In the Journals

Intensive glucose control may increase mortality risk

An HbA1c of 7.5% was associated with the lowest all-cause mortality and lowest progression to adverse events, but an increase or decrease from this value was associated with increased risk for adverse outcomes, prompting researchers to recommend lower and upper limits for blood glucose targets to lower risk for patients with diabetes.

“Low and high mean HbA1c levels were associated with increased all-cause mortality and cardiac events,” Craig J. Currie, PhD, of Cardiff University in the United Kingdom, and colleagues wrote in The Lancet. “If confirmed, diabetes guidelines might need revision to include a minimum HbA1c value.”

Researchers identified two cohorts of patients aged 50 years or older with type 2 diabetes in the U.K. General Practice Research Database from November 1986 to November 2008. Cohort one (n=27,965; mean baseline HbA1c, 9%) included patients whose treatment was intensified from oral monotherapy to combination therapy with oral blood glucose-lowering agents (sulfonylureas plus metformin); cohort two (n=20,005; mean baseline HbA1c, 10%) included patients previously treated with oral agents who changed regimens to include insulin.

An average follow-up of 4.5 to 5.2 years revealed a U-shaped curve between all-cause mortality and HbA1c levels. Patients who had a median HbA1c of 7.5%, the fourth decile, carried the lowest risk for mortality.

Using the HbA1c level with the lowest mortality risk (7.5%) as a reference point, the researchers found a HR of 1.52 (95% CI, 1.32-1.76) for all-cause mortality among patients in the lowest HbA1c decile (6.4%) and 1.79 (95% CI, 1.56-2.06) among those in the highest HbA1c decile (10.5%).

Treatment differences

The researchers found a similar U-shaped curve for both oral combination therapy and insulin therapy. In oral therapy-treated patients, only those in the highest (median, 10.5%) and lowest (median, 6.4%) HbA1c deciles were at elevated risk for mortality. In insulin-treated patients, those in the three lowest and two highest groups had a significantly elevated risk compared with the lowest risk decile (median 7.5%).

When they excluded patients with high CV risk or renal impairment, the HR for insulin-based therapy vs. oral combination therapy was 1.46 (95% CI, 1.34-1.59).

All-cause mortality in patients given insulin-based regimens (n=2,834 deaths) was 49% higher than those given combination oral agents (n=2,035 deaths).

Another similar U-shaped curve was also observed for all-cause mortality and patients with new-onset, large-vessel cardiac disease events. The HR was 1.54 for patients in the lowest HbA1c decile compared with the median HbA1c decile (95% CI, 1.28-1.84). For the highest decile, the HR was 1.36 (95% CI, 1.14-1.61). Insulin treatment was also associated with an increased likelihood for progression to first large-vessel disease event (adjusted HR=1.31; 95% CI, 1.22-1.42).

“These data imply for oral combination therapy that a wide HbA1c range is safe with respect to all cause mortality and large vessel events, but for insulin-based therapy, a more narrow range might be desirable,” the researchers wrote.

Other studies

The researchers said these data “lend support” to the ACCORD trial data, which demonstrated increased mortality (HR=1.22) among patients with CV disease or related risk factors and an HbA1c of 7.5% who were assigned to intensive glycemic control. However, the results are “at variance” with the UKPDS follow-up data, which suggested intensive treatment was associated with a reduced risk for all diabetes-related endpoints.

“Since publication of the troubling results from the ACCORD trial in mid-2008, which showed that intensive treatment of type 2 diabetes was associated with a higher all-cause mortality than was conventional therapy, an explanation has been sought,” Beverly Balkau, PhD, and Dominique Simon, MD, PhD, both at the INSERM Center for Research in Epidemiology and Population Health, Villejuif, France, wrote in an accompanying editorial.

The editorialists acknowledged that the study did not provide causes of death or information about insulin or oral doses and drugs used for treatment.

“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 with the lowest death rate and lowest event rate for large-vessel disease,” they wrote. “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 risk of hypoglycemia.”

The study was funded by Eli Lilly and Company. – by Matthew Brannon

Currie CJ. Lancet. 2010;doi:10.1016/S0140-6736(09)61969-3.

Balkau B. Lancet. 2010;doi:10.1016/S0140-6736(09)62192-9.

PERSPECTIVE

The legacy of the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study has been to show us that good glycemic control makes an enormous, measurable difference in lessening the risk for the development of severe and potentially disabling complications of diabetes. In both of these landmark trials, the mean HbA1c attained in the 'intensive' control groups was about 7%. New therapeutic options, including new classes of oral antihyperglycemics , 'smart' insulin pumps, insulin analogues tailored to physiologic needs and precision self-blood glucose monitoring equipment, have enabled us to coach patients to near-normoglycemia (<6.5%), based on the understandable logic that 'more might be better.' The study by Currie and colleagues, suggesting a U-shaped curve of mortality based on HbA1c, adds to concerns raised by the ACCORD trial that glycemic control can at times be 'too good.' Data from these studies show only association, not causation. But, remembering that HbA1c reflects an average of blood glucose concentration over time, simple logic tells us that a 'normal' HbA1c may be attained by very frequent hypoglycemia off-setting equally frequent hyperglycemia. Until we know more, I believe we should only advocate HbA1c <6.5% as a target for those patients receiving therapies for diabetes that are not apt to cause hypoglycemia. For those on insulin therapy and other forms of treatment with potential to cause hypoglycemia, an 'ideal' HbA1c might well be 6.9%.

- Stephen A. Brietzke, MD
Endocrine Today Editorial Board member

PERSPECTIVE

Increased mortality has been reported in randomized controlled trials during more aggressive compared with less aggressive glucose-lowering therapy in patients with type 2 diabetes (ACCORD) and in patients with hyperglycemia in intensive care units (NICE-SUGAR), and now in patients with type 2 diabetes with HbA1c levels in the lower, as well as the higher, deciles (U.K. General Practice Research Database). The clinical implication of these findings is straightforward. Overly aggressive glucose-lowering therapy, with currently available methods, causes excess mortality. The mechanistic implication is seemingly straightforward. Given sufficient glycemic separation between the groups, more aggressive glucose-lowering therapy and lower HbA1c levels result in a higher frequency of hypoglycemia. Hypoglycemia can be fatal; it causes sudden presumably cardiac arrhythmic death or, if it is prolonged and profound, brain death. In the absence of plasma glucose measurements at the time of each death, a causal connection between increased iatrogenic hypoglycemia and excess mortality remains to be proven, although it is likely. In any event, we need to avoid hypoglycemia as well as hyperglycemia.

- Philip E. Cryer, MD
Endocrine Today Editorial Board member

An HbA1c of 7.5% was associated with the lowest all-cause mortality and lowest progression to adverse events, but an increase or decrease from this value was associated with increased risk for adverse outcomes, prompting researchers to recommend lower and upper limits for blood glucose targets to lower risk for patients with diabetes.

“Low and high mean HbA1c levels were associated with increased all-cause mortality and cardiac events,” Craig J. Currie, PhD, of Cardiff University in the United Kingdom, and colleagues wrote in The Lancet. “If confirmed, diabetes guidelines might need revision to include a minimum HbA1c value.”

Researchers identified two cohorts of patients aged 50 years or older with type 2 diabetes in the U.K. General Practice Research Database from November 1986 to November 2008. Cohort one (n=27,965; mean baseline HbA1c, 9%) included patients whose treatment was intensified from oral monotherapy to combination therapy with oral blood glucose-lowering agents (sulfonylureas plus metformin); cohort two (n=20,005; mean baseline HbA1c, 10%) included patients previously treated with oral agents who changed regimens to include insulin.

An average follow-up of 4.5 to 5.2 years revealed a U-shaped curve between all-cause mortality and HbA1c levels. Patients who had a median HbA1c of 7.5%, the fourth decile, carried the lowest risk for mortality.

Using the HbA1c level with the lowest mortality risk (7.5%) as a reference point, the researchers found a HR of 1.52 (95% CI, 1.32-1.76) for all-cause mortality among patients in the lowest HbA1c decile (6.4%) and 1.79 (95% CI, 1.56-2.06) among those in the highest HbA1c decile (10.5%).

Treatment differences

The researchers found a similar U-shaped curve for both oral combination therapy and insulin therapy. In oral therapy-treated patients, only those in the highest (median, 10.5%) and lowest (median, 6.4%) HbA1c deciles were at elevated risk for mortality. In insulin-treated patients, those in the three lowest and two highest groups had a significantly elevated risk compared with the lowest risk decile (median 7.5%).

When they excluded patients with high CV risk or renal impairment, the HR for insulin-based therapy vs. oral combination therapy was 1.46 (95% CI, 1.34-1.59).

All-cause mortality in patients given insulin-based regimens (n=2,834 deaths) was 49% higher than those given combination oral agents (n=2,035 deaths).

Another similar U-shaped curve was also observed for all-cause mortality and patients with new-onset, large-vessel cardiac disease events. The HR was 1.54 for patients in the lowest HbA1c decile compared with the median HbA1c decile (95% CI, 1.28-1.84). For the highest decile, the HR was 1.36 (95% CI, 1.14-1.61). Insulin treatment was also associated with an increased likelihood for progression to first large-vessel disease event (adjusted HR=1.31; 95% CI, 1.22-1.42).

“These data imply for oral combination therapy that a wide HbA1c range is safe with respect to all cause mortality and large vessel events, but for insulin-based therapy, a more narrow range might be desirable,” the researchers wrote.

Other studies

The researchers said these data “lend support” to the ACCORD trial data, which demonstrated increased mortality (HR=1.22) among patients with CV disease or related risk factors and an HbA1c of 7.5% who were assigned to intensive glycemic control. However, the results are “at variance” with the UKPDS follow-up data, which suggested intensive treatment was associated with a reduced risk for all diabetes-related endpoints.

“Since publication of the troubling results from the ACCORD trial in mid-2008, which showed that intensive treatment of type 2 diabetes was associated with a higher all-cause mortality than was conventional therapy, an explanation has been sought,” Beverly Balkau, PhD, and Dominique Simon, MD, PhD, both at the INSERM Center for Research in Epidemiology and Population Health, Villejuif, France, wrote in an accompanying editorial.

The editorialists acknowledged that the study did not provide causes of death or information about insulin or oral doses and drugs used for treatment.

“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 with the lowest death rate and lowest event rate for large-vessel disease,” they wrote. “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 risk of hypoglycemia.”

The study was funded by Eli Lilly and Company. – by Matthew Brannon

Currie CJ. Lancet. 2010;doi:10.1016/S0140-6736(09)61969-3.

Balkau B. Lancet. 2010;doi:10.1016/S0140-6736(09)62192-9.

PERSPECTIVE

The legacy of the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study has been to show us that good glycemic control makes an enormous, measurable difference in lessening the risk for the development of severe and potentially disabling complications of diabetes. In both of these landmark trials, the mean HbA1c attained in the 'intensive' control groups was about 7%. New therapeutic options, including new classes of oral antihyperglycemics , 'smart' insulin pumps, insulin analogues tailored to physiologic needs and precision self-blood glucose monitoring equipment, have enabled us to coach patients to near-normoglycemia (<6.5%), based on the understandable logic that 'more might be better.' The study by Currie and colleagues, suggesting a U-shaped curve of mortality based on HbA1c, adds to concerns raised by the ACCORD trial that glycemic control can at times be 'too good.' Data from these studies show only association, not causation. But, remembering that HbA1c reflects an average of blood glucose concentration over time, simple logic tells us that a 'normal' HbA1c may be attained by very frequent hypoglycemia off-setting equally frequent hyperglycemia. Until we know more, I believe we should only advocate HbA1c <6.5% as a target for those patients receiving therapies for diabetes that are not apt to cause hypoglycemia. For those on insulin therapy and other forms of treatment with potential to cause hypoglycemia, an 'ideal' HbA1c might well be 6.9%.

- Stephen A. Brietzke, MD
Endocrine Today Editorial Board member

PERSPECTIVE

Increased mortality has been reported in randomized controlled trials during more aggressive compared with less aggressive glucose-lowering therapy in patients with type 2 diabetes (ACCORD) and in patients with hyperglycemia in intensive care units (NICE-SUGAR), and now in patients with type 2 diabetes with HbA1c levels in the lower, as well as the higher, deciles (U.K. General Practice Research Database). The clinical implication of these findings is straightforward. Overly aggressive glucose-lowering therapy, with currently available methods, causes excess mortality. The mechanistic implication is seemingly straightforward. Given sufficient glycemic separation between the groups, more aggressive glucose-lowering therapy and lower HbA1c levels result in a higher frequency of hypoglycemia. Hypoglycemia can be fatal; it causes sudden presumably cardiac arrhythmic death or, if it is prolonged and profound, brain death. In the absence of plasma glucose measurements at the time of each death, a causal connection between increased iatrogenic hypoglycemia and excess mortality remains to be proven, although it is likely. In any event, we need to avoid hypoglycemia as well as hyperglycemia.

- Philip E. Cryer, MD
Endocrine Today Editorial Board member