HbA1c: How Low Should You Go?
The National Heart Lung and Blood Institute has terminated the intense glycemic control arm of the ACCORD clinical trial due to a 20% increase in the mortality rate. The increase was seen irrespective of which glucose lowering medication was used. In light of the unsuccessful trial, it has been suggested that tailoring therapy to specific patients' cardiovascular risk should now be considered.
The ACCORD trial was designed to investigate the effect on cardiovascular risk of a more aggressive approach to blood glucose levels. It aims to reduce blood glucose levels, as measured by glycylated hemoglobin (HbA1c) levels, to levels recorded in healthy individuals. An increase of three deaths/1000 patients/year was observed in the patient group with a target HbA1c level of less than 6% rather than the standard group with a 7-7.9% HbA1c target. The study also found that there was a 10% reduction in the number of non-fatal cardiovascular events, primarily non-fatal heart attacks, but when a heart attack occurred it was more likely to be fatal. The study specifically targeted type 2 diabetes patients who have been diagnosed for 10 years and have increased cardiovascular risk; the average patient age was 62.
This is a highly unexpected result as conventional wisdom has promoted the closer control of glucose levels to reduce diabetic complications. A 1% drop in HbA1c levels, from 8% to 7%, is associated with a 40% reduction in the risk of eye, nerve and kidney disease in both type 1 and type 2 diabetics. Furthermore, intensive glucose control in type 1 diabetics (average HbA1c is 7.4%) led to a decrease of cardiovascular disease events by 42% and the risk of heart attack, stroke or death by 57% in type 1 diabetes patients. Researchers have noted that type 1 and type 2 diabetes are caused by very different mechanisms and clinical data from one group can not be transferred to the other.
The ACCORD trial will continue investigating the effects of aggressive blood pressure control and the improvement in blood lipid profile. All patients with the aggressive blood glucose target will be moved to the standard glucose target.
At present, clinicians do not know the cause of the increase in mortality, although the high degree of polypharmacy involved in reaching the lower HbA1c target and the lowering of blood glucose too quickly have been suggested. This result will present a quandary for regulatory authorities in setting blood glucose targets not only in the population studied but also in younger patients who have been more recently diagnosed. A successful conclusion to the ACCORD trial would have seen the HbA1c target set at 6% but with the failure of the trial this is now highly unlikely. Currently, clinicians use higher HbA1c targets in patients who regularly experience hypoglycemia or who have limited life expectancy. The research team suggests that in tailoring therapy to specific patients' cardiovascular risk should now be considered.
The increased mortality rate in aggressive glucose control will come as a hit for pharmaceutical companies, as to achieve the lower glucose targets more aggressive drug therapy at an earlier time would have been necessary. There was one bright spot for GlaxoSmithKline in the study, which found that Avandia (rosiglitazone) increased the cardiovascular risk in line with a broad range of other antidiabetics. Following Dr Steve Nissen's controversial meta-analysis of Avandia suggesting an increased risk of myocardial infarction, labeling changes have been made in the US and EU.
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