Intensive glucose control for diabetes can lower blood glucose too far (hypoglycemia), and increase mortality risk

January 26, 2010

Uncontrolled high blood glucose (hyperglycaemia) in patients with diabetes is known to increase mortality. But new research shows that intensive treatment to control blood glucose can lower it too far (hypoglycaemia), which also increases mortality. Thus blood glucose level targets should have lower as well as upper limits, to lower the risk to patients. Furthermore, patients with type 2 diabetes given insulin-based regimens have a 50% increased mortality risk compared to those given combination oral therapy. The findings are reported in an Article Online First ( and in an upcoming edition of The Lancet--written by Dr Craig Currie, School of Medicine, Cardiff University, UK, and colleagues.

The specific goal for control of blood sugar is to return glycated haemoglobin (HbA1c)* to a normal range, because good blood sugar (glycaemic) control is known to reduce risk of long-term small blood vessel complications in both type 1 and type 2 diabetes. Reports of potentially raised mortality rates associated with intensive glycaemic control have triggered discussion about recommendations for treatment of type 2 diabetes, specifically relating to the optimum target for HbA1c. Researchers have suggested that hypoglycaemia contributes to a heightened risk of mortality in patients with diabetes. Because intensive glycaemic control increases risk of hypoglycaemia with some drugs more than with others, assessment of risks associated with the different blood glucose-lowering regimens is important. In this study, the authors assessed the association between all-cause mortality and HbA1c in patients with type 2 diabetes in a primary-care setting, and established whether any evident association was independent of the diabetes treatment regimen.

Two cohorts of patients aged 50 years and older with type 2 diabetes were generated from the UK General Practice Research Database from November 1986 to November 2008. The researchers identified 27 965 patients whose treatment had been intensified from oral monotherapy to combination therapy with oral blood-glucose lowering agents (metformin plus sulphonylurea), and 20 005 who had changed to regimens that included insulin. Those with diabetes secondary to other causes were excluded. All-cause mortality was the primary outcome. Age, sex, smoking status, cholesterol, cardiovascular risk, and general morbidity were identified as important confounding factors, and the data were subsequently adjusted for these factors.

Using the glycated haemoglobin (HbA1c) level with the lowest mortality risk (7.5%) as a reference point, the researchers found that for the two combined cohorts, mortality risk in the lowest HbA1c decile (6•4%) was 52% higher, and in the highest HbA1c decile (10•6%) was 79% higher. The typical HbA1c target for diabetes treatment is 7.0%. Results showed a similar U-shaped curve for both oral combination therapy and insulin therapy. However, all-cause mortality in people given insulin-based regimens (2834 deaths) was 49% higher than those give combination oral agents (2035 deaths).

The authors say that while the data suggest that insulin could increase the risk of death in type 2 diabetes, differences in the baseline characteristics of the insulin treated patients (older, more comorbidities, longer duration of diabetes) could be one reason behind this risk; they also point out a possible link between use of insulin and cancer progression that has been reported in a previous study. However, the authors wish to make clear they are not suggesting diabetes patients who are prescribed insulin should stop taking their medication. They say: "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, Dr Beverley Balkau and Dr Dominique Simon, CESP Centre for Research in Epidemiology and Population Health, Inserm, Villejuif, France, say: "In patients with type 2 diabetes, when using insulin secretagogues or insulin itself, today's study does provide a rationale for an HbA1c threshold of 7•5%, corresponding to the lowest death rate and lowest event rate for large-vessel disease. Priority should be given to insulin sensitisers 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. 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--intensive treatment seems to be more beneficial for cardiovascular outcomes for those who are younger than 60 years, with a short duration of diabetes, and absence of microvascular and macrovascular disease."
Dr Craig Currie, School of Medicine, Cardiff University, UK. T) +44 (0) 7769 974438 E)

Dr Beverley Balkau, CESP Centre for Research in Epidemiology and Population Health, Inserm, Villejuif, France. T) + 33 6 88 21 44 97 E)

For full Article and Comment, see:

Note to editors: Glycated haemoglobin is a form of haemoglobin used to identify the average plasma glucose concentration over prolonged periods of time. The HbA1c level is proportional to average blood glucose concentration over the previous four weeks to three months.


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