Biomarkers associated with severe hypoglycaemia and death in ACCORD.
In patients with Type 2 diabetes, intensive glycaemic control is associated with hypoglycaemia and possibly increased mortality. However, no blood biomarkers exist to predict these outcomes. Using participants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, we hypothesized that insulin deficiency and islet autoantibodies in patients with clinically diagnosed Type 2 diabetes would be associated with severe hypoglycaemia and death.



A nested case-control study design was used. A case (n = 86) was a participant who died with at least one episode of severe hypoglycaemia, defined as hypoglycaemia requiring assistance, at any point during ACCORD follow-up. A control (n = 344) was a participant who did not die and did not have severe hypoglycaemia during follow-up. Each case was matched to four controls (glycaemic intervention arm, race, age and BMI). 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 (ZnT8)] were measured. Conditional logistic regression with and without adjustment for age, BMI and diabetes duration was used.



Death during ACCORD in those who experienced at least one episode of severe hypoglycaemia was associated with insulin deficiency [OR 4.8 (2.1, 11.1): P < 0.0001], GAD antibodies [OR 2.3 (1.1, 5.1): P = 0.04], the presence of IAA or baseline insulin use [OR 6.1 (3.5,10.7): P < 0.0001], which remained significant after adjusting for age, BMI, and diabetes duration. There was no significant association with IA2 or ZnT8 antibodies.



In patients with Type 2 diabetes, C-peptide or GAD antibodies may serve as blood biomarkers predicting higher odds of subsequent severe hypoglycaemia and death. (Clinical Trial Registry No: NCT00000620, www.clinicaltrials.gov for original ACCORD study).
Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
L S
LS
Chow
Department of Biostatistical Sciences, Wake Forest School of Medicine, NC, USA.
H
H
Chen
Department of Biostatistical Sciences, Wake Forest School of Medicine, NC, USA.
M E
ME
Miller
Department of Medicine, University of Washington, WA, USA.
S M
SM
Marcovina
Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
E R
ER
Seaquist
D000368:Aged; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D015415:Biomarkers; D002096:C-Peptide / Q000097:blood*; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy / Q000453:epidemiology; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology; D006801:Humans; D007003:Hypoglycemia / Q000097:blood* / Q000139:chemically induced / Q000453:epidemiology; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D007328:Insulin / Q000097:blood* / Q000276:immunology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009026:Mortality; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000276:immunology; D012720:Severity of Illness Index; D000075703:Zinc Transporter 8 / Q000276:immunology
D001323:Autoantibodies; D015415:Biomarkers; D002096:C-Peptide; D007004:Hypoglycemic Agents; D007328:Insulin; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase