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

Abstract

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 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. 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 nonsignificantly 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 registratio...

Central nervous system: a conductor orchestrating metabolic regulations harmed by both hyperglycaemia and hypoglycaemia

“…However, because of the associated sympthoadrenergic drive, profound hypoglycaemia may be deleterious for the heart, potentially leading to myocardial infarction and severe arrhythmias (which may explain the so called 'dead in bed' syndrome) [31,32]. Recent data from the ACCORD ("Action to Control Cardiovascular Risk in Diabetes ") trial emphasizes the increased risk of cardiovascular mortality associated to severe hypoglycaemia in patients with type 2 DM, treated intensively or not [33].…”

Meta-analysis: Association between hypoglycaemia and serious adverse events in older patients

“…We screened 1273 citations and included 17 studies with a total of 1498358 participants in the meta-analysis (Bonds et al, 2010, Chiba et al, 2015, Duckworth et al, 2011, Hsu et al, 2013, Origin Trial Investigators et al, 2013, Johnston et al, 2012, Johnston et al, 2011, Khunti et al, 2015, Majumdar et al, 2013, McCoy et al, 2012, Rajpathak et al, 2015, Rathmann et al, 2013, Signorovitch et al, 2013, Zhao et al, 2012, Zoungas et al, 2010. The flow chart of the study selection in shown in the supplementary eFigure.…”

“…Two studies provided participants with diaries and glucose meters (Origin Trial Investigators et al, 2013) (Bonds et al, 2010) and two studies relied on questionnaires (Chiba et al, 2015) ( McCoy et al, 2012). Two of the studies relied on routine trial monitoring (Duckworth et al, 2011) (Zoungas et al, 2010.…”

Comparison of cardiovascular and metabolic outcomes in people with type 2 diabetes on insulin versus non-insulin glucose-lowering therapies (GLTs): A systematic review and meta-analysis of clinical trials

“…[54] This link is best explained by resultant increased myocardial activity, platelet-aggregation and activity, and haematocrit which can trigger cardiac and ischaemic events in diabetic (highrisk) patients. [55][56][57][58] None of these studies however compared between insulin and sulfonylurea, the latter an important glucose lowering therapy which is known to be associated with an increased risk of hypoglycaemia.…”