The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study.
OBJECTIVE
To determine whether there is a link between hypoglycaemia and mortality among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.


METHODS
Retrospective epidemiological analysis of data from the ACCORD trial. Setting Diabetes clinics, research clinics, and primary care clinics.


METHODS
Patients were eligible for the ACCORD study if they had type 2 diabetes, a glycated haemoglobin (haemoglobin A(1C)) concentration of 7.5% or more during screening, and were aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of subclinical disease or two additional cardiovascular risk factors. Intervention Intensive (haemoglobin A(1C) <6.0%) or standard (haemoglobin A(1C) 7.0-7.9%) glucose control.


METHODS
Symptomatic, severe hypoglycaemia, manifest as either blood glucose concentration of less than 2.8 mmol/l (<50 mg/dl) or symptoms that resolved with treatment and that required either the assistance of another person or medical assistance, and all cause and cause specific mortality, including a specific assessment for involvement of hypoglycaemia.


RESULTS
10 194 of the 10 251 participants enrolled in the ACCORD study who had at least one assessment for hypoglycaemia during regular follow-up for vital status were included in this analysis. Unadjusted annual mortality among patients in the intensive glucose control arm was 2.8% in those who had one or more episodes of hypoglycaemia requiring any assistance compared with 1.2% for those with no episodes (53 deaths per 1924 person years and 201 deaths per 16 315 person years, respectively; adjusted hazard ratio (HR) 1.41, 95% CI 1.03 to 1.93). A similar pattern was seen among participants in the standard glucose control arm (3.7% (21 deaths per 564 person years) v 1.0% (176 deaths per 17 297 person years); adjusted HR 2.30, 95% CI 1.46 to 3.65). On the other hand, among participants with at least one hypoglycaemic episode requiring any assistance, a non-significantly lower risk of death was seen in those in the intensive arm compared with those in the standard arm (adjusted HR 0.74, 95% 0.46 to 1.23). A significantly lower risk was observed in the intensive arm compared with the standard arm in participants who had experienced at least one hypoglycaemic episode requiring medical assistance (adjusted HR 0.55, 95% CI 0.31 to 0.99). Of the 451 deaths that occurred in ACCORD up to the time when the intensive treatment arm was closed, one death was adjudicated as definitely related to hypoglycaemia.


CONCLUSIONS
Symptomatic, severe hypoglycaemia was associated with an increased risk of death within each study arm. However, among participants who experienced at least one episode of hypoglycaemia, the risk of death was lower in such participants in the intensive arm than in the standard arm. Symptomatic, severe hypoglycaemia does not appear to account for the difference in mortality between the two study arms up to the time when the ACCORD intensive glycaemia arm was discontinued.


BACKGROUND
NCT00000620.
Bonds
Denise E
DE
National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. bondsde@nhlbi.nih.gov
Miller
Michael E
ME
Bergenstal
Richard M
RM
Buse
John B
JB
Byington
Robert P
RP
Cutler
Jeff A
JA
Dudl
R James
RJ
Ismail-Beigi
Faramarz
F
Kimel
Angela R
AR
Hoogwerf
Byron
B
Horowitz
Karen R
KR
Savage
Peter J
PJ
Seaquist
Elizabeth R
ER
Simmons
Debra L
DL
Sivitz
William I
WI
Speril-Hillen
Joann M
JM
Sweeney
Mary Ellen
ME
D000368:Aged; D000959:Antihypertensive Agents / Q000009:adverse effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000401:mortality*; D003925:Diabetic Angiopathies / Q000097:blood / Q000188:drug therapy / Q000401:mortality*; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D006949:Hyperlipidemias / Q000401:mortality / Q000517:prevention & control; D006973:Hypertension / Q000401:mortality / Q000517:prevention & control; D007003:Hypoglycemia / Q000097:blood / Q000139:chemically induced / Q000401:mortality*; D007004:Hypoglycemic Agents / Q000009:adverse effects; D000960:Hypolipidemic Agents / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D012307:Risk Factors
D000959:Antihypertensive Agents; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents