The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study

By D. Bonds, Michael E. Miller, R. Bergenstal, John B. Buse, R. Byington, J. Cutler, R. Dudl, F. Ismail-Beigi, A. Kimel, Byron J. Hoogwerf and 7 more. British medical journal, 2010

933 citations recorded by the source corpus.

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. Design Retrospective epidemiological analysis of data from the ACCORD trial. Setting Diabetes clinics, research clinics, and primary care clinics. Participants Patients were eligible for the ACCORD study if they had type 2 diabetes, a glycated haemoglobin (haemoglobin A1C) 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 A1C <6.0%) or standard (haemoglobin A1C 7.0-7.9%) glucose control. Outcome measures 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. Conclusion 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. Trial registration NCT00000620.

Subfields: Endocrinology, Diabetes and Metabolism

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In Endocrinology, Diabetes and Metabolism

Citations in the corpus

KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update. (2012, background): “The reasons for this finding are uncertain, although further analysis showed that increased mortality was not directly attributable to hypoglycemia.(30) Therefore, lowering HbA1c to levels 7.”
Standards of Medical Care in Diabetes—2012 (2011, background): “Severe hypoglycemia was associated with excess mortality in either arm, but the association was stronger in those randomized to the standard glycemic control arm (87).”
Flash Glucose-Sensing Technology as a Replacement for Blood Glucose Monitoring for the Management of Insulin-Treated Type 2 Diabetes: a Multicenter, Open-Label Randomized Controlled Trial (2016, background): “However, intensification of insulin therapy increases the risk of hypoglycemia [4] which is associated with adverse clinical outcome [5], impacts on quality of life [6], and increases treatment costs secondary to hospital admissions, ambulance call-outs, and clinic attendance [7].”
Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2012, background): “It remains unknown whether hypoglycaemia was the cause of the increased mortality in the intensive group [130, 131].”
Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach (2012, background): “It remains unknown whether hypoglycemia was the cause of the increased mortality in the intensive group (130,131).”
CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM--2016 EXECUTIVE SUMMARY. (2016, background): “In ACCORD, severe hypoglycemia may have accounted for a substantial portion of excess mortality among patients receiving intensive therapy, although the hazard ratio for hypoglycemia-associated deaths was higher in the standard treatment group (80).”
Update on the treatment of type 2 diabetes mellitus. (2016, background): “On the other hand, both hypoglycaemia and CKD are related with increased morbidity and mortality from cardiovascular disease [276-278] .”
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee (2013, background): “8 mmol/L) is associated with increased mortality (15).”
Standards of Medical Care in Diabetes—2013 (2012, background): “Severe hypoglycemia was associated with excess mortality in either arm, but the association was stronger in those randomized to the standard glycemic control arm (97).”
Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013, background): “In the opinion of the blinded adjudication committee assigned to investigate mortality in ACCORD, hypoglycemia was judged to have a definite role in only one death, a probable role in three deaths, and a possible role in 38 deaths (46), which represents a role in less than 10% of the deaths recorded”