8 February 2010
An epidemiological analysis  of data from the ACCORD study identified an association between symptomatic hypoglycaemia and mortality. However, this did not explain the increased mortality seen in the intensive glucose-lowering arm of the study compared with the standard treatment arm. Another analysis  of the ACCORD study identified factors that appear to put patients at increased risk of hypoglycaemia when receiving intensive glucose-lowering therapy.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
Health professionals should follow NICE guidance on the management of type 2 diabetes. Individual targets for HbA1c should be agreed with each patient, which could be greater than the general target of 6.5% (48mmol/mol). Highly intensive management to levels of less than 6.5% (48mmol/mol) should be avoided.
Severe hypoglycaemia carries an increased risk of mortality. When intensifying treatment for control of hyperglycaemia, clinicians need to be aware of the factors that put patients at increased risk of severe hypoglycaemia; these may include patients with higher HbA1c and those whose HbA1c levels do not respond promptly to treatment. Women, African Americans, people with lower education levels, older people, and those using insulin also appear to have a greater risk of severe hypoglycaemia.
What is the background to this?
Hypoglycaemia is a major risk of intensive glucose control. Although mild episodes generally are well tolerated, severe hypoglycaemia can cause serious injury, unconsciousness, seizures, coma, myocardial ischaemia, angina, residual neurological impairment, or death. We have also recently blogged about an association between lower HbA1c levels and an increased risk of car crashes (a relative risk increase of 26% for every 1% (11 mmol/mol) reduction.
The ACCORD study of patients with type 2 diabetes was stopped early when interim analysis detected greater mortality in the intensive glucose-lowering treatment arm compared with standard treatment. These post-hoc analyses were carried out to examine the relationship between increased incidences of severe hypoglycaemia and mortality, and to examine factors associated with the increased risk of hypoglycaemia seen in patients receiving intensive therapy in the ACCORD study.
What do the studies claim?
Symptomatic, severe hypoglycaemia was associated with an increased risk of death within the intensive (adjusted hazard ratio (HR) 1.41, 95%CI 1.03 to 1.93) and standard (adjusted HR 2.30, 95% CI 1.46 to 3.65) glucose-lowering treatment arms of the ACCORD study. However, symptomatic, severe hypoglycaemia did not appear to account for the difference in mortality between the two study arms up to the time when the ACCORD intensive treatment arm was discontinued. 
The annual incidence of hypoglycaemia was 3.14% in the intensive treatment group and 1.03% in the standard treatment group. Statistically significant increased risks for hypoglycaemia were found among women, African-Americans (compared with non-Hispanic whites), those with less than a high school education (compared with college graduates), older patients, and those who used insulin at trial entry. Patients with poorer glycaemic control (i.e. higher baseline HbA1c) had a greater risk of hypoglycaemia than those with better control, irrespective of treatment group. A greater drop in HbA1c between baseline and four months was not associated with an increased risk for hypoglycaemia. The authors suggest that individuals started on intensive therapy who do not respond promptly with a fall in HbA1c may be at increased risk of severe hypoglycaemia than those that do. 
As we have blogged previously, the role of intensive glucose control is uncertain. In terms of cardiovascular outcomes, the addition of hypoglycaemic drugs to reduce HbA1c to levels significantly below that of standard treatments does not appear to offer any significant benefit in addition to that achievable by successful implementation of other interventions to reduce cardiovascular risk (including smoking cessation, exercise, losing weight, controlling blood pressure, taking statins, etc).
In contrast, intensive glucose lowering carries an increased risk of severe hypoglycaemia, as found in the intensive treatment arm of the ACCORD study. However, according to the first analysis , although severe hypoglycaemia may be a contributor, it does not appear to explain much of the increased risk of mortality seen in the two treatment arms of the ACCORD study.
The second analysis  suggests a number of risk factors for hypoglycaemia that may help clinicians identify those patients who may be susceptible to a greater risk of hypoglycaemia when intensifying glucose-lowering therapy. These include patients who do not respond promptly with a fall in HbA1c and those with poorer glycaemic control (i.e. a greater initial HbA1c). Patients receiving insulin, women, African-Americans, the less-well educated, the elderly and those with longer duration of diabetes were all identified as being at greater risk of hypoglycaemia. However, caution is needed when extrapolating the findings of these analyses beyond the patient populations and interventions studied in ACCORD.
Design: Retrospective epidemiological analysis of data from the ACCORD trial.
Patients: Patients were eligible for the ACCORD study if they had type 2 diabetes, an HbA1c concentration of 7.5% (59mmol/mol) 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. 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 the analysis.
Outcomes: Symptomatic, severe hypoglycaemia, manifest as either blood glucose concentration of less than 2.8mmol/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: 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% CI1.46 to 3.65). Among participants with at least one hypoglycaemic episode requiring any assistance, no significant difference in the risk of death was seen in those in the intensive arm compared with those in the standard arm (adjusted HR 0.74, 95%CI 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).
 Miller ME, et al. 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. BMJ 2010;340:b5444
Design: Post hoc epidemiological analysis of the ACCORD study.
Patients and interventions: as above
Outcomes: 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 2.8mmol/l (<50mg/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 treatment group. Significantly increased risks for hypoglycaemia were found 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), older 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 HbA1c from baseline to 4 month visit, there was a 28% (95% CI19% to 37%) and 14% (95%CI 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 HbA1c (standard arm: HR 1.76, 95% CI 1.50 to 2.06; intensive arm: HR 1.15, 95% CI 1.02 to 1.21).
The studies were supported by grants from the National Heart, Lung, and Blood Institute and other components of the National Institutes of Health. Several pharmaceutical companies provided study medications, equipment, or supplies.
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