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Tight Glucose Control Raises Mortality Risk in Heart Failure in a New Study
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MedPage Today
July 21, 2009
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SAN FRANCISCO, July 21 -- Near-normal glucose control in heart failure patients with diabetes paradoxically appears to increase mortality risk, researchers found.
Modest glucose control with a hemoglobin A1c between 7.1% and 7.8% showed 27% lower mortality risk than tight control with an A1c of 6.4% or lower (P=0.001), David Aguilar, MD, of Baylor College of Medicine in Houston, and colleagues reported.
This high-risk population had a U-shaped mortality curve, they wrote in the July 28 issue of the Journal of the American College of Cardiology.
Several recent trials have also shown no macrovascular benefit to tight glucose control in general diabetes populations, Dr. Aguilar noted.
In the ACCORD trial, intensive management that brought A1c levels close to 6% (and under the standard 7% target) resulted in an as-yet-unexplained 22% excess mortality risk. (See ADA: ACCORD Diabetes Trial a Complete Bust)
Action Points
* Explain to interested patients that tight glucose control involves intensive management of diabetes to achieve a hemoglobin A1c below the standard target of 7.0%.
* Note that the observational study could not determine causality.
While researchers have offered many explanations for the unexpected mortality risk with "better control," hypoglycemia may be particularly relevant in the heart failure population, according to an accompanying editorial.
"Symptoms of hypoglycemia in these patients may be masked by the customary use of beta-blockers and by symptoms of heart failure such as fatigue and dizziness," wrote Larry A. Weinrauch, MD, of Harvard's Joslin Diabetes Center, and Eldrin F. Lewis, MD, MPH, of Brigham and Women's Hospital and Harvard.
They added that Dr. Aguilar's group may have revealed "the 'real-world' risk of unawareness of spontaneous or iatrogenic hypoglycemia in the cardiac population."
However, neither hypoglycemia nor the lower A1c levels themselves appeared to be at fault in the ACCORD trial, or in the similar VA Diabetes Trial. (See ADA: Still No Culprit for Excess Mortality with Tight Glucose Control)
In-depth analysis of ACCORD revealed a U-shaped mortality curve with standard therapy targeted to the traditional 7.0% hemoglobin A1c goal, similar to that found in Dr. Aguilar's study.
But in the intensive therapy group, with a 6.0% A1c goal, the relationship was linear, with the lowest risk of death for those who achieved the lowest A1c levels.
ACCORD researchers concluded that pushing too hard for tight glucose control in typically older, sicker patients who couldn't easily achieve it might have been the culprit.
Dr. Aguilar agreed that the message may be the importance of individualized diabetes treatment goals for patients who may be more severely ill, such as those with heart failure.
However, he noted that lower glycosylated hemoglobin levels in their population may simply have been a surrogate marker for illness, treatment adherence, or some unmeasured factor.
Regardless, there is little evidence that the typical heart failure patient with diabetes gets more benefit than harm from an A1c below 7.1%, Drs. Weinrauch and Lewis concluded.
To look farther down the disease spectrum than the analysis in ACCORD, Dr. Aguilar's group retrospectively examined outcomes for a national cohort of 5,815 ambulatory diabetic patients with established heart failure who were treated in ambulatory clinics at VA medical centers.
During two years of follow-up, mortality rates were:
* 25.0% in the bottom quintile with hemoglobin A1c levels of 6.4% or less.
* 23.0% in the group with A1c levels of 6.5% to 7.1%.
* 17.7% in the middle quintile with glycosylated hemoglobin levels above 7.1% but no more than 7.8%.
* 22.5% in the group with A1c levels of 7.9% to 9.0%.
* 23.2% in the top quartile with hemoglobin A1c levels above 9.0%.
After adjustment for other factors, the modest glycemic control group with A1c levels of 7.1% to 7.8% had significantly lower risk of death over two years than any other group. Compared with this middle quintile, the adjusted hazard ratios were:
* 1.37 for the bottom quintile with hemoglobin A1c levels of 6.4% or less. (P=0.001).
* 1.31 for the groups with A1c levels of 6.5% to 7.1% and 7.9% to 9.0% (both P=0.004).
* 1.45 for the highest glyosylated hemoglobin quintile (P<0.001).
For hospitalization outcomes, both all-cause and heart-failure specific admission risk appeared to rise linearly with hemoglobin A1c. But neither relationship was significant after adjustment for other factors.
The researchers cautioned that residual confounding from unmeasured factors may have remained in the observational data, which was subject to "the inherent limitations of this type of study design."
They said further study is needed to determine the mechanism.
The study was supported in part by VA Health Services Research and Development Service grant.
Dr. Aguilar reported support from an award from the National Institutes of Health.
The researchers reported no conflicts of interest.
The editorialists provided no information on conflicts of interest.
Primary source: Journal of the American College of Cardiology
Source reference:
Aguilar D, et al "Relationship of Hemoglobin A1C and Mortality in Heart Failure Patients With Diabetes" J Am Coll Cardiol 2009; 54: 422-8.
Additional source: Journal of the American College of Cardiology
Source reference:
Weinrauch LA, Lewis EF "Aiming for the Best Control of Glycemia in Patients With Heart Failure and Type 2 Diabetes: The 'Sweet Spot'" J Am Coll Cardiol 2009; 54: 429-31.
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