MedWire News: There is a U-shaped relationship between glycated hemoglobin (HbA1c) levels and mortality in people with diabetes, say researchers, meaning that intensive glucose-lowering therapy could be as harmful as uncontrolled hyperglycemia.
Writing in The Lancet, Craig Currie (Cardiff University, UK) and team say that if their findings are confirmed then diabetes guidelines may need to be revised to include a lower as well as an upper HbA1c threshold.
Currie’s team used the UK General Practice Research Database from November 1986 to November 2008 to obtain data on two cohorts of patients aged 50 years and older with Type 2 diabetes.
The patients comprised 27,965 individuals whose treatment had been intensified from oral monotherapy to combination therapy with oral blood-glucose lowering agents, and 20,005 who had changed to insulin-containing regimens.
The primary endpoint was all-cause mortality. In analyses adjusted for important confounders, and using the HbA1c level with the lowest mortality risk (7.5%) as the referent, Currie et al found that the risk for all-cause mortality was 52% higher in the lowest HbA1c decile (6.4%, adjusted hazard ratio[HR]=1.52) and 79% higher in the highest HbA1c decile (10.6%, HR=1.79).
A similar U-shaped association was seen when each of the two treatment cohorts (ie, oral combination therapy or insulin therapy) was analyzed individually. However, all-cause mortality in people given insulin-based regimens was 49% higher than in people on combination oral agents (HR=1.49).
The researchers say that their findings lend support to those of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which was stopped after an interim analysis detected increased mortality among patients assigned to intensive compared with standard glucose control.
Nevertheless, they admit that it has not yet been proven that intensive glucose-lowering per se leads to higher mortality; importantly, insulin-treated patients tend to be older and have more comorbidities and have a longer duration of diabetes. A previous study has also reported a possible link between the use of insulin and cancer progression.
“Whether intensification of glucose control with insulin therapy alone further heightens risk of death in patients with diabetes needs further investigation and assessment of the overall risk balance,” they conclude.
“Low and high mean HbA1c values were associated with increased all-cause mortality and cardiac events. If confirmed, diabetes guidelines might need revision to include a minimum HbA1c value.”
In an accompanying comment, Beverley Balkau and Dominique Simon (INSERM, Villejuif, France) say that the new data support an HbA1c target of 7.5% as offering the greatest risk reductions for both all-cause mortality and cardiac events.
“Priority should be given to insulin sensitizers for as long as possible in patients with Type 2 diabetes, because these drugs allow a low HbA1c to be targeted without any risk of hypoglycaemia,” they write.
“More research is needed to establish HbA1c thresholds and the combination of drugs to be recommended for intensive treatment, with perhaps differing recommendations according to the patient.”
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New ACCORD analyses focus on severe symptomatic hypoglycemia