIONS
  C-peptide and islet autoantibodies may serve as biomarkers to predict the risk of severe hypoglycaemia during intensification of type 2 diabetes treatment.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00000620 (original ACCORD study).
authors: Department of Medicine, University of Minnesota, 420 Delaware St SE, MMC 101, Minneapolis, MN, 55455, USA, chow0007@umn.edu.
authors: Lisa S
authors: LS
authors: Chow
authors: Haiying
authors: H
authors: Chen
authors: Michael E
authors: ME
authors: Miller
authors: Santica M
authors: SM
authors: Marcovina
authors: Elizabeth R
authors: ER
authors: Seaquist
mesh_terms: D000368:Aged; D001323:Autoantibodies / Q000737:chemistry / Q000276:immunology; D015415:Biomarkers / Q000097:blood*; D015992:Body Mass Index; D002096:C-Peptide / Q000097:blood; D002318:Cardiovascular Diseases / Q000150:complications / Q000517:prevention & control*; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000097:blood; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000276:immunology; D005260:Female; D005968:Glutamate Decarboxylase / Q000097:blood; D006801:Humans; D007003:Hypoglycemia / Q000097:blood* / Q000276:immunology; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000276:immunology; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000097:blood; D000075703:Zinc Transporter 8
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D002096:C-Peptide; D027682:Cation Transport Proteins; D007328:Insulin; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8; C516862:PTPRN protein, human; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase
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