Uncontrolled high blood glucose (hyperglycemia) in patients with diabetes is known to increase mortality. However, new research shows that intensive treatment to control blood glucose can lower it too far (hypoglycemia), which also increases mortality. Thus blood glucose level targets should have lower as well as upper limits, to reduce risk to patients, according to a study published online Jan. 26 in the Lancet.
Furthermore, the authors reported that patients with type 2 diabetes given insulin-based regimens have a 50 percent increased mortality risk compared to those given combination oral therapy.
In this study, Craig Currie, MD, from the school of medicine at Cardiff University in Cardiff, Wales, and colleagues assessed the association between all-cause mortality and glycated hemoglobin (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.
Researchers generated two cohorts of patients aged 50 years and older with type 2 diabetes from the U.K. Using the General Practice Research Database from November 1986 to November 2008, they 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.
The authors reported that 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 HbA1c level with the lowest mortality risk (7.5 percent) as a reference point, Currie and colleagues found that for the two combined cohorts, mortality risk in the lowest HbA1c decile (6.4 percent) was 52 percent higher, and in the highest HbA1c decile (10.6 percent) was 79 percent higher. The typical HbA1c target for diabetes treatment is 7 percent.
Results showed a similar U-shaped curve for both oral combination therapy and insulin therapy, according to the authors. However, all-cause mortality in people given insulin-based regimens (2,834 deaths) was 49 percent higher than those give combination oral agents (2,035 deaths).
The authors wrote 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 attempted to clarify that they are not suggesting diabetes patients who are prescribed insulin should stop taking their medication. "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 wrote.
“Low and high mean HbA1c values were associated with increased all-cause mortality and cardiac events,” Currie and colleagues concluded. “If confirmed, diabetes guidelines might need revision to include a minimum HbA1c value.”
In an accompanying commentary, Beverley Balkau, MD, and Dominique Simon, MD, from the CESP Centre for Research in Epidemiology and Population Health at Inserm in Villejuif, France, wrote: "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 percent, corresponding to the lowest death rate and lowest event rate for large-vessel disease.”
They added: “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 hypoglycemia. 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.”