High-Normal Glucose Boosts Heart Failure Risk

STOCKHOLM, March 7 -- Glucose levels at the top end of the normal range ratchet up the congestive heart failure hazard for patients already at high risk, revealed an analysis of two international studies.

Among more than 31,000 patients with one or more coronary, peripheral, or cerebrovascular diseases, or diabetes with end-organ damage, fasting plasma glucose levels at baseline independently predicted hospitalization for congestive heart failure, found Claes Held, M.D., Ph.D., of the Karolinska University Hospital here, and colleagues.

Even a "high-normal" glucose level may not be so normal for the risk of heart failure, they reported online in Circulation, Journal of the American Heart Association.

"You can look at blood glucose much like blood pressure or cholesterol," Dr. Held said. "Even if you have normal blood glucose, there is a gradual increase in risk wherever you start on the scale. If the blood sugar is 'high normal' there is a higher risk than those with 'low normal' fasting blood glucose levels."

The authors found that after controlling for age and sex, each increase of 1 mmol/L (18 mg/dL) in fasting plasma glucose was associated with a 1.10-fold-increased risk of hospitalization for congestive heart failure (95% confidence interval, 1.08 to 1.12; P<0.0001).

"This illustrates that blood glucose by itself is a continuous risk factor for developing heart failure because all of these patients were free of heart failure when they enrolled in the trials," said Dr. Held.

The authors, including investigators from Sweden, Canada, England, Germany, and Australia looked at the associations between fasting plasma glucose and risk of hospitalization for congestive heart failure during follow-up in patients who were enrolled in two clinical trials of the antihypertensive agent telmisartan (Micardis).

The cohort included 25,620 patients enrolled in ONTARGET (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial), and 5,926 enrolled in TRANSCEND (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease).

The patients, all with one or more coronary, peripheral, or cerebrovascular diseases, or diabetes with end-organ damage, had baseline fasting plasma glucose levels measured.

The authors conducted interim analyses blinded for randomized treatment to compare baseline glucose with the adjusted congestive heart failure event rate at a mean follow-up of 886 days. They also created multivariable Cox regression models controlling for age, sex, smoking, previous myocardial infarction, diabetes status, hypertension, medications (aspirin, ?-blockers, and statins), creatinine and waist-to-hip ratio.

The mean age of the patients was 67, and 69% were men. Of the total 31,546 patients, 37% (11,708) had a diabetes diagnosis prior to enrollment, and 3.2% (1,006) were newly diagnosed with diabetes at study entry.

During follow-up in the two trials, there were 2,882 primary events, including 1,067 cardiovascular deaths, 926 MI, 823 strokes, and 668 hospitalizations for congestive heart failure.

The association between glucose and congestive heart failure hospitalization persisted when the investigators controlled for the additional factors of smoking, previous myocardial infarction, hypertension, waist-to-hip ratio, creatinine, diabetes, and use of aspirin, ?-blockers, or statins (hazard ratio, 1.05; 95% confidence interval, 1.02 to 1.08; P<0.001).

Higher glucose levels were also associated with increased risk for a composite endpoint of congestive heart failure hospitalization and/or cardiovascular death. The hazard ratio for each increment of 1 mmol/L glucose was 1.09 (95% CI, 1.07 to 1.10; P<0.001) in a model adjusted for age and gender.

Each 1 mmol/L rise increased the risk for the composite endpoint by 9% for all patients, 3% for patients without diabetes, 5% for patients with diabetes.

"These findings for congestive heart failure are consistent with a previous study that showed that an abnormal response of the two-hour glucose value on the standard oral glucose tolerance test was an independent predictor of congestive heart failure in a prospective population-based cohort of elderly men," the authors wrote.

"Our data also are consistent with accumulating evidence showing that elevated glucose is a progressive risk factor for cardiovascular disease outcomes even with levels below the threshold for a diagnosis of diabetes mellitus, and that an elevated fasting plasma glucose is associated with higher mortality in healthy subjects and in those with established congestive heart failure without known diabetes mellitus."

They acknowledged that the results of the analysis, which come from ongoing randomized trials, could have been influenced by treatment assignment. They also did not have access to information on blood pressure, glucose control, time since diabetes diagnosis, or left ventricular function at baseline.