The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study.
OBJECTIVE
To investigate potential determinants of severe hypoglycaemia, including baseline characteristics, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the association of severe hypoglycaemia with levels of glycated haemoglobin (haemoglobin A(1C)) achieved during therapy.


METHODS
Post hoc epidemiological analysis of a double 2x2 factorial, randomised, controlled trial.


METHODS
Diabetes clinics, research clinics, and primary care clinics.


METHODS
10 209 of the 10 251 participants enrolled in the ACCORD study with type 2 diabetes, a haemoglobin A(1C) concentration of 7.5% or more during screening, and aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or two or more additional risk factors for cardiovascular disease (dyslipidaemia, hypertension, current smoker, or obese). Interventions Intensive (haemoglobin A(1C) <6.0%) or standard (haemoglobin A(1C) 7.0-7.9%) glucose control.


METHODS
Severe hypoglycaemia was defined as episodes of "low blood glucose" requiring the assistance of another person and documentation of either a plasma glucose less than 2.8 mmol/l (<50 mg/dl) or symptoms that promptly resolved with oral carbohydrate, intravenous glucose, or glucagon.


RESULTS
The annual incidence of hypoglycaemia was 3.14% in the intensive treatment group and 1.03% in the standard glycaemia group. We found significantly increased risks for hypoglycaemia among women (P=0.0300), African-Americans (P<0.0001 compared with non-Hispanic whites), those with less than a high school education (P<0.0500 compared with college graduates), aged participants (P<0.0001 per 1 year increase), and those who used insulin at trial entry (P<0.0001). For every 1% unit decline in the haemoglobin A(1C) concentration from baseline to 4 month visit, there was a 28% (95% CI 19% to 37%) and 14% (4% to 23%) reduced risk of hypoglycaemia requiring medical assistance in the standard and intensive groups, respectively. In both treatment groups, the risk of hypoglycaemia requiring medical assistance increased with each 1% unit increment in the average updated haemoglobin A(1C) concentration (standard arm: hazard ratio 1.76, 95% CI 1.50 to 2.06; intensive arm: hazard ratio 1.15, 95% CI 1.02 to 1.21).


CONCLUSIONS
A greater drop in haemoglobin A(1C) concentration from baseline to the 4 month visit was not associated with an increased risk for hypoglycaemia. Patients with poorer glycaemic control had a greater risk of hypoglycaemia, irrespective of treatment group. Identification of baseline subgroups with increased risk for severe hypoglycaemia can provide guidance to clinicians attempting to modify patient therapy on the basis of individual risk.


BACKGROUND
ClinicalTrials.gov number NCT00000620.
Miller
Michael E
ME
Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1063, USA. mmiller@wfubmc.edu
Bonds
Denise E
DE
Gerstein
Hertzel C
HC
Seaquist
Elizabeth R
ER
Bergenstal
Richard M
RM
Calles-Escandon
Jorge
J
Childress
R Dale
RD
Craven
Timothy E
TE
Cuddihy
Robert M
RM
Dailey
George
G
Feinglos
Mark N
MN
Ismail-Beigi
Farmarz
F
Largay
Joe F
JF
O'Connor
Patrick J
PJ
Paul
Terri
T
Savage
Peter J
PJ
Schubart
Ulrich K
UK
Sood
Ajay
A
Genuth
Saul
S
D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D003925:Diabetic Angiopathies / Q000097:blood / Q000188:drug therapy*; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D007003:Hypoglycemia / Q000097:blood / Q000139:chemically induced* / Q000628:therapy; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D012307:Risk Factors
D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents